The End of Alzheimer’s: The First Program to Prevent and Reverse Cognitive Decline

Overall score

Scientific accuracy

Reference accuracy

Healthfulness

How hard would it be to apply the book's advice? Very difficult

Book published in 2017

Published by Avery

First Edition, Hardcover

Review posted February 22, 2021

Primary reviewer: Morgan Pfiffner

Peer reviewer: Stephan Guyenet

Table of contents

1. Introduction
2. Scientific accuracy
3. Reference accuracy
4. Healthfulness
5. Most unusual claim
6. Other
7. Conclusion
8. Updates

Claim 1

The intake of various nutrients can influence cognitive decline and Alzheimer’s disease.

Supporting quote(s) and page number(s)

Page 121: “Keeping homocysteine optimally low requires sufficient levels of vitamins B6, B9 (folate), and B12, all in their active forms.”

Page 126: “Reduced vitamin D activity is associated with cognitive decline.”

Page 132: “…aging is associated with lower zinc levels, and Alzheimer’s disease with still lower zinc levels.”

Page 134: “Magnesium is critical for brain function.”

Page 135: “Selenium plays a key role in regenerating glutathione when it is used up scavenging free radicals, so it is not surprising that reductions in selenium have been shown to be associated with cognitive decline.”

Page 142: “Vitamin E is an important protector of your cell membranes, an antioxidant with an anti-alzheimer’s effect.”

Criterion 1.1. How well is the claim supported by current evidence?

2 out of 4

This claim received a score of 2, indicating that the claim is weakly supported by current evidence. A number of nutrients, primarily vitamins and minerals, are emphasized in TEOA as being important factors in the development of Alzheimer’s disease and cognitive decline. Perhaps most emphasized is a sufficient intake of several B vitamins, primarily B6, folate, and B12, largely on the basis that these nutrients lower levels of homocysteine, high levels of which TEOA claims are “important contributors to Alzheimer’s disease” (page 119). There is some evidence to support this claim, as these nutrients do play key roles in homocysteine metabolism and elevated homocysteine has been associated with an increased risk of Alzheimer-type dementia. Additionally, some evidence suggests a severe insufficiency or outright deficiency of vitamin B12 or folate can lead to (often reversible) cognitive impairment. However, the effect of B vitamin supplementation has been disappointing. A 2019 meta-analysis of multiple randomized trials reports that B vitamin supplementation lowers homocysteine levels but has no significant cognitive benefit in individuals with or without dementia, though a possibility of benefit was hinted at in subgroups (e.g. those with elevated homocysteine). It may be that these vitamins are helpful in some cases, but more research is likely needed.

TEOA also regularly suggests vitamin D status may benefit cognitive function. Perhaps the strongest evidence in favor of this suggestion comes from Mendelian randomization studies, several of which have observed that genetically lower vitamin D levels are linked to an increased risk of Alzheimer’s disease. However, not all of these studies have been supportive. One clinical trial also found daily supplementation of 400 IU of vitamin D for 12 months had some positive effects on some markers of cognitive function among elderly people with mild cognitive impairment. While not conclusive, the balance of the evidence points to a possible benefit from vitamin D supplementation in the context of cognitive impairment.

Magnesium is cited as a beneficial nutrient, with magnesium L-threonate cited as especially helpful for brain health. The evidence for this comes largely from a randomized controlled trial in which supplementation of magnesium L-threonate for 12 weeks improved performance on a composite of cognitive tests compared to a placebo. This study was conducted on people with mild-to-moderate anxiety, sleep issues, and self-reported cognitive issues, but with no cognitive impairment on objective assessment. This study offers compelling evidence for a beneficial effect of magnesium, though its relevance to Alzheimer’s disease is uncertain, and given the short duration and inclusion criteria, additional research is warranted. It’s also worth noting that three of the five authors disclosed financial interests related to the supplement being tested.

Another nutrient proposed by TEOA as potentially important in the prevention and management of dementia is zinc. However, while zinc levels are often found to be lower in individuals with Alzheimer’s disease, this does not necessarily mean lower zinc actually contributes to the development of Alzheimer’s disease. Meanwhile, one randomized controlled trial (the ZENITH study) failed to find convincing evidence that zinc supplementation benefits cognitive function in older adults. However, because this study did not examine individuals with Alzheimer’s disease or established dementia a beneficial effect of zinc can’t be ruled out. A 2,166-person randomized controlled trial reports that supplementing with zinc and copper for 6.9 years did not significantly impact cognitive function relative to placebo in elderly people, although there was a non-significant trend toward lower risk of developing cognitive impairment. TEOA suggests that copper is harmful to cognitive function, so that could be the book’s counterargument, but we are uncertain if that is the case at the dose used in this study (2 mg of copper daily as cupric oxide).

Finally, TEOA recommends a number of nutrients partly on the basis that they can increase antioxidant status. These nutrients include selenium, vitamin C, alpha lipoic acid, CoQ10, and vitamin E. By and large, most of these compounds have little to no convincing evidence of benefit in the context of dementia or Alzheimer’s disease. Interestingly, one randomized trial on individuals with mild to moderate Alzheimer’s disease found that subjects randomly assigned to take 500mg of vitamin C, 800IU of vitamin E, and 900mg of alpha lipoic acid for 16 weeks saw a greater decline in cognitive function (as assessed using an MMSE test) than those taking a placebo. A second large randomized controlled trial reports that daily supplementation of the antioxidants vitamin C, vitamin E, and beta carotene for 6.9 years did not impact cognitive function or the risk of developing cognitive impairment among elderly people.

Vitamin E supplementation (in the form of a-tocopherol) has also been tested several times on its own and although some studies have reported benefits (e.g one 1997 trial reported a slowing of Alzheimer’s disease progression), analysis of the entire body of evidence does not appear to support a clear benefit of vitamin E on cognitive function related to dementia.

In most cases, there is not strong evidence supporting the claims in TEOA regarding the ability of various nutrients to reduce risk and slow progression of dementia and Alzheimer’s disease. Two exceptions are that B vitamin supplementation may be helpful in people with elevated homocysteine, and vitamin D supplementation may also be helpful. While we don’t have enough evidence to judge whether the remaining claims are true or false, they appear to be speculative.

Criterion 1.2. Are the references cited in the book to support the claim convincing?

2 out of 4

The book received a score of 2, indicating the references are weakly convincing overall. In many cases, the book does not provide references for these claims. For example, no references are provided to support the claimed beneficial effects of vitamin D, vitamin C, vitamin B1, among several other nutrients. When the book does cite research, the references are variable in how convincing they are. For example, when discussing the benefits of magnesium and vitamin E, the book references clinical trials testing the effects of these nutrients on cognitive function. The trial of vitamin E cited suggests that it can modestly slow cognitive decline in Alzheimer’s disease, although of note several secondary outcomes related to cognitive function in this trial showed no significant effect. The trial of magnesium did report a benefit to cognitive function.

At other points, references are not very convincing, albeit still consistent with the author’s claims. For example, the proposed benefits of selenium are based on a single observational study looking at the association between selenium intake and cognitive impairment. Because this is an observational study, it is unclear whether low selenium status causes cognitive impairment or is merely along for the ride.

Criterion 1.3. How well does the strength of the claim line up with the strength of the evidence?

2 out of 4

The claims received a score of 2, indicating the claim is moderately overstated. In the majority of cases the claims about nutrients exceeded the strength of the evidence. Associations, mechanisms, and case studies are often discussed to persuade the reader of the possible benefits. Shortcomings of this evidence are not typically addressed. In most of these cases, TEOA does not clearly claim a nutrient will have a beneficial effect on Alzheimer’s, though it is strongly implied. Cases where causation is claimed more strongly include vitamin E, which is said to have an “anti-Alzheimer’s effect” (page 142). In this case a clinical trial is cited which, despite some limitations, is in line with the claim However, as mentioned previously, not all clinical trials support a beneficial effect of vitamin E and such strong claims about its efficacy seem unjustified. On the other hand, the claim regarding vitamin D, namely that lower levels are “associated with cognitive decline” (page 126), aligned well with the strength of the evidence.

Overall (average) score for claim 1

2 out of 4

Claim 2

Certain dietary factors can promote Alzheimer’s disease by causing inflammation.

Supporting quote(s) and page number(s)

Page 124: “There is a direct mechanistic link between inflammation and Alzheimer’s disease”

Page 125: “Your hs-CRP should be below 0.9 mg/dL. If it is higher, you want to determine the source of inflammation. This may be from too much sugar and other simple carbohydrates, or bad fats (for example, trans fats), a leaky gut (more on this later), gluten sensitivity, poor oral hygiene, specific toxins, or any of many other sources”

Page 145: “One of the most important contributors to Alzheimer’s disease is inflammation, and one of the most common ways to create systemic inflammation is a leaky gut”

Page 199: “Inflammation is one of the most important drivers of cognitive decline, and it feeds directly into the Alzheimer’s disease mechanisms”

Criterion 1.1. How well is the claim supported by current evidence?

1 out of 4

This claim received a score of 1, indicating that it is poorly supported by current evidence overall.

TEOA repeatedly states that inflammation is an important driver of Alzheimer’s disease and cognitive decline. However, the actual relationship between inflammation and Alzheimer’s disease may not be as simple as described in TEOA. For example, while there is evidence suggesting inflammation occurs in Alzheimer’s disease and may even contribute to the disease, it is not clear that inflammation markers in the blood (such as hsCRP) tell us much about inflammation in the brain. This is apparent in observational studies, which have typically failed to find significant correlations between markers of systemic inflammation (many of which are touted as clinically important in TEOA) and the risk of developing Alzheimer’s disease. However, it’s worth noting that markers of systemic inflammation are correlated with dementia more broadly, just not Alzheimer’s disease specifically. Similar findings have also been reported in genetic studies.

There is only a limited amount of experimental evidence testing the idea that suppressing inflammation reduces the risk of Alzheimer’s disease in humans, and results are not particularly compelling. One randomized controlled trial administered the anti-inflammatory drugs celecoxib or naproxen to individuals with a family history of dementia. This trial found no effect of celecoxib on the development of Alzheimer’s, but a possible benefit among those taking naproxen who had not yet developed symptoms. Unfortunately, a later trial appeared to contradict this latter finding. This evidence does not necessarily discredit the idea that inflammation contributes to Alzheimer’s disease, but it does suggest that the connection is probably not as simple as laid out in the book.

TEOA recommends avoiding a number of foods and dietary compounds on the basis that they are inflammatory. Setting aside the role of inflammation on Alzheimer’s disease, the evidence appears mixed regarding whether the recommendations in TEOA will meaningfully impact inflammation. One proposed cause of inflammation is dietary Advanced Glycation End Products, or AGEs, a compound produced with dry heat cooking methods (e.g. frying, barbecuing, roasting). A number of clinical trials have indeed found evidence that a higher AGE intake may have an inflammatory effect, typically indicated by an increase in the inflammatory mediator TNFa. Trans fats are also cited as inflammatory in TEOA and at least some evidence does seem to support this. On the other hand, many of the claims regarding inflammatory foods are not well supported by evidence. Dairy foods are said to be inflammatory and should be avoided “as much as possible” (page 183), but a 2020 meta-analysis of various clinical trials testing the effect of dairy products on markers of inflammation reported no apparent pro-inflammatory effects from dairy foods (if anything, the opposite finding was indicated). While it’s possible for an individual to have a dairy sensitivity, existing evidence suggests this is not typical.

The claim is also made that omega-6 fatty acids, particularly when consumed significantly in excess of omega-3 fatty acids, are inflammatory. This is used as a rationale to eat meat and eggs from pastured animals. However, a number of human experimental studies have failed to find clear evidence to support the claim that an increased intake of omega-6 fat invariably leads to an increase in markers of inflammation, particularly in the amounts found in animal foods.

TEOA also contends that sugar and refined carbohydrates are inflammatory. In general, the evidence to support this assertion is weak, although there may be certain contexts in which sugar and refined carbohydrates can have inflammatory effects. For example, some sugar containing foods (e.g. sugary beverages like soda) seem to promote body fat gain. In these cases, sugar could well be capable of promoting inflammation, though this is a less direct mechanism than described in TEOA.

Finally, TEOA regularly implicates gluten as a source of inflammation, writing “Gluten can compromise the integrity of the gut barrier (and potentially the blood-brain barrier), leading to leaky gut, systemic inflammation, and increasing risk for cognitive decline” (page 266). However, outside of some in vitro research with questionable applicability to the human body (e.g. incubating intestinal cells with enzymatically treated gluten extracts), only a few experimental studies have examined the effect of gluten consumption on biomarkers of inflammation and these have largely not supported the authors claims. A 2011 study, for example, randomly assigned people with irritable bowel syndrome (IBS) and suspected gluten sensitivity to a diet with or without gluten for 6 weeks, ultimately noting no apparent rise in the inflammation marker CRP and no change in intestinal permeability as a result of gluten consumption. A 2018 cross-over study on apparently healthy adults also reported that a high gluten diet, compared with a low gluten diet, did not lead to higher markers of systemic inflammation (namely, circulating levels of CRP, TNF-a, IL-6) or increased intestinal permeability. This study did observe one possible marker of inflammatory potential was comparatively higher with more gluten intake (namely, IL-1b secretion from incubated blood exposed to lipopolysaccharide), but the practical and statistical significance of this finding is questionable. By and large, there is little evidence that eating gluten causes inflammation (excluding those with gluten allergies or Celiac disease).

Ultimately, the available evidence provides limited support for the idea that avoidance of the aforementioned foods will decrease inflammation. Furthermore, the evidence is unclear whether focusing on the blood-borne markers of inflammation discussed in TEOA can modify the risk of Alzheimer’s disease.

Criterion 1.2. Are the references cited in the book to support the claim convincing?

1 out of 4

The book’s references received a score of 1, as no references were provided to support this claim.

Criterion 1.3. How well does the strength of the claim line up with the strength of the evidence?

1 out of 4

The claim received a score of 1, indicating that the claim is greatly overstated.  As discussed previously, inflammation in the brain is linked to Alzheimer’s disease, but the relationship between inflammation and Alzheimer’s disease risk is far less straightforward than portrayed in the book. Furthermore, there is little evidence that most of the factors said to be inflammatory are in fact inflammatory.

Overall (average) score for claim 2

1 out of 4

Claim 3

Insulin resistance contributes to Alzheimer’s disease.

Supporting quote(s) and page number(s)

Page 122: “High insulin and high glucose are two of the most important risk factors for Alzheimer’s disease.”

Page 50: “Therefore, a critical part of ReCODE is reducing insulin resistance, restoring insulin sensitivity, and reducing glucose levels, thereby restoring optimal metabolism.”

Page 177: “If your fasting insulin is over 4.5 milli-international units per liter, your hemoglobin A1c over 5.5 percent, or your fasting glucose over 93 milligrams per deciliter, you likely have insulin resistance, arguably the single most important metabolic contributor to Alzheimer’s disease development and progression.”

Criterion 1.1. How well is the claim supported by current evidence?

3 out of 4

This claim received a score of 3, indicating that it is moderately well supported by current evidence.

A number of recommendations are made in TEOA based on the claim that insulin resistance is a key risk factor in the development of Alzheimer’s disease. Several mechanisms are proposed to explain this connection, including neuro-protective effects of insulin signaling in the brain and damage caused by elevated glucose.

Several lines of evidence have indicated a possible link between impaired insulin signaling in the brain and characteristics of Alzheimer’s disease (e.g. cognitive impairment), leading some researchers to refer to Alzheimer’s disease as “type 3 diabetes”. Though it’s worth noting that the type of insulin resistance related to Alzheimer’s disease is somewhat distinct from the systemic insulin resistance seen with type 2 diabetes. While insulin resistance underlying type 2 diabetes involves a reduced insulin sensitivity of major body tissues (e.g. muscle, liver, and fat cells), in the case of Alzheimer’s disease this reduction in insulin sensitivity is thought to be brain specific. In other words, the insulin resistance in Alzheimer’s disease and the insulin resistance discussed in TEOA are distinct entities. Still, there may be a correlation between systemic insulin resistance and brain insulin resistance. A 2006 study found insulin infusion stimulated brain glucose consumption to a lesser degree among people with systemic insulin resistance compared with those who were more insulin sensitive, suggesting brain insulin resistance and systemic insulin resistance may be associated.

Several studies have also noted a correlation between diabetes and Alzheimer’s disease, with one meta-analysis of prospective cohort studies reporting a 56% increased risk of Alzheimer’s disease among people with type 2 diabetes. Additional studies have also reported an association between both elevated fasting glucose and increased HbA1C (a marker of blood glucose levels) and a higher risk of Alzheimer’s disease, even among people without diabetes, consistent with the claims in TEOA that elevated glucose contributes to Alzheimer’s. Unfortunately, this evidence is observational (and thus causality is difficult to claim) and only a limited number of experimental trials have been done examining how lowering blood glucose and/or improving insulin sensitivity impacts cognitive decline. One of the largest of these studies, the ACCORD MIND trial examined the effect of more intensive glucose lowering strategies versus standard therapy in 2,977 older people with type 2 diabetes. Despite lower glucose levels in the intensive group, tests of cognitive function over the course of the 40-month trial showed no benefit. This study therefore did not support the role of blood glucose in cognitive function. However, the finding is somewhat hard to interpret because glucose lowering increased the risk of hypoglycemia. It’s also not clear that lowering glucose through an intensive drug regimen that includes insulin injection, as in this trial, has the same effect as lowering glucose through diet.

There is limited data looking at whether changes in insulin sensitivity achieved via dietary strategies can lead to beneficial effects on cognitive function. A 3 month trial on older people reported that a calorie restricted diet improved memory testing scores and this improvement in memory score was correlated with reduction fasting insulin, consistent with the idea that improving insulin signaling may benefit cognition. In a year long weight loss trial participants randomly assigned to either a low fat or a low carbohydrate diet improved their score on a working memory test to a similar extent and this change was also correlated with decreasing fasting insulin. On the other hand, one study found that a reduced calorie DASH diet, combined with aerobic exercise, improved insulin sensitivity as well as tests of neuro-cognitive performance, but there was no apparent relationship between the two; changes in insulin and glucose regulation did not correlate with improvements in cognitive function. Unfortunately, none of these diet studies were conducted on subjects experiencing dementia or age related cognitive decline, possibly limiting their relevance to these conditions. For this we look to a 2016 trial study on older people with obesity and mild cognitive impairment. Subjects were randomly assigned to standard care or a diet “rich in fiber, fruits, vegetables, and whole grains and included at least 1 g/kg of weight of protein per day, with a recommended calorie deficit of approximately 500 kcal/d”. This diet led to weight loss, improvements in an insulin resistance marker HOMA-IR (among other changes), and benefits to tests of cognitive function. Some, but not all cognitive improvements were correlated with the apparent improvements in insulin resistance.

Several studies have also administered insulin sensitizing agents (i.e. metformin, pioglitazone, and rosiglitazone) to individuals with cognitive impairment and Alzheimer’s disease. Some of these trials, particularly smaller trials, have shown positive effects on markers of cognitive function. However, in several trials no clear benefit was found. One six month study found that the diabetes drug Liraglutide increased glucose metabolism in the brain (indicating improved cerebral insulin sensitivity), but this did not correspond to cognitive benefits. These mixed results provide only limited support to the claims that insulin sensitivity is an important modifiable risk factor in Alzheimer’s disease. Ultimately, the evidence appears compelling but not conclusive that insulin resistance is an important contributor to Alzheimer’s disease and the interventional data is currently limited.

Criterion 1.2. Are the references cited in the book to support the claim convincing?

1 out of 4

The book’s references received a score of 1, as no references were provided to support this claim.

Criterion 1.3. How well does the strength of the claim line up with the strength of the evidence?

2 out of 4

The claim received a score of 2, indicating that the claim is moderately overstated. The role of impaired insulin signaling in the development of Alzheimer’s disease does appear compelling, but whether this process is as important as indicated in TEOA remains uncertain, given that the current body of evidence remains somewhat preliminary and occasionally contradictory.

Overall (average) score for claim 3

2 out of 4

Overall (average) score for scientific accuracy

1.7 out of 4

Reference 1

Reference

Chapter 7, reference 4.  Chausmer, A. B. Zinc, insulin and diabetes. Journal of the American College of Nutrition 17: 109-115 (1998)

Associated quote(s) and page number(s)

[Page 133: “…zinc is critical for insulin synthesis, storage, and release”

Criterion 2.1. Does the reference support the claim?

4 out of 4

This reference received a score of 4, indicating that it offers strong support for the claim.  This review covers the physiological role of zinc in the production of insulin, which is generally well established. It’s perhaps worth noting that this review cites research where zinc supplementation had conflicting effects on insulin dynamics.

Reference 2

Reference

Appendix D, reference 5.  Lu, D. C., et al. A second cytotoxic peptide derived from amyloid-beta-protein precursor. Nature Medicine 6: 397-404. (2000)

Associated quote(s) and page number(s)

Page 285: “APP is a dependence receptor” (reference 7 was also associated with the claim)

Criterion 2.1. Does the reference support the claim?

4 out of 4

This reference received a score of 4, indicating that it offers strong support for the claim.

Reference 3

Reference

Chapter 8, reference 4. https://articles.mercola.com/sites/articles/archive/2014/09/21/hilary-boynton-mary-brackett-gaps-cookbook-interview.aspx

Associated quote(s) and page number(s)

Page 201: “…there are complementary methods for gut healing. One method is bone broth”

Criterion 2.1. Does the reference support the claim?

1 out of 4

This reference received a score of 1, indicating that the reference does not convincingly support the claim.  The reference is to a video interview with two authors who claim bone broth is beneficial to gut health, but no apparent scientific evidence is mentioned.

Reference 4

Reference

Chapter 7, reference 8.  Basha, M. R., et al. The fetal basis of amyloidogenesis: exposure to lead and latent expression of amyloid precursor protein and beta-amyloid in the aging brain. Journal of Neuroscience 25: 823-829 (2005)

Associated quote(s) and page number(s)

Page 138: “Exposure to lead–typically through old paint and dust in cities–also increases amyloid formation later in life, rodent studies have shown”

Criterion 2.1. Does the reference support the claim?

3 out of 4

This reference received a score of 3, indicating it offers moderate support for the claim. This study did find that the addition of lead to drinking water of pregnant mice resulted in offspring that developed elevated brain expression of APP and amyloid beta later in life. However, the suggestion that this mouse study therefore demonstrates that such a phenomenon will occur in humans is perhaps overstated.

Reference 5

Reference

Chapter 7, reference 1.  den Heijer, T., et al. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 126 (Pt. 1): 170-175 (2003)

Associated quote(s) and page number(s)

Page 119: “High levels of homocysteine are important contributors to Alzheimer’s disease”

Criterion 2.1. Does the reference support the claim?

2 out of 4

This reference received a score of 2, indicating that it offers weak support for the claim. It is an observational study examining blood levels of homocysteine and brain atrophy in older individuals without dementia. This study found that higher homocysteine levels was associated with lower cortical volume. However, while this study seems consistent with the hypothesis that homocysteine contributes to Alzheimer’s disease, several issues limit its use for inferring causation. Perhaps most importantly, other factors could lead to both higher homocysteine and lower brain volume (e.g. certain nutrient deficiencies and health conditions), meaning homocysteine could be associated with but not necessarily contribute to Alzheimer’s disease.

Reference 6

Reference

Chapter 8, reference 5. http://draxe.com/scd-diet/

Associated quote(s) and page number(s)

Page 202: “Another approach is to follow a diet that uses specific carbohydrates to allow gut healing, called the SCD diet”

Criterion 2.1. Does the reference support the claim?

2 out of 4

This reference received a score of 2, indicating that it offers weak support for the claim.  It is a popular health website article discussing the Specific Carbohydrate Diet (SCD). This article does make some references to scientific research on the possible gut benefits of the SCD, but these appeared to be entirely case studies, which are not a particularly strong form of evidence, and all were on individuals with IBD, meaning that the findings may not be relevant to people with normal gut function.

Reference 7

Reference

Appendix D, reference 4.  Lourenco, F. C., et al. Netrin-1 interacts with amyloid precursor protein and regulates amyloid-beta production. Cell Death and Differentiation 16: 655-663 (2009)

Associated quote(s) and page number(s)

Page 285: “APP is a dependence receptor” (reference 2 was also associated with this claim)

Criterion 2.1. Does the reference support the claim?

4 out of 4

This reference received a score of 4, indicating that it offers strong support for the claim.

Reference 8

Reference

Chapter 7, reference 3.  Brewer, G. J. Copper excess, zinc deficiency, and cognition loss in Alzheimer’s Disease. Biofactors 38: 107-113 (2012)

Associated quote(s) and page number(s)

Page 133: “…zinc supplements enhance cognition”

Criterion 2.1. Does the reference support the claim?

1 out of 4

This reference received a score of 1, indicating that the reference does not convincingly support the claim.  The article discusses the hypothesis that inadequate zinc promotes Alzheimer’s disease. The review covers results of several trials examining the effect of zinc on cognition, most of which failed to find improvements in markers of cognition. In fact, contrary to the claim in the book the summary section from the paper states “our data so far indicate zinc therapy does not improve cognition, but rather stabilizes it and at least partially prevents cognition loss occurring otherwise. We should know within 1-2 years, when our definitive study is completed…” While this may seem somewhat persuasive at first glance, the findings were only significant in a subgroup analysis of participants over 70. Such unplanned subgroup analyses often return unreliable results, so the finding should be interpreted with caution.

Reference 9

Reference

Chapter 7, reference 9.  Bakulski KM, Rozek LS, Dolinoy DC, Paulson HL, Hu H. Alzheimer’s disease and environmental exposure to lead: the epidemiologic evidence and potential role of epigenetics. Current Alzheimer Research Jun;9(5):563-73 (2012)

Associated quote(s) and page number(s)

Page 138: “In people, there is both epidemiological and toxicological evidence that lead raises the risk of age-related cognitive decline”

Criterion 2.1. Does the reference support the claim?

4 out of 4

This reference received a score of 4, indicating that it offers strong support for the claim. The review cited provides various lines of evidence suggesting lead increases cognitive decline.

Reference 10

Reference

Chapter 5, reference 6.  Clarkson TW, Magos L, Myers GJ. The toxicology of mercury–current exposures and clinical manifestations. New England Journal of Medicine Oct 30;349(18):1731-7 (2003)

Associated quote(s) and page number(s)

Page 87: “Tropisetron blocks four of the thirty-six contributors we knew about at the time”

Criterion 2.1. Does the reference support the claim?

1 out of 4

This reference received a score of 1, indicating that the reference does not support the claim. The reference is to a review article on mercury. Meanwhile, the statement referencing this paper is about the possible anti-Alzheimer’s drug tropisetron. After checking several times to make sure the claim and the reference did in fact correspond we conclude this reference was likely placed erroneously.

Overall (average) score for reference accuracy

2.6 out of 4

There has been some research on ketogenic (often very-low-carbohydrate) diets on Alzheimer’s disease, based largely on the idea that cognitive deficits in Alzheimer’s disease are driven by a reduced ability of neurons to produce energy from glucose (related to the insulin resistance discussed in claim 2) and supplying ketones could help address this energy deficit. A handful of studies on ketogenic diets have observed possible benefits on some cognitive tests in people with Alzheimer’s disease, though these trials have limitations, including lack of control groups, small sample sizes, and variability in outcome.

In general, there is very little experimental evidence examining the effect of any type of dietary changes on Alzheimer’s disease, meaning it was unclear whether the overall diet in TEOA would provide benefit. Among the supplements, most appeared to have very little or even no evidence supporting the contention that they reduce the risk of Alzheimer’s disease, or improve existing disease. Some evidence exists for vitamin D and possibly context-specific use of certain B vitamins, though this evidence had limitations (see claim 1, criterion 1.1). Still, exercise and physical activity do show compelling, albeit preliminary evidence of benefit and observational evidence also suggests adequate sleep may be beneficial, at least for prevention. Patient case studies described in TEOA tested the effect of the complete plan, but this is low-quality evidence. The author has published some of these case studies, but for reasons detailed in the scoring section, we do not find these studies very convincing.

Overall, there was not enough evidence to say whether the program reduces the risk of Alzheimer’s disease or improves established disease. However, we note that this does not necessarily mean the program is ineffective.

Summary of the health-related intervention promoted in the book

TEOA recommends an extensive number of possible interventions. This includes exercise, adequate sleep, minimizing stress, taking various supplements, and eating a plant-based, mildly ketogenic diet. The book makes the following dietary recommendations:

• Majority of diet volume composed of various non-starchy vegetables
• Include fat from avocado, nuts, seeds, olive oil, and MCT oil (to help achieve ketosis)
• Aim to eat fermented foods and/or take probiotics
• Moderate amounts of meat (a few ounces per day) with preference to grass-fed/pastured meat
• Limited amounts of refined carbohydrates and saturated fat
• Avoidance of gluten and dairy
• Daily fasting (at least 12 hours, including sleep)
• Gentle cooking of food

The book also recommends a large number of supplements, some of which are only recommended in specific contexts.

Condition targeted by the book, if applicable

Alzheimer’s disease and age-related cognitive decline.

Apparent target audience of the book

This book is written for individuals, caregivers, and medical professionals interested in preventing, managing, or treating Alzheimer’s disease and age-related cognitive decline.

Criterion 3.1. Is the intervention likely to improve the target condition?

2 out of 4

The intervention received a score of 2, indicating that its effect on Alzheimer’s disease appears very uncertain. With respect to the treatment of cognitive impairment and probable Alzheimer’s disease (perhaps the main focus of the book), the large majority of recommendations made in TEOA appeared to lack evidence of their benefit individually. There did appear to be evidence for a few parts of the plan (e.g. physical activity, vitamin D, ketogenic diet), but these nearly all came from preliminary research that seems promising but requires further study.

The book’s author has published papers claiming to show evidence of the effectiveness of the program on cognitive decline. This research is cited as evidence of effectiveness of the plan. The most comprehensive paper covers 100 patients, all of whom are claimed to have benefited from treatment with the protocol outlined in TEOA. However, this paper has major limitations.

First, this article is published in a very-low-impact journal and is not available on the widely-used biomedical database PubMed. In and of itself, this doesn’t necessarily mean it’s not rigorous, but it’s a bad sign and it suggests that the Alzheimer’s disease research community is not convinced by the finding.

Second, this was a case series, considered a weak form of evidence. This type of study is usually viewed as a starting point for research rather than an endpoint. In this particular case, we don’t know how many patients were included in the paper, and how many were excluded. 100 patients improving sounds like a lot, but how many patients didn’t improve and were excluded from the paper? None? 100? 1,000? This has a large impact on how we interpret the findings. Second, this type of study doesn’t have a control group and doesn’t randomize people to different groups (as in a gold-standard randomized controlled trial), which makes it harder to come to firm conclusions based on its findings.

Third, given the lack of randomization and a control group to compare with, we can’t rule out the possibility that some cases would have improved without intervention. This may seem unlikely given the typical pattern of decline in Alzheimer’s disease, however many patients didn’t have an actual diagnosis of Alzheimer’s disease, but rather mild cognitive impairment. This means that health conditions other than brain degeneration could have been responsible for their condition, and these may be more likely to wax and wane. Furthermore, if a person is given a particular cognitive test repeatedly, they’re likely to improve on it simply due to practice, so an increase in score may not reflect an actual improvement in cognitive ability. Control groups are typically used to rule out effects like this.

Fourth, the paper doesn’t provide much evidence that the program improves objective markers of Alzheimer’s disease. A number of patients did have tests indicative of Alzheimer’s (e.g. PET scans) and in such cases cognitive tests appeared to be the most common method of assessing improvement (e.g. MoCA, MMSE, and SLUMS). Many of the improvements did appear impressive in the context of Alzheimer’s disease, but it remains to be seen if this represents a true and sustained reversal. Only 4 of 100 cases were noted to have experienced improvements in objective measures of disease pathology. Three cases experienced some degree of improvement in an EEG reading of their brain. However, none of these cases had a positive Alzheimer’s disease diagnosis. One case which did have evidence of Alzheimer’s disease experienced an increase in hippocampus volume, but at 1 case out of 100 patients, and an unknown number of additional patients not included in the paper, this effect is of unclear significance.

Overall, the findings in this paper are intriguing, but until a randomized controlled trial is published in a reputable journal supporting the TEOA program, the evidence of its effectiveness remains uncertain.

It’s important to distinguish between two different claims the book makes. The first is that the protocol can improve cognition in the context of cognitive impairment–this seems within the realm of possibility, though overall the evidence is weak. The second is that the protocol can reverse the brain damage underlying Alzheimer’s disease. This is a higher bar and seems poorly supported by current evidence.

Criterion 3.2. Is the intervention likely to improve general health in the target audience?

3 out of 4

The intervention received a score of 3, indicating that it is likely to moderately improve general health. Many characteristics of the diet (low carbohydrate, limited refined carbohydrates, emphasis on vegetable intake) seem likely to benefit cardiometabolic health based on results from clinical trials. Additionally, some of the major components of the diet (leafy greens, crucifers, nuts and seeds) are frequently associated with various positive health outcomes.

However, a diet is arguably only beneficial if it can be followed and some may find adherence to the diet difficult. Beyond its restrictions on various processed foods, the diet also advocates complete avoidance of dairy products, wheat (both refined and whole grain), tropical fruits (e.g. mango and pineapple) and limits grains, starchy vegetables, and meat (the latter to 2-3 ounces per day). A daily 12-16 hour fast is also part of the dietary plan. While some may find this all easy to adhere to, others, perhaps especially those experiencing cognitive impairment, may struggle to adopt the diet.

Finally, numerous supplements are recommended and a few seem uncertain in their safety. As an example, TEOA recommends supplementing vitamin E at a dose of 400-800 IU’s per day, though evidence from clinical trials suggests this may increase the risk of dying (albeit modestly). And while TEOA recommends vitamin E as mixed tocopherols and tocotrienols rather than the a-tocopherol form used in all long term clinical trials, whether this removes the risk is uncertain. Another supplement recommended in TEOA comes from a plant known as skullcap. Several case studies have noted a possible (though not definitive) connection between skullcap supplementation and liver toxicity. It’s also worth mentioning that the cost of all these supplements may be substantial, and that Bredesen’s company Apollo Health sells some of them.

Criterion 3.3. Does the diet portion of the intervention promote an adequate nutrient intake for general health in the target audience?

4 out of 4

The diet received a score of 4, indicating it is likely substantially more than nutritionally adequate. Upon examination, someone following the diet recommended in TEOA seems likely to achieve an adequate intake of most vitamins and minerals and any shortcomings would likely be met by the various supplements recommended. Additionally, intake of various non-essential nutrients would also be notable, either from foods or supplements.

Overall (average) score for healthfulness

3 out of 4