@desertshores I think the ability to effortlessly sustain concentration is the hallmark of the diamond mind. I can get a lot done at a high level IF I concentrate, but it’s now all of a sudden very hard to. I feel the mind’s muscles tiring out fast. In my school days it was widely assumed that I was a bookworm who spent all day hitting the exercise section of our algebra and geometry textbooks, because I was so good. The truth was I never did my homework and could just pull it all out of my ass impromptu because… I could pay attention in class like no one. I could follow the proof and derivation of complicated theorems from the most basic premises by absorbing it as it was laid out on the black board, step by step, so all I had to memorize was the beginning — while others took notes, I just stared at the blackboard and sucked it all in. At the time I didn’t even realize how unusual this was and just shrugged at seemingly everyone else’s “inefficient” way of doing things. I had attention to spare, even on trivial stuff — if I watched a show or movie, every little plot twist was etched in my mind forever, even shitty ones I wished I could unsee and never remember. I’d meet people at a corporate party and make small talk, then next year meet them again and remember exactly what they’d said and bring it up. They’d always be super flattered and impressed. It was just natural. Now it feels like focused attention is a scarce, precious commodity, and my brain is turning into a miser.
There HAS to be something going on metabolically, because it feels like an insufficiency of “fuel” rate limiting my ability to think all the thoughts I need to think at once. Even though my blood markers look great it’s possible to have some sort of cerebral insulin resistance without any peripheral sign of it.
I’m also ambivalent about the notion of “cognitive reserve” @Tim so kindly brought to bear on my situation. On the one hand it helps to have “excess fat to burn,” so to speak. On the other hand I wonder if my brain was just unusually wired in such a way that it took a very generous supply of energy for granted and is more sensitive to any restrictions. I’m 5’3” but my head is very big—finding sunglasses and hats that fit is a challenge. It’s got to be a big brain in there, probably an energy hog. Any small bump in supply might lead to nonlinear deteriorations in performance. Losing Africa as a province was catastrophic to the Roman Empire due to its huge population and lavish habits. A subsistence economy is less vulnerable to outside shocks like that. So perhaps someone with a more modest original setup can be more resilient….
Yes melatonin is on my radar. I have seen that apoE4 individuals tend to have lower serum levels of melatonin for unknown reasons — it might be getting depleted or not produced in sufficient quantities to begin with. But I think it will take a lot more than just that to right this ship. I doubt it will be any one single thing though the closest thing to a silver bullet is probably rapamycin. Dr. Green mentioned having many apoE4 patients doing great — he just treats them more aggressively with a higher dose of rapa and starting earlier. I did definitely feel an improvement while on rapa even though I thought I was taking a huge dose (5mg + GFJ) while in fact I was taking a minuscule effective one because, siroboon…. So I can’t wait to get on the real thing (I’ve bought it, and it’s the Pfizer original from Turkey, not even a generic, but only my husband can take it for now, since he’s not gestating ).
Another mom I was chatting with yesterday told me when she was pregnant she once introduced herself to someone at the grocery store who was the dad of her kid’s bff, at whose house she had done pick up and drop off a dozen times, and consequently had conversation with countless times. So that’s demented, isn’t it? But par for the course during pregnancy. Baby brain is a real thing, a series of physiological changes that really scramble the woman’s ability to think straight. I don’t understand the evolutionary purpose of it but it is what it is. It is reversible in principle but there’s fat tails in the distribution of its duration. So part of me is hoping that I’ll slowly and naturally crawl my way out of this hole once I give birth but time waits for no one so I don’t know that I’ll be the same person upstairs as after my last pregnancy.
I have read several studies using thiamine therapy… Vit B1, to prevent and even reverse different types of dementia. You might want to look up the PubMed studies and consider taking more B1?
I was taking both of those before I got pregnant. My memory and focus were getting better but I don’t know which of my many supplements contributed to it — I think the very careful low carb eating might have been helping more. But I was still a ways off from brilliance. There’s something more fundamental going on, I think related to mitochondrial function.
Another thing possibly going on during pregnancy that could be exacerbating run of the mill baby brain is that my immune response goes down. I’m normally NEVER sick, MAYBE one cold a year, tops, perhaps every other year. Since I got pregnant I’ve been sick non stop which is actually normal. But I wonder if Epstein Barr or HAV-1 are going from latent to active, and wreaking neurological chaos. I haven’t had cold sores but it’s possible that herpes could be activated in the brain even if not systematically.
To be clear, I function normally and come across as a quick thinking intelligent person. I often get to “genius” level on the NYT spelling bee. But I’m much declined from my peak.
Part of that is that women live longer and AD incidence goes exponential around 70-80 and beyond, so men die before it explodes in prevalence.
For virtually anyone who wants to live to 100 or beyond, if you don’t have Apo E2/2 you will be at an extremely high probability of getting AD unless you (and future science and medicine) find way to mitigate it.
See here for an example of what things look like for late 90s and 100s:
Full paper and discussion below. The conclusion of who will get AD is fundamentally different if we are talking about people who on average die by 77-82 years of age or who on average die in their 90s, 100s or beyond.
(perhaps unless you are Apo E2/2 - even Apo E2/3 start dropping off the cliff with age,
and Apo E2/2 might also once passed 100 years old we just don’t have the data)
So all of us should be focusing on AD prevention as much as @AnUser focuses on minimizing cardiovascular risks.
Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study
Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer’s dementia, while the APOE2 allele is associated with a lower risk of Alzheimer’s dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer’s dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer’s dementia cases and controls. APOE2/2 was associated with a low Alzheimer’s dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer’s disease could have a major impact on the understanding, treatment and prevention of the disease.
What is the most cost-effective way to get tested for the APOE2 allele? I have not looked into this yet - does the SNP testing that 23andMe cover this area, or is it just the full genome companies?
Many think inflammation is a key driver of aging and a possible driver of Alzheimer’s
“Inflammation is believed to play a key role in the pathogenesis of AD. As such, anti-inflammatory drugs have been investigated as potential treatments to slow disease progression.”
None of this is proven to prevent AD.
IMO:
Naproxen is the safest NSAID for anti-inflammatory properties.
Boswellia serrata is one of the best anti-inflammatory supplements
“The active compounds in boswellia resin, called boswellic acids, have been found to have potent anti-inflammatory properties. Research indicates that boswellia inhibits the production of key inflammatory mediators in the body”
Effective Anti-Inflammatory Dietary Supplements:
Curcumin
Quercetin
Omega-3 Fatty Acids
Ginger
Garlic
Vitamin D
Vitamin C
Green Tea Extract
high intensity CARDIO exercise—think lots of zone 5, not just zone 2, but don’t neglect strength
sauna if you can
rule out any toxic exposure (mercury, lead, etc.) and chelate if suspected
plasmalogens
a ketogenic AND Mediterranean diet (find the intersection point) — that’s a very clean diet. If you can’t / won’t do keto, watch blood sugar like a hawk
exogenous ketones, MCT (high in capric acid C:10, as it upregulates mitochondrial biogenesis)
green tea 3-4 cups a day, coffee is good too
Higher dose rapa
trehalose
higher dose Omega 3 — min 2g a day, combo of triglyceride form and phospholipid form as ApoE4 has defective uptake
High dose vit B complex in certain ratios and specific forms of folate (not getting in the weeds here, check genetic variants that might make you deficient in uptake hence needing much higher dose)
Selenium, magnesium
Either CoQ10 (ubiquinol) or GG or both as there’s something wrong with e4 mitochondria
Metformin seems to also stimulate mitochondrial biogenesis but the data is more controversial
Sidenafil to improve NO availability and address the vascular aspect of dementia
In general care in maintaining the NO synthesis pathways (l-arginine if on the younger side, oral biome cultivation + dietary nitrates if middle aged or older—methylene blue is a good adjunct here)
Some possible benefits from intranasal red + IR light treatment (synergistic with MB), 35-40hz multi sensory stimulation
Lower Homocysteine and keep blood pressure in ideal range
Pioglitazone also stimulates mitochondrial biogenesis
Hyperbaric oxygen treatment and hypoxic training both seem to work but only in males
Hormone replacement in females post menopause
If you have Herpes, periodic antiviral treatment for that
Curcumin does pop up a lot in the literature
Got a lot more in my notes from my PubMed deep dive but that’s more than enough for a protocol and a half
Anyone know what the mechanism of action is of an A2 versus 3 or 4? What exactly happens at the cell level that makes a A4 so much more likely than an A2 to get AD? I read that Alan Green said that the A4 patients are especially responsive to Rapamycin. What could that be telling us about what might be happening at the cell level?
There’s a cascade of downstream effects from the very shape of ApoE4 — it’s more squiggly, less open than apoe3 and certainly apoe2. It affects its docking behavior. This small difference in shape seemingly leads to everything else. There’s a novel therapy under the final stages of iteration (but still who knows how long before human trials) that actually modifies the shape of a person’s apoe4 to make it functionally identical to apoe3.
Have you listened to Attia podcast #252: Latest Insights on Alzheimer’s with Rhonda Patrick?
She is a cell biologist focusing on Alzheimer’s “because Alzheimer’s disease and Parkinson’s disease both run in her family and she has a genetic predisposition”.
@hitch She’s apoe3/4. I covered her recommendations in my loose bullet list. Basically omega3, vit D, magnesium, selenium, HEAVY exercise and no alcohol. There’s more than that though that they don’t go into in the podcast.
An analysis of 21 studies found exercise reduced dementia risk by 28% overall, and 45% for Alzheimer’s disease specifically.
“however, the dose-response association remains unclear.”
Oddly, farmers (agricultural workers) who you would think get more exercise than the average city dweller have a higher incidence of dementia and Alzheimer’s disease.
Maybe because they have more exposure to pesticides etc?
“The cohort study found longest-held jobs in agriculture, fishing, and forestry were associated with 46% higher odds of dementia compared to other occupations. The relationship was stronger in younger and retired adults as well as those with longer tenure in these fields.”
It’s almost certainly pesticide exposure. Also when you get into the weeds heavy exercise makes a lot bigger difference than 45% — there’s noise in the data from studies that relied on surveys and questionnaires. Those actually measuring fitness level empirically had much starker conclusions.
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