Abating Risk of AD
Dementia seems to appear out of nowhere. People feel like helpless victims of their genes. But this is a misconception. How much does the dreaded ApoE4 gene increase your chance of getting dementia? This is not a straightforward calculation precisely because the correlation must be controlled for many diet and lifestyle factors that are proving to be just as important as genetics. For women with ApoE4 from one parent, risk of AD is doubled, but this factor is easily reclaimed with diet, exercise and supplements. For men, the effect of one copy of ApoE4 is small enough to be lost in the noise. For men and women with two copies of ApoE4, risk of AD is very high, but even here factors under your control offer hopeful remediation.
I confess that I love public attention. For a long time, I thought of this as a personal failing, and consciously avoided pursuing publicity. When I came up with radical notions about evolutionary biology and the direction of medical research, I counted on people to think for themselves and evaluate the evidence; if they looked only at the credentials of the theorist, I was seriously outgunned.
Reputation shouldn’t matter, but it does Only in the last decade, I have come to realize that people are receptive to ideas from those they already trust, and skeptical of ideas that come from an unknown source. I’m learning to burnish my reputation…
So when I got an inquiry from a CBS news intern asking “What can we do to improve our odds of avoiding dementia?”, I set aside time to review the literature before I talked to him. Here’s what I found.
Exercise is most important
Five areas that I investigated are:
- Physical exercise
- Mental stimulation and social factors
- Metabolic syndrome / insulin sensitivity
- Brain-targeted drugs and supplements
As I set out on my quest, I was prepared to find that #2 was the most important. For longevity, social connections are more important than anything else; and I reasoned that for keeping the brain healthy in late life, this should be even more true. But I was surprised. #2, mental stimulation and social factors are effective in some studies but not others. The clear winner in the literature is #1. There is robust evidence that physical exercise lowers your risk of dementia. Here’s a meta-analysis from 2011 and a review from 2017. Modest amounts of exercise are way better than being a couch potato. There is some extra benefit from being a gym rat, but there are diminishing returns with intensity.
Social connection and intellectual stimulation
The most positive study connecting social factors with a slowing of cognitive decline was in 2001. A team from UCLA followed 1200 men and women over 7.5 years, and concluded that, among social factors, “emotional support” was the most important factor.
But in subsequent studies, the importance of emotional support faded. In a review in 2010, no social variables made the list of protective factors. And this 2016 study found social connectivity to be connected to base levels of cognitive function at midlife but not to 20-year change in cognitive performance.
The MIND diet
Of several diets that have been tested for neuroprotective benefit, the MIND diet, developed by Martha Morris of Rush University in Chicago seems to be the best documented. In the only test so far, Morris claims it can cut AD risk by 50%. The M in MIND is for Mediterranean, of which the MIND diet is a variant. Start with lots of leafy greens, berries and nuts, fruits and vegetables, olive oil, whole grains and fish for protein and omega 3s. The MIND variant emphasizes blueberries and walnuts, which seem especially good for the brain. [Details at WebMD]
Habitual coffee drinking is associated with a modest decrease in risk , but tea, especially green tea is better . This study  found a factor of 2 benefit for the heaviest tea drinkers in Japan. Caffeine seems to be moderately neuroprotective , but the best benefit comes from catechins=polyphenols, for which decaf tea works as well.) Green tea is part of the MIND diet.
Beginning 20 years ago, a strong association was found between metabolic syndrome and AD . Insulin treatments seemed to worsen the risk  — indeed, excessive insulin seems to be at the heart of the connection. Some people started saying we should think of AD as type 3 diabetes. Metformin is the standard treatment for diabetes, and this study  found that taking metformin brought the risk of AD in diabetics back down to a rate comparable with age-matched non-diabetics. But this study  found that taking metformin actually increases risk of AD. A strong hypothesis is that metformin uses up vitamin B12. B12 is essential for functioning of neurons, and is concentrated in the brain. Many people are deficient in B12 even without metformin, and anyone taking metformin should be supplementing with B12. Whether there is residual risk of AD from metformin even with B12 remains to be seen, but probably it’s not just people on metformin who should be supplementing with B12 [2014, 2015]. Low protein diets are protective for many aspects of aging, and the MIND diet is mostly vegetarian. B12 is one essential nutrient that can’t be derived from vegetable sources.
Drugs, Hormones and Supplements
The most common pharmaceutical approach is to enhance the neurotransmitter acetylcholine. Acetylcholine is found wherever nerves are found, for cognition, sensation and motor control, and it seems especially imortant for memory. Alpha GPC (glyceryl phosphoryl choline) is an acetylcholine precursor which can be taken orally. In this study , 132 AD patients taking Alpha-GPC tested better after 90 and 180 days than at the outset, compared to worsening in those taking placebo. Whether A-GPC is nootropic or neuroprotective is less clear. Here is a bibliography from Examine.com.
I’ve been slow to recognize the potential of angiotensin receptor blockers (ARBs), prescription drugs which seem to be a new class of age-slowing drugs which I have not discussed previously. The best known is Losartan. This study  found a 25% reduction in AD. And in studies with rats, ARBs increase lifespan . They work by relaxing the arteries, lowering blood pressure, relieving in the process the risk of all cardiovascular diseases. The trouble with ARBs is that people don’t like them. Some people feel lethargic, weak and unmotivated. Some people cough. Telmisartan is supposed to be the drug in this class with the least side effects.
Both male and female sex hormones are protective against dementia . A modest way to get this benefit without taking sex hormones is by supplementing with DHEA. DHEA levels decline with age, and serum DHEA is lower in AD patients, suggesting but not proving that DHEA might be protective.
Pregnenolone is another hormone precursor, and in fact the body makes DHEA from pregnenolone. As with DHEA, we have less pregnenolone as we get older. Studies with mice have found pregnenolone leads to increased memory retention in the here and now. Evidence that it is neuroprotective is lacking.
Poor sleep quality, sleeping more than 8 or less than 7 hours per night, and sleep apnea are all risk factors for dementia . The effect is large, but the data is thin. Sleep is commonly disrupted in AD, with melatonin levels that are low and not synched to the circadian cycle. Melatonin supplementation is a natural thing to try, and there has been some limited success with melatonin as a treatment for AD [2010 review]. I found no data on whether it helps as a preventive, but sleep-inducing pharmaceutical alternatives are associated with increased risk.
These supplements are reported to be neuroprotective or nootropic or both. It’s interesting to me that there is an overlap. We don’t have to choose “now or later”, but can have our cake and eat it, too.
|Primarily nootropic||Primarily neuroprotective|
Lion’s Mane Mushroom
Nigella sativa (=kalonji=charnoucha)
Omega 3 fatty acids
Alpha lipoic acid
Hope for the doubly unlucky
One person in 50 has two copies of the ApoE4 gene. Age-adjusted risk of dementia is more than 10 times higher for both male and female. For these folks, there is a theory  that keeping blood cholesterol low can completely ameliorate the risk. The theory comes from a mechanistic analysis and extrapolates from the odd fact that Nigeria has the highest prevalence of ApoE4 in the world, but there is no elevation of dementia. More recent  is speculation that ApoE4 carriers need much more omega 3 than the rest of us.
My favorite Alzheimer’s study comes from Dale Bredesen at Buck Institute , who offered intensely personalized treatment protocols to ten Alzheimer’s patients, and dramatically improved cognitive performance for 9 of the 10. This is a stunning example demonstrating what medical science is capable of when institutional barriers are removed and clinicians have time to work with patients individually.
Bredesen’s work offers incidentally the hopeful possibility that the benefits of some of the measures I have described are cumulative, and that with carefully crafted individual programs they can be combined to push Alzheimer’s risk back many years.
and all>>> anyone who is interested in this topic should really check out my book about Alzheimers…Josh found one abstract about limited success with melatonin as helpful for Alzheimers it was a paper by Brazilian researchers ..It was very understated..these are the same researchers who monitored two identical twins who both got Alzheimers at the same age..one took 6 mg of melatonin at night the other didn’t (for sleep)…after a few years ..The melatonin taking twin DID NOT PROGRESS and remained at stage 5 where he just needed help picking out his clothes in the morning. The twin who did not take melatonin progressed to stage 7 in just a few years, could not hold his head up, vocabulary decreased to about 7 different grunts and he could not control his bladder or bowel.
Josh’s favorite study from the Buck Institute included taking MELATONIN every night…
And a recent study in a mouse model of Alzheimers showed that mice did not get Alzheimers if they exercised and took melatonin.
One effect of melatonin is that it suppresses the age related increase in Luteinizing Hormone (LH). The NIH awhile back declared that LH was intimately involved in causing Alzheimers. Confirming quite a few prior studies.
A company was formed in early 2000’s called Voyager Pharmaceuticals where they used Lupron which suppresses LH to treat patients recently diagnosed with Alzheimers. After 6 months of treatment a group of 50 women did not progress, while the 50 controls continued to decline.
The company did not survive after it was found it does not work in men whose LH levels are only about 1/10th that of women.
I and others have suggested that Alzheimers in men is caused not by an increase in LH but rather by a decline in the highly neuroprotective hormone progesterone.
Melatonin also boosts progesterone production in men and women.
This is probably why smoking seems to be protective against Alzheimers in women because nictotine suppresses LH, but also seems to promote Alzheimers in men, because it also suppresses progesterone.
Also, pregnenolone is the direct precursor to progesterone and it declines with age. I have found by testing in a younger man that eating 3 table spoons of coconut oil for a month boosted his pregnenolone levels by 250%! This is likely the reason for the large number of books on the market claiming that coconut oil reverses Alzheimers disease….First discovered by a female doctor who gave coconut ol to her afflicted husband- I think her book is titled “What if there was a cure?”
It’s all in my book>>> ALZHEIMER’S TREATMENTS THAT ACTUALLY WORKED IN SMALL STUDIES! (BASED ON NEW, CUTTING-EDGE, CORRECT THEORY!) THAT WILL NEVER BE TESTED & YOU WILL NEVER HEAR ABOUT FROM YOUR MD OR BIG PHARMA ! availble at Amazon
Josh you should read it!
Thanks for all these suggestions! I would have had an easier time with my literature search if I had started with your book.
If I’m less enthusiastic than you about some of the remedies you recommend, it is because I am sticking to the cases for which there are controlled trials or large epidemiological studies. I agree with you that some of the most promising remedies have not attracted enough support for such trials, and we should do all we can to advocate for testing these unprofitable, orphaned supplements that have high potential for good.
Great post – as ever. Could we quote you on our UK ageing blog? http://www.kaleandcocoa.com
Thank you once again Josh for a very interesting read.
Josh, I enjoy and benefit from your data driven log plus value your editorial and occasional personal comments. Thanks for the service. I joke with my wife that were I to write a blog I would wish it to have similar content and style as what you write. However being now 69 and in joyful pursuit of ballroom and tap dancing, plus trying to be the husband and friend I always wanted to be, I read yours with great interest interest and pleasure.
Thanks, John. I’m not too far behind you at 68, but hoping there’s time for (at least) one more career. After I’m done with aging science, I want to study quantum biology.
It has been very well established since 2010 that rapamycin prevents Alzheimer’s disease in mice models of Alzheimer’s disease if started early. The best review paper is “How longevity research can lead to therapies for Alzheimer’s disease: The rapamycin story.”Arlan Richardson 2014. All the studies come out of Galvan group and Oddi group in Texas.
Rapamycin prevents a half dozen pathways involving amyloid beta, Tau and cerebral vascular impairment which lead to dementia of Alzheimer’s disease.
There is one catch, money. Prevention of Alzheimer’s disease is a huge prize for Big Pharma worth many Billions. That prize can only go to a NEW brand name drug, not a cheap generic like rapamycin; so zero clinical studies with rapamycin in humans.
ApoE4 is major risk factor. Anybody with history of Alzheimer’s disease in family should have genetic test for ApoE offered at “Life extension” for $120. they are only ones offering test I could find.
My suggestion: Be tested for ApoE4, if positive for ApoE4, start reading papers about Rapamycin and Alzheimer’s disease. Note: rapamycin only PREVENTS Alazheimer’s disease in mice, once disease well established with plaques and tangles, rapamycin no help; so must start early. However, some studies suggest that even in early stage of MCI (mimimal cognitive impairment) rapamycin might help.
The failure to do clinical human studies of rapamycin for prevention Alzheimer’s disease is a failure of medicine of the highest degree.
Alan Green, M.D.
Thanks for the information about data with the mouse model. I agree with your sentiments about the politics of medicine. The US system is about to collapse of its own weight, and people like you and me should be ready with a better proposal when it does. In my mind, one key element would be that clinical trials are performed by university or government labs, not by the very companies that have a powerful interest in the outcome. Another key element would be single payer insurance.
“Preventing Dementia” is very important paper by Josh and he did very well to start with ApoE4. Here is quote from “Apolipoprotein E and Alzheimer disease: risk, mechanism, and therapy” Li, 2013 a combined paper from China and Mayo clinic. “The frequency of AD and mean age of clinical onset are 91% and 68 years for E4 homozygotes, 47% and 76 years of age for E4 heterozygotes and 20% and 84 years in E4 noncarriers.” So for heterozygotes not only is risk 47% compared to 20%; but age of onset is 8 years sooner. ApoE4 also factor in atherosclerosis. ApoE4 is prime suspect in mechanism of disease in AD and damage to cerebral micro circulation. Even when ApoE4 carriers, don’t develop AD; they still have high frequency of memory impairment starting @ 60 years of age.
The Alzheimer’s association have a disinformation campaign about risk of ApoE4. The policy is to prevent panic. My belief is if you have family member with Alzheimers you should find out your ApoE status. If you are carrier for E4; you should panic; and after the panic take steps to prevent AD.
Preventing AD is about decreasing mTOR and increasing autophagy. The things that Josh mentioned as most effective, exercise and low protein diet are ways to decrease mTOR. High insulin levels which Josh mentions as very bad is major driver of high mTOR.
One thing Josh and I are in complete agreement about is the importance of exercise. Josh is still running half-marathons in very respectable times and I plan to cycle 1000 miles month of June. Alan Green, M.D.
Hello, I think if you take the 23andme.com DNA test, they can give you all your health related genetic info again (it was temporarily banned for a year or so by the FDA)…and I think it only costs $99 and it gives you A LOT of genetic info and calculates your risk of getting Alzheimer’s and a huge number of other diseases
A much better value than a $120 test for a single gene
AND it also gives you the fun stuff like your entire genetic family tree, and even how much Neanderthal DNA you have!
True, I’ve done it, the 23andme service is very good and includes diseases risk factors such as AD and Parkinson’s, plus you can access the raw data to look up more specific stuff.
Phlebotomy to lower iron has been suggested for the prevention and treatment of Alzheimer’s disease. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2732125/
One way that iron may lead to Alzheimer’s is through the promotion of bacterial and fungal growth in the brain. Iron is a limiting element in microbial growth. http://roguehealthandfitness.com/does-fungal-infection-cause-alzheimers/
I had no idea. Just like phytoplankton in the ocean!
Cautionary notes on Piracetam: Joseph Cohen reports caveats and side effects associated with adverse effects worth a read to prevent potential long term deleterious effects.
This is such a well researched and realistic perspective. We would love for you to feature as a guest writer on our blog. Please get in touch if this is something that you would be interested in – firstname.lastname@example.org
Thanks for writing this blog and thanks to the intern who asked the question about preventing dementia. You found the most widely publicized ways to prevent dementia. Yes topping the list: aerobic exercise, aerobic exercise, aerobic exercise, followed by diet and sleep. I am glad you found Dr. Bredesen’s work. I wish his work was available to more people.
You can add cardiovascular health, preventing head trauma, drinking in moderation, not smoking, as lifestyle choices which will reduce a person’s risk of dementia.
My husband who is a skeptic, a scientist, chemist and retired began searching the internet to find a treatment for Alzheimer’s as his mother has Alzheimer’s. He thought he would find ways to help her very quickly. His search took him several years (remember he is retired). What he learned helped slow the progression of the disease for his mother. In addition, the information he found was so important he was compelled to write a book. The book is scientifically based citing around 600 scientific papers. The book is titled Prevent Alzheimer’s Autism and Stroke with 7 Lifestyle choices, 7 Supplements and a Dissolved Mineral. The introduction and first 2 chapters are available on his website: http://prevent-alzheimers-autism-stroke.com/index.php/chapter-1/
I wanted to reach a larger audience so with the help of our local community access TV station we made 2 videos. The title of the videos are:
Brain Fitness in the Aluminum Age – Preventing Alzheimer’s
Brain Fitness in the Aluminum Age – Eliminating Aluminum
Before you can find ways to prevent or treat a disease you need to know the cause. Research has reached a tipping point and a cause of Alzheimer’s is known, Aluminum which is a known neurotoxin.
Thank you Josh for an intelligent post. May I ask your opinion on the role of magnesium status of a person and the risk of developing dementia ? Magnesium seems to be a very important factor in brain health. Thank you.
There are lots of good reasons to supplement with Mg. Perhaps most important is its role in maintaining insulin sensitivity.
Here is a recent review of the epidemiology. There is indeed an association between lower Mg levels in the body and higher AD risk. But it’s not eye-poppingly strong, and my guess is that it is mediated through insulin sensitivity. In other words, Mg helps avoid metabolic syndrome, and metabolic syndrome contributes mightily to the danger of Alzheimer’s.
Josh, if you were to design a study for tracking and/or studying anti-aging efforts, I’d love to participate, including design and analysis.
I would urge caution in using the Nigeria study as an example. This particular study has been politicized by some to say things it doesn’t say. A 2014 follow-up by the same authors said this (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012422/):
“After adjusting for covariates, one or two copies of the APOE ε4 allele were significant risk factors for incident AD (p < 0.0001) and cognitive decline in the African-American population (p < 0001). In the Yoruba, only homozygosity for APOE ε4 was a significant risk factor for AD (p = 0.0002) but not for cognitive decline (p = 0.2346), however, possession of an e4 allele was significant for both incident AD (p = 0.0489) and cognitive decline (p = 0.0425)."
Basically the E4/4 effect is the same in Nigeria and US, but E3/4 in Yoruba is the same as E3/3, while E3/4 in U.S. African-Americans is intermediate between E4/4 and E3/3. The Yoruba diet may be particularly protective in E3/4 and the American diet is quite bad for E3/4.
Lewy Body dementia runs in the men in my paternal family. Is the ApoE4 gene or any of the other info regarding Alzheimer’s relevant?
small comment from a lay men. Some years ago I watched a video about the Axolotl regeneration from sens.org at youtube. At the end of the video they also talk about AD and that retinoic acid is lower in people with AD.
so maybe supplementing with Vitamin A could also improve AD
Been reading for awhile, 1st time posting.
This post about dementia prevention is much more in depth than my recent one on the same subject. In retaliation for your oneupmanship, I’ve added a link to your (this one) post at the end of mine. Hope you don’t mind…
Tried to put some links up to studies regarding Intranasal Insulin treatment for AD but neither one showed up.
In the randomized double-blind, placebo-controlled trial led by Dr. Suzanne Craft, the investigators studied 104 adults who had mild cognitive impairment (MCI) or were in the early to moderate stages Alzheimer’s disease (AD) (1). The subjects were treated with either a placebo, or one of two doses (20 – 40 IU) of intranasal insulin. At the end of a 4-month protocol, memory and cognitive performance were assessed to objectively determine if the intranasal insulin treatments were effective, and whether the effects were insulin dose-dependent. The investigators found that subjects who received the lower insulin dose had significantly improved performance on memory/recall tasks compared with the placebo group, and that subjects who received either of the intranasal insulin doses had better preservation of cognitive function based on standardized ADAS–Cog and ADCS–ADL scales. In a limited number of subjects, cerebrospinal fluid (CSF) was obtained to examine the effects of intranasal insulin therapy on typical biomarkers of AD, i.e. Aβ42 levels and Tau–to–Aβ42 ratios.
any opinion concerning nicotine to prevent AD ?
Have seen a study which indicated using the nicotine patch increased the memories of those with early signs of AD. Other studies indicate nicotine alters amyloid proteins so that fewer plaques can form.
HI there Jack>
i cover this question in my bookabout Alzheimers treatments that worked in small studies but you will never hear about>>Jeff T Bowles , on Amazon
Oddly there are studies that suggest nicotine protects against alzheimers but then there are some that say it accelerates it like in the Finland Male smokers study. The bottom line that I am coming up with and will confirm one of these days is that smoking and nicotine are very protrective for women for Alzhiemers as it suppresses LH which has been shown to be invloved in promoting/driving AD by the NIH..
But here is the weird twist, while it is very protecticve for women, it promotes alzheimers in men! Why? because it also suppresses progesterone which is highly neuroprotective.
LH attacks the brain at high enough levels which women have (about 10X that of men’s LH levels) while progesterone protects the brain . Progesterone decline is a more important factor in driving AD in men than LH increase!
All I have to do is to look into the studies where nicotine was protective and see if it had a lot of women and compare to the studeis where nicotine exacerbated AD and see if the studies contain mostly men… Maybe you can do it!!??
Oh one more thing
I have a friend with a mother with Alzheimers, and I suggested he have her chew nicotine gum
He said he noticed a big imjprovbement in her within 3 days!!
Search for ‘new-role-major-alzheimers-gene-identified’
This is the begining of the end for Alzheimer’s.
Posted by Josh on behalf of Alan Green:
I just published new website aimed at providing APOE4 carriers with update of very exciting new developments since 2010. There are 20 million APOE4 carriers in 40-70 age group who are extremely vulnerable. Main two sections are Mouse studies and Basic science. The most important mouse study was 2015 study in which rapamycin prevent AD like pathology in transgenic mice with human APOE4 genes. PET scans on APOE4 carriers show deterioration of cerebral blood flow in 20-39 age group, many decades before any symptoms and providing a large window for prevention. Basic science has revealed the specific defect in which ApoE4 causes AD in APOE4 carriers. On a molecular level, ApoE4 forms a very weak ligand with LRP1, a brain transport protein. This results in activation of CypA, a proinflammatory substance, which activates NF-kB (the usual suspect) which then activates MMP9 a proteolytic enzyme, which dissolves the protein junctions holding the cells together which maintain the BBB (blood brain barrier). Result is leaky BBB and impaired function of cerebral vascular system which leads to accumulation of amyloid. Amyloid-beta then triggers the familiar cascade including hyperphosphorylated Tau. Same finding regarding CypA, NF-kB , MMP9 and brain capillaries shown in human AD brains from APOE4 carriers. 8 very interesting studies in mice with human AD genes. [Spoiler alert: in each study rapamycin prevents the development of AD-like pathology and prevents cognitive deficits.] .
Hope to be able to collaborate with world leading expert to provide documentation with advanced neuroimaging that rapamycin ameliorates deficits in early stages and thus can prevent AD in APOE4 carriers.