#8

Hello Deborah,
Have you checked of your ApoE4 allele status? People with one or both are at an increased risk for AD.

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#9

Thanks for your responses. The paper that talks about the potential harms of RAPA after onset of AD is: “Rapamycin and Alzheimers Disease: A Double-Edged Sword?” published 5/22/2019 in Autophagy.

If you read it I would appreciate your assessment –

I am encouraged by your inputs that Rapa has actually helped after onset of disease.

No, I do not have the APOE4 phenotype – I am APOE3. My main concern is actually that I will live long but be demented, as my mother (age 97 today) is now, even though my health and behaviors are very different from hers.

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#10

@Deborah_Hall I took a look at the literature. Seems like you won’t get a clear answer because there just isn’t one yet. Human studies ongoing.

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#11

Yes. See our thread here: Rapamycin and Alzheimer disease: a double-edged sword?

Other discussion threads related to Alzheimer’s and rapamycin:

  1. Rapamycin and Alzheimer Disease: a Hypothesis for the Effective use of Rapamycin

  2. Fighting Alzheimer’s with Increased Autophagy via Rapamycin + Trehalose

  3. UT Health San Antonio gains $2M to study rapamycin for Alzheimer’s

  4. New Study: Rapamycin protects against Alzheimers in Mouse Model

  5. Intranasal Rapamycin Lessens Alzheimer-like Cognitive Decline in a Mouse Model of Down Syndrome

  6. Rapamycin increases Alzheimer's-associated plaques in mice, study finds

  7. A drug cocktail of rapamycin, acarbose, and phenylbutyrate enhances resilience to features of early-stage Alzheimer's disease in aging mice

  8. Rapamycin restores peripheral blood flow in aged mice and in mouse models of atherosclerosis and Alzheimer's

  9. Rapamycin and AD

  10. Mitophagy Activation by Rapamycin Enhances Mitochondrial Function and Cognition (New Study)

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#12

I would try this https://pendulumlife.com/products/pendulum-glucose-control-2-og

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#13

Definitely want to get the blood glucose under control: Diabetes, air pollution and alcohol consumption could be the biggest risk factors for dementia

And, it seems research may support the idea that you want to get the blood glucose well under control before you start rapamycin: People With These Health Conditions Should Not Take Rapamycin?

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#14

Indeed - Type 3 Diabetes - is essentially what many of us think is a substantial cause of late dementia. This is a different situation, potentially, than early dementia, which is multi-factorial, including ApoE4 positivity.
Insulin resistance and lack of proper utilization of glucose in the brain is likely a cause of some of the pathological changes in the brain with late Alzheimer’s Dementia.
I suspect this is why, diabetic drugs are having such strong signals as medications to decrease cognitive decline and probably also Parkinson’s Disease.
Other factors including solid use of the brain, include optimizing Omega 3 index, tight blood glucose/pressure control, management of stress/sleep/social connections, adequate whole food plant based diet for photochemicals/gut health, and adequate exercise.
It’s a big package to implement - and rapamycin is certainly part of the mix here - but it’s only part of a bigger lifestyle to obtain better health outcomes.
Those of us in the longevity medicine space advise our patients that only 15% of health outcome is genetics — 85% is life choices. This is a double edged sword, as so many people look at their elders and think that their parents living to 95 is relevant. Their exposures, diet and activity are often dramatically different. On the other side, people who have parents with huge comorbidities and death earlier in life - should be encouraged, in general - if their parents made very poor lifestyle choices (smoking, lack of proper management of medical conditions, sedentary, obese, etc) - that it is not going to be their health outcome if they manage their conditions and co-morbidities.

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#15

Are you aware of any independent data supporting this product?

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#16

Both from experience and from research available at PubMed, I strongly (that really should be all caps) recommend looking into taurine. In animals, it prevents or halts neurodegenerative diseases including Alzheimer’s and Parkinson’s. Last I looked, there were promising results in early human trials.

Experience: Two years ago, when I was 73, I began taking 2000 mg a day of taurine. Two days later, waking up was like waking up to a whole new reality. For some time, I had been forced to enter the first three digits of a six-digit security code and then look at the second half again. That problem was gone. Two weeks after that, I needed a 15-digit part number, read it twice, and still remembered it weeks later.

I also recovered cognitive abilities I had not been aware of losing. For some time, when faced with a minor difficulty in some minor chore, I had simply plodded on until it was done. Suddenly, I was automatically reaching for something nearby that would solve the problem–a paper, a bit of string, a spreading knife–whatever was handy and none of them used for their original purpose.

Owing to that research on lifespan a year or so ago, I now take 5500 mg per day at 160 lb weight. That is how the standard animal-to-human conversion came out. Adjust as required.

Strongly recommended.

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#17

Thank you for this. Have been taking a low dose of Taurine but will increase and start my husband on it as well.

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#18

Below is a new review on composition of drinking water and incidence of cognitive decline in the elderly. Alkaline water and silica may be protective. Silica may also reduce absorption of aluminum. Perhaps avoid acidic beverages like soda in favor of alkaline teas.

Both alkaline water and organic silicon may have general anti-aging benefits per animal studies as well. I take an orthosilicic acid supplement in my daily collagen drink. Promotes collagen synthesis, improves nail quality.

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#19

No independent data yet, I don’t think. But some confirmation from people (anecdotal)… discussed here: Akkermansia mucciniphila improves healthspan and lifespan in old female mice - #3 by Pestodude

#20

I work with Alzheimer’s patients, am one of the authors on the Precision Medicine Trial published 8/22. The biggest contributors to AD for ApoE3/3 women are insulin resistance and failure to replace hormones (bio-identically) @ menopause. Toxins also play a role, especially mold and Lyme. Lab Corp now has an even better test, ATN panel with measurements of amyloid beta, pTau, and Neuofilaments.

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#21

Hey there!

I had a very bad experience with the Quest test. The results came back “bad,” which completely freaked me out. I made massive lifestyle changes, including looking for clinical trials to join.

Fortunately, I found one, called the AHEAD trial, that gives you some sense of what their screening tests show (not always the case). After more extensive testing through them, they told me I did not qualify for their trial, which I interpret to mean that my results aren’t as bad as shown in the Quest test.

I had a discussion with the investigators about how their results could be so different from the Quest results and how it had upended my life, which ended with them saying, “That company is going to get sued.” My understanding now is that the test results don’t correlate well with actual progression to dementia. “Bad” test results don’t mean much in practical terms.

As an aside, the Quest doctor who went through my scary test results with me on the phone was absolutely worthless. First, he told me the results were the opposite of what they actually were because he was reading it wrong, and second, he answered every question with “You’ll need to talk to your doctor about that.”

But there is actually a better test that just became available that researchers seem to think is more predictive called the p-tau 217 test, which I’m thinking about getting (because all the lifestyle changes that might prevent or delay Alzheimer’s are freaking hard and time-consuming, so I don’t want to do them all if I don’t need to).

If you want good information about preventing Alzheimer’s, I recommend this forum for people who have the APOE e4 allele (which raises genetic risk): https://www.apoe4.info/

Dale Bredesen’s book “The End of Alzheimer’s Program” is also good. (He recommends many tests, but I found out after I took the Quest test that he doesn’t recommend that particular test.)

Good luck! I know that fear of watching close relatives go through Alzheimer’s and wanting to do everything you can to avoid it.

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#22

Thanks for the post - sorry to hear about the roller coaster. May I ask what battery of lifestyle changes you made?

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#23

Sure, none of them alone are that hard. It’s just doing all of it that becomes taxing.

  1. Following a strict “healthy” keto diet. This is mostly fish, vegetables, and berries with lots of high polyphenol (read “expensive”) olive oil.

  2. Doing aerobic exercise 5 times a week. I did a mix of HIIT and regular aerobics.

  3. Weight training every other day.

  4. Meditating every day.

  5. Walking every morning outside for ~30 minutes.

  6. Flossing twice a day.

  7. Making sure I move at least once an hour and don’t just sit at my desk for hours.

  8. Making sure I always get enough sleep. (This is one of the most important things and was hard to achieve, but easy to keep doing once I figured it out. We put blackout curtains in our bedroom, and I take melatonin plus a big dose of tryptophan (2g) right before bed.)

The following are all just ways to challenging the brain with new and different activities:

  1. Upping the time I spend learning Spanish.

  2. Playing the piano.

  3. Daily Brain HQ games. (These have some data behind them for AD prevention, but I hate them. They are hard, and they were the first thing I quit when I wasn’t so scared. “Games” is a misnomer! When I mention this to people, they often say something like “Oh, I do crossword puzzles.” It is nothing like that.)

  4. Actively trying to have more social interactions with people.

  5. Making sure I smell a lot of different scents every day. (This probably has the least evidence of being helpful of anything I did, but it’s also easy.)

I think these are the big things off the top of my head. They aren’t everything you could possibly do (some people do sauna, exercise while breathing oxygen, etc.), but they are what I felt I could do.

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#24

Very helpful. Thanks a bunch.

#25

I think your list is good, but it is certainly impractical for me to do many of the things you mention.
Unfortunately, genetics plays a big role. The number of things on your list that you must do probably depends on your genes.

“Early-Onset Alzheimer’s Disease
Caused by mutations in APP, PSEN1, PSEN2 genes
Autosomal dominant inheritance
Symptoms develop before age 65
Late-Onset Alzheimer’s Disease
APOE e4 allele is the strongest known genetic risk factor
Over 20 other genetic loci associated with small increases in risk
Heritability estimates around 60-80% for late-onset A”

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#26

Its interesting… Alzheimer’s risk in men is significantly lower than females. And, if you don’t have the APEO4 allele, and none of the other major risk factors (e.g for dementia; diabetes, alcohol, air pollution) I suspect your risk is extremely low. I’m not sure I’d worry about it.

The average 65-year-old man, for example, has a 6.3 percent risk of developing AD during the remainder of his life while the risk for a 65-year-old woman is 12 percent, nearly twice as great. There is still uncertainty about whether this is because women live longer. Sex-related effects help to lower men’s risk. One way that sex affects risk is through the male hormone, testosterone. Some testosterone is transformed into estrogen, and estrogen seems to protect healthy brain cells. Men in later life do not experience the massive decrease in estrogen levels that women do after menopause, and that may reduce men’s risk for AD. Sex also affects the danger of various risk factors. One of these, the E4 version of the apolipoprotein gene, referred to as ApoE4, is a less potent risk factor for men than for women.
Source: Alzheimer’s Disease in Men | BrightFocus Foundation.

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#27

What about apoE4, heterozygous? Humor, if you will, my n=1 case.

I’ve known about my 3/4 status for 15 years but never took it too seriously until recently because one of my grandmothers who got some very mild AD before she passed in her 80s seemed mildly cognitively impaired ever since I could remember and she wasn’t otherwise healthy either, nor very smart to begin with. My other grandmother passed at 99 with only a year or two of mild cognitive impairment and she had been a paragon of ill health for life — no physical activity, overweight, frail, diabetic, poor diet, the works — and right up to the very end she had a mind sharp as a razor. Both of them apoe3/4.

I don’t have credentials to show for it and if I weren’t anonymous I’d be too embarrassed to put this in writing, but I’ve always had a mind like a diamond — was identified as a sort of child prodigy, with a measured IQ of 140. At 12 I was reading War and Peace for fun, won several international awards through my teens for fine art productions, was competitive in math meets, published poetry in my home country and someone with whom I spent a couple of weeks at 17 and hadn’t since since, recently reminded me I was casually quoting Schopenhauer. English I only learned in my late teens but at such a level that at some point I had a gig as an editor at a prestigious magazine correcting finer points of usage and grammar in the native English speaking Ivy League literary types who wrote for us. My old boss used to joke that I could pick up the violin over a weekend if I felt like it (though the one thing I’ve never been is musical). But I’ve always been learning something new and eclectic on the side as I seemed to always have extra mental bandwidth that needed channeling. Anyway I’m going on and on not to toot my own horn but to paint a picture.

Fast forward to the present, and I feel like the diamond tip is shattered. It started with the proverbial baby brain since I first got pregnant at 25 and the mental fuzz would wax and wain over the following few years with four back to back pregnancies. Overall the effect was very mild though. When I thought I was done, in 2019, I went on rather strict keto and a serious exercise regimen and toward the end of the year was starting to feel like my old self again. But then caught mono and experienced for the first time true brain fog — cognitively demanding tasks almost made my head hurt. It was a slow recovery over a few months then COVID caught me by storm — after 2 years of unprecedented stress my brain seemed to settle in a suboptimal equilibrium state.

Last year I cleaned up my act again, was on and off of ketosis with very clean eating overall, but very little exercise too other than long walks (it’s my Achilles heel). Got serious about supplements and went on rapamycin too. All this seemed to help although it turned out I was probably getting very little Rapa as I opted for a cheap Indian product that was lately discovered on this forum to increase sirolimus blood levels very little. But my mind was sharpening and I was starting to look great too. Then BAM! — got pregnant again and I feel like baby brain has never been this bad. I have plenty of “mental reserve” to compensate for it outwardly, but on the inside it feels like scrambled eggs up there and it’s a terrible feeling for someone like me, whose lifelong source of inner pride and self esteem was to dance circles around anyone, no matter how smart.

I get forgetful of what I was about to do next, or what I might have just found out. It doesn’t help that my organization skills are piss poor as I’ve always relied on infallible memory. Sometimes I struggle for the word I’m looking for even when it’s nothing complicated — there’s a little delay between when I need it and when I can retrieve it. I’m a US immigrant and English is my 3rd language so maybe my brain is changing in ways that affect the most recently acquired language (meaning maybe I wouldn’t be experiencing this if it were my native language) but the fact that it’s happening at all gives me pause. Also learning difficult things effortlessly, something people used to marvel at my ability of, is now a lost superpower. I’ve been working on teaching myself Latin and Attic Greek and, oh my God, it is hard! I’m making some steady but embarrassingly slow progress in Latin but the Greek just hurts.

I’ve read about the changes happening to the hippocampus during pregnancy and it honestly reads a lot like early, preclinical AD. What is not commonly known because presumably we wouldn’t want to freak out would-be mothers or further depress the abysmal birth rates is that many of these changes are actually long lasting, some perhaps permanent. Also it appears that 5 or more pregnancies are associated with greater odds of dementia perhaps due to the reasons above or due to the dramatic increase in overall estrogen exposure. This being my 5th pregnancy I’ve already seemingly put myself at a higher risk category.

What has changed for the better is I’ve started to make biohacking one of my eclectic interests and know a lot more today about how to optimize my health than I did even a year ago. However, the more I go down the ApoE4 rabbit hole the gloomier things look. PubMed is teeming with articles delineating interventions that are effective both in humans and animal models of AD — but only in non ApoE4 carriers. I’m reading so much that I’m starting to develop my own intuition on the matter, which is that for at least some of these interventions, the lack of response among ApoE4 carriers actually means they didn’t get enough of the dose or they weren’t followed up with long enough. One example is the role of Omega 3 PUFAs — healthy apoE4 carriers in their 30s (people like me) actually displayed a much higher uptake of DHA probably as a compensatory mechanism, so they likely need supplementation at a much higher level than those studied in order to make a dent. Meaning it’s likely not the case that fish oil supplementation is ineffective for us, it’s that we need a lot more of it to make a difference.

The same might be true of ketogenic interventions. They appear largely ineffective for apoE4 carriers in meta analyses and large studies but the few n=1 interventions I’ve seen in the literature of specific subjects being put on a strict keto regimen seem to work — perhaps because they’re stricter, happening under medical guidance and supervision, compared to the looser self directed dieting being assessed via questionnaires, etc.

ApoE4 is the oldest variant among the three, and is probably the evolutionary product of living conditions in hunter gatherer societies where ketosis was the default metabolic state and high cardio output a daily fact of life. So between those conditions and the likelihood of surviving into old enough age for Alzheimer’s to kick in, slim, it was good enough.

Strict keto seems like a must — a necessary condition for staving off dementia, but probably not sufficient.

What else works to move the needle for us ApoE4 folks? All the fancy interventions I’ve researched, from hyperbaric oxygen to hypoxic training seem to all come with the apoE4 disclaimer. Besides I’m a woman with many children so that’s a triple whammy. Some interventions even work for apoE4 males but not females. :disappointed:

I’ve got a backlog of protocols to try but can’t get to them until after weaning the new baby, so roughly August 2024. And I feel I’ll still be shooting in the dark. Exercise of the cardio intensive type that makes me winded and that’s supposed to work I do hate with a passion, but in this case I feel I’ll be doing it at gunpoint. It’s either that or likely going demented.

I want to get back to the diamond sharpness I once knew but don’t know if that’s a pipe dream at this point. Anyway any research you can share about what looks most promising for apoE4 females, I’m all ears. The most intriguing route right now actually seems to be @John_Hemming’s protocol as impaired oxidative phosphorylation and a shortage of AcetylCoA seem to be implicated in the metabolic aspects of apoE4 neurodegeneration. Sidenafil is also on my to-try list. Deprenyl under serious consideration.

Lower brain metabolism in apoE4 young adults, even the very young, has been observed, and it’s even suspected to be congenital. Yet I remember having seemingly inexhaustible pools of mental energy to tackle very demanding, high level cognitive acrobatics so perhaps there are other, rarer genetic combinations we haven’t discovered yet that confer advantages on some apoE4 carriers. And it could be that I’m overreacting as baby brain is real and happens to all women, regardless of apoE status, and I might just be more keenly aware of it now. Either way it’s all in my head, either literally or figuratively.

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