#42

This goes for everyone but with emphasis on e4:

  • go teetotal on alcohol if e4
  • nail sleep
  • 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

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#43

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?

#44

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.

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#45

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”.

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#46

@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.

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#47

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.”

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#48

Or perhaps it’s related to lower screening rates?

#49

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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#50

Ah - I like this. I’d rather not give all my DNA / SNP data to 23 and Me.

Price is only $99. I will do this:

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#51

I’ll let others do their pubmed searches - BUT in addition to Rapamycin, I’d recommend people look at SGLT2-i, PDE5-i, GLP-1/GIP drugs, and yes a lot of the items I’ve seen other’s list below. Optimization of vascular risk, vitamin B12/Omega 3/Vitamin D/Diet/Exercise is all important.
I’d say the evidence is mounting for the items just mentioned. Lifestyle is clearly a critical partner.

7 Likes
#52

Scientists Find Gene Variant Giving Up to 70% Protection Against Alzheimer’s

A newly discovered variant in the FN1 gene, which is responsible for making thefibronectin protein, reduces the likelihood of developing Alzheimer’s by up to 70 percent. This finding could lead to more effective treatments for the disease.

Led by a team from Columbia University, researchers looked closely at a particular group of people: those with another gene variant called APOEe4 who had never developed Alzheimer’s. Considering APOEe4 significantly increasesthe risk of getting the disease, they suspected there might be a counterbalance.

Sure enough, genome sequencing of 10,763 individuals across two groups of people, revealed the protective effects of a specific FN1 variant in people with APOEe4. The FN1 variant seems to be helping to regulate the amount of fibronectin in the brain.

The researchers estimate that hundreds of thousands of people with the APOEe4 allele in the US alone have this protective FN1 variant, potentially stopping Alzheimer’s from developing – though plenty more research is going to be needed to work out exactly how this gene variant is helping.

The fibronectin variant was found in people who carry APOEe4, but it may also protect people with other variants of APOE from getting Alzheimer’s.

Full Reserch Paper (open access):

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#53

Memory self-test via smartphone shows promise in early detection of Alzheimer’s disease

Full Open Access Paper:

https://www.nature.com/articles/s41746-024-00999-9

Company website:

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#54

Do you know where we can check if we have this variant assuming we can download our raw data from 23&me and such?

Would love to check for me, my husband, and my daughters who are all apoe3/4.

#55

Random aside but I’m currently in the Dominican Republic on vacation — was typing my bullet point list while on the plane. So it’s completely mysterious but my mind is working 10x better here: I’m able to multitask more, keep track of an evolving todo list and even nag my husband about unfinished business we left behind at home which I can’t even think of clearly when we’re there. And no word retrieval latency since we touched down. I don’t know if it’s the weather, sun exposure, great food and rest, but I’m relieved to find out that whatever is happening to me at home in my cold ass New England state does not mean I’m actually cognitively impaired or that my apoE4 chickens have come home to roost…just yet.

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#56

I’m guessing it’s the sun, weather and temperature.

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#57

I’m no doc., but many of your symptoms may relate to depression.

I decided long- long ago that 9 months of winter was something I didn’t like.

That’s why I moved to the sunny far Southwest. Only about 3 months of the year are too hot, but I have adapted to it. I could never adapt to 9 months of winter.

So, you are experiencing excitement and sunny skies both anti-depressants.

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Depression rates by state.

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#58

Why is Oregon so depressed? Seems like a nice place to live.

#59

Taking a Boswellia supplement gives me wicked insomnia that lasts all night long and all day long the next day even when taken in the morning.

#60

I’m in a very dark blue place where I’ll likely stay for at least the next 10 years for the kids’ sake and as a native of the Mediterranean I really hate it most of the time climate wise. I just don’t perform at my best — whenever I visit my native country in the summer I become a super version of myself. But my mood is not depressed really at all so maybe it’s sub clinical. I did go to university in Canada and experienced true seasonal depressive disorder there. It was as subtle as a sledgehammer. My husband is a northerner in both ancestry and upbringing and seems to deflate in the upper ranges of sun and humidity that I find optimal — even though the Mediterranean hits a sweet spot for us both. Right now he’s in his native milieu and I’m just coping.

It’s true that since I moved to New England I’ve been far from at my best but I moved from NYC where the climate is not THAT much better but where I functioned at my highest for years before kids.

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#61

It doesn’t seem to be in the 23 and Me data. Some people in this APOE4 forum are saying you need a whole genome done, or some new version of 23 & me. I’m not sure how accurate this is.

“Two mutations (rs116558455 and rs140926439) in the FN1 gene (Fibronectin-1) were found in healthy elderly ε4 homozygous carriers in EFIGA/WHICAP and NIA AD-FBS cohorts with MAF=1.85% and 3.33%, respectively…”

See this thread: New Study. FN1 modifiers and APOE4 - ApoE4.Info

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