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. 
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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