The Scientific Evidence Applied to Developing the ReVite Program for Cognitive Preservation/Reversal of Cognitive Decline and Early Dementia

This is an evolving summary of the rapidly-changing evidence we are examining (as well as generating based on our emerging experience) to serve as the foundation for our cognitive preservation/dementia-reversing program.  

I’ve highlighted the agents/strategies with at least some genuinely supportive, higher-quality data that either have adequate supportive evidence or appear to be headed in that direction.

Not addressed to date are the combinations of strategies that may yield effects more effective than single strategies in isolation.

Nutritional supplements

Acetyl-L-Carnitine

Carnitines, of which the acetyl-L-carnitine form is best studied, have been proposed, sometimes alongside alpha-lipoic acid, as a therapy to prevent cognitive decline because of its role in mitochondrial energy generation. Acetyl-L-carnitine is mentioned in passing by Bredesen and only in the context of case studies with no explanation or justification.

How do we reconcile the potential benefits of various carnitine derivatives with the atherogenic potential of carnitine as proposed by the TMAO data from Hazen et al? I believe this is yet another reason to hold the TMAO data suspect (considered separately).

Experimental evidence:

Summary of the experimental evidence suggesting reversal of age-related mitochondrial ultrastructural decay by ALA and acetyl-carnitine:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790461/

Acetyl-L-carnitine abolished tau hyperphosphorylation, beta-amyloid accumulation, and cognitive impairment in rats with memory deficits induce in a hyperhomocysteinemia model:

https://www.ncbi.nlm.nih.gov/pubmed/21978079

Observational evidence:

In the continuum from normal cognition (n =46), to subjective memory complaints (n = 24), to mild cognitive impairment (n = 18), to AD (MMSE <24; n = 29), serum levels of acetyl-L-carnitine and other acyl-carnitines (e.g. malonyl-, hexenoyl, decanoyl-, myristoyl- and others) all decreased with progressive degrees of cognitive impairment, the dose-response suggesting, but incapable of proving, a cause-effect association. Age was not controlled, a major oversight, as there was also an age-related trend to the cognitive data (controls youngest, subjective memory complaint and MCI group younger, AD oldest), raising the question of an age-related, non-cognitive related association.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873244/

People with AD have lower plasma levels of medium-chain acyl-carnitines that correlated with lower prefrontal gray matter volumes and cognitive impairment, as well as lower plasma levels of 2-hydroxybutyric acid (as an index of ketogenesis):

https://www.ncbi.nlm.nih.gov/pubmed/27255810

CSF levels of l-carnitine were lower in non-apo E4 carriers in early onset AD that correlated with CSF amyloid-beta levels and MMSE score:

https://www.ncbi.nlm.nih.gov/pubmed/24595197

Clinical treatment data:

People with AD (n = 130) were randomized to acetyl-L-carnitine vs. placebo over one year. Both groups showed deterioration in cognitive measures, with less deterioration in the treated group:

https://www.ncbi.nlm.nih.gov/pubmed/1944900

A small trial (n = 20) of 1000 mg acetyl-L-carnitine twice per day vs. placebo over 24 weeks showing a non-significant trend towards less deterioration in the treated group:

https://www.ncbi.nlm.nih.gov/pubmed/2178869

People with AD were randomized to acetyl-L-carnitine 1000 mg three times per day (n = 112) vs. placebo (n = 117) and followed for 12 months. Of the several cognitive measures used, only MMSE showed less decline in the treated group, specifically reduced decline in attention:

https://www.ncbi.nlm.nih.gov/pubmed/10994000

People with AD were treated with 1000 mg acetyl-L-carnitine three times per day vs. placebo (total n = 431) with no difference in rate of decline over one year. Post hoc analysis of those less than 65 years old may have experienced slower decline:

https://www.ncbi.nlm.nih.gov/pubmed/8797468

A small proprietary study in which 106 participants with AD were randomized to a combination of folate, alpha-tocopherol, B12, s-adenosyl methionine, N-acetyl cysteine, and acetyl-L-carnitine vs. placebo for 6 months, followed by an open-label 6-month extension showed improvement in cognitive measures in the treated arm and during the open-label extension:

https://www.ncbi.nlm.nih.gov/pubmed/25589719

A cocktail of folate, vitamin B12, alpha-tocopherol, S-adenosyl methionine, N-acetyl cysteine, and acetyl-L-carnitine slowed cognitive decline over 9 months in 12 participants randomized to treatment or placebo with moderate to advanced dementia:

https://www.ncbi.nlm.nih.gov/pubmed/19056706

People with mild-moderate AD (n = 30) were randomized to acetyl-L-carnitine 2500 mg per day for 3 months, then 3000 mg per day for 3 more months vs. placebo. The treated group showed less deterioration in several cognitive measures (Digit Span and verbal fluency):

https://www.ncbi.nlm.nih.gov/pubmed/1444880

Cochrane review of the 11 clinical trials of acetyl-l-carnitine showing evidence for benefit on “clinical global impression” but none on objective cognitive measures:

https://www.ncbi.nlm.nih.gov/pubmed/12804452

Conclusions:

The evidence in total suggest that acetyl-L-carnitine may have modest benefits in slowing cognitive decline at a dose of 3000 mg per day, though many of the positive findings come via relatively tortured post hoc assessments. The data combining acetyl-L-carnitine with alpha-lipoic acid is low in quality and it remains unclear whether the two should be used in combination.

Once again, it is impossible to conclude from the data whether acetyl-L-carnitine simply exerts a nootropic or a neurotrophic effect, as no neuroimaging or long-term follow-up studies have been conducted.

As a personal aside, I have taken acetyl-L-carnitine and did indeed notice a modest increase in energy and focus, but it was short-lived with subsequent doses yielding less and less effect, suggesting a tolerance/tachyphylactic effect. Does this apply to its cognition-enhancing effect, also?

Alpha-linolenic Acid

Summary of experimental data:

ALA, but not linoleic acid, reduced oxidative injury and increased BDNF in a mouse model:

https://www.ncbi.nlm.nih.gov/pubmed/27696934

Observational data:

The observational data are fairly consistent in associating low ALA serum levels with increased risk for cognitive decline/dementia.

Increased serum levels of the omega-3 fatty acids, alpha-linolenic acid, stearidonic acid, and eicosatrienoic acid, were associated with greater "fluid intelligence," left frontoparietal volume and total gray matter volume:

https://www.ncbi.nlm.nih.gov/pubmed/28492102

Serum ALA levels were inversely associated with progression to dementia:

https://www.ncbi.nlm.nih.gov/pubmed/27265182

Higher dietary intakes of ALA were associated with slower cognitive decline but only in apo E4 people:

https://www.ncbi.nlm.nih.gov/pubmed/27164694

Total omega-3 and linolenic acid plasma levels were lower in people with mild cognitive decline and dementia compared to controls:

https://www.ncbi.nlm.nih.gov/pubmed/17921425

Post-mortem studies of human brains demonstrated dementia neuropathology was inversely associated with seafood consumption (lower density neuritic plaques and neurofibrillary tangles), higher levels of ALA were associated with fewer cerebral microinfarctions, and level of mercury had no association:

https://www.ncbi.nlm.nih.gov/pubmed/26836731

In the Rotterdam Study, EPA/DHA and linolenic acid intake by food questionnaire was not correlated with cognitive decline over nearly 10 years:

https://www.ncbi.nlm.nih.gov/pubmed/19474131

Human clinical trials:

There is a lack of human clinical treatment trials, with data limited to two studies.

ALA "supplemented" as 1500 mg per day yielded 40% increase in serum BDNF levels in humans:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4353682/

Supplementation of 384 mg of EPA-DHA, 1.9 g of ALA, or both vs. placebo per day over 40 months in coronary patients yielded no slowing of cognitive decline:

https://www.ncbi.nlm.nih.gov/pubmed/21967845

Conclusion:

Despite the lack of clinical human treatment data, given the strongly suggestive observational and experimental data, as well as the fact that linolenic acid is an essential fatty acid, purposeful inclusion of ALA-rich foods that can provide 2000 mg or more per day of ALA seems like the best route without need for supplementation. (The Adequate Intake for ALA is 1.1 grams per day for adult females, 1.6 grams per day for adult males.)

Small servings of flaxseed, chia, and walnuts provide several-fold more than 2000 mg, while grass-fed beef provides about 40% more ALA than non-grass fed beef. While pigs do not graze on grass and there is no such designation for pork, pork tends to have 3-fold higher ALA levels than beef or chicken.

There are also benefits to ALA outside of cognitive preservation, such as a modest reduction in cardiovascular risk. (The negative reports associating ALA with increased prostate cancer risk have been debunked/refuted.)

Alpha-lipoic Acid

The anti-oxidative mitochondrial nutrient, alpha-lipoic acid, or ALA, has been studied for its cognitive-preserving effects, though often in combination with acetyl-carnitine and other presumptive mitochondrial-influencing nutrients. ALA is naturally occurring cofactor for the mitochondrial enzymes pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase of the Kreb’s cycle.

Note that there are two enantiomers: R- and L-ALA, with the dextrorotatory form exerting biological effects, not the levorotatory form. In all data, the racemic mixture of ALA was used.

Summary of the experimental evidence suggesting reversal of age-related mitochondrial ultrastructural decay by ALA and acetyl-carnitine:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790461/

Experimental evidence:

ALA administered in a rat model of vascular dementia (bilateral carotid occlusion) resulted in less cognitive impairment, decreased production of reactive oxidative species, and increased hippocampal levels of reduced glutathione:

https://www.ncbi.nlm.nih.gov/pubmed/25534501

ALA administered in a mouse model of AD exerted an insulin-mimetic effect that increased brain glucose uptake, activation of the insulin receptor substrate and improved synaptic plasticity:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714252/

Clinical treatment data:

A pilot study 39 people with AD were randomized to omega-3 fatty acids (675 mg DHA + 975 mg EPA per day), omega-3 (675 mg DHA + 975 mg EPA per day)+ ALA (600 mg/day), or placebo and tracked with cognitive measures (ADAS-Cog, MMSE, ADL/IADL) over 12 months. Combination treatment slowed cognitive and functional decline (MMSE and IADL) over placebo:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3886557/

126 people with AD (MMSE 12-26) with (n = 61) or without (n = 65) type 2 diabetes were given ALA (uncontrolled) 600 mg/day in combination with conventional dementia treatment over 16 months. Participants with DM given ALA showed significant slowing of cognitive measures, with 43% of participants with DM showing improved MMSE compared to non-DM given ALA:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437336/

53 people with Down’s syndrome were randomized to a combination of alpha-tocopherol 900 IUs, ascorbic acid 200 mg, and ALA 600 mg per day vs. placebo over two years with no improvement in cognitive measures nor a slowing of decline:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410645/

Conclusions:

While limited, the existing data suggest a potential cognition-preserving effect, though we cannot say whether it is a nootropic or neurotrophic effect based on the human clinical data. The experimental data make it tempting to believe that there is indeed a neurotrophic effect but, until we have confirmatory evidence such as volumetric MRI or improved psychometric measures after stopping treatment, we can only presume that the effect is limited to a modest nootropic effect.

Ashwaghanda

Ashwaghanda is listed as a basic supplement in ReCODE as an agent to stop/reverse neurodegenerative disease. Unfortunately, there is no rationale or science listed in the program nor the book.

The evidence for ashwaghanda:

A summary of the experimental model evidence in mice and in vitro, which is varied and compelling (on the surface):

https://www.jstage.jst.go.jp/article/bpb/37/6/37_b14-00022/_pdf

If we believe the experimental data, ashwaghanda can:

Reverse numerous forms of cancer

Protect the brain from stroke

Reverse neurodegenerative damage

Protect from aspergillus infection

Increase sexual interest/function, i.e., aphrodisiac properties

Subdues mania in bipolar illness

Improves insulin resistance

Normalizes cortisol responses

Protects neurons against changes associated with Parkinson’s disease

Protects against tooth decay by degrading the biofilm produced by Streptococcus mutans

Reverses macular degeneration

Reduces pulmonary hypertension

Immunomodulatory activity including suppression of anaphylactic reactions

Exert antifungal effects against a variety of pathogenic fungi

Substantially improves cardiovascular endurance and generates substantially greater muscle growth with strength training

Yields reduced pain and inflammatory markers in rheumatoid arthritis

Has a nootropic effect

Reduces anxiety

Yield beta-blocking and ACE-inhibitor effects

Reduces alcohol craving in experimental alcoholism

Reduces blood sugar and insulin

Exerts anti-hyperlipidemic effects

Enhances efficacy of radiation therapy for cancer

Human data:

Reverses fatigue and improves survival in chemotherapy-treated breast cancer:

https://www.ncbi.nlm.nih.gov/pubmed/23142798

Reduces symptoms of obsessive-compulsive disorder:

https://www.ncbi.nlm.nih.gov/pubmed/27515872

Enhanced sexual function in females:

https://www.ncbi.nlm.nih.gov/pubmed/26504795

Improved cardiorespiratory performance:

https://www.ncbi.nlm.nih.gov/pubmed/26730141

Reduced joint pain, swelling, and inflammatory markers in rheumatoid arthritis:

https://www.ncbi.nlm.nih.gov/pubmed/25857501

Improved cognitive measures in bipolar illness:

https://www.ncbi.nlm.nih.gov/pubmed/24330893

No data on dementia or cognitive decline.

Problem: Virtually ALL experimental and human data were generated in India, where most of the world’s ashwaghanda is grown.

Hmmm. Do we believe the (too-good-to-be-true experimental and clinical) data, nearly all of it generated by potentially biased sources?

Bacopa monnieri

Bacopa is an Ayurvedic preparation with a history dating back over 1000 years with long-purported benefits of improved cognition, in addition to a list of other purported effects that include anti-inflammatory, anti-convulsant, analgesic, anti-microbial (a red flag in my view, as agents such as berberine that also has antimicrobial effects, there is potential for altering bowel flora in uncertain ways), neuroprotective, anti-oxidative and others.

Experimental evidence:

The experimental evidence is plentiful and robust, in total suggesting numerous plausible means of exerting a brain-protective effect.

The active component is uncertain but likely resides in the dozen “bacosides” that occur along with nicotine, several flavonoids, and others. This is a summary of the experimental evidence including inhibition of beta-amyloid deposition, acetylcholinesterase inhibition, choline acetyltransferase activation, monoamine enhancement, and increased cerebral blood flow, including that involving hippocampal tissue:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746283/

Effects appear most prominent in enhancing dopamine and serotonin (nootropic effects), but no effect on norepinephrine in cerebral tissue. Increased dendritic branching and interconnection has been observed in brain preparations (suggesting a neurotrophic effect).

Clinical treatment data:

Bacopa as part of a multi-component treatment (Bacopa monnieri, L-theanine, Crocus sativus, copper, folate, B-complex, and vitamin D) vs. placebo on cognitive measures in patients with dementia with MMSE of 20-27, n = 30, suggesting improved cognition with treatment:

https://www.ncbi.nlm.nih.gov/pubmed/29188854

Extracts of Bacopa monnieri (whole plant), Hippophae rhamnoides (leaves and fruits), and Dioscorea bulbifera (bulbils), 500 mg per day vs. donepezil 10 mg per day vs. placebo in a randomized, controlled trial over 12 months in both cognitively normal (n = 97) and people with AD (n= 103) showed improved cognitive measures and measures of oxidation and inflammation in the plant extract group compared to both donepezil and placebo groups:

https://www.ncbi.nlm.nih.gov/pubmed/25316430

(Though no commercial affiliations/funding was disclosed, this study felt like something that was very commercial.)

A combination of bacopa (100 mg extract containing 20 mg bacosides), phosphatidylserine (soy-derived; 30 mg); vitamin E (form unspecified), astaxanthin 2 mg, and micro algae dry extract (74 mg), uncontrolled, improved cognitive measures in people (n = 102) with mild cognitive impairment, MMSE 22-28, over 3 months:

https://www.ncbi.nlm.nih.gov/pubmed/24523587

Bacopa extract 125 mg twice per day (55% bacoside content) vs. placebo in people (n = 35) over age 55 with memory complaints but MMSE >24 suggested improved cognition with treatment over 12 weeks:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2915594/

Randomized trial bacopa extract 150 mg vs. placebo in 60 cognitively normal medical students over 2 weeks suggested improved cognitive measures (nootropic effect), especially attention and memory, that persisted for 15 days after the intervention (suggested a durable neurotrophic effect):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075615/

Proprietary randomized, controlled study of bacopa extract 320 mg or 640 mg vs. placebo on cognitive measures in healthy volunteers (n = 17) demonstrating acutely improved cognitive measures, mood, and reduced salivary cortisol within 2 hours of administration:

https://www.ncbi.nlm.nih.gov/pubmed/23788517

Bacopa extract 300 mg or 600 mg vs placebo in healthy elderly (n = 60) over 12 weeks improved memory, attention, and cognition:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537209/

Bacopa extract 300 mg per day vs. placebo in cognitively normal people (n = 98) over 12 weeks improved measures of memory:

https://www.ncbi.nlm.nih.gov/pubmed/20590480

Bacopa extract 300 mg per day vs. placebo in cognitively normal people (n = 54) over 12 weeks improved measures of memory:

https://www.ncbi.nlm.nih.gov/pubmed/18611150

Meta-analysis of 12 prospective, randomized trials (n = 437) of bacopa on cognitive testing of at least 12 weeks duration suggests that cognitive improvements are experienced:

https://www.ncbi.nlm.nih.gov/pubmed/24252493

Curiously, studies cited and labeled “unbiased” or “good quality” I found to be potentially biased (e.g., branded proprietary products used) or low quality, especially with small numbers of participants, uncontrolled, or including a smorgasbord of other treatment components. This suggests that this meta-analysis (among several others I found) was likely biased.

Conclusion:

It’s the same familiar theme: Plentiful and compelling experimental data suggesting plausible biological neuroprotective mechanisms, but small, sloppy clinical studies, purported by some to be sufficient to prove cause-effect, including what appear to be biased meta-analyses. All studies are short-term, do not involve any imaging measure, and do not look at long-term outcomes.

I think one conclusion can be made with moderate confidence: Bacopa is likely an effective nootropic agent, i.e., enhances cognition during the period of administration. But there are virtually no data beyond that in experimental preparations to make us believe that there is any neurotrophic effect, i.e., no durable effect upon removal of treatment, no volumetric MRI or other imaging measure of disease, no change in long-term outcomes.  

We are back to the same question we have with piracetam, vinpocetine, acetylcholinesterase inhibitors, dimethylaminoethanol, and other nootropics: Is demonstration of a nootropic effect enough for us to consider inclusion in a program that purports to stall/reverse neurotrophic effects and cognitive decline? I don’t think it is. Note that there has been NO head-to-head comparison of the various nootropics to help us make sense of superiority of one agent or another, either.

Citicoline

Citicoline, 250 mg twice per day, is listed as one of the supplements in ReCODE without justification except to say that it “supports synaptic growth and maintenance.” Citicoline (cytidine-5′-diphosphate choline) is a precursor for the neurotransmitter, acetylcholine, and the phospholipid, phosphatidylcholine, and is the most prescribed agent for dementia in parts of Europe.

There are a number of other acetylcholine precursors, such as dimethylaminoethanol and choline, but there is experimental evidence to suggest that citicoline is also involved in phospholipid metabolism to synthesize phosphatidylcholine essential for brain function. Choline toxicity (acetylcholine effects such as tachycardia and gastrointestinal hyperactivity) are much less prominent compared to other acetylcholine precursors but for unclear reasons.

Experimental data:

Experimental data suggest that citicoline supports neuroplasticity, anti-apoptotic, SIRT1-increasing, cardiolipin-sparing, cerebral ischemia-protective effects, summarized here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933742/.

Clinical treatment studies:

There are a number of studies that examine citicoline’s nootropic effects, such as:

https://www.ncbi.nlm.nih.gov/pubmed/25046515

Citocoline 2000 mg per day improved verbal memory in people with “inefficient memories” (n = 32) vs. placebo over 60 days:

https://www.ncbi.nlm.nih.gov/pubmed/8624220

The Citicholinage Study was a retrospective case-control study in which combined therapy with an (unspecified) acetylcholinesterase inhibitor and citicoline 1000 mg per day or placebo (n = 448) over 9 months in people with Alzheimer’s dementia was assessed. Improved cognitive measures were seen at 3 months, no change at 9 months. (Oddly, study authors claimed that the combination slowed disease progression, not recognizing the difference between a nootropic and a neurotrophic effect.)

https://www.ncbi.nlm.nih.gov/pubmed/28035929

The CITIRIVAD Study used the same retrospective case-control design of Citicholinage (above) but specifically compared the acetylcholinesterase inhibitor, rivastigmine, with or without citicoline 1000 mg per day in people over age 65 with Alzheimer’s or mixed dementia (n = 174). Combined treatment was superior in maintaining cognitive measures over 9 months compared to rivastigmine alone. Once again, the study authors appeared not to understand the distinction between nootropic and neurotrophic effects, making claims about the slowing of disease progression.

https://www.ncbi.nlm.nih.gov/pubmed/27587069

163 people were enrolled 6 weeks following ischemic stroke in an open-label, randomized, parallel study of citicoline vs. usual treatment observed over 2 years with citicoline-treated participants demonstrating less cognitive decline:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4813246/

A summary of the negative outcomes of the two prospective clinical trials in ischemic stroke, the Citicoline Brain Injury Treatment Trial (COBRIT; n = 1213) and the International Citicoline Trial on Acute Stroke (ICTUS; n = 2298), are summarized here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933742/

Conclusions:

The unexpectedly unsophisticated literature on citicoline fails to distinguish nootropic from neurotrophic effects, much like the literature supporting use of prescription acetylcholinesterase inhibitors. Note that there are no data demonstrating prevention or reduction in risk for cognitive impairment, only improvement in cognitive testing in established dementia in studies of low quality. At best, citicoline potentiates the nootropic/cognitive benefits of acetylcholinesterase inhibitors. The science to include citicoline is weak.

Coenzyme Q10/Ubiquinol

Coenzyme Q10/ubiquinol is included in the mix of supplements in the ReCODE program. While positive effects have been demonstrated in animal and limited human trials at high doses for Parkinsonism, ALS, and Huntinton’s disease, the only data on cognitive decline/dementia are mouse data and surrogate measures in humans:

Less hippocampal atrophy with mega-dose CoQ10 in mice:

https://www.ncbi.nlm.nih.gov/pubmed/19096113

Reduced amyloid plaque deposition in mice:

https://www.ncbi.nlm.nih.gov/pubmed/19834824

Reduced amyloid deposition in mice with the presenilin 1-L235P SNP:

https://www.ncbi.nlm.nih.gov/pubmed/18181031

Serum CoQ10 levels are inversely associated with dementia in humans (thereby suggesting association, not necessarily causation):

https://www.ncbi.nlm.nih.gov/pubmed/25463064

Lower serum CoQ10 levels in humans with Lewy body dementia:

https://www.ncbi.nlm.nih.gov/pubmed/12203046

A mix of antioxidants (vit C, E, alpha lipoic acid, and CoQ10 1200 mg) was associated with accelerated cognitive decline in humans:

https://www.ncbi.nlm.nih.gov/pubmed/22431837

So there are no good data suggesting that CoQ10 (with virtually no data on ubiquinol) has efficacy in cognitive decline. There are data, on the other hand, of CoQ10’s effectiveness in reducing blood pressure and improving left ventricular function in heart failure/dilated cardiomyopathy, as well as reversing muscle pain/weakness on statin drugs. And it is benign, though expensive.

Gingko

Despite the popularity of this supplement, probably the most widely-ingested nutritional supplement for preservation of cognitive health, the sum total of data over the years have demonstrated little if any cognitive benefit in normal people and in those with cognitive decline. Even though it is not included in the DeCODE program, people may be taking ginkgo, believing it may be of benefit. An awareness of the data may therefore be useful.

A summary of the experimental evidence suggesting increased cerebral perfusion, anti-oxidative, amyloid beta-reducing, and nootropic neurotransmitter effects:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832285/

Clinical treatment studies:

A number of smaller studies demonstrated varied effects, some with improvement of cognitive decline in cognitively normal people and those with mild cognitive decline, while others showed no effect.

An example of one of the smaller studies suggesting short-term benefit:

Gingko biloba as EGb 761 180 mg per day vs. placebo over 6 weeks in people (n = 262) 60 years or older with normal cognition was associated with modest improvement in several measures of cognitive function:

https://www.ncbi.nlm.nih.gov/pubmed/12404671

This is one of the analyses from the GEM Study, funded in part by the National Center for Complementary and Integrative Health, that essentially settled the question—adequately-powered, a cohort of people at risk, long-term follow-up, using the preferred preparation EGb 761 from the German Schwabe Pharmaceuticals. Ginkgo biloba 120 mg twice per day was associated with no difference in cognitive measures over 6.1 years (n = 3069) vs. placebo in cognitively normal people age 72-96 years:

https://www.ncbi.nlm.nih.gov/pubmed/20040554

Another report from the same GEM Study group (above) Gingko 120 mg twice per day vs. placebo yielded no difference in cognitive measures in participants aged 75 years or older with normal cognition (n = 2587) or MCI (n = 482) over 6.1 years of treatment:

https://www.ncbi.nlm.nih.gov/pubmed/19017911

A meta-analysis of short-term trials of gingko as 240 mg per day of EGb 761 for 22-26 weeks showed moderate effects on slowing progression of cognitive decline and dementia (Alzheimer’s and vascular), but no effect on preventing the development of cognitive decline in normal people (?):

https://content.iospress.com/download/journal-of-alzheimers-disease/jad140837?id=journal-of-alzheimers-disease%2Fjad140837

Conclusion:

The rigor, number of participants, and length, I believe, of the GEM Study trump the smaller, shorter analyses and suggest that gingko is not associated with any appreciable preservation of cognitive health, despite the promising findings from experimental models.

Glutathione and N-Acetyl Cysteine

Glutathione also figures prominently in ReCODE. Glutathione (GSH) is the most abundant anti-oxidative molecule in brain tissue, presumably providing protection from oxidative injury. (Oxidative biomarkers are increased in the brain tissue of people with mild cognitive impairment an dementia.)

Glutathione is synthesized in vivo from the amino acids glutamate, cysteine, and glycine, with cysteine being the rate-limiting substrate. For this reason, N-acetyl cysteine (NAC) has been explored as a means of increasing brain glutathione. In vitro experimental evidence to support an anti-oxidative, beta amyloid plaque-blocking, cognitive decline-slowing effect of N-acetyl cysteine is robust. However, NAC is known to be a biofilm disrupter, i.e., it disrupts the mucous lining of the stomach and intestine (though it is not clear how far down the jejunum and ileum its effects extend) and therefore has potential to cause or worsen dysbiosis/SIBO.

Notably, antioxidants such as vitamins E and C have failed in prior human studies to block cognitive decline.  

Selected experimental evidence:

Overview and plausible basis for biological effect:

https://www.ncbi.nlm.nih.gov/pubmed/23249101

Brain glutathione levels are decreased in the hippocampus and frontal cortex of people with mild cognitive decline and Alzheimer’s dementia by MRI:

https://www.ncbi.nlm.nih.gov/pubmed/26003861

Omega-3 fatty acid (2000 mg EPA+DHA in 3:2 ratio) supplementation increased brain glutathione and was associated with less depression in humans over 12 weeks:

https://www.ncbi.nlm.nih.gov/pubmed/26333890

Increasing serum levels of glutathione peroxidase and glutathione predict deteriorating MMSE scores in Alzheimer’s dementia:

https://www.ncbi.nlm.nih.gov/pubmed/25589716

Common glutathione-S-transferase variants (GSTP1 Val105 and GSTM1 deletion) amplify the cognition-impairing effects of lead exposure:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844089/

Human clinical studies:

NAC improves psychometric measures of cognition in humans with Alzheimer’s dementia over 6 months:

https://www.ncbi.nlm.nih.gov/pubmed/11673605

A cocktail of folate, vitamin B12, alpha-tocopherol, S-adenosyl methionine, N-acetyl cysteine, and acetyl-L-carnitine slowed cognitive decline over 9 months in 12 participants randomized to treatment or placebo with moderate to advanced dementia:

https://www.ncbi.nlm.nih.gov/pubmed/19056706

Conclusion:

The experimental evidence for increased oxidative injury/impaired anti-oxidative protection/reduced glutathione in relevant regions of the brain (and perhaps increased GSH levels in ant/post cingulate as a compensatory response) is overwhelming. The human clinical evidence is, as expected, underwhelming but encouraging. There have been no dose-exploring studies in humans, though a wide range of doses from 400 mg to 7000 mg per day have been used for psychiatric/neurological/immunological treatment.

Bredesen includes 500 mg of NAC but only if measures of high blood glucose/insulin resistance are present, but instead advises glutathione 250 mg twice per day as a liposomal preparation, another conversation.

To me, NAC looks like a pretty good idea, though I cannot argue that it is superior/inferior to direct use of GSH.

Gotu Kola

The four human clinical trials conducted with gotu kola for cognitive impairment/dementia were mostly of low quality: no control group, unblinded, all were from Southeast Asia in countries (India, Sri Lanka, China, Indonesia, Malaysia, Madagascar) in which the supplement was sourced (meaning potential for support for local/regional/national bias).

There was one small placebo-controlled, double-blind study suggesting improved cognition, performed in Thailand:

https://www.ncbi.nlm.nih.gov/pubmed/18191355

There is therefore very little reliable human data on its efficacy.

There is, however, legitimate U.S. data on its anti-oxidative and mitochondrial protective effects:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412033/

https://www.ncbi.nlm.nih.gov/pubmed/22506133

Lead toxicity from gotu kola may be an issue, at least if sourced from Malaysia:

https://www.ncbi.nlm.nih.gov/pubmed/26687083

Infertility, induction of "spontaneous" abortion, liver toxicity, rise in blood sugar and cholesterol values have also been reported, though also generally weak evidence.

I think this supplement moves to the bottom of the list of potentially useful cognitive-enhancing, dementia-reversing agents, at least until better data are generated.

Green tea catechins ?

Epigallocatechin is, of course, the primary polyphenol in green (and, to lesser extents, black and white) teas that has been identified as exerting most of the biologically important health effects. Other components of tea include tannins, caffeine, boheic acid, theophylline, theanine, theobromine, anthocyanins, and gallic acid, but most studies have studied the effects of tea catechins.

There are plenty of data suggesting that caffeine and/or theanine, both components of tea, acutely improve some aspects of cognition, especially accuracy during task-switching and alertness (i.e., transient nootropic effects), so we shall focus here on the data focusing mainly on green tea catechins. An example of the data surrounding caffeine/theanine:

https://www.ncbi.nlm.nih.gov/pubmed/21040626

Review and meta-analysis: https://www.ncbi.nlm.nih.gov/pubmed/24946991

Experimental evidence:

The experimental evidence is plentiful, primarily demonstrating reduction of inflammation, microglia-mediated injury, TNF signaling, and reduction of amyloid-beta, summarized here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477123/

Despite only small proportions of epigallocatechin and epigallocatechin gallate crossing the blood-brain barrier, a neurotrophic and cognitive dysfunction-preventing effect were seen in mice:

https://www.ncbi.nlm.nih.gov/pubmed/28956003

Theanine administration alone was associated with reduction in beta-amyloid deposition and other neuropathological changes associated with dementia in mice:

https://www.ncbi.nlm.nih.gov/pubmed/19766184

Observational evidence:

Green tea consumption by questionnaire correlated with cognitive ability by MMSE in 1003 subjects age 70 or older with RR 0.46 for 4-6 cups/week:

https://www.ncbi.nlm.nih.gov/pubmed/16469995

Green consumption assessed by questionnaire was associated with a HR of 0.73 for incident dementia (n = 13,645) over 5.7 years:

https://www.ncbi.nlm.nih.gov/pubmed/27594507

A summary of the observational data yielding mixed findings on tea consumption and dementia incidence in large population studies:

https://www.ncbi.nlm.nih.gov/pubmed/29231231https://www.ncbi.nlm.nih.gov/pubmed/16469995

Green tea, but not black tea or coffee, was associated with a reduction in incidence of mild cognitive impairment and dementia with an odds ratio of 0.32 for daily green tea consumption, OR 0.47 for consumption 1-6 days per week compared to no consumption:

https://www.ncbi.nlm.nih.gov/pubmed/24828424

Meta-analysis of the observational data (n = 48,435) yielding an OR or 0.64 with green tea consumption, OR 0.75 with black tea consumption with a linear dose-response relationship:

https://www.ncbi.nlm.nih.gov/pubmed/28496007

Assessing green and black tea consumption by questionnaire among 0,375 Chinese, black tea consumption was associated with an odds ratio for dementia of 0.52, while green tea yielded an OR of 1.04:

https://www.ncbi.nlm.nih.gov/pubmed/26359663

Green tea consuming China, Taiwan, and Japan do not have lower incidence rates of dementia:

https://academic.oup.com/ije/advance-article/doi/10.1093/ije/dyy007/4850989

https://www.jstage.jst.go.jp/article/clinicalneurol/52/11/52_962/_article/-char/ja/

Clinical treatment data:

5.4 grams (not milligrams) of green tea extract (45% epigallocatechin-3-gallate) without caffeine vs. placebo yielded improved reading abilities in women 50-63 years old, but not in women in their 20s (n = 20) (suggesting a nootropic effect):

https://www.ncbi.nlm.nih.gov/pubmed/29484360

A proprietary study assessing the effects of matcha tea (4 grams), matcha tea bar (containing 4 grams matcha) vs. placebo on acute measures of cognition demonstrating improved attention and psychomotor speed with better performance after tea over bar. Matcha tea contains caffeine and theanine, as well as epigallocatechin gallate.

https://www.ncbi.nlm.nih.gov/pubmed/28784536

Acute administration of epigallocatechin gallate extract 135 mg or 270 mg vs. placebo (n = 27) in healthy adults during cognitive tasks chosen to involve the frontal cortex was associated with reduced cortical blood flow by near-infrared spectroscopy with the 135 mg dose:

https://www.ncbi.nlm.nih.gov/pubmed/22389082

30 people with severe AD were given “green tea pills” for 60 days (2000 mg per day) without placebo control. Oxidative measures, such as malondiadehyde, and MMSE scores improved:

https://www.ncbi.nlm.nih.gov/pubmed/27757204

33 people with MMSE of <28 were randomized to green tea powder containing 220 mg catechins vs. placebo for 12 months. Levels of malondiadehyde-modified low-density lipoprotein were lower but there was no change in MMSE score:

https://www.ncbi.nlm.nih.gov/pubmed/27142448

12 people with MMSE <28 were given 2000 mg per day green tea powder, uncontrolled, for 90 days with improvement in MMSE (15.3 before, 17.0 after):

https://www.ncbi.nlm.nih.gov/pubmed/25268837

A proprietary study in which 91 people with mild cognitive impairment/dementia with MMSE 21-26 were randomized to a proprietary combination of green tea extract and theanine  with improvement in memory and attention and increased theta waves by EEG (presumptively indicating increased cognitive alertness):

https://www.ncbi.nlm.nih.gov/pubmed/21303262

Conclusions:

An astounding amount of experimental data suggest a plausible basis for benefit to tea catechins, perhaps to theanine. Observational data likewise suggest an effect. Although observational data is typically as good as no-data-at-all, the association is strengthened by clear-cut dose-response effects.

The clinical treatment data are poor: proprietary, small sample sizes, uncontrolled, and there are no data that would lead us to believe that a neurotrophic effect is at work, rather than just a nootropic effect.

I believe it is safe to conclude that green tea via catechins exerts an acute nootropic effect. There are no—zero—data beyond experimental models to conclude that there is a neurotrophic effect and insufficient evidence to conclude that there is any effect on halting/reversing cognitive decline/dementia. That said, green tea is benign and available and there is no harm in consuming it.

MTHFR, folate, vitamin B12, and homocysteine

Higher serum homocysteine levels clearly correlate with cognitive decline and dementia (Alzheimer’s and vascular), as they do with reduced serum/RBC folate and B12 levels. Higher homocysteine also correlates with reduced cortical brain volumes in regions associated with cognitive decline by volumetric MRI.

But does reduction of homocysteine and/or supplementation of folate/folic acid/methyl-folate, B12 as cyano-, hydro-, or methylcobalamin (+B2 and B6/pyridoxine/pyridoxal-5’-phosphate?) result in slowing of cognitive decline? The data remain incomplete.

A summary:

Observational studies:

No effect on of folic acid + B12 on cognitive decline, despite homocysteine reduction (not segregated by MTHFR SNPs):

https://www.ncbi.nlm.nih.gov/pubmed/14584018

MTHFR 6685TT vs. CC: 10-fold greater risk for ischemic stroke

https://www.ncbi.nlm.nih.gov/pubmed/28963520

MTHFR C677T associated with increased likelihood of both Alzheimer’s and vascular dementia:

https://www.jstage.jst.go.jp/article/jea1991/10/3/10_3_163/_pdf

MTHFR hetero- and homozygosity for the T allele occurs with higher frequency in Alzheimer’s:

https://www.ncbi.nlm.nih.gov/pubmed/22034983

MTHFR C677T associated with modestly increased risk for Alzheimer’s dementia in Asians but not in Caucasians:

http://www.tandfonline.com/doi/full/10.3109/00207454.2011.578778

Prospective treatment studies:

Folic acid (800 mcg /day) modestly reduces risk of ischemic stroke regardless of MTHFR genotype:

https://www.ncbi.nlm.nih.gov/pubmed/25771069

A mixture of folate forms including L-methylfolate reduced measures of depression (which, of course, is a common confounder/concurrent condition with cognitive decline) in MTHFR C677T and A1298C carriers:

http://www.psychiatrist.com/jcp/article/Pages/2016/v77n05/v77n0523.aspx

Clinical trials of folic acid and vitamin B12 (non-methyl forms) have generated varied results. However, this meta-analysis of 20,000 individuals demonstrated that, while folic acid and vitamin B12 reduce homocysteine by 25%, they did not impact cognitive decline by psychometric testing (no segregation by MTHFR genotype):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4095663/

(In my view, using serum homocysteine as a proxy for folate and vitamin B12 status is flawed. Not segregating by MTHFR genotype assumes that everyone absorbs non-methyl forms equally, which is not true, of course. Also note that there are other causes for increased homocysteine. For example, even marginal degrees of hypothyroidism--very common--and renal insufficiency--also fairly common in the elderly, and increased alcohol intake are among the other causes of increased homocysteine, in which cases B vitamins would be expected to have no impact.)

Emerging observations on cognitive decline and MTHFR:

The MTHFR C677T variant is associated with reduced medial orbitofrontal cortical volumes by volumetric MRI, phenomena associated with higher homocysteine and lower serum B12 levels:

https://www.ncbi.nlm.nih.gov/pubmed/28435933

The MTHFR C677T variant may require apo E4 to exert its cognition-impairing effects:

https://www.ncbi.nlm.nih.gov/pubmed/26774227

Be aware that homozygotes for the C677T SNP (i.e., TT) may have an unusually exuberant response to B2/riboflavin with up to 40% reduction in homocysteine:

http://circ.ahajournals.org/content/113/1/74.long

Conclusions:

Given the above incomplete data, I think we can draw several practical conclusions, subject to change as the data expand:

1) I think it would be reasonable to treat everybody with methylfolate and methylcobalamin without testing for MTHFR. MTHFR genotyping can be pursued, of course, but given the high likelihood of folate and B12 deficiency unrelated to MTHFR (e.g., prior grain consumption, parietal cell autoimmunity, Crohn’s disease, small intestinal bacterial overgrowth, vegetarianism, etc.), coupled with the lack of any known toxicity of these two forms, giving it to everyone as part of a core multivitamin would be reasonable. The methyl form of folate also circumvents the potential toxicity of folic acid in MTHFR variants unable to process folic acid properly.

2) I think that increased homocysteine is only a crude proxy for folate/B12/MTHFR but should also raise questions about kidney and thyroid status that need to be approached individually.

3) Look for MTHFR variants in the presence of apo E4? Will this alter management in any way?

Nicotinamide riboside:

While theoretically promising as both a nootropic (mentation-enhancing) and a neuroprotectant, there are no data documenting beneficial effects in humans.

Nicotinamide riboside is present in cows’ milk (a crude proxy for safety):

http://jn.nutrition.org/content/146/5/957.long

Prevention of neuronal damage in an experimental model:

https://www.ncbi.nlm.nih.gov/pubmed/28842432

Prevention of cognitive decline and reduction in beta amyloid production in mice:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3632303/

Oddly, deterioration of exercise capacity in mice:

https://www.ncbi.nlm.nih.gov/pubmed/27489522

A pilot exploration of nicotinamide riboside pharmacokinetics and metabolites in humans, though proprietary and thereby subject to bias:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5062546/

The most coherent and logical review of NAD+ and sirtuin metabolism I’ve come across:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963347/

Toxicity data, though proprietary (paid for by the manufacturer of Niagen, the patent holder):

https://www.ncbi.nlm.nih.gov/pubmed/26791540

Conclusion: The data are limited to in vitro and non-therapeutic human experiences with no experiences documenting effect on slowing cognitive decline or enhancing any measure of mentation.

Nootropics

Recall that we distinguish nootropics (mentation-enhancing agents) from neurotrophic agents (neuronal/synaptic/astrocytic growth-enhancers), though there may be overlap among selected agents.

Over the years, I have experimented with selegiline (Deprenyl; a dopamine-enhancer), ergoloid mesylates (unknown mechanism), tyrosine/phenylalanine (noradrenaline-enhancers), dimethylaminoethanol (an acetylcholine enhancer), huperzine (an acetylcholinesterase inhibitor), singly or in combinations. The only one I experienced any positive effect with was huperzine, but the benefits were very modest. I’ve also experienced nothing with gingko and have not yet tried bacopa.

I have tried all 3 "racetams": piracetam, aniracetam, pramiracetam. Piracetam, though the oldest, works without question: accelerated learning, better data recall, improved data synthesis, increased creativity, accelerated pattern recognition. However, it has never been put through the FDA approval process and is unavailable in the U.S. (I obtain mine from the U.K., below.)

I am unsure how deeply we get into such things in Revite; I suspect little, if at all. But, as with tDCS, I think it helps to be acquainted with these agents. If anyone is interested in trying some of these agents to get better acquainted with them, they are obtainable via the International Antiaging Systems: https://www.antiaging-systems.com/

Omega-3 Fatty Acids EPA and DHA (linolenic acid discussed separately)

Observations from experimental models demonstrate reduced formation of beta-amyloid, reduce production of phosphorylated tau, increases BDNF, reduced omega-6-sourced arachadonic acid, and reduced neuroinflammation, all consistent with reduced potential for cognitive decline/dementia:

https://www.ncbi.nlm.nih.gov/pubmed/20181786

Observational data:

In total, 8 of 10 epidemiological studies suggested that higher blood levels of omega-3 fatty acids were associated with reduced cognitive decline, though benefits may be confined to non-apo E4 subsets. A sample:

Higher fish consumption/omega-3 intake inversely associated with cognitive decline ages 45-70 years:

https://www.ncbi.nlm.nih.gov/pubmed/14745067

Higher plasma omega-3 levels associated with less decline in selected measures of cognitive function (sensorimotor speed) but not in memory or word fluency over 3 years, ages 50-70:

https://www.ncbi.nlm.nih.gov/pubmed/17991662

Lower RBC DHA/EPA levels associated with lower total brain volumes, greater white matter hyperintensity volumes, and lower scores on visual memory, executive function, and abstract thinking in a large (n=1575) subset of the Framingham cohort:

https://www.ncbi.nlm.nih.gov/pubmed/22371413

Higher omega-3 intake associated with greater hippocampal, amygdalar, and total gray matter volume:

https://www.ncbi.nlm.nih.gov/pubmed/17574755

Higher omega-3 serum levels partially offset the cognitive impairment of low physical activity:

https://www.ncbi.nlm.nih.gov/pubmed/24813150

Higher RBC EPA + DHA levels associated with less cognitive decline:

http://ajcn.nutrition.org/content/77/4/803.long

Human clinical trials:

DHA 1700 mg + EPA 600 mg did not slow/reverse cognitive decline in people with dementia over 6 months, but did slow decline in people with mild cognitive dysfunction with MMSE of 27 or greater:

https://www.ncbi.nlm.nih.gov/pubmed/17030655

EPA + DHA 1800 mg per day did not affect cognitive measures over 6 months in people with Alzheimer’s but did slow cognitive decline in people with mild cognitive impairment: https://www.ncbi.nlm.nih.gov/pubmed/18573585

EPA + DHA 1800 mg per day did not impact cognition in people with MMSE scores of 21 or greater over 6 months:

https://www.ncbi.nlm.nih.gov/pubmed/18678826

EPA 200 mg + DHA 500 mg had no effect on cognitive decline in older, cognitively healthy people over 2 years:

https://www.ncbi.nlm.nih.gov/pubmed/20410089

In a proprietary study, 900 mg DHA improved cognitive measures in people 55 years or greater over 6 months:

https://www.ncbi.nlm.nih.gov/pubmed/20434961

DHA 2000 mg slowed cognitive decline in people with mild-moderate Alzheimer’s dementia but only in apo E3, not apo E4:

Quinn JF. A clinical trial of docosahexaenoic acid (DHA) for the treatment of Alzheimer’s disease. Alzheimers Dementia. 2009;5(4) supplement: P84.

Conclusion:

The biological plausibility of maintaining higher omega-3 fatty acid levels as a factor in preventing cognitive decline is solid and well-founded. Likewise, epidemiological/observational data suggest an association.

The experience from human prospective clinical studies is uneven, but on the whole suggest a benefit in people with mild cognitive decline who are non-apo E4. However, the prospective data suffer from too short time periods, low doses of omega-3s (I’ve been using 3600 mg EPA + DHA in a 3:2 ratio for years for cardiovascular protection, an intake generally associated with an RBC omega-3 index of 10% or greater), and lack of confirmatory neuroimaging data (e.g., hippocampal volumes). What is not clear is whether omega-3 supplementation would exert beneficial effects in the apo E4 subset if other efforts, e.g., anti-inflammatory efforts (vitamin D, reduced glycation, grain elimination, correction of dysbiosis, etc.) were added, since apo E4 is an activator of inflammasome transcription.

However, given the numerous other non-cognitive benefits of EPA and DHA (cardiovascular, reduced posprandial lipoprotein excursions, reduced VLDL/triglycerides and thereby reduced small LDL particles, reduced platelet activation), fish oil remains at the top of the list for essential supplements.

Phosphatidylserine (PS)

PS is among the most thoroughly studied nutritional supplements, despite not being mentioned in ReCODE, including several placebo-controlled clinical intervention studies.

Prior to the early 1990s, clinical trials demonstrated that phosphatidylserine supplementation improves cognitive measures in people with mild cognitive impairment and dementia. However, it fell into disrepute due to its original sourcing from bovine brains and risk for prion disease.

More recently, non-bovine sources (soy, krill) have been identified and clinical trials further explored. While bovine-sourced PS yielded consistent improvements in cognitive function in people with cognitive impairment/dementia, the data with soybean-sourced PS have been somewhat inconsistent, an effect that some claim is due to lack of DHA. Nonetheless, the bulk of data suggest improved cognition.

Experimental evidence:

PS increased dendritic density in mice neurons, both apical and basal, suggesting a neurotrophic effect:

https://www.ncbi.nlm.nih.gov/pubmed/3431625

Krill-sourced PS increased hippocampal neuronal BDNF and IGF in mice, a neurotrophic effect:

https://www.ncbi.nlm.nih.gov/pubmed/22889566

PS increased hippocampal neuronal proliferation and survival in mice:

https://www.ncbi.nlm.nih.gov/pubmed/25795377

Clinical intervention studies:

Small (n= 30) pilot study in which 300 mg per day of soy-PS improved cognitive measures in people with “memory complaints” over 12 weeks:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665496/

Bovine phosphatidylserine, 300 mg per day, improved cognitive measures in people with moderate to severe cognitive impairment over 6 months compared to placebo (n = 494):

https://www.ncbi.nlm.nih.gov/pubmed/8323999

Bovine phosphatidylserine, 100 mg three times per day, improved cognitive measures in people with various levels of cognitive impairment compared to placebo (n = 149):

https://www.ncbi.nlm.nih.gov/pubmed/2027477

Soybean-derived phosphatidylserine, 300 or 600 mg per day, did not improve cognitive measures over 12 weeks compared to placebo (n = 120):

https://www.ncbi.nlm.nih.gov/pubmed/11842880

Soy PS, 100 mg or 300 mg per day, improved verbal cognitive measures modestly in people (n = 78) with mild cognitive impairment compared to placebo with benefit confined to people with greater starting degrees of cognitive impairment. Benefits increased from month 3 to month 6.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2966935/

Soy PS, 100 mg per day, with DHA attached yielded improved cognitive measures over 15 weeks compared to placebo (n= 157)

https://www.ncbi.nlm.nih.gov/pubmed/20523044?dopt=Abstract

Open-label follow-up over 15 weeks, with previous placebo-takers demonstrating improved cognition and previous treatment group demonstrating sustained improvement (n = 122):

https://www.karger.com/Article/FullText/357793

Conclusion:

Despite not being mentioned in ReCODE, phosphatidylserine is among the most thoroughly studied of nutritional agents in cognitive decline/dementia with results that, as a whole, demonstrate positive, though modest, effects on improving cognitive measures and slowing cognitive decline. It is one of the few nutritional agents that has also been demonstrated to exert neurotrophic, not just nootopic, effects, at least in experimental models.

PS is costly; importantly, no dose advantage has been observed at the 300 mg per day dose over 100 mg per day. We will include, of course, the EPA + DHA of fish oil, though it is unclear whether DHA complexed directly to PS is superior to the two taken separately.  

Pyrroloquinoline Quinone (PQQ)

It is becoming a familiar refrain: biological plausibility, promising observations in experimental and in vitro experiments, perhaps limited nootropic benefits, but no real evidence for halting/reversing cognitive/neurotrophic decline.

PQQ is a naturally-occurring participant in mitochondrial energetics and antioxidation.

A review of the in vitro and experimental model data on PQQ’s effects as an antioxidant and neuroprotectant with nanomolar content in foods such as tea, milk, and vegetables, promoter of mitrochondriogenesis, inhibitor of beta amyloid plaque, and cellular growth factor:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140972/#!po=23.6842

Prospective human studies

PQQ (approximately 20 mg per day) acutely reduced inflammatory measures in humans  (c-reactive protein, IL-6, and trimethyl amino oxide).

https://www.ncbi.nlm.nih.gov/pubmed/24231099

PQQ 20 mg per day of the disodium salt improved subjective measures of stress, fatigue, and sleep quality with gradual effects developing over 8 weeks.

http://functionalfoodscenter.net/files/56592277.pdf

20 mg per day of the disodium salt of PQQ preserved mentation (a presumed nootropic, not necessarily neurotrophic, effect) over 12 weeks.

https://www.ncbi.nlm.nih.gov/pubmed/26782228

Conclusion:

There is a plausible biological basis to believe that mitochondrial/neuronal function/number are enhanced or preserved with PQQ availability, though no evidence of deficiency has ever been demonstrated. There is limited evidence for a nootropic effect in humans, as well as improvements in subjective measures of stress, fatigue, and sleep, but no evidence of a neurotrophic/cognition-preserving effect.

Once again, we are confronted with the same question: Is that enough? If our end-game is cognition/neural preservation, is this sort of preliminary information enough to recommend supplementation? Is the key to provide several key mitochondrial/neural active components that, in combination, provide benefits? Or are we treating phantom deficiencies and obtaining nothing more than placebo benefits?

Resveratrol

Unlike most other nutritional supplements, there is an abundant, robust, and a scientifically sophisticated literature on resveratrol. As with some of the other supplements, because it is a component of food, a polyphenol, this serves as a crude proxy for safety.

An overview of the potential for neuroprotective, beta amyloid-reducing and tau phosphorylation-blocking and tau aggregation-inhibiting, anti-inflammatory, and longevity-promoting effects of resveratrol:

www.sciencedirect.com/science/article/pii/S0925443914002920/pdfft?md5=a00f947bb24db1530651a24531c1e44e&pid=1-s2.0-S0925443914002920-main.pdf

The neuroprotective effects of polyphenols, such as those in cocoa and tea, as well as resveratrol and its metabolites, resveratrol-3-sulfate and resveratrol-3-O-glucuronide:

http://www.sciencedirect.com/science/article/pii/S0925443914003123

Accordingly, epidemiological studies have demonstrated dramatic reductions in dementia with moderate (3-4 glasses/day) consumption (though subject to country-of-origin, selection, and healthy survivor bias) though benefits appear to derive from non-resveratrol polyphenols:

https://www.ncbi.nlm.nih.gov/pubmed/15455646

Experimental evidence (only representative sample; the evidence is among the most robust of all nutraceuticals; mostly administered intraperitoneally). There are additional data demonstrating that resveratrol provides protection against oxidative, homocysteine-derived, and inflammasome-driven neuronal damage.

Resveratrol is neuroprotective in a hypoxia/ischemia model:

https://www.ncbi.nlm.nih.gov/pubmed/26544861

Resveratrol reverses cognitive decline associated with aging in an experimental model, likely via reducing inflammatory cytokines:

https://www.ncbi.nlm.nih.gov/pubmed/27040098

Resveratrol reversed age-related cognitive decline and exerted substantial neurotrophic effects and reduced microglial activation (2.4-fold increased net neurogenesis) in the hippocampus over 4 weeks of administration in a rat model:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894403/

Resveratrol extended lifespan, reduced beta amyloid plaque tau phosphorylation/accumulation in a dementia-prone mouse model:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776096/

Resveratrol did not improve cognitive performance nor prevent the pathological changes of dementia in a dementia-prone mouse model, but the related congener, pterostilbene, did:

https://www.ncbi.nlm.nih.gov/pubmed/21982274

Human clinical trials

Dose-dependent increase in cerebral blood flow (trans-resveratrol 250 mg, 500 mg) in humans:

https://www.ncbi.nlm.nih.gov/pubmed/20357044

Lack of cognition-enhancing (nootropic) effects in normal humans over 4 weeks:

https://www.ncbi.nlm.nih.gov/pubmed/26344014

No cognitive benefits of 250 mg resveratrol with 20 mg piperine in normal humans:

https://www.ncbi.nlm.nih.gov/pubmed/24804871

75 to 300 mg of resveratrol administered as a single acute dose improved cerebral blood flow and cognitive performance, though a proprietary study:

https://www.ncbi.nlm.nih.gov/pubmed/27420093

Single-dose trans-resveratrol 250 and 500 mg administered acutely improved cerebral blood flow but did not improve cognitive measures:

https://www.ncbi.nlm.nih.gov/pubmed/20357044

Resveratrol (200 mg per day trans-resveratrol + 320 mg quercetin over 6 months) resulted in improved memory performance and a MRI-derived functional surrogate of hippocampal/frontal/parietal/occipital function, but no change in hippocampal volume. (HbA1c decreased slightly and leptin increased, as well, suggesting metabolic benefits with resveratrol):

http://www.jneurosci.org/content/34/23/7862.long

75 mg trans-resveratrol twice per day improved cerebral blood flow and measures of cognition (and mood non-significantly) in 80 postmenopausal women with type 2 diabetes (without cognitive impairment/dementia) over 14 weeks (with 2-year follow-up study currently ongoing):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295071/

Conclusion:

The low absorption/bioavailability of resveratrol is a limiting factor in the clinical trials and practical use, requiring gram quantities (about 100 bottles of red wine) for meaningful serum levels and biological effect. Unfortunately, clinical trials have used smaller doses, though with the suggestion of meaningful effects even at lower doses. Efforts to identify a congener (SRT50) with greater absorption have failed due to unacceptable toxicity, while pterostilbene has proven promising in experimental models, though clearly not ready for prime-time.

There are 85 clinical trials of resveratrol that are ongoing, including 5 in dementia; results are pending. Doses of up to one gram (1,000 mg) twice per day were well-tolerated aside from mild nausea and diarrhea.

Is this sufficient to justify broad use? I think it is. I had not reviewed the resveratrol data for about 2-3 years and I was pleasantly surprised at how much it had advanced, uncommon for a nutritional supplement (though driven by the holy grail of trying to craft a patent-protectable congener).

Tocopherols and Tocotrienols

From the start, I am skeptical that tocotrienols will have a substantial protective effect because they are present in sub-milligram amounts in natural human foods. They are found in larger quantities in grains and palm, neither of which was present in most evolving human cultures. In other words, tocotrienols (less so tocopherols) were not part of the adaptive human experience and are therefore extrinsic agents. Extrinsic agents almost always are not as powerful an influence over health as intrinsically-necessary agents such as vitamin D or DHA.

Another hazard: Much, though not all, of the data supporting tocotrienol supplementation originates from Malaysia, Singapore, etc., i.e., countries that have a vested interest in supporting the large palm industry, therefore a potential source of bias. It accounts for "reviews" like this from Singapore that are little more than marketing:

https://www.ncbi.nlm.nih.gov/pubmed/28789906

Quick review: Vitamin E is typically the d-alpha tocopherol form that has generally been shown to have no beneficial effects in dementia, heart disease, etc. There is suspicion that gamma tocopherol may be more effective or that the combination of tocopherols (alpha, beta, delta, gamma) and tocotrienols (alpha, beta, delta, gamma) may be required for full benefit.

Nonetheless, there is biological plausibility for the neuronal protective effects of tocotrienols, though not tocopherols. But these arguments are tenuous, as they suggest that cholesterol-reducing strategies would reduce dementia. The best data (i.e., randomized, controlled, not observational) suggest that statins have no benefit in slow cognitive decline, even atorvastatin at 80 mg per day.

https://www.ncbi.nlm.nih.gov/pubmed/27133418

Rats experience better cognitive preservation with tocotrienols:

https://www.ncbi.nlm.nih.gov/pubmed/21533313

Alpha tocopherol increases production of amyloid beta in vitro:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133810/

Weak (observational) evidence of beneficial effects of tocopherols in humans from the Chicago Health and Aging Project:

https://www.ncbi.nlm.nih.gov/pubmed/15699242

Is tocopherol-content of diet nothing more than a marker for intake of higher-quality foods?

More weak observational data suggesting a beneficial effect of tocopherol/tocotrienol-rich diet intake on human cognitive decline:

https://www.ncbi.nlm.nih.gov/pubmed/24113154

Vitamin E as d-alpha tocopherol does not exert any protective benefit in dementia nor mild cognitive impairment; meta-analysis of 4 randomized, double-blind studies in humans:

https://www.ncbi.nlm.nih.gov/pubmed/28128435

Clinical intervention studies:

Prospective treatment with 400 mg/day tocotrienols tracking a surrogate measure of neuronal health, "white matter lesions," demonstrating no progression with tocotrienols vs. progression on placebo over 2 years. However, this study was Malaysian and is therefore, at least in my view, highly subject to potential bias:

https://www.ncbi.nlm.nih.gov/pubmed/24699052

The weak evidence for neuronal/cognitive benefits for tocotrienols, of course, does not negate the stronger evidence for tocotrienols in "chemoprevention" of cancer:

https://www.ncbi.nlm.nih.gov/pubmed/27669218

Over the mean (SD) follow-up of 2.27 (1.22) years, participants receiving alpha tocopherol had slower decline than those receiving placebo as measured by the ADCS-ADL. The change translates into a delay in clinical progression of 19% per year compared with placebo (approximately 6.2 months over the follow-up period). Caregiver time increased least in the alpha tocopherol group.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109898/

Summary:

There are in vitro and experimental model evidence for a beneficial effect of tocotrienols in neuronal preservation and preventing cognitive decline. The only human experimental data outside of observational studies originates from a potentially biased source following a surrogate measure. There are no objective data demonstrating a beneficial effect of tocopherols or tocotrienols on psychometric measures nor on measures such as hippocampal or temporal lobe volumes.

Once again, we are confronted with the question: Is that enough? I don’t think it is. I think this is enough to conclude that tocopherols/tocotrienols should not be part of our core list of supplements, but something that can be decided on an individual basis.

Vinpocetine

Vinpocetine is a nootropic with phosphodiesterase-inhibiting and antioxidative activity that has been around for about 30 years, widely used in Eastern Europe and Japan. While it was originally declared a pharmaceutical agent, it is available as a “nutritional supplement” in the U.S. While studied with variable effects in the 1980s and 1990s, there has not been much recent work. Absorption is minimal but markedly enhanced in the presence of food. No adverse effects have been reported with doses up to 60 mg. (I have personally taken 30 mg with no perceived ill-effect but a modest nootropic effect.)

A quick summary of the nootropic, though no neurotrophic, data:

Vinpocetine 10 mg three times per day improved cognitive measures in people with vascular dementia:

https://www.ncbi.nlm.nih.gov/pubmed/3553281

No effect on cognitive measures at doses of 30-60 mg per day compared to placebo in people with established dementia:

https://www.ncbi.nlm.nih.gov/pubmed/2715559

Better, though modest, preservation of cognition in people with multi-infarct dementia compared to placebo:

https://www.ncbi.nlm.nih.gov/pubmed/16100299

Possible benefits post-multi-infarct in cognitive measures and glucose/O2 consumption:

https://www.ncbi.nlm.nih.gov/pubmed/17631470

A review of the studies up until 2002:

http://www.altmedrev.com/publications/7/3/240.pdf

Conclusion:

The data taken as a whole suggest a modest potential neuroprotective effect in ischemic brain disease as well as a nootropic effect. But there are no data to suggest a neurotrophic effect useful for our purposes.

Turmeric

Turmeric provides a mixture of curcuminoids: curcumin, demethoxycurcumin, and bisdemethoxycurcumin, of which curcumin is believed to be the most bioactive, though the others may also exert lesser effect (though reviewed by a Pakistani group, Pakistan being a commercial source of turmeric):

https://www.ncbi.nlm.nih.gov/pubmed/23873

Curry consumption associated with decreased dementia incidence (which, of course, is only an association, not necessarily cause-effect):

https://www.ncbi.nlm.nih.gov/pubmed/16870699

Experimental data:

Rationale and review of beneficial neuronal effects via blocking accumulation of beta-amyloid plaque, anti-inflammatory effects, increased BDNF, as well as improved cognition (i.e., a nootropic effect):

https://www.ncbi.nlm.nih.gov/pubmed/26420724

Curcumin is a chelator of iron and copper:

https://www.ncbi.nlm.nih.gov/pubmed/15345806

Curcumin blocks aluminum-induced neuronal toxicity/cognitive decline:

https://www.ncbi.nlm.nih.gov/pubmed/19616038

Turmeric reduces IL-6 levels:

https://www.ncbi.nlm.nih.gov/pubmed/27392742

Turmeric reduces c-reactive protein:

https://www.ncbi.nlm.nih.gov/pubmed/23922235

Turmeric reduces TNF-alpha levels:

https://www.ncbi.nlm.nih.gov/pubmed/27025786

Review of the anti-inflammatory effects of turmeric, 150-500 mg per day, including reduction in LPS-mediated inflammation and TNF-alpha-mediated health conditions:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753829/

Human clinical studies:

Modest reduction in serum beta-amyloid levels with a low-dose (80 mg) of a "lipidated" form of curcumin:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518252/

Case report of 3 people given turmeric with one obtaining benefit in psychometric testing:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665200/

A branded preparation called Curcumax 1500 mg per day prevented cognitive decline (but did not improve cognitive function) vs. placebo:

https://www.ncbi.nlm.nih.gov/pubmed/27102361

No cognitive effect of turmeric (branded preparation) on cognition, serum amyloid beta, or CSF phosphorylated tau levels (proprietary study), n = 30:

https://www.ncbi.nlm.nih.gov/pubmed/23107780

No benefit on cognitive measures over 6 months:

https://www.ncbi.nlm.nih.gov/pubmed/18204357

Conclusion:

The experimental and human data supporting an anti-inflammatory effect are robust and provide a plausible basis for a dementia-preventing/reversing effect. As with so many other agents, however, the human treatment data are limited/flawed, limited by doses used and length of treatment time.

Given the broad anti-inflammatory benefits, I believe it would be reasonable to include turmeric (dose? form?) in the list of core supplements. Of course, toxicity is extremely uncommon, consistent with its presence in food.

Vitamin D

Vitamin D, of course, is crucial to any overall program for health with implications for bone density, cardiovascular health/protection from heart failure, seasonal mood, protection from autoimmune conditions, etc. Given the extensive network of vitamin D receptors in the human brain, we’d expect effects on cognition. But does it preserve cognition/prevent dementia? While vitamin D is included in ReCODE, there is no review of the supportive data. So here we go:

Experimental data:

Neuronal and glial cell vitamin D receptors in the brain:

https://www.ncbi.nlm.nih.gov/pubmed/24607320

Beta-amyloid plaque blocks the vitamin D receptor and accelerates vitamin D degradation:

https://www.ncbi.nlm.nih.gov/pubmed/23752060

In a mouse model, vitamin D improved cognitive performance and was associated with activation of several hippocampal genes responsible for neuronal/synaptic growth:

Observational data:

Note that most studies compared vitamin D deficiency defined as a serum 25-OH vitamin D serum level of 20 or 30 ng/ml with levels above, a cutoff that I would regard as deficient even in the presumed vitamin D-replete population. It would be interesting to have a prospective trial aim for levels of, say, 60 ng/ml, at an earlier point in life, rather than at the onset or midst of early cognitive decline.

Lower 25-OH vitamin D serum levels were associated with modestly greater risk for dementia/AD (though non-demented also had low levels):

https://content.iospress.com/articles/journal-of-alzheimers-disease/jad170407

Parathyroid hormone (PTH) serum levels, an inverse proxy for vitamin D status, did not predict cognitive decline over 20 years:

https://www.ncbi.nlm.nih.gov/pubmed/28768841

2017 meta-analysis of 25-OH vitamin D as a predictor of cognitive decline showed an association. Authors speculate that there may be a window of opportunity earlier in life during which vitamin D restoration may have a larger effect on delaying/preventing cognitive decline. Note that there are no data associating 25-OH vit D levels with apo E genotype.

https://www.ncbi.nlm.nih.gov/pubmed/28758188

The combination of low 25-OH vitamin D, higher homocysteine, and lower serum folate was associated with greater risk for dementia, especially subcortical vascular dementia:

https://www.ncbi.nlm.nih.gov/pubmed/28611659

Four SNPs involved in vitamin D metabolism/lower serum 25-hydroxy vitamin D levels were associated with Alzheimer’s dementia:

https://www.ncbi.nlm.nih.gov/pubmed/27856775

Cognitive benefits of vitamin D may apply only to those 65 years old and older:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969697/

Lower 25-hydroxy vitamin D levels were associated with poorer cognitive measures, especially executive function, processing speed, and visuo-perceptual skills, as well as reduced hippocampal volume (especially for those with 25-hydroxy vitamin D serum levels of 10 ng/ml or less (Framingham cohort):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911705/

Retrospective analysis of people supplementing or not supplementing vitamin D with slowed cognitive decline in those taking vitamin D, time to onset of severe Alzheimer’s dementia delayed by one year.

https://www.ncbi.nlm.nih.gov/pubmed/25153973

Human clinical studies:

The data are skimpy, especially any long-term data:

Vitamin D3 supplementation, 4000 units per day vs. 400 units per day, improved measures of non-verbal/visual memory over 6 months with a 25-hydroxy vitamin D serum level of 52 ng/ml achieved in the "high-dose" group (a nootropic, but not necessarily neurotrophic, effect):

https://www.ncbi.nlm.nih.gov/pubmed/28167237

Vitamin D3 5000 units per day did not improve cognitive measures in young adults, average age 22 years, over 6 weeks (i.e., no nootropic effect):

https://www.ncbi.nlm.nih.gov/pubmed/22073146

Combined memantine + vitamin D vs. memantine alone vs. vitamin D alone improved MMSE scores by 4 points compared to no change in the single treatment arms over 6 months:

https://www.ncbi.nlm.nih.gov/pubmed/22960436

Conclusion:

As with omega-3 fatty acids, the overall benefits of vitamin D readily justify its inclusion, even though the prospective clinical data are lacking.

Zinc

I’ve been doing more thinking about zinc lately. After all, zinc is one of the several cations that are blocked almost entirely from being absorbed by grain phytates (along with calcium, magnesium, and iron). Just as iron deficiency anemia with hemoglobins of 7 or 8 g/dl resistant to iron supplementation commonly develops in grain-consuming populations, so a parallel zinc deficiency also develops (although not reflected by well-preserved serum zinc levels at the expense of tissue levels). Zinc, like magnesium, is a catalytic cofactor in thousands of reactions and is therefore crucial for many aspects of health. Zinc therefore appears to be just as important to overall health as iron, though not at the top of our thinking like iron.

Zinc is proving to be a bigger player in health than originally thought with zinc deficiency contributing to insulin resistance, inflammatory phenomena, hormonal disruption, and, of course, cognitive impairment and dementia.

Zinc is given only passing mention in DeCODE and highlighted in the context of a copper/zinc ratio, which Bredesen claims should be 1:1 (based on serum levels and a calculation involving ceruloplasmin levels).

Note that zinc, like vitamin B12, is obtained primarily from animal products, not unexpectedly yielding substantial deficiencies in people who are vegan/vegetarian. Humans, through our adaptation and substantial reliance on carnivory, have developed reliance on nutrients that are obtained exclusively or primarily via consumption of animal organs and flesh. (Look at the impaired immunity, for instance, of vegans/vegetarians who also consume plentiful phytate-containing grains.) A listing of zinc-rich sources (from the USDA Database):

Table 2: Selected Food Sources of Zinc [11]

Zinc is not stored in any organ and regular daily intake is therefore required to preserve all zinc-related functions.

A quick review of the evidence:

NHANES III: 42.5% of American elderly take in less than the RDA for zinc: deficiency is widespread and common:

https://www.ncbi.nlm.nih.gov/pubmed/10801945

As a reflection of the importance and ubiquity of zinc-related processes, 3% of the human genome encodes zinc-containing proteins that include enzymatic roles including peptidases, hydroxylases, isomerases, ligases, etc.:

https://www.ncbi.nlm.nih.gov/pubmed/23319127 (An excellent review of zinc biochemistry.)

Inflammatory markers, c-reactive protein and interleukin-6, were reduced with 30 mg (elemental) zinc as zinc gluconate in obese women with starting higher levels of these markers compared to normal controls. Leptin and adiponectin levels were unchanged.

https://www.ncbi.nlm.nih.gov/pubmed/24402636

A compilation of 6 clinical trials that, in total, demonstrate a reduction in measures of insulin resistance with zinc supplementation:

https://www.ncbi.nlm.nih.gov/pubmed/27587022

A 2015 Cochrane review revealing insufficient evidence that zinc supplementation prevents development of type 2 diabetes:

https://www.ncbi.nlm.nih.gov/pubmed/26020622

Zinc supplementation of 30 mg (elemental) as zinc gluconate increased T-cell number and proliferative response as gauges of immune response (with impaired T-cell driven immunity previously demonstrated in other studies). Note that this dose did not achieve normal serum zinc levels in all participants.

http://ajcn.nutrition.org/content/103/3/942.long

In experimental models, zinc deficiency is associated with the pathological hallmarks of dementia, including oxidative injury and accumulation of beta amyloid plaque:

https://www.ncbi.nlm.nih.gov/pubmed/24247360

Zinc acetate supplementation reduced production of beta-amyloid plaque in mice:

https://www.ncbi.nlm.nih.gov/pubmed/24595193

People with Alzheimer’s dementia (and Parkinsonism) have lower serum (but not urinary) zinc levels compared to controls:

https://www.ncbi.nlm.nih.gov/pubmed/20841345

There is an age-related decline in serum zinc levels not necessarily specific to people with dementia:

https://www.ncbi.nlm.nih.gov/pubmed/24676028

Zinc can be a double-edged sword with toxic neuronal effects following ischemic or traumatic injury:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856052/

Zinc dyshomeostasis accounts for beta-amyloid plaque sequestration of zinc and zinc deficiency may not be the primary driver of the process, but an "innocent bystander" phenomenon.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3311647/

Conclusion:

There is biological plausibility for neuronal impairment/beta-amyloid accumulation etc. with zinc deficiency, along with common dietary deficiency that carries immune, gastrointestinal, inflammatory, and insulin-resistance provoking consequences.

We lack human evidence, both observational and prospective, that zinc deficiency plays a role in cognitive decline. However, given the ubiquity of deficiency and the well-established immune-enhancing effects of zinc supplementation, it seems reasonable and necessary to include some form of zinc, e.g., as a multivitamin or multimineral that includes other nutrients in our list of essentials such as iodine, B2, methylfolate, etc.

As we discuss chelation and detoxification of heavy metals, we shall have to remain mindful of the potential for inadvertent chelation of zinc as an innocent bystander.

Apo E4

Some data/thoughts on apo E4, the genotype associated with increased risk for cognitive decline/dementia, as well as cardiovascular disease:

People with apo E4 have a harder time quitting cigarettes. Smoking, of course, increases risk for dementia. People with apo E4 suffer greater cognitive impairment with the effort to quit smoking and therefore have more recidivism. Nicotine patches appear to address this issue.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3604077/

Moderate alcohol consumption does not increase risk for cognitive decline in non-Apo E4 people but hastens cognitive decline in apo E4+ people:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865814/

Apo E4 people need to join the convent!

Apo E4-related dementia is dependent on factors in modern Western life, as populations with apo E4 living in areas such as Nigeria are relatively spared:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012422/

PPI use is associated with dementia:

https://www.ncbi.nlm.nih.gov/pubmed/25341874

(Though selection bias may be an alternative explanation.)

The incredibly dense in vitro work from Bredesen’s group on the transcriptional mechanism by which apo E4 exerts its inflammatory and insulin-blocking effects:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719010/

One of the very few trials of diet, though making the fundamental nutritional mistake of lumping saturated fats together with carbohydrates:

https://www.ncbi.nlm.nih.gov/pubmed/23779114

Among the studies demonstrating the greater effects of traumatic brain injury in apo E4 people compared to apo E3/apo E2.

https://www.ncbi.nlm.nih.gov/pubmed/10981753

Speculation:

If apo E4 shows a "preference" to bind to VLDL, could the dramatic reductions in VLDL hepatic production and serum levels that develops with carbohydrate limitation be at play in reducing dementia risk? It means that serum triglycerides, VLDL, and postprandial measures of lipoproteins may be among the important predictors/risk factors for cognitive impairment but only in apo E4 people. This will require prospective confirmation.

http://www.jbc.org/content/269/35/22358.long

Making sense out of the apo E4 science and discussion is nearly impossible at current levels of understanding, though Bredesen pares it down to simply addressing multiple inflammatory markers, given apo E4’s nuclear transcriptional ability to activate numerous genes involved in the inflammasome.

Heavy metals

The literature on heavy metals becomes overwhelming quite readily. So I’ll only share the relevant reviews that each of us can explore further via references as needed.

Aluminum:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651828/

Conclusion:

There is indeed an aluminum toxicity syndrome that is distinct from Alzheimer’s dementia but is only observed with aluminum salts administered as part of dialysis and in aluminum workers, but not in the general public. Although aluminum has been detected at higher concentrations in the presence of beta-amyloid plaque, it is not clear whether this is causal or an accompaniment.

Mercury:

This autopsy study demonstrated reduced dementia-associated pathological findings with increasing seafood consumption in apo E4 people but no correlation with brain levels of mercury. Interestingly, look at linolenic acid intake across all tertiles of omega-3 and mercury intake: all low by our standards. The impressive internal consistency of the data in this study, along with the use of hard end-points means this study carries more weight, despite its observational design. (There are other pathological studies that demonstrate increased brain mercury associated with Alzheimer’s dementia.)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460535/

Cognitive impairment of methylmercury from industrial contamination and seafood consumption, stratified by serum methylmercury levels:

https://www.ncbi.nlm.nih.gov/pubmed/18675410

Inorganic mercury may be a cofactor that requires the presence of other heavy metals to exert its pathological effects:

https://www.ncbi.nlm.nih.gov/pubmed/20847438

Large (n = >200,000) observational study associating modest increase in dementia occurrence (R = 1.132) with presence of mercury dental amalgams:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642684/

It may be helpful to be aware of the factors that are suspected to play a role in Finland, the country with the world’s highest mortality rate from dementia:

https://www.ncbi.nlm.nih.gov/pubmed/28687259

Use of hair methylmercury levels and association with cognitive impairment:

https://www.ncbi.nlm.nih.gov/pubmed/12844364

Hair and blood total mercury track well together, meaning either method is a reliable index of mercury exposure from fish consumption:

https://www.jstage.jst.go.jp/article/jts/37/1/37_1_123/_pdf

An excellent review of the data on the mercury toxicity of dental amalgams but provides little direction on how to manage in the setting of cognitive decline:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905169/

Iron

Going through the data on heavy metals and dementia, the issue of iron comes up over and over again, an issue not covered in ReCODE.

Interestingly, it is apparently not just an issue of body iron overload, as in hemochromatosis, but it is a matter of iron dysregulation even in the absence of extra-cerebral iron overload. In experimental models, iron is a potent trigger of oxidative injury and the hallmark pathological changes associated with dementia have been reproduced, e.g., beta-amyloid plaque accumulation and hyperphosphorylated tau.

Hemochromatosis and ferritin

Hemochromatosis genetic variants may be associated with dementia or MCI:

https://www.ncbi.nlm.nih.gov/pubmed/21346098

Risk may especially be magnified in the presence of apo E4:

https://www.ncbi.nlm.nih.gov/pubmed/12584430)

However, the clinical association remains in question:

http://jn.nutrition.org/content/141/4/729S.long

(There are no data that explore an association between polycythemia, idiopathic or otherwise, and dementia or MCI.)

Pivotal study:

CSF ferritin levels are a strong predictor of dementia, including likelihood of MCI conversion to dementia, with higher CSF ferritin levels in people with apo E4:

https://www.ncbi.nlm.nih.gov/pubmed/25988319

Unanswered question: Given the association of higher CSF ferritin levels with MCI/AD, along with the inflammasome-activating effect of apo E4, is inflammation that is associated with sustained elevation of ferritin as an acute phase reactant part of the explanation? In other words, perhaps ferritin is not the cause, but a consequence of inflammation that, in turn, adds to iron dysregulation and oxidative injury. Note, for instance, that type 2 diabetics have dramatically higher serum ferritin levels than non-diabetics: https://www.ncbi.nlm.nih.gov/pubmed/15606699.

If the driving force is inflammation, then we need to focus on inflammation, not necessarily on chelating iron. But it highlights the potential tracking usefulness of following serum ferritin levels (or CSF ferritin, if available).

The data on brain/blood brain barrier/endothelial iron dysmetabolism as a contributor to cognitive decline/dementia:

An excellent review:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672943/

MRI imaging shows increased iron accumulation in brain regions that include the hippocampus:

https://www.ncbi.nlm.nih.gov/pubmed/23792695

Post-mortem brain examination shows 10-16% higher cortical iron in people with dementia:

https://www.ncbi.nlm.nih.gov/pubmed/25024342

Greater cortical iron is independent of serum iron, with greater cortical iron occurring with lower levels of serum iron:

https://www.ncbi.nlm.nih.gov/pubmed/24916541

Desferroxamine, a chelator of both iron and aluminum (that, in animal models, has been shown to reduce amyloidogenesis and phosphorylated tau accumulation), administered to humans, slowed cognitive decline substantially:

https://www.ncbi.nlm.nih.gov/pubmed/8122302

Interestingly, the OTC (in the US; by prescription in China) acetylcholinesterase inhibitor, huperzine, in addition to reversing characteristic pathological changes associated with dementia in mice, also reduced brain iron accumulation:

https://www.ncbi.nlm.nih.gov/pubmed/24332448

The experimental turmeric derivative, J147, has been shown to dramatically reverse dementia pathology and behavior in mice, while also reducing cortical iron:

https://www.ncbi.nlm.nih.gov/pubmed/23673233

I shall explore clinical studies for reduction/chelation of metals separately. At the very least, the iron question mandates focusing on the inflammasome, serum ferritin in particular.

Cadmium

Here’s a review of the evidence implicating cadmium, a ubiquitous environmental pollutant from natural and man-made sources (mining, fossil fuel combustion, manufacturing). The association is confounded by cigarette smoking, a major source of cadmium exposure. The data are exclusively experimental and observational with no prospective human treatment clinical studies. Most of the data also surprisingly lack any segregation of blood/urinary/tissue samples between smokers and non-smokers.

Note that blood cadmium levels reflect recent exposure while urinary cadmium is a better reflection of tissue levels.

Experimental data have demonstrated increased beta-amyloid plaque and tau deposition with cadmium:

https://www.ncbi.nlm.nih.gov/pubmed/17920001

Observational data:

Blood cadmium levels of 0.6 mcg/L or greater are associated with nearly 4-fold increased mortality from dementia, with the dose-response curve showing increasing mortality beginning at 0.3 mcg/L (NHANES). Blood cadmium (oddly) did not correlate with serum cotinine levels, a marker for cigarette smoking (and thereby calling the value of the data into question).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908725/

Serum cadmium levels are not associated with dementia:

https://www.ncbi.nlm.nih.gov/pubmed/24164932

Data associating urinary cadmium and Alzheimer’s disease mortality are mixed:

https://www.ncbi.nlm.nih.gov/pubmed/28511080

Higher urinary cadmium (particularly above 0.8 mcg/L) is associated with greater cognitive impairment (NHANES III):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3599125/

Hepatic cadmium levels are higher in people with dementia:

https://www.ncbi.nlm.nih.gov/pubmed/2358624

Mass spectrometry of brain tissue yields no evidence for increased cadmium content in people dying of dementia:

https://www.ncbi.nlm.nih.gov/pubmed/11867068

Conclusion:

While there is no question that cadmium has been proven to be toxic in experimental models, the data are woefully inadequate in suggesting that cadmium exposure in and of itself is a biologically meaningful risk for cognitive decline or dementia, especially given the failure to factor out cigarette smoking in most studies.

However, given the fact that cadmium can be detoxified via sweating (e.g., saunas), I predict that we can address the uncertainty surrounding cadmium by simply advocating a broad program of heavy metal detoxification that includes sauna use, exercise (to augment sweating), and inclusion of cruciferous veggies. Obviously, any smokers should be alerted to the fact that they are exposing themselves to the potential for cadmium-associated cognitive decline as the primary means of cadmium detoxification.

Arsenic

As with all heavy metal issues, there is no question that acute arsenic exposure can be toxic. Also, higher levels that prevailed in drinking water in the past have been shown to have carcinogenic potential, with levels having been reduced over the past 15-20 years. The question is: In someone presenting with mild cognitive decline or early dementia, is heavy metal(s) toxicity partly at fault and does its removal permit recovery?

Note that we are talking about the health implications of inorganic arsenic, not organic arsenic.  

Of note, 13.6% of municipally-provided drinking water delivers 5.0 mcg/L (5 ppb) or more arsenic, levels that may lead to chronic toxicity manifest as coronary disease, hypertension, type 2 diabetes, and increased cancer risk, as well as impaired cognitive performance, even though it is below the EPA and WHO cutoff of 10 ppb for tolerable levels of drinking water arsenic. Note that private wells can represent a substantial potential source, as they are not regulated and have been found to be a substantial source of arsenic exposure.

Review:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083674/

This review also summarizes the experimental data demonstrating that arsenic triggers accumulation of beta-amyloid plaque, phosphorylated tau, oxidative injury and inflammation, including such effects in hippocampal tissue.

Arsenic’s potential toxicity on cognitive function is influenced by the gene for arsenic methyltransferase (AS3MT), with mean arsenic exposure of 6.4 ppb, below the EPA cutoff of 10 ppb shown to impair cognitive function:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234288/

Arsenic disrupts bowel flora composition in a mouse experimental model at exposure levels 1000-fold higher than relevant human exposure levels:

https://www.ncbi.nlm.nih.gov/pubmed/24413286

Blood arsenic levels markedly underestimate exposure, while hair, urine, and finger/toe nails provide better measures of chronic exposure:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977337/

Add to arsenic exposure from drinking water the exposure we obtain via rice consumption, rice being a natural concentrator of soil arsenic. Arsenic exposure occurs at high levels from rice consumption, particularly anything containing rice bran, such that many countries outside the U.S. are recommending that children avoid some rice products, especially rice drinks that include the bran/husk:

http://www.zora.uzh.ch/id/eprint/119850/1/HojsakI%2C%202015.pdf

While most seafood contains organic arsenic that is almost completely excreted in urine and does not appear to share the toxic effects of inorganic arsenic, filter-feeding shellfish such as clams and mussels have higher levels of inorganic arsenic:

https://www.ncbi.nlm.nih.gov/pubmed/25666158

Regulation of food arsenic may be patterned after the criteria used for water arsenic, meaning rice milk that commonly contains 10 ppb or greater arsenic is a toxic and carcinogenic substance:

https://www.ncbi.nlm.nih.gov/pubmed/24884827

Green tea blocks the oxidative and other forms of neuronal injury from arsenic in an animal model (study performed in India, a tea-producing nation):

https://www.ncbi.nlm.nih.gov/pubmed/28155600

The data associating chronic arsenic exposure and cognitive decline/dementia:

Observational/cross-sectional:

Increased arsenic drinking water levels are associated with impaired cognitive function and dementia in Texas with a mean chronic exposure of 6.33 ppb:

https://www.ncbi.nlm.nih.gov/pubmed/24506178

Post-mortem brain and cerebrospinal fluid levels of arsenic were lower in people with Alzheimer’s compared to normal controls:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881830/

Conclusion:

There is no doubt that arsenic impairs cognition, but it remains unclear how much of a role it plays in the setting of adult cognitive decline/dementia, as compared to impaired learning in children. Nonetheless, the self-contained setting of the Villas means that ongoing exposure is remedied simply by filtering the water. I believe it also means making rice a minor component of diet, if it is included at all. Rice drinks such as rice milk should be completely off the menu, of course.

Lead

There is no question that lead impairs cognition in children and adults. But is it a relevant factor in dementias/cognitive decline and, if lead exposure occurred decades earlier, can there be benefit from its removal later in life when much of the dementia-related pathology has already occurred with the main repository for body lead being bone remains persistent?

Experimental data:

Arsenic, cadmium, and lead given chronically to rats at levels approximating that in the drinking water in India caused pathological changes associated with Alzheimer’s. The effect was dominated by lead, but the combination of the three acted synergistically:

https://www.ncbi.nlm.nih.gov/pubmed/25288670

Early life lead exposure increases Alzheimer’s dementia-associated brain pathology via an epigenetic and oxidative injury mechanism later in life in a primate model:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2486412/

An excellent review: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567843/

Lead exposure occurred commonly and on a widespread basis until the late 20th century:

"Between 1976 and 1991, the mean blood Pb levels for people in the US dropped 78% from 12.8 μg/dL to 2.8. Since 1991 the standard elevated blood Pb level defining the need for action from Pb poisoning in children has been set to 10 μg/dL. The previously elevated mean blood Pb level of 12.8 μg/dL is a sobering testament to the high levels of Pb exposure endured by the general US population and other countries in the recent past."

Observational data:

It is well established that lead exposure is associated with cognitive decline:

https://www.ncbi.nlm.nih.gov/pubmed/15583371

https://www.ncbi.nlm.nih.gov/pubmed/14569188

Lead is also associated with Parkinsonism and amyotrophic lateral sclerosis (Lou Gehrig’s disease), suggesting a broad neurodegenerative effect:

https://www.ncbi.nlm.nih.gov/pubmed/16909025

Bone lead levels (the gold standard for lifetime lead exposure, as it is cumulative) correlate with cognitive impairment:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2719051/

Bone lead reflects prior/lifelong cumulative exposure, while blood levels are helpful for ongoing exposure:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1849945/

Conclusion:

Ongoing lead exposure in the Villas setting will obviously not be an issue. The question for our setting specifically is whether there is benefit to reducing the body-wide/bone burden of lead, given that ongoing/recent exposure is solved simply by the setting. Is bone lead accessible to chelation or other detoxification efforts?

Detoxification conversation to follow.

Heavy metal detoxification/chelation

The world of chelation of heavy metals made a major leap in credibility with publication of the long-awaited TACT trial, summarized in this discussion below. I had a long conversation with Dr. Lamas, the primary investigator, who reviewed the data in detail and his rationale. (Interestingly, when I asked him why he performed the trial, which involved a mountain of work, he said that he wanted to prove that chelation was a fairy tale. He was shocked when the data were unblinded and showed dramatic benefits.) While EDTA chelation was indeed associated with reduction in cardiovascular events, especially in diabetics, no serum or other metal levels were tracked. Dr. Lamas said that it was his personal opinion was that it was likely cadmium, but had no data to substantiate. Also note that 40 intravenous sessions were employed, an extraordinary commitment. This was devoted exclusively to cardiovascular outcomes with no cognitive measures made.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162329/

Experimental models:

Chelation of iron using iron chelators able to cross through the blood-brain barrier in a rat model improved cognitive measures:

https://www.ncbi.nlm.nih.gov/pubmed/26159898

The experimental iron chelating agent, M30, reduces dementia-related cognitive measures over 9 months in a mouse model, and reduced brain iron deposition, beta-amyloid plaque, and tau pathology:

https://www.ncbi.nlm.nih.gov/pubmed/22360429

The detoxification effects of glucosinolates from cruciferous vegetables: a review of mechanisms and summary of the evidence. The benefits remain largely theoretical, as there is no clinical trial evidence that this is a biologically meaningful effect.

http://jn.nutrition.org/content/132/10/2991.long

Non-proprietary case reports of use of a food-derived product, PectaSol modified citrus pectin (MCP) (EcoNugenics) for heavy metal chelation:

https://www.ncbi.nlm.nih.gov/pubmed/18219211

Modified citrus pectin reduces serum lead levels and increases urinary lead in children over 28 days:

https://www.ncbi.nlm.nih.gov/pubmed/18616067

Proprietary report of increased urinary clearance of lead, cadmium, and arsenic with modified citrus pectin, 15-20 mg over one week:

https://www.ncbi.nlm.nih.gov/pubmed/16835878

Cilantro, often held up as a miracle green food, probably does not work as a mercury chelator, summarized here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654245/

Selenium 100 mcg per day may increase renal excretion of mercury:

https://www.ncbi.nlm.nih.gov/pubmed/23033886

Anthocyanins have a protective/reversing effect on Alzheimer’s pathology in animal models, benefits that may represent a class effect not uni

A summary of pharmaceutical oral/IV chelating agents:

From Sears:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654245/Lifestyle practices:

Exercise

Unlike many of the nutritional supplements, with exercise we have far better data, both observational and clinical intervention studies tracked with both psychometric testing and volumetric brain imaging.

Biomarker studies:

Elderly non-cognitively impaired people reduced c-reactive protein and interleukin-6 (but not TNF-alpha) with 180 minutes/week exercise:

https://www.ncbi.nlm.nih.gov/pubmed/15209647

A small experience demonstrating modest reduction of homocysteine in elderly non-demented people with strength training over 6 months:

https://www.ncbi.nlm.nih.gov/pubmed/14605513

Exercise increased serum BDNF by 400% in cognitively normal males over 3 months:

https://www.ncbi.nlm.nih.gov/pubmed/19923361

Strength training does not raise serum BDNF but raises IGF-1alpha that also possesses neurotrophic effects, summarized here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258000/

Observational data:

The cross-sectional data are abundant and consistent: More physically active people have less cognitive decline, less dementia, less brain atrophy. The quantity and intensity of exercise required varied from study to study, but typically involved a minimum of 30 minutes per day, 4-5 days per week involving common activities such as walking.

Regular mid-life aerobic exercise reduces incidence of dementia by approximately 30%:

https://www.ncbi.nlm.nih.gov/pubmed/18570697

Women (n = 9300) who exercised at various times along their life course reduced incidence of mild cognitive impairment by about 50%:

https://www.ncbi.nlm.nih.gov/pubmed/20609030

Clinical intervention studies:

A large Chinese experience (n = 15,000+) demonstrating that aerobic exercise, but not stretching or toning, reduces development of dementia by about 20% in cognitively normal people over 6 years. Exercise involved 45 minutes per day, 7 days per week (!).

https://www.ncbi.nlm.nih.gov/pubmed/26433864

Cognitively normal people with pre-diabetes and type 2 diabetes experienced improved executive function, but not memory, over 6 months of aerobic exercise (45-60 minutes x 4 days/week):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049111/

6 months of aerobic exercise in cognitively normal, sedentary adults increased white and gray matter brain volumes:

https://www.ncbi.nlm.nih.gov/pubmed/17167157

Hippocampal volume (specifically the dentate gyrus) increased by 2% over one year in people engaged in aerobic exercise compared to a similar magnitude of loss of brain volume in people not engaged in exercise, changes that correlated with increased serum BDNF levels. Memory also improved:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041121/

Meta-analysis showing improved cognitive function with exercise in people with mild cognitive impairment:

https://www.ncbi.nlm.nih.gov/pubmed/24927709

A meta-analysis of intervention studies that suggests that, once established, exercise does not impact on dementia although it can reduce depression that accompanies dementia:

https://www.ncbi.nlm.nih.gov/pubmed/26369357

Another meta-analysis of aerobic exercise in people with dementia (Alzheimer’s and other forms) that showed improved cognitive function:

https://www.ncbi.nlm.nih.gov/pubmed/26607411

One year of walking at 60% max heart rate in non cognitively impaired people improved MRI-measured "functional connectivity," the intensity of neuronal interaction between various brain regions (frontal, temporal, posterior):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947936/

Conclusion:

The data are refreshingly abundant and consistent: Exercise increases brain volume, specifically the dentate gyrus of the hippocampus, consistent with the concept that neuronal plasticity is preserved; increases overall white and gray matter volumes; increases serum BDNF, with increased IGF-1 alpha with strength training; and improves psychometric measures including memory and executive function.

Given the expected loss of hippocampal volume of 1-2% per year, the magnitude of increased hippocampal volume appears to be a one-to-one tradeoff: One year of consistent exercise achieves the equivalent of one year of reversed brain atrophy.

Sleep

There is no question that people with mild cognitive decline and Alzheimer’s dementia are more prone to shorter sleep duration and fragmented sleep, disturbances of circadian rhythmicity, and greater potential for sleep-disordered breathing. More recently, however, such sleep disturbances are being viewed as risks for cognitive decline and not just accompaniments. This opens the door to intervening in sleep disturbances as a means of slowing/stopping/reversing cognitive decline.

Bear in mind that there is also substantial potential for confounding factors, e.g., obesity and type 2 diabetes as common covariants with sleep apnea (though the clinical solutions may still remain clear).

Self-reported sleep duration less than 7 hours or more than 8 hours was associated with cognitive decline over 22 years. Use of sleeping medication was also associated with cognitive decline (though is clearly subject to selection bias):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773203/

Self-reported reduced sleep quality was associated with 23% increased risk for dementia over 4 years:

https://www.ncbi.nlm.nih.gov/pubmed/23905991

An important aside: Self-reported vs. actigraphic monitored sleep can differ substantially, a phenomenon that worsens as cognitive decline proceeds. This essentially mandates use of an actigraphic device to track/quantify sleep duration and patterns:

https://www.ncbi.nlm.nih.gov/pubmed/18321246

Sleep fragmentation monitored via actigraphy predicted 22% increased risk for cognitive decline over 6 years. Individuals in the 90th percentile of sleep fragmentation had a 1.5-fold risk of developing Alzheimer’s disease compared with someone in the 10th percentile of sleep fragmentation:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669060/

Sleep disordered breathing, specifically hypoxic episodes, correlated with cognitive decline, but sleep fragmentation did not. (Should nocturnal O2 be introduced?)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600944/

One night of sleep deprivation in cognitively normal men, mean age 50 years, increased CSF levels of amyloid-beta 42 levels, a surrogate marker for brain amyloid-beta deposition, by 6%:

https://www.ncbi.nlm.nih.gov/pubmed/24887018

Clinical intervention studies

Human intervention trials are limited to those using CPAP and melatonin, ramelteon, and trazodone. There are no intervention trials in MCI or dementia involving benzodiazepine or non-benzodiazepine hypnotics or other agents/practices that impact sleep duration/architecture/quality except for those addressing sleep "hygiene," below. This does not mean, of course, that sleep duration and quality, as well as circadian "reprogramming," cannot be achieved; we simply cannot make the claim that such practices stall/prevent/reverse cognitive decline. The CPAP data, however, suggest real improvements, though it is not clear whether this is achieved via improved sleep, reduced hypoxic episodes, or other mechanism.  

Slow-release melatonin, 6 mg, had no effect on sleep duration or quality via actigraphy in people with Alzheimer’s dementia (though no validation of the actual melatonin content of the preparation used was made, a problem with melatonin):

https://www.ncbi.nlm.nih.gov/pubmed/12461760

Melatonin 2.5 mg sustained-release vs. melatonin 10 mg immediate-release vs. placebo generated only a non-significant trend towards increased nocturnal (as opposed to daytime) sleep time in people with established Alzheimer’s:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418658/

A small (n = 25) experience in people with mild cognitive impairment administered DHA + melatonin + tryptophan vs. placebo, with the treatment group showing improved cognitive measures over 12 weeks:

https://www.ncbi.nlm.nih.gov/pubmed/22334085

A retrospective analysis of 96 people with mild cognitive impairment given 3-24 mg immediate-release melatonin over 15-60 months showed improved cognitive measures:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560473/

An excellent review of melatonin effects in mild cognitive decline and dementia. These authors also make the argument, based on the experimental data suggesting diminished amyloid-beta plaque deposition, decreased oxidative injury, and reduced phosphorylated tau, that high doses of melatonin may be required to generate meaningful benefits.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665493/

Trazodone, 50 mg at bedtime, increased total sleep time by 42 minutes by actigraphy but had no effects on cognitive measures:

https://www.ncbi.nlm.nih.gov/pubmed/24495406

Small (n = 10) experience demonstrating marked improvements in cognitive function with CPAP in people with sleep apnea:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725246/

Modest improvements in cognitive measures in people with mild-moderate Alzheimer’s with CPAP vs. sham CPAP:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585146/

CPAP improved cognitive measures and increased hippocampal and frontal lobe volumes over 3 months:

https://www.ncbi.nlm.nih.gov/pubmed/21037021

Sleep hygiene interventions

Beyond caffeine and alcohol, lighting management plays a role.

A review of the importance of managing blue wavelengths from interior lighting. Notably, Steve has already arranged for common areas in the Villas to have daylight-mimicking LED lighting to be installed, no blue wavelength lighting in sleep areas.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734149/

UV-B wavelength from LED lighting activates vitamin D in the skin:

https://www.nature.com/articles/s41598-017-11362-2

6200 lux morning light exposure combined with 5 mg bedtime melatonin substantially increased daytime activity and reduced daytime fatigue but had no effect on sleep architecture by actigraphy in people with moderate to advanced Alzheimer’s dementia (mean MMSE 9.3). No "hard" endpoints were tracked (e.g., hippocampal volume, PSG sleep phases, CSF amyloid-beta 42).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2642966/

Conclusions:

I believe moderately strong arguments can be made for the (benign) strategies of evening melatonin + morning high-intensity (10,000 lux?) lighting along with LED daytime light in common, non-sleep areas. At the very least, this increases daytime activity substantially that may exert other benefits, even if there is no effect on direct slowing of cognitive decline.

Nocturnal hypoxia and sleep apnea justify conventional treatment, along with the weight loss-inducing efforts of our dietary approach. How routinely do we screen for nocturnal desaturations via oximetry?

Use of actigraphic devices, e.g., Apple Watch, are clearly superior to self-reported sleep times/phases, even if they do not correspond precisely to PSG measures. Actigraphy also provides the potential for serial monitoring of, say, duration of phase 4 and REM sleep in response to any intervention, as well as total sleep time and sleep efficiency.

Oral health, gingivitis, periodontitis and cognitive decline

While it is no news that people with dementia have worse dental health/gingivitis/periodontitis, it has not been clear that the dental health-cognitive decline relationship is a cause-effect relationship. Some recent observations:

Observational:

People with Alzheimer’s disease have higher levels of TNF-alpha and antibody titers against oral pathogens than controls:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2783848/

Higher levels of antibodies against oral pathogens are associated with greater potential for cognitive decline over 12.5 years in people starting with normal cognition:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712346/

People with normal cognitive function have greater brain amyloid-beta burden (by PET) that correlates with greater degrees of periodontal disease:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399973/

Greater degrees of periodontitis are associated with more rapid decline in cognitive measures (though such an observational study cannot rule out confounding factors, such as differing diets among the two groups):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786266/

Prospective clinical studies:

No surprise: There are no reliable prospective clinical trials of treatment/management of gingivitis/periodontitis and rate of cognitive decline.

The closest we have at present is a small (n = 29) open-label uncontrolled study of people who underwent a variety of treatments for gum/dental diseases (antibiotics, extractions, etc.). Treatment resulted in reduced pain, improved quality of life, but no apparent effect on MMSE scores over 6 months (no control group).

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0004-282X2014001200919&lng=en&nrm=iso&tlng=en

Conclusion:

As with so much of the data exploring cognitive decline, we are left with the suspicion or hypothesis that gingivitis/periodontitis may contribute to cognitive decline, but insufficient hard data to establish a solid cause-effect relationship. It is, however, consistent with the broader literature that has established numerous forms of infection/inflammation with cognitive decline. But is oral health somehow special in its proximity and shared venous drainage/biofilm with the brain? Is this sufficient to encourage everyone to undergo dental treatment?

This may be an issue that is worth bringing to the residents’ attention for individual exploration.

Cognitive training

In the world of cognitive training, we now have prospective clinical trial data that helps clear up the multitude of strategies, aspects of mentation, and commercial platforms that have been examined.

However, the prospective results of the ACTIVE trial on dementia incidence, not just cognitive measures, below, substantially clarify how we should approach this area.

Prospective clinical trials:

There are abundant data demonstrating that cognitive measures in mild to moderate dementia are improved by a variety of cognitive exercises, but the ACTIVE trial (below) is the only prospective clinical trial that examined the incidence of dementia.

Cognitive training can improve memory, attention, executive function, and language skills, with benefits that may transfer to learning new skills and may generalize to other spheres of life functioning (e.g., reading a map, managing money). Summary of the clinical trials demonstrating that cognitive training improves cognitive measures:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679699/

The multi-center Advanced Cognitive Training in Vital Elderly (ACTIVE) trial was a recent prospective trial demonstrating that speed-of-processing training, but not memory or reasoning exercises, reduced dementia incidence by 6% over 10 years (RR reduction 29%). Only psychometric and self-reported changes were tracked, no volumetric imaging. If this is true, it means that the common advice to learn new skills, learn a new language, or play a new musical instrument are not as effective, but something like playing video games is effective. (In the Villas’ demographic, it could be something like playing Pacman that involves speed-of-processing as well as spatial awareness/processing multiple simultaneous sensory inputs:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700828/

Secondary analysis of the ACTIVE database demonstrating that speed of processing training generated benefits regardless of level of education:

https://www.ncbi.nlm.nih.gov/pubmed/26644115

Secondary analysis of the ACTIVE database demonstrating reduced depressive symptoms at 1 and 5 years after speed-of-processing training.

https://www.ncbi.nlm.nih.gov/pubmed/19181719

In the IHAMS study, speed-of-processing exercises (Brain HQ Double Decision) was superior to doing crossword puzzles in improving cognitive measures with benefits independent of age:

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0061624

Conclusions:

Given the apparent superiority of speed-of-processing and spatial awareness training, what activities would yield the greatest benefit with the least effort and resistance? Given our demographic, how about stations with built-in video games such as Pac-Man or Galaxian that involve speed, awareness of multiple spatial sensory inputs, and can be made competitive (e.g., Pac-Man contests/parties)?

Brain HQ is the proprietary cognitive learning program that provided the speed-of-processing software for ACTIVE using the Double Decision method illustrated here:

https://www.brainhq.com/world-class-science/published-research/active-study?lead_id=google-search-text-custom-ACTIVE_Study&gclid=CjwKCAiAmb7RBRATEiwA7kS8VDQVQUgHN5eNfpVCZydvXCrQ6T0vQjh7N3E2KPz1R4gpgXZfgdTIyxoC2vcQAvD_BwE

Of course, group classes that encourage social interaction as well as learning are of value, also.

More on video games:

We’ve previously briefly discussed the role of video games as a means of preventing/reversing cognitive decline, especially in light of the recent release of the ACTIVE Study results that showed 6% reduction in Alzheimer’s over 10 years (RR reduction 29%; 41% in participants who engaged in the most training sessions over the initial 5 years).

Unlike ACTIVE, most other studies only examine acute or short-term, e.g., 3 months, effects with variable results. Consensus has emerged, however, that engagement needs to be ongoing, not short-term engagement followed by no activity.

There is debate over whether video games only enhance the cognitive activities being training and do not translate to other activities. This remains unsettled, though there are clearly training effects that may develop independent of the platform used, as illustrated by this study in which Lumosity (non-action video game using variety of challenges) was compared to playing Sims:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5671951/

This same study by Ballesteros also provides a fairly comprehensive review of the literature.

Putting it all together, I believe that it is safe to conclude:

1) Despite the preference of older participants for non-action video games, the bulk of data suggest that action video games are more likely to yield "transfer" effects, i.e., transfer to cognitive and real-life abilities beyond that of the trained activity. I think making action video games that incorporate ACTIVE-like speed-of-processing pressures and multiple simultaneous stimuli are the best route. We need better data, but I believe this is a safe conclusion, especially given the lack of downside risk in just engaging in various games. See this review of studies comparing cognitive performance of people who play video games vs. those who do not, with the bulk of data demonstrating sizeable differences:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171788/

2) When comparing non-action video games such as Lumosity or BrainHQ, there appears to be advantage over placebo activity but no substantial differences among the non-action platforms.

I continue to believe that making classic video games such as Pac-Man, Ms. Pac-Man, Galaga, etc. available is a practical means of putting this knowledge to work is the best solution that will engage, get over the aversion-to-action-games, and yield the greatest likelihood of cognitive benefit that transfers to other activities. We shall have to educate residents that these are not just games for play but games that are a part of a comprehensive effort to preserve cognition through incorporation of speed-of-processing pressure with processing of multiple simultaneous visual and auditory stimuli. Whether non-action exercises such as BrainHQ or Lumosity provide additive benefit is unclear to me, but not harmful, of course.

Speculation: If cognitive decline principally involves loss of executive function and attentional control, abilities mediated by the dorsolateral prefrontal cortex, abilities amplified by engagement in video games, what would be the combined effect of transcranial direct-current stimulation (tDCS)  using the DARPA montage (anode at the dorsolateral prefontal cortex; cathode neutral shoulder) worn while playing games? Recall that preliminary human data suggest that tDCS yields a neurotrophic effect with durable effects recorded at 3 months (after initial 10-days of tDCS sessions) and increases BDNF.

Transcranial direct current stimulation (tDCS)

Transcranial direct current stimulation has been shown to lift depression, increase concentration, and accelerate learning. It has been applied to cognitive decline/dementia with positive results, though protocols used have been wildly variable (mA applied, duration of treatment, anode/cathode placement variations or "montages", psychometric variables measured). Studies also involved limited numbers of participants.

Here is a review of both tDCS and transcranial magnetic stimulation:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496249/

Also, note that transcranial magnetic stimulation is now a health insurance/Medicare-reimbursable procedure that we can offer and is therefore a potential revenue source for treatment of depression:

https://neurostar.com/neurostar-health-insurance-coverage/

(I believe the device costs around $12,000.)

I subjected myself to three different anode/cathode montages over 20 minutes each with up to 1.5 mA current. See this montage mapping discussion for the variations:

http://totaltdcs.com/

However, note that there are modest negative effects: burning/tingling at the cathode site, particularly at higher milliamperages such as 1.5 mA and greater; saline-soaked sponges are kind of messy when applied to the scalp; people with pacemakers cannot use the device; prominent dry mouth requiring water to be consumed during the session.

When I applied the anode to the right dorsolateral prefontal cortex location (FP2), I experienced flashing white lights in both eyes. I experienced heightened capacity for concentration and focus after both right and left dorsolateral prefontal cortex anodal locations with effects persisting for about 3 hours afterwards.

Transcranial direct current stimulation is proving to be very interesting. I have personally used several 20+ minute rounds of various cortical stimulation montages with varying results, but there is clearly a cognitive enhancement function.

Some more background on tDCS:

Helpful surface maps of anode/cathode placement for various tDCS montages:

http://totaltdcs.com/

An NIH experimental study demonstrating that tDCS is neurotrophic via BDNF:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864780/

A small (n = 15) study of bilateral temporal tDCS in people with dementia. Visual recognition memory improved modestly with 5 30-minute 2 mA sessions with effects persisting for 4 weeks after delivery:

https://www.ncbi.nlm.nih.gov/pubmed/21840288

tDCS with anode at the left dorsolateral prefrontal cortex improved word recall consolidation acutely:

https://www.ncbi.nlm.nih.gov/pubmed/23137702

5 days of tDCS with anode at the M1 primary cortex coupled with learning a new motor skill provided persistent performance advantage 3 months later, suggesting a durable effect:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635787/

Anode placement at the left inferior frontal gyrus (responsible for language) acutely conferred improved word recall capability in normal elderly (mean age 68 years) to that of normal younger people (mean age 26 years):

http://www.jneurosci.org/content/33/30/12470.long

Small randomized, controlled study of left temporal anode (T3) tDCS in people with Alzheimer’s (with MMSE >18) showing no effect by multiple psychometric measures after 6 sessions (30 minutes, 2 mA):

https://www.ncbi.nlm.nih.gov/pubmed/27005937

Temperoparietal tDCS over 3 30-minute sessions acutely improved word recall:

https://www.ncbi.nlm.nih.gov/pubmed/18525028

Temporal and left dorsolateral prefontal tDCS 3 sessions over 30 minutes at 2 mA improved visual recognition memory acutely, but not attention:

https://www.ncbi.nlm.nih.gov/pubmed/18977813

A multi-center collaboration summarizing the technical aspects of tDCS to promote uniformity in delivery:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747791/

Anyway, I’m not sure what role this or the magnetic form should play in Revite, if any. But it is worth knowing about and perhaps being conversant about.

For future reference, we will have to watch for the University of Michigan’s prospective clinical trial of transcranial direct current stimulation that has previously been shown to improve memory and concentration:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651427/

A summary of transcranial direct current stimulation from the NIH, mostly based on work enhancing motor skill learning:

https://www.ncbi.nlm.nih.gov/pubmed/20633394

Should one of us develop expertise in transcranial magnetic stimulation to manage depression, then we will need to explore 1) how to apply in cognitive areas and 2) how financially feasible this is.

Nutrition (omega-3 fatty acids, vitamin D, B12, folate considered elsewhere)

We have to be especially careful when interpreting nutritional studies, as they have been traditionally and systematically plagued by flawed logic and incorrect conclusions, not to mention largely based on crude dietary questionnaires that do not completely characterize dietary patterns. One rule worth keeping in mind is the logical error made by the following:

Replace something unhealthy (e.g., white flour products) with something less unhealthy (e.g., whole grains)—if there is an apparent health benefit, such as reduced cardiovascular disease, reduced dementia, reduced colorectal cancer, reduced type 2 diabetes (which is true), we can NOT then conclude that lots of whole grains must therefore be good. (The effects of no grains has examined been in numerous studies, though conducted under various labels such as low-carb, ketogenic, Atkins’, etc.)

For this reason, we cannot conclude:

If a standard American diet that includes soft drinks, polyunsaturates, refined grains, etc. is replaced by a Mediterranean diet and there is an apparent health benefit, then a Mediterranean diet is therefore the ideal diet for health. Instead, the conclusion should be that the Mediterranean style of diet is less harmful and perhaps more beneficial than a standard American diet, but it does not prove that it is therefore the ideal diet. You will find this logical fallacy used over and over again in nutritional thinking.

With that in mind:

Mediterranean diet:

A Mediterranean diet with added nuts and olive oil modestly improved cognitive measures over 4 years compared to a low-fat diet:

https://www.ncbi.nlm.nih.gov/pubmed/25961184

Predimed-Navarra Trial: A Mediterranean diet with one liter added olive oil per week and 30 grams nuts per day improved cognitive measures (MMSE and clock drawing) over 6.5 years compared to a low-fat diet:

https://www.ncbi.nlm.nih.gov/pubmed/23732551

https://www.ncbi.nlm.nih.gov/pubmed/23670794

The Rush University MIND trial (a diet that makes little sense in that it is an a la carte deconstruction/reconstruction dietary hybrid of the Mediterranean and DASH diets emphasizing low saturated fat/animal product intake but increased flavonoids/K1 etc. via berries and green leafy vegetables). Participants with a higher MIND score (The MIND diet score has 15 dietary components including 10 brain healthy food groups (green leafy vegetables, other vegetables, nuts, berries, beans, whole grains, fish, poultry, olive oil and wine) and 5 unhealthy food groups (red meats, butter and stick margarine, cheese, pastries and sweets, and fried/fast food) had 53% less likelihood of dementia over 4.5 years.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532650/

No cognitive benefit to a Mediterranean style diet over 13 years in cognitively normal people (observational, dietary questionnaire):

http://ajcn.nutrition.org/content/97/2/369.long

The Maine Syracuse Longitudinal Study observational data over 18 years:

“Higher Wechsler Adult Intelligence Scale (WAIS) scores at baseline were prospectively associated with higher intakes of vegetables, meats, nuts and legumes, and fish, but inversely associated with consumption of total grains and carbonated soft drinks. After adjustment for sample selection, socioeconomic indicators, lifestyle factors (smoking and physical activity), and cardiovascular risk factors, the relations between higher cognitive performance and greater consumption of vegetables, meat, and fish, and lower consumption of grains remained significant.”

https://www.ncbi.nlm.nih.gov/pubmed/26878011

TMAO

Recall the headlines from Dr. Stan Hazen’s lab at Cleveland Clinic announcing that meat and fish consumption, rich in choline and carnitine, yields higher serum levels of trimethyl-N-amino oxide, or TMAO, that is associated with increased cardiovascular risk. Limited data also demonstrated that a vegetarian eating style was associated with lower TMAO serum levels. The media jumped on this, declaring that this confirms that red meat and fish are atherogenic and cause heart disease.

Problem: Bowel flora was not factored in, dismissed as a black-box effect. More recent data have demonstrated that TMAO serum levels are dependent on bowel flora composition (though the clinical correlates of dysbiosis and SIBO remain uncharted).

My conclusion: TMAO is a epiphenomenon in dysbiosis/SIBO that converts the native human diet to a potentially unhealthy situation, but it does not necessarily mean that choline/carnitine are atherogenic, inflammatory, or contribute to cognitive decline. It means that media pronouncements that meat and fish cause heart disease or dementia are unfounded and premature, based on insufficient microbiome assessment:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390365/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127123/

https://www.ncbi.nlm.nih.gov/pubmed/27585440

Blood sugar effects

Though observational, this study suggests an association of higher blood sugar and cognitive decline over time (up to 16 years). (However, I would recommend ignoring the silly conclusion that low-glycemic foods are therefore advantageous; low-glycemic index foods should be re-labeled “less-high-glycemic index” as they also raise blood sugar to high levels, just not as high as high-glycemic index foods.)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447796/

Calorie intake

This cross-sectional observational study suggests that higher calorie intake is associated with increased risk for mild cognitive impairment, 5-fold greater risk in people who are apo E4+. But is it higher calorie intake per se or some aspect of diet that is causal, e.g., greater sugar/soft drink intake, greater grain intake and thereby exposure to gliadin protein-derived opioid peptides, or some genetic susceptibility to these effects that is associated with dementia risk?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679320/

Glycemic index

Higher glycemic index foods (carbs, sugars) were associated with greater beta-amyloid accumulation by PET and cognitive decline:

https://www.ncbi.nlm.nih.gov/pubmed/29070566

Specific foods/nutrients:

Cocoa flavonoids not only increase hippocampal blood flow, but also increase dentate gyrus function and reduce reaction time but not memory (prospective, randomized):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940121/#SD1

Selenium 280 mcg obtained through one Brazil nut per day prospectively improved cognitive measures in people with mild cognitive impairment over 6 months:

https://www.ncbi.nlm.nih.gov/pubmed/25567069

An observational study in which dietary acrylamide was associated with increased dementia over 4 years in men, but not women:

https://www.ncbi.nlm.nih.gov/pubmed/28743904

An observational study suggesting increased dementia with grain consumption, decreased with dairy in a Japanese cohort:

https://www.ncbi.nlm.nih.gov/pubmed/29251743

ARIC observational data suggesting greater cognitive decline with milk consumption:

https://www.ncbi.nlm.nih.gov/pubmed/29039795

Combined observational data suggesting reduced cognitive decline with 4 servings or more of fish per week compared to 1 serving:

https://www.ncbi.nlm.nih.gov/pubmed/29053784

Phenol components of extra-virgin olive oil, such as oleocanthal, have beneficial effects in experimental preparations relevant to the neuropathology of dementia:

https://www.ncbi.nlm.nih.gov/pubmed/23414128

A summary of most of the nutritional evidence from Canevelli et al 2016 at

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808873/

The recent small trial of ketogenic diet and cognitive decline discussed previously:

A new, though small, clinical trial of a low-carb ("ketogenic") diet was published by a group from the University of Kansas:

http://www.trci.alzdem.com/article/S2352-8737(17)30070-7/pdf

Though small with only n = 10 completing the 3-month protocol, the effects were substantial. Among the findings:

1) The degree of ketosis achieved was modest with beta-hydroxybutyrate serum levels of only 0.5 mmol/L, a level easily exceeded by any of us trying to achieve ketosis. A beta-hydroxybutyrate level as high as 0.4 mmol/L can be achieved via MCT oil alone. This was achieved via carb limitation and MCT oil supplementation.

2) Participants showed improved psychometric measures including a 4.1 point improvement in ADAS-cog and 0.8 point improvement in MMSE score.

3) The 1.5-3.0 tablespoons of MCT oil per day yielded diarrhea in the majority of participants.

Most importantly, this study will help defuse the absurd notion that a low-fat diet is the answer in cognitive preservation. Yes, high-fat intake is inflammatory, but only in the setting of dysbiosis/increased intestinal permeability/lack of Lactobacillus and Bifidobacteria, factors we address aggressively.

Also, we have previously discussed the hazards of continual long-term ketosis such as the 10-100-fold increase in kidney stones (oxalate and urate). So I do not feel that we need to enforce dietary ketosis, but just  grain/sugar-free diet with MCT oil/oil powder supplementation that permits intermittent ketosis. By the way, we’ve not been seeing diarrhea with use of MCT oil powder as a coffee creamer, though I’m not sure why.

Additional thoughts on ketosis and ketones:

Some further thoughts on ketogenic diets. As you recall, Bredesen advises a ketogenic diet--"Ketoflex"--low-carb with 12-15 hour daily fasting built into the scheduling of meals, e.g., late breakfast, early dinner, nothing until following day’s breakfast. This is based on the observation that glucose metabolism in cortical tissue is reduced and that ketones potentially provide an alternative substrate for energy.

Be aware that many conventional thinkers still believe that saturated fat/high fat intake are the causes for dementia and that, especially in apo E4(+) people, a low-fat diet is therapeutic (which it most definitely is not, typically yielding explosive quantities of small LDL particles, high triglycerides, low HDL, higher blood sugars, and insulin resistance. Insulin resistance is, of course, one of the fundamental etiologies of cognitive decline).

Glucose hypometabolism is indeed present in various brain regions in cognitive decline:

https://www.ncbi.nlm.nih.gov/pubmed/28709938

But ketone metabolism remains normal in cortical tissue:

https://www.ncbi.nlm.nih.gov/pubmed/26766547

MCTs 20 grams yielded cognitive benefits in non-demented elderly adults over 3 hours of consumption of a single meal in a small study (n = 19)

https://www.ncbi.nlm.nih.gov/pubmed/27568199

A proprietary study (Accera) demonstrating improved cognition in apo E4(-) but not apo E4(+) subjects with 10 grams twice-per-day of an MCT oil preparation yielding serum betahydroxybutyrate levels as high as 0.4 mmol/L.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731764/

A case study of early dementia in an apo E4 individual responding initially to high-dose MCTs (165 ml of a 4:3 mixture of MCTs and coconut oil, divided into 3-4 doses per day) which yielded improved cognitive function initially with betahydroxybutyrate serum levels of up to 0.4 mmol/L. Deterioration over time prompted addition of a ketone monoester 28.7 grams per day (not the ketone salts commercially available to us) yielded further substantial improvement. Betahydroxybutyrate serum levels as high as 7 mmol/L were obtained with peak levels lasting 3-4 hours.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300286/

Caffeine may add to the ketogenic effects of MCTs/exogenous ketones:

https://www.ncbi.nlm.nih.gov/pubmed/28177691

(I have personally been using an MCT oil powder in my coffee every morning, as it is an excellent coffee creamer with perfect mouthfeel. It yields 3-4 hours of mental focus and clarity. Introducing MCTs as a coffee creamer (or oil added to various foods) may be an easy way to insert MCTs into the daily habit while potentially obtaining the synergies between the modest betahydroxybutyrate serum rise of MCTs with that of caffeine.

Note the much higher doses of MCTs discussed, e.g., 20-30 grams per dose, not the 1-3 grams quoted in ReCODE.

Are there factors in coconut and coconut oil besides the 15% MCTs that potentially benefit health and cognition?

https://www.ncbi.nlm.nih.gov/pubmed/25997382

Potential problems, however:

1) A ketogenic diet is difficult to maintain, particularly as preference for sweet foods increases as cognitive decline progresses

2) Long-term ketogenic diets, as practiced by children who remain ketogenic for years to suppress intractable seizures, have 10-100 fold greater risk for calcium oxalate and urate kidney stones (increased serum uric acid; dysbiosis from failure to cultivate bowel flora, as ketogenic diets mistakenly leave out all prebiotic fiber sources). Children on ketogenic diets also experienced stunted growth, typically falling in the 10th percentile for growth, suggesting there may be something fundamentally wrong with prolonged, sustained ketosis. There are also sporadic reports of selenium deficiency, cardiomyopathy, and sudden cardiac death. Some of the latter complications may be at least in part due to the use of a corn oil-based oil supplement that was used to increase fat consumption in ketogenic kids.

3) Some of the ketone salts available to us commercially are toxic with potential for hyperkalemia and toxic intakes of calcium. I review the available ketone salts and future direction of ketone supplements in the attached. Should we choose to use a ketone salt, we shall have to choose carefully and not dose current products more than twice per day to avoid mineral excess. I am also in the process of helping formulate a betahydroxybutyrate product with an improved safety/mineral profile. I suspect that the real answer will come with availability of the D-enantiomer without the biologically inert L-form that will be more effective at much lower doses, thereby avoiding the toxic potassium/calcium issue.

4) Dysbiosis and small intestinal bacterial overgrowth are virtually assured--As a diet essentially free of carbs is also free of prebiotic fibers. This means that constipation, metabolic distortions (higher blood sugar and insulin, higher blood pressure, higher triglycerides), diverticular disease, and risk for colon cancer, as well as mental/emotional/sleep consequences develop unless we purposefully and consistently provide prebiotic fibers, as well as address SIBO.

Trophic sex hormones

Bear in mind that it may be hazardous to view hormones in isolation, e.g., estrogen or testosterone alone. Hormones are best viewed in their entirety, a complex orchestration of estradiol/estrone/testosterone/DHEA/pregnenolone/dihydrotestosterone/progesterone/oxytocin/sex hormone-binding globulin, etc., as well as the responsivity of their target organs. The literature is therefore tainted with efforts to address/administer single hormones to assess their effects. Nonetheless, we can discern several effects of single hormones.

Testosterone

Experimental data:

The experimental data suggesting a neurotrophic effect, especially on hippocampal tissue/function, including reduced beta amyloid production and hyperphosphorylated tau, is summarized here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002217/

Bisphenol A blocks both testosterone- and estradiol-mediated hippocampal synaptogenesis, even at levels declared tolerable by the EPA:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275360/

A summary of the neurotrophic effects of testosterone, estradiol, and progesterone in experimental models:

https://www.ncbi.nlm.nih.gov/pubmed/28571999

Observational data:

There are abundant cross-sectional studies that associate low testosterone levels/bioavailability with cognitive decline/dementia in males, summarized here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3980008/

This same study found an association between apo E4 and testosterone on cognitive performance, suggesting that testosterone levels assume greater importance in apo E4 males.

Postmenopausal females (n = 402) with higher serum testosterone performed worse on cognitive testing, especially if combined with apo E4. Higher serum DHEA was associated with less cognitive impairment.

https://www.ncbi.nlm.nih.gov/pubmed/28883857

Serum levels of sex hormone-binding globulin (SHBG) did not predict cognitive decline over 8 years of observation in men or women:

https://www.ncbi.nlm.nih.gov/pubmed/27767986

Testosterone serum levels were not associated with brain volumes in men followed from their second to fourth decades:

https://www.ncbi.nlm.nih.gov/pubmed/29075555

Meta-analysis of cross-sectional data of total testosterone, estradiol, and serum hormone-binding globulin (sHBG) levels in people with dementia vs. normal controls. There was no difference in testosterone or estradiol, but sHBG was higher in those with dementia:

https://www.ncbi.nlm.nih.gov/pubmed/26679858

Clinical intervention studies:

Testosterone and finasteride administered to men with serum testosterone level of 300 ng/ml or less (n = 60) experienced modest improvement in mood/relief from depression and improved visuospatial memory:

https://www.ncbi.nlm.nih.gov/pubmed/25143719

Testosterone and finasteride administered to men with serum testosterone of 350 ng/ml or less (n = 46) did not experience any change in cognitive performance over 3 years compared to placebo:

https://www.ncbi.nlm.nih.gov/pubmed/17609296

Testosterone gel administered to men with clinical hypogonadism, serum testosterone 275 ng/ml or less, and age-associated cognitive impairment (n = 493) experienced no improvement in cognition over one year compared to placebo:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433758/

Testosterone administration to young and middle-aged hypogonadal males (n = 19) yielded improved measures of cognition over 2 years (improved attention and visual scanning ability, executive function and psychomotor speed):

https://www.ncbi.nlm.nih.gov/pubmed/27545990

Testosterone administration to cognitively normal males aged 50-80 (n = 25) experienced improved cognitive measures over 6 weeks. However, there was 77% increased in estradiol, also, and it was not clear whether the cognitive improvement was associated with testosterone per se or increased estradiol via aromatization:

https://www.ncbi.nlm.nih.gov/pubmed/11445632

Men with mild Alzheimer’s dementia and serum testosterone of 240 ng/ml or less experienced modest improvement in cognitive measures with 12 months of testosterone replacement (n = 36):

https://www.ncbi.nlm.nih.gov/pubmed/12809076

Testosterone (oral) had no effect on cognition over 6 months (n = 207):

https://www.ncbi.nlm.nih.gov/pubmed/18167405

Men (n = 280) with low to normal testosterone demonstrated no change in cognition over 36 months of testosterone replacement:

https://www.ncbi.nlm.nih.gov/pubmed/27377542

Testosterone replacement had no cognitive effect on 71 hysterectomized FEMALES with low baseline total/free testosterone over 6 months:

https://www.ncbi.nlm.nih.gov/pubmed/25430996

Testosterone replacement in men (n = 44) with mild cognitive impairment experienced modest improvement in cognitive measures after 6 months:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078598/

Conclusion:

Unlike most other purported strategies, with testosterone replacement there are abundant clinical prospective treatment data, likely because there are branded forms of testosterone. (How much of the above data was proprietary or paid for by the manufacturer of testosterone replacement forms was not entirely clear in the studies.) Contrary to the bulk of observational data that suggests a positive relationship with serum testosterone levels and cognition, the clinical treatment data suggest only a modest improvement in cognitive measures, if any, in men with low testosterone levels and cognitive impairment and early dementia. Because there are other benefits from testosterone replacement, such as increased muscle mass, reduction in visceral fat, increased bone density, increased sexual performance, but also negative effects such as increased cardiovascular risk, increased non-calcified coronary atherosclerosis, and decreased HDL cholesterol, the decision to replace testosterone will need to be individualized. But testosterone replacement by itself is by no means a robust strategy for preservation of cognitive health.

In females, the modest data available suggest that testosterone replacement by itself does not benefit cognition nor prevent cognitive decline.   

Estrogens

Estrogens have been explored as preventive/treatment for cognitive decline/dementia, as it may underlie the excess risk for dementia that applies to females. Unfortunately, the observational and clinical treatment data are muddied by the dominant use of conjugated equine estrogens (CEE; equilin, equilenin, hippulin and others) which are substantially different from the estrone, estradiol, and estriol of humans. Note that the majority of data with CEE show no or negative effects, while the bulk of data with estradiol show beneficial effects.

Experimental evidence:

There are robust and plentiful experimental observations demonstrating both positive and negative effects on neuronal health.

Summary of the experimental data suggesting a neurotrophic effect of estrogens:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2048656/

Summary of the data suggesting neurotrophic, neuroprotective, synaptogenic, and antioxidative neuronal effects, but also pro-inflammatory effects and distortions of local cytokine/chemokine production. The divergent nature of brain vs. serum/non-CNS estrogens is also discussed:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040318/

This review also summarizes the data describing local astrocytic production of estrogens from cholesterol.

Review of the data documenting declining brain/systemic estrogen as a cause for brain mitochondrial dysfunction/mitochondrial beta-amyloid accumulation:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024050/

Observational data:

The potential for misleading conclusions commonly drawn from observational studies is typified by Premarin. Recall that this drug was the most widely prescribed drug for many years based on the observational data suggesting reduced risk for heart disease, endometrial and breast cancer in women who took Premarin. Of course, prospective clinical trials, such as the Women’s Health Initiative, demonstrated the opposite. Observational data suggest that estrogens (as Premarin) are associated with reduced risk for dementia, but I would suggest that we ignore such associations in favor of prospective clinical data. Nonetheless, the observational data are summarized here:

https://www.ncbi.nlm.nih.gov/pubmed/11113299

The Premarin debacle did not stop some groups from making bold pronouncements re: estrogen based on observational data:

https://www.ncbi.nlm.nih.gov/pubmed/9484355

Unspecified estrogen replacement was associated with greater cerebral blood flow by PET in the hippocampus, parahippocampal gyrus, and temporal lobe and higher measures of cognitive performance over 2 years compared to non-users (n = 28):

https://www.ncbi.nlm.nih.gov/pubmed/10867223

Females on estrogen replacement (unspecified) had better preservation of posterior cingulate cortex glucose metabolism by PET over two years compared to females not on estrogen replacement:

https://www.ncbi.nlm.nih.gov/pubmed/15582750

Women who underwent unilateral or bilateral oophorectomy for non-cancer indications experienced greater cognitive decline than matched controls. Excess risk was eliminated if estrogen replacement (unspecified) was initiated after surgery and continued to age 50 or beyond.

https://www.ncbi.nlm.nih.gov/pubmed/17761551

Unilateral or bilateral oophorectomy was associated with increased risk for dementia, with greater risk the younger the age at time of surgery:

https://www.ncbi.nlm.nih.gov/pubmed/20689282

Two cohorts (Religious Orders Study, Rush Memory and Aging Project) of females (n = 1884) were observed for cognitive decline following “surgical menopause” (though data distinguishing hysterectomy from unilateral or bilateral oophorectomy were not obtained). Earlier age at surgical menopause was associated with decline in global cognition, episodic and semantic memory and associated with increased Alzheimer’s neuropathology at autopsy. Hormone replacement (unspecified) initiated within 5 years of surgical menopause was associated with decreased decline in cognition.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902759/

Timing of hormonal replacement after surgical or natural menopause may determine risk for cognitive decline. These are all observational studies and thereby subject to confounding, but the consistency is striking (From Rocca et al 2014):

Following the release of the Women’s Health Initiative Memory Study (WHIMS), a prospective double-blind study demonstrating increased risk of dementia/cognitive decline in women taking CEE, three observational studies were conducted in younger cohorts than that examined in WHIMS: the Multi-Institutional Research on Alzheimer Genetic Epidemiology Study (MIRAGE), a Kaiser Permanente study, the Cache County study. All suggested that, if hormone replacement (estrogens in any form, topical or oral) was initiated between ages 49-63 or within 5 years of menopause, risk for Alzheimer’s disease was reduced, but not if initiated after age 64. Data are summarized here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040304/

Prospective clinical data:

High-dose topical 17-beta estradiol (0.10 mg per day) improved measures of cognition (visual memory, verbal memory, attention) in postmenopausal women (n = 20) with Alzheimer’s disease over 8 weeks compared to placebo, i.e., a nootropic effect:

https://www.ncbi.nlm.nih.gov/pubmed/11524467

A similar study to the above was conducted with a lower dose of topical 17-beta estradiol (0.05 mg/day) in postmenopausal females (n = 12) with mild-moderate Alzheimer’s with similar improvements in cognitive measures vs. control. Improvements did not persist after cessation of estradiol, again suggesting a nootropic, not a neurotrophic, effect.

https://www.ncbi.nlm.nih.gov/pubmed/10399774

CEE 1.25 mg per day for 16 weeks had no measurable cognitive effects in postmenopausal females (n = 42) with mild-moderate Alzheimer’s:

https://www.ncbi.nlm.nih.gov/pubmed/10668686

CEE 0.625 mg per day or 1.25 mg per day vs. placebo in postmenopausal females (n = 120) with mild-moderate Alzheimer’s demonstrated no improvement in cognition over one year with either dose. The Clinical Dementia Rating Scale showed deterioration with CEE vs. placebo.

https://www.ncbi.nlm.nih.gov/pubmed/10697060

CEE 1.25 mg per day vs. placebo was associated with no improvement in cognitive measures nor SPECT examination of cerebral blood flow in postmenopausal females (n = 50) with Alzheimer’s disease over 12 weeks:

https://www.ncbi.nlm.nih.gov/pubmed/10851363

Transdermal estradiol improved cognitive measures over 3 weeks compared to placebo in non-demented postmenopausal females (n = 37):

https://www.ncbi.nlm.nih.gov/pubmed/10805607

The Women’s Health Initiative Memory Study was an arm of the WHI. In this study, CEE alone, 0.625 mg per day (n = 2947), vs. CEE 0.625 mg per day plus medroxyprogesterone acetate (MPA, a synthetic progestin), 2.5 mg per day (n= 4532), were examined in a double-blind, placebo-controlled trial. Participants were non-demented postmenopausal females, 65 to 79 years of age. After 5.4 years, both treatment arms showed increased risk for dementia. (Note that this trial was faulted for enrolling older women. This was the trial that prompted the idea that an ideal “window” for hormonal treatment may exist and that 65 years of age is beyond this window.)

Estradiol injection in women initiated immediately following bilateral oophorectomy preserved cognition compared to women who did not receive estradiol:

https://www.ncbi.nlm.nih.gov/pubmed/1484915

Postmenopausal females (n = 417) without dementia, age 60-80, received low-dose transdermal estradiol (0.014 mg/day) vs. placebo. After two years, there was no difference in cognitive performance:

https://www.ncbi.nlm.nih.gov/pubmed/16831962

In the Heart and Estrogen/progestin Replacement Study (HERS), women with coronary disease were randomized to CEE 0.625 mg/day plus medoxyprogesterone acetate (MPA) 2.5 mg/day vs. placebo, followed for 4.2 years (n = 1063). Mean age 71 years. No difference in cognitive performance was measured except for declining performance in verbal fluency in women on CEE + MPA:

https://www.ncbi.nlm.nih.gov/pubmed/12459399

A small (n = 29) study in which recently postmenopausal, age 45-55 years, women were randomized to 90 days of oral estradiol 1 mg/day or progesterone 200 mg/day vs. placebo. Progesterone improved verbal memory; both estradiol and progesterone improved verbal processing compared to placebo; there was increased activation of the prefontal cortex and hippocampus by MRI with progesterone, increased activation of the left prefontal cortex with estradiol. Both treatments modestly, though non-significantly, improved verbal memory. This paper also reviews the largely negative cognitive and neurotrophic effects of synthetic progestins, while human progesterone has shown positive cognitive and neurotrophic effects in experimental models.

https://www.ncbi.nlm.nih.gov/pubmed/26010861

Estriol/estradiol (80:20), progesterone, testosterone, DHEA delivered topically and tailored individually, yielded no deterioration in hemostatic or inflammatory markers. Female subjects receiving compounded transdermal bio-identical hormone therapy showed favorable changes in Greene Climacteric Scale scores, Hamilton Anxiety Scale, Hamilton Depression Scale, Visual Analog Pain Scale, fasting glucose, fasting triglycerides, MMP-9, C-reactive Protein, fibrinogen, Factor VII, Factor VIII, IGF-1alpha, and number of prescribed medications. Antithrombin III levels were significantly decreased at 36 months. The small number of participants (n = 75) prevented comparison across treatment arms.

https://www.ncbi.nlm.nih.gov/pubmed/23627249

The evidence in support of phytoestrogens, e.g., from soy, is inconclusive, largely observational, summarized here:

https://www.ncbi.nlm.nih.gov/pubmed/17997703

https://www.ncbi.nlm.nih.gov/pubmed/24486046

Conclusion:

There is a critical gap in the knowledge base surrounding estrogen and cognition: There are no WHI-like prospective clinical data in a younger cohort, e.g., age 50-55, nor are there WHIMS-like data using non-CEE human estrogens/progesterone. While WHI demonstrated adverse effects with CEE with or without MPA in women 65 and older, we can only conclude that CEE/MPA are cognitively harmful or ineffective in older women.

Limited evidence suggests that topical estradiol is cognitively beneficial in postmenopausal women with dementia and without dementia. Although there are no data directly comparing CEE vs. human forms of estrogen in a head-to-head fashion, the bulk of data suggest that human forms are superior. I know of no data that suggest any reason to favor CEE over human forms, just as there would be no reason to favor, say, horse testosterone over human testosterone in males.

Observational studies have, time and time again, led to conclusions that proved untrue in prospective, blinded clinical trials. However, given the consistency in age-dependent differences in cognition across estradiol and CEE observational data supporting the notion of an age-dependent “critical window” for hormonal replacement, it is tempting to conclude that estradiol, probably with progesterone, introduced at menopause and continued for at least 5 years but not beyond age 65, may be beneficial. But this needs confirmation via prospective blinded clinical trials.

DHEA

DHEA is the most abundant circulating serum steroid. Recall that endogenous DHEA production begins to decline in the third decade, declining approximately 10% per decade, such that serum DHEA/DHEA-S (hereafter DHEA/S) levels are typically less than 50% of youthful levels, sometimes only 10-20%, by the eighth decade. DHEA is also produced in the brain, thus it is labeled a “neurosteroid,” with brain levels typically 6- 7-fold greater in brain tissue than in serum. Endogenous non-CNS DHEA production is in the range of 6-8 mg per day up until the fourth decade.  

An excellent review of the overall physiology and metabolism of DHEA/S:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746247/

However, an appreciation for the cognitive effects of DHEA/S may necessitate an appreciation for its context within the broader effects of the hypothalamic-pituitary-adrenal (HPA) axis and its changes with aging and activation of the inflammasome:

https://www.ncbi.nlm.nih.gov/pubmed/15996533

A review of the experimental data describing the interface between the HPA axis and the inflammasome, particularly on the changes in HPA feedback control:

https://www.ncbi.nlm.nih.gov/pubmed/24553014

(The tangle of HPA and inflammasome interaction is, all by itself, complicated but critical. Perhaps we should explore this line of reasoning separately in future.)

A reminder that, in females with a history of PCOS, the HPA axis and adrenal androgens like DHEA-S demonstrate unique behaviors due to intrinsic differences in adrenal sensitivity to adrenal secretagogues:

https://www.ncbi.nlm.nih.gov/pubmed/9661602

Experimental studies:

If there is only one review you read to gain an understanding of DHEA metabolism and implications for cognitive health, this is the one. Included are reviews of the dendritic stimulation, neuron-protective, neurotrophic, anti-oxidative, anti-inflammatory, central anti-glucocorticoid, and acetylcholine- and catecholamine-enhancing effects of DHEA in experimental models, along with an excellent discussion of the progression of DHEA levels and metabolism from embryo to senescence, differential CNS vs. peripheral levels/metabolism. This review includes a discussion of the data—experimental, post-mortem, and observational—that, in total, suggest that higher brain DHEA-S is protective against dementia, lower brain DHEA-S is associated with dementia; brain (non-sulfated) DHEA correlates positively with dementia. Also reviews the correlation of serum DHEA-S with increased hippocampal perfusion, less loss of hippocampal volume.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725024/

DHEA increased BDNF expression as well as levels of neurotransmitters acetylcholinene, dopamine, and norepinephrine in mice:

https://www.ncbi.nlm.nih.gov/pubmed/24622829

In vitro, DHEA increases release of growth factors IGF-1, VEGF and TGF:

https://www.ncbi.nlm.nih.gov/pubmed/19836631

Observational data:

Observational data are plagued by the obvious development of stress-induced hormonal changes with the development of cognitive decline/dementia, resulting in increased ACTH/cortisol/DHEA and inflammatory markers. An illustration of this effect:

https://www.ncbi.nlm.nih.gov/pubmed/21521348

3044 females followed for up to 23 years showed no relationship of baseline levels of estrone sulfate, estradiol, androstenedione, testosterone, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S)  with eventual cognitive status. Only estrone showed a borderline positive association: higher estrone baseline levels were associated with higher cognitive scores:

https://www.ncbi.nlm.nih.gov/pubmed/26806389

Higher serum DHEA-S levels were associated with higher levels of cognitive performance (executive function, concentration, and working memory) in 295 females age 21-77 years:

https://www.ncbi.nlm.nih.gov/pubmed/18073302

DHEA-S levels correlated with cognitive performance by MMSE in the InCHIANTI study of 775 participants age 65 and older, with the lowest levels predicting accelerated decline over 3 years:

https://www.ncbi.nlm.nih.gov/pubmed/19620821

In a frail, institutionalized population, higher DHEA-S and estradiol were associated with greater cognitive decline but only in females:

https://www.ncbi.nlm.nih.gov/pubmed/10664831

Serum DHEA-S did not correlate with cognitive decline 16+ years later in a 437-subject subset of the Rancho Bernardo cohort. (Note that DHEA-S levels were not tracked, only baseline levels correlated with eventual cognitive performance, a substantial study flaw.)

https://www.ncbi.nlm.nih.gov/pubmed/8144828

DHEA serum levels correlate with cognitive measures and ability to navigate activities of daily life in elderly people (n = 208), as did testosterone in males and estradiol in females:

https://www.ncbi.nlm.nih.gov/pubmed/19702939

In established Alzheimer’s, serum DHEA and DHEA-S levels are lower (n = 70):

https://www.ncbi.nlm.nih.gov/pubmed/19665809

One of numerous studies examining serum/CSF levels of DHEA and DHEA-S in people with dementia vs. normal controls with the bulk of data suggesting higher serum cortisol and greater peripheral cortisol:DHEA-S ratios in people with dementia:

https://www.ncbi.nlm.nih.gov/pubmed/16702789

The cortisol/DHEA-S ratio increases with aging, but more so in people with dementia. Specifically, aging involves increased nocturnal serum cortisol and decreased serum DHEA-S with an exaggerated effect in people with dementia, effects that correlate with decreased hippocampus volume:

https://www.ncbi.nlm.nih.gov/pubmed/16702789

Hypothalamic-pituitary-adrenal dysfunction overactivity and impaired negative feedback, as revealed by dexamethasone-suppression testing, distinguishes people with vascular and Alzheimers’s-type dementia (n = 163):

https://www.ncbi.nlm.nih.gov/pubmed/7825888

A number of other observational studies have corroborated this pattern of HPA overactivity and impaired negative feedback, along with hippocampus atrophy, such as this one:

https://www.ncbi.nlm.nih.gov/pubmed/16125145

Prospective treatment data:

50 mg oral DHEA vs. placebo, double-blind, administered to 110 men, 115 women age 55-85 did not result in any effect on cognitive decline over 12 months. Serum DHEA-S increased two- to four-fold, and testosterone increased 60% and estradiol 40% in women.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574781/

DHEA-S 50 mg per day administered to non-cognitively impaired males age 62-76; both salivary DHEA and cortisol were tracked. Higher cortisol levels were associated with impaired episodic memory and mood/anxiety which was attenuated by DHEA:

https://www.ncbi.nlm.nih.gov/pubmed/11403980

DHEA 50 mg per day was administered to perimenopausal cognitively normal females vs. placebo for 3 months. DHEA resulted in 242% increase in DHEA-S, 94.8% increase in testosterone, and a 13.2% decline in cortisol compared to baseline but no difference in mood, memory, or cognition compared to placebo:

https://www.ncbi.nlm.nih.gov/pubmed/10566625

Females (n = 27) with mild to moderate cognitive impairment were randomized to receive DHEA 25 mg vs. placebo over 6 months. The DHEA-treated subset experienced modest improvement in cognitive measures while placebo group experienced decline:

https://www.ncbi.nlm.nih.gov/pubmed/20497239

DHEA 50 mg administered to people with Alzheimer’s disease demonstrated a mild, though non-significant effect over 6 months compared to placebo:

https://www.ncbi.nlm.nih.gov/pubmed/12682308

A NIH study in which DHEA 50 mg per day administered to non-demented postmenopausal females (n = 24) resulted in marked improvement in visual-spatial performance over 4 weeks (Mental Rotation, Subject-Ordered Pointing, Fragmented Picture Identification, Perceptual Identification, and Same-Different Judgment).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715689/

Conclusions:

The question of DHEA and DHEA-S may really be a question of the function/integrity of the hypothalamic-pituitary-adrenal axis that declines with age (and amplification of the inflammasome) that also includes questions about cortisol/cortisone, oxytocin, as well as estrogens and androgens. In other words, increased basal adrenocorticotropic hormone (ACTH) and cortisol secretion; decreased glucocorticoid (GC) negative feedback at the level of the paraventricular nucleus (PVN) of the hypothalamus, hippocampus (HC), and prefrontal cortex (PFC); and flattening of diurnal pattern of cortisol release with decrease in the a.m. surge and increase in nocturnal levels may be the real issues, of which a decline in central and peripheral DHEA/S may simply be a component. In particular, declining DHEA/S leave higher ACTH/cortisol levels unopposed, a phenomenon that has been shown to be neurotoxic.

Given the bulk of clinical treatment data and the generally benign nature of DHEA supplementation along with benefits that include increased mood, libido, and muscle mass, I believe it would be reasonable to supplement DHEA. However, there are still unanswered questions surrounding the influence/correction of the HPA axis, ACTH/cortisol dysregulation and distorted cortisol circadian rhythmicity; an understanding of these issues may enhance our ability to select which individuals will benefit most from DHEA supplementation. I believe we would be on solid ground if we argued that anyone with higher levels of morning, afternoon, evening, or mesor cortisol would benefit from DHEA supplementation. The timing of such supplementation (in anticipation of the inappropriate rise?) has not been explored, although the extended 20-hour half-life of both DHEA and DHEA-S suggest that timing may be immaterial.  

Note that oxytocin is a modulator of hypothalamic ACTH release, suppressing ACTH; oxytocin declines with aging but is readily restored to youthful levels via manipulation of bowel flora composition. (Is oxytocin and HPA dysregulation therefore nothing more than yet another manifestation of modern and ubiquitous dysbiosis?) I will discuss oxytocin issues separately.

Oxytocin

The hypothalamic nona-peptide, oxytocin, is not generally considered a player in cognitive decline nor is it discussed in ReCODE. However, it is proving to be a major player in the phenomena of aging, recently explored exhaustively in animal experimental, and to some degree in human, models at MIT. Because hypothalamic-pituitary-adrenal (HPA) dysregulation is proving to be a consistently observed phenomenon in aging and dementia, and oxytocin that declines with age (senescent vs. pathological?) is a determinant of HPA activity, in particular blunting the rise in ACTH and cortisol with stress (e.g., emotional, sleep deprivation, visceral fat) should we focus on factors/strategies that enhance oxytocin, endogenously or exogenously?

In the context of cognitive decline, oxytocin is a regulator of hypothalamic paraventricular nuclear release of corticotropin-releasing hormone (CRH) that becomes dysregulated with aging and dementia, as evidenced in the DHEA research. Also, in separate data, oxytocin is proving to be a potent stimulator of bone density (osteoblastic stimulation).

Experimental data:

Oxytocin from paraventricular nuclear modulates, but mostly suppresses, CRH release from neighboring CRH-producing neurons:

https://www.ncbi.nlm.nih.gov/pubmed/28872712

The MIT studies, mostly in mice but limited skin observations in normal human females, demonstrating the oxytocin-stimulating effects of L. reuteri:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354898/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3813596/

Oxytocin dramatically accelerates wound healing (as a surrogate for skin health; mice and human); dramatically increases total skin thickness and dermal thickness, collagen deposition (mice and human); increases testosterone (male mice); increases sebum production (mice); increases hair follicular density (mice); prevents weight gain on an obesogenic diet (mice; separate data in humans with 19.8 pounds lost over 8 weeks without change in diet or exercise); preserves youthful activities, e.g., grooming and social behavior (mice).  

Observational data:

Higher endogenous oxytocin levels do not blunt the HPA stress response, but is associated with greater recovery of the parasympathetic response:

https://www.ncbi.nlm.nih.gov/pubmed/27608360

Increased brain oxytocin may be associated with dementia:

https://www.ncbi.nlm.nih.gov/pubmed/3587615

Clinical treatment studies:

The effects of intranasal oxytocin are varied, depending on context and measure, but with no clear-cut effects on memory:

https://www.ncbi.nlm.nih.gov/pubmed/27633648

An observation of limited significance: improved social and emotional cognition in people with front-temporal dementia after a single dose of 24 IU intranasal oxytocin.

https://www.ncbi.nlm.nih.gov/pubmed/21859765

Conclusion:

The data remain too preliminary to come to firm conclusions for practical application. However, given the magnitude and thoroughness of the MIT data, coupled with the Chinese data demonstrating marked weight loss benefits of intranasal oxytocin, I have been putting these concepts to work by having my audience:

1. Obtain the BioGaia ATCC PTA 6475 and DSM 17938 strains of L. reuteri used in the MIT studies. (We do not know how strain-specific these effects are; until we do, we shall only use this strain.) Each tablet provides 100 million CFUs of each strain—low counts that may be insufficient for demonstrable effects. Anecdotally, people taking the BioGaia, e.g., 2 tablets per day, perceive no effects.  

2. Make yogurt to amplify microbial counts. The yogurt we make is rich, thick, and delicious. It is cream cheese-like in solidity. Because the yogurt is converted from a soupy liquid to firm solid, I take this to reflect a dramatic increase in L. reuteri counts, probably to hundreds of billions or trillions, along with metabolites such as butyrate. We also ferment yogurt by adding the prebiotic fiber, inulin or a glucose source such as raw potato starch, which further amplifies CFUs. I have been advocating one quart organic half-and-half (or coconut milk but with added sugar to enhance fermentation), one tablespoon inulin, one billion CFUs L. reuteri ATCC PTA 6475 and DSM 17938  (10 tablets crushed with mortar and pestle), then fermented at 110 degrees F for 36-48 hours. Subsequent batches can be made by using 2-4 tablespoons of the prior batch. (There may be need for subsequent “reseeding” of the BioGaia product, though this is unclear. In my Gram stain analysis, there remains a uniform population of Gram-positive bacilli even after 8-10 batches without re-inoculation.) People consume approximately 1/2 cup per day. (I am working on obtaining a measure of CFU dose with this serving size.)

3. Anecdotally, we have been witnessing dramatic effects that include complete indifference/aversion to food for about 6 hours or longer in overweight (but not underrweight) people (a leptin resistance-reversing effect? Leptin resistance-reversal has indeed been demonstrated elsewhere); modest loss of visceral fat; dramatic improvements in skin health (reversal/prevention senile purpura, thicker skin, reduced wrinkles) that develop starting at 3-4 weeks; accelerated skin wound healing; faster recovery from exercise; increased libido.  

I mention this to get us all thinking about this unique and potentially exciting strategy. There is no commercial product available to provide this; we would have to make the yogurt ourselves. However, in my preliminary experience in a couple dozen people, I have been floored by the effects. In the context of cognitive preservation, this strategy at the very least can be expected to blunt the brain-destructive effects of excess cortisol, given the hypothalamic/pituitary modulating effects of oxytocin.

Bowel flora

Experimental evidence:

Experimental models make use of observations that involve germ-free (gnotobiotic) animals, antibiotics, implantation of specific species/probiotics, prebiotics, and microbial metabolites. The data as a whole are pointing towards disruption of the hypothalamic-pituitary axis allowing higher ACTH-cortisol levels to be expressed and higher levels of inflammation in the presence of various forms of dysbiosis.

Aging is associated with impaired spatial memory, increased anxiety-like behaviors, and increased intestinal permeability in a mouse model compared to young mice. Cecal microbiome revealed increases in phylum TM7, family Porphyromonadaceae and genus Odoribacter in aged mice compared to youthful, a pattern that mimics that seen in inflammatory diseases.

https://www.ncbi.nlm.nih.gov/pubmed/28179108

Fructooligosaccharides (FOS) administered to a unique mouse dementia model (fed galactose intraperitoneally or Aβ1-42 protein injected into the hippocampus) reversed dementia-associated behaviors. Aβ1-42-induced animals animals developed increased abundance of Clostridia and Clostridiales, while Firmicutes, Bacteroidetes, Bacteroidia, Bacilli, Lactobacillales, Bacteroidales, Lactobacillaceae, and Lactobacillus were reduced. Administration of FOS reversed these patterns.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727096/

Amyloid precursor protein (APP) transgenic mice developed changes in bowel flora composition compared to wild type mice. Transgenic APP gnotobiotic mice showed reduced amyloid beta pathology. This study suggests that the brain and associated pathology of dementia may be a cause, not just an effect, of dysbiosis. Transgenic mice showed decreased Allobaculum and Akkermansia and increased Rikenellaceae and S24-7.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297247/

An interesting review of bioactive lipids, such as N-arachidonoylethanolamine (AEA), palmitoylethanolamide (PEA) and oleoilethanolamide (OEA), and short chain fatty acids (SCFAs), such as butyrate, as mediators of CNS changes associated with cognitive decline and dementia in experimental models:

https://www.ncbi.nlm.nih.gov/pubmed/28215162

A review of the data demonstrating that gnotobiotic mice have higher cortisol/ACTH, lower cortical and hippocampal levels of BDNF, and lower levels of oxytocin and vasopressin:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4934620/

Amyloid precursor protein transgenic mice injected with Gram negative lipopolysaccharide developed several-fold greater levels of cerebral amyloid beta:

https://www.ncbi.nlm.nih.gov/pubmed/13678674

Higher levels of lipopolysaccharide-binding protein is associated with greater levels of impaired physical function and IL-6, TNF-alpha, and c-reactive protein in normal individuals:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636679/

Post-mortem comparison of brains from people with Alzheimer’s vs. normal demonstrated protein fragments of E. coli and Gram-negative lipopolysaccharide co-localizes with beta-amyloid:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135029/

Administration of a microbial species isolated from the supernatant of traditionally-fermented kimchi, Lactobacillus pentosus var. plantarum C29, reversed cognitive impairment and increased hippocampal BDNF in a mouse model:

https://www.ncbi.nlm.nih.gov/pubmed/22925033

Administration of FOS in a mouse model reversed cognitive decline, reduced markers of oxidation and inflammation, increased release of acetylcholine, and reversed dysbiotic changes:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727096/

A commercially-supported study in which the eight species of gram positive microbes in VSL#3 were administered to aged mice and increased the populations of Actinobacteria and Bacterioidetes, changes associated with increased transcription of genes associated neuronal plasticity, BDNF and synopsin:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159266/

Administration of Lactobacillus rhamnosus (strain JB-1) to mice decreased stress-induced serum cortisol, an effect blocked by vagotomy:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179073/

A review of the effects of tryptophan and serotonin depletion on cognition in animals and humans, improvement with microbial metabolism of tryptophan to serotonin in animals:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728667/

A review of the association between oral flora and dementia:

https://www.ncbi.nlm.nih.gov/pubmed/25125469

https://www.ncbi.nlm.nih.gov/pubmed/28453484

Observational data:

The stool abundance of Escherichia/Shigella, Pseudomonas aeruginosa, Eubacterium rectale, Eubacterium hallii, Faecalibacterium prausnitzii, and Bacteroides fragilis in people with brain amyloid (by amyloid PET imaging) vs. normals (n = 83) showed increased Eschericia/Shigella, reduced E. rectale in dementia with beta-amyloid cohort, along with increased inflammatory markers:

https://www.ncbi.nlm.nih.gov/pubmed/27776263

16S mRNA analyses of bowel flora in people with Alzheimer’s vs. normal controls (n = 50) showed decreased species diversity (as in type 2 diabetes, obesity, Parkinson’s and other conditions) and relative increase in Bacteriodetes and Actinobacteria, reduction in Firmicutes, effects that could not be attributed to differences in diet, age, or medications:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648830/

Data analysis from this study:

A cross-sectional analysis of 32,000+ Chinese demonstrating that people with irritable bowel syndrome (now believed to be synonymous with small intestinal bacterial overgrowth, SIBO) show increased relative risk for dementia:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701489/

Clinical treatment data

People with moderate-severe AD were randomized to a probiotic milk containing 2 billion CFUs of each of L. acidophilus, L. casei, B. bifidum, and L. fermentum (strains not specified, a major oversight) for 12 weeks vs. placebo. MMSE scores improved from 8.67 to 10.57 in the treatment group, while the control group dropped from 8.47 to 8.00. Serum levels of malondialdehyde (an index of oxidative stress), c-reactive protein, HOMA and triglycerides were improved in the treatment group:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5105117/

Conclusion:

The experimental data are robust and consistent: the microbiome (intestinal and oral) influences inflammatory responses, beta-amyloid deposition, and other dementia-related pathologies. The observational data, though few, likewise suggest that dysbiotic changes are associated with dementia. However, because the data are observational, we cannot surmise whether dysbiosis per se is the cause, or whether one or more causes of dysbiosis are causal, e.g., components of diet, exposure to antibiotics, herbicide/pesticide exposure, etc.

Obviously, there are minimal clinical treatment data to help us decide whether addressing the microbiome/dysbiosis/SIBO or supplementing specific probiotic species will impact risk for cognitive decline. However, given the bulk of data demonstrating the beneficial effects of various Lactobacillus, Bifidobacteria, and other species, as well as probiotics and probiotics, I believe that a comprehensive program to work towards eubiosis is still worth pursuing.

Pharmacologic agents

Pirebedil

This dopaminergic agent used for Parkinsonism may have positive effects on slowing cognitive decline in people with mild cognitive impairment:

https://www.ncbi.nlm.nih.gov/pubmed/11532743

Hyponatremia

It is not clear whether hyponatremia is genuinely a cause for dementia or whether it is only a separate and distinct cause of cognitive impairment, as the “dementia” can reverse with correction of the hyponatremia, regardless of cause (although severe hyponatremia results in irreversible cognitive impairment, presumably due to cerebral hypoxia). Reversal of hyponatremia-associated cognitive impairment is believed to be due to reversal of cerebral edema.

SIADH accounts for approximately a third of cases of hyponatremia. Most of the evidence makes no effort to dissect out SIADH from other causes, a major confounder. SIADH raises the chicken-or-egg question: Which comes first, hyponatremia or cognitive decline/cerebral pathology? (Here is a helpful review of SIADH: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474650/). Note that efforts to augment oxytocin status can worsen SIADH. Hyponatremia can also serve as a marker for hypothyroidism.

In a setting (i.e., The Villas) in which vigorous hydration is encouraged for health, we may end up exacerbating the problem, so the connection between hyponatremia and cognitive impairment is worth being aware of. Note that, among commonly prescribed drugs, SSRIs, tricyclics, HCTZ and other thiazides, NSAIDs, and seizure medications can cause SIADH.

Experimental evidence:

An experimental rat model of SIADH-induced hyponatremia was associated with gait disturbances and cognitive impairment:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769197/

While brain volume accommodates to chronic hyponatremia, there are alterations in cerebral glutamate metabolism and in synaptic transmission resulting in gait disturbance and cognitive impairment, reversed with correction of hyponatremia:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769197/

Observational evidence:

Greater severity of hyponatremia was associated with greater degrees of cognitive decline, as well as greater rates of cognitive decline over time (n = 5435 males; 4.6 years):

https://www.ncbi.nlm.nih.gov/pubmed/29439092

Case-control study of people with hyponatremia, mean Na+ of 126 mEq/L (n = 122) with 244 matched controls demonstrating reductions in measures of attention, response time, and gait, along with increased frequency of falls:

https://www.ncbi.nlm.nih.gov/pubmed/16431193/

Retrospective analysis of people with mild (RR 2.08) and severe hyponatremia (RR = 4.29) (n = 4900 with hyponatremia, 19,000+ controls) were substantially more likely to develop dementia:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462431/

As much as I bash observational studies, this study has the strength of 1) a clear “dose-response” relationship, i.e., the worse the hyponatremia, the greater the likelihood of dementia, and 2) a substantial RR after adjustment for diabetes, hypertension, etc. (potential causes of SIADH), not the anemic 1.2 or 1.4 that is often used to suggest causation but is nothing of the sort.

Clinical treatment data:

The proprietary (drug-sponsored) SALT trials of the renal tubule receptor ADH-blocker, tolvaptan 15 mg/day vs. placebo (n = 448) demonstrated improved cognitive measures of self-reported vitality, social functioning, emotionally limited accomplishment, calmness, and sadness in treated participants with corrected hyponatremia:

http://www.nejm.org/doi/10.1056/NEJMoa065181?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.nih.gov

Proprietary (drug-sponsored) INSIGHT trial, randomized, double-blind trial of tolvaptan 15 mg per day (titrated to 30 and 60 mg based on serum Na+) vs. placebo demonstrating near-normal neurocognitive measures in both treatment and control group at baseline, but with improvement in rapid motor movement in treated participants:

https://www.ncbi.nlm.nih.gov/pubmed/26874645

Conclusion:

Hyponatremia is common and has been confidently associated with various forms of cognitive impairment, though cause-effect is confounded by the several varied causes such as SIADH, depression/SSRIs/tricyclics, hypothyroidism and others. Nonetheless, hyponatremia is a potentially reversible contributor to cognitive impairment/dementia.

It is not clear at what serum Na+ cognitive impairment becomes an issue, though it is clearly a continuous function: the worse the hyponatremia, the worse the cognitive impairment, including irreversible impairment at severe levels (e.g., <120 mEq/L).

SSRIs

Antidepressant medication commonly improve cognitive and ability to navigate activities of daily living due to their antidepressant effect. But do they actually exert a cognition-enhancing (nootropic) or dementia-preventing (neurotrophic) effect, as well?

Experimental evidence:

Citalopram reduced cerebral beta-amyloid and improved cognitive measures/behavior in mice:

https://www.ncbi.nlm.nih.gov/pubmed/29241655

Duloxetine provides a neuroprotective effect in cerebral hypoperfusion in mice:

https://www.ncbi.nlm.nih.gov/pubmed/28365975

Observational evidence:

Long-term (4 or more years) administration of SSRI citalopram was associated with delayed conversion by 3 years from mild cognitive impairment to dementia by cognitive testing:

https://www.ncbi.nlm.nih.gov/pubmed/29179578

Case-control study of people, all with migraine headaches, with dementia vs. no-dementia and use of various antidepressants demonstrating an association between SSRI and reduced OR of 0.59:

https://www.ncbi.nlm.nih.gov/pubmed/28392483

Clinical treatment data:

20 younger and 20 older cognitively normal volunteers were subjected to single 20-minute session of transcranial direct current stimulation (anode at T6, right temperoparietal; cathode frontopolar cortex) with or without 20 mg citalopram 2 hours prior to tDCS. Citalopram or tDCS alone did not improve immediate recall or memory performance, but the combination improved immediate recall (note the acute nature of both treatments, not chronic):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399237/

The CitAD study of citalopram 10 mg titrated to 30 mg in people with AD (n = 94) vs. control (n = 92) for 9 weeks demonstrated modest worsening of cognitive measures:https://www.ncbi.nlm.nih.gov/pubmed/24549548

Escitalopram 20 mg per day vs. placebo over 12 months in people with AD (n = 74) resulted in no changes in hippocampal or whole brain volume by MRI:

https://www.ncbi.nlm.nih.gov/pubmed/26553313

Escitalopram vs. placebo (n = 60) over 12 weeks resulted in no difference in cognitive measures:

https://www.ncbi.nlm.nih.gov/pubmed/27716660

Meta-analysis of vortioxetine vs. placebo in people with major depressive disorder appeared to improve cognitive independently of depression over 8 weeks:

https://www.ncbi.nlm.nih.gov/pubmed/27312740

People with fibromyalgia were treated with duloxetine (n = 80) vs. placebo (n = 76) with no change in cognitive measures (meaning no nootropic effect) over 12 weeks:

https://www.ncbi.nlm.nih.gov/pubmed/22753629

Conclusion:

Once again, the experimental and observational evidence suggests potential for beneficial effects, but the actual clinical treatment data do not bear this out. There is therefore no role for SSRIs in improving/preserving cognition outside of depression.

Spearmint extract

The data supporting spearmint extract using a strain of the plant selected for enrichment the flavonoid, rosmarinic acid, has been explored via proprietary studies funded by the manufacturer, Kemin. Nonetheless, just so that we are aware of such data, here are the results of a 90-day randomized, blinded treatment trial (n = 90) using 900 mg of the rosaminic acid-enriched extract with improvements in cognitive measures, sleep, and mood:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5779242/

NSAIDs

I’ve heard many colleagues claim that NSAIDs prevent dementia. Is this true?

Most agree that inflammatory pathways underlie much of dementia pathology. Experimental evidence did indeed suggest reduced beta-amyloid accumulation and neuronal anti-inflammatory effects.

Because this could potentially yield a pot of gold for Big Pharma, there is continued exploration of this issue despite the negative outcomes of clinical treatment studies, propped up by the (generally false) hopes created by positive observational data. This means that the typical medical practitioner may still believe that NSAIDs prevent/treat dementia, an area we should therefore be familiar with.

Experimental evidence:

This is just a sample:

NSAIDS and flurbiprofen prevent amyloid-beta oligomer induced neuronal cell death in an in vitro hippocampal cell model:

https://www.ncbi.nlm.nih.gov/pubmed/29314866

Ibuprofen, indomethacin and sulindac reduce amyloid-beta in a cultured neuronal cell model:

https://www.ncbi.nlm.nih.gov/pubmed/27447424

Observational evidence:

A total of 15 observational studies have been published examining the association between AD and NSAID/aspirin use. Here is a sample:

Case-control study of 31,000 people with AD, 23,465 with vascular dementia showed no association of NSAID use and AD or Lewy body disease, but an increase in risk for vascular dementia with NSAID use:

https://www.ncbi.nlm.nih.gov/pubmed/26177125

Case-control study of 33,000 people with rheumatoid arthritis taking NSAIDs showing reduced RR for AD in the subset taking NSAIDs for longer than 2191 days (6 years). Note the misleading title of this study that should never have been permitted by the editors: “Prolong [sic] Exposure of NSAID in Patients With RA Will Decrease the Risk of Dementia.” An observational case-control cannot be used to make such a statement but misleads many readers.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998914/

Meta-analysis of observational studies of 36,000 people taking low-dose aspirin (<300 mg per day) showed no association with development of AD over mean follow-up of 6 years:

https://www.ncbi.nlm.nih.gov/pubmed/28425093

Retrospective analysis of 28,000 people with type 2 diabetes with those taking aspirin having a HR for AD of 1.37:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102734/

Clinical treatment data:

Meta-analysis of randomized, controlled treatment data involving NSAIDs and COX-2 inhibitors showing no slowing of cognitive decline:

https://www.ncbi.nlm.nih.gov/pubmed/25644018

Among the individual studies:

People with mild-moderate AD were randomized to ibuprofen 400 mg twice per day (n = 51) or placebo (n = 46) and followed by ADAS-Cog for 12 months with no difference in rate of cognitive decline:

https://www.ncbi.nlm.nih.gov/pubmed/19448381

People with mild-moderate AD ((MMSE 13-26) were randomized to rofecoxib 25 mg per day, naproxen sodium 220 mg twice daily, or placebo over 12 months. No difference in rate of cognitive decline by ADAS-Cog and other measures was seen:

https://www.ncbi.nlm.nih.gov/pubmed/12783912

51 people with mild-moderate AD were randomized to indomethacin 100 mg per day vs. placebo with no change in ADAS-Cog or MMSE resulted in no significant difference in rate of cognitive decline over 12 months:

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0001475

41 people with mild-moderate AD were randomized to diclofenac with misoprostol with no difference in cognitive measures over 25 weeks:

https://www.ncbi.nlm.nih.gov/pubmed/10408559

2100 people with a family history of AD were randomized to celecoxib 200 mg twice daily, naproxen sodium 220 mg twice daily, or placebo and followed by cognitive testing over 3 years. There was no difference in rate of cognitive decline with possible accelerated worsening in participants taking naproxen:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925195/

Despite the negative/neutral outcomes, efforts continue to make NSAIDs an AD treatment, such as intranasal delivery to circumvent the limited CNS availability or this effort to conjugate NSAIDs with other compounds:

https://www.ncbi.nlm.nih.gov/pubmed/27376271

Conclusion:

Despite the negative findings of clinical treatment studies, there is persistent adherence by some to the notion that anti-inflammatory drugs reduce dementia. Here is a recent (2016) review that claims, based on the observational data, that NSAIDs do indeed reduce AD, despite the clinical treatment data that disprove the observational study findings, illustrating the harm done by misinterpretation/misunderstanding of the role of observational data:

https://www.ncbi.nlm.nih.gov/pubmed/27716676

However, there remains no clinical treatment evidence that NSAID use is associated with slowing or reversal of cognitive decline and, of course, use of this class of agents is associated with substantial toxicity.