Does the protectiveness of APOE 2 cancel the 4, in a 2/4?

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Does the protectiveness of APOE 2 cancel the 4, in a 2/4?

Post by JoannaElizabeth »

A friend tells me they are APOE 2/4. Does that exist? If so, does their 2 cancel out their 4?

I know 2 is protective, at least when paired with other numbers.
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Re: Does the protectiveness of APOE 2 cancel the 4, in a 2/4?

Post by shug »

Lucky her - yes APOe2/4 is a thing. I'm not sure that they know yet how much protective benefit the e2 provides; whether it completely cancels the added risk of e4. But Lexeo therapeutics is trying to do that very thing. In one of their studies they are adding the e2 gene into the CNS of Apoe4/4 patients to see if this will stop or slow alzheimer's progression.
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Re: Does the protectiveness of APOE 2 cancel the 4, in a 2/4?

Post by JoannaElizabeth »

Thank you, Shrug! I just looked up CNS - do you mean central nervous system?
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Re: Does the protectiveness of APOE 2 cancel the 4, in a 2/4?

Post by shug »

Yes that's the central nervous system; I think they inject it into the cerebrospinal fluid. And it adds in the "good" APOe2 gene without actually removing the E4s, hopefully eliminating some or all of the risk of the E4.
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Re: Does the protectiveness of APOE 2 cancel the 4, in a 2/4?

Post by JoannaElizabeth »

Whoa. They can add a gene to the CNS? Do you know how they're doing that? Are they using CRISPR?

Thank you, this is really interesting. Do you know when they may have results?
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Re: Does the protectiveness of APOE 2 cancel the 4, in a 2/4?

Post by shug »

They’re not using CRISPR; not actually deleting the e4 but only *adding* the e2 with an adenovirus to see if the addition will result in lowered risk the same as having been born with 4/2. I have been watching the lexeo website for a couple of years and they’ve had the same post up this whole time that they’re in clinical trials phase I/II. They haven’t moved into the (final?) phase II/III yet. I have no idea how long it will be before we have results of that. They also have two other studies in the pipeline: one that adds e2 and *suppresses* the e4, and another that adds in the “Christchurch” e2. I have read that crispr is also doing studies (with mice?) to cut out the bad gene and insert a better allele. I don’t think they have any human studies yet.
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Re: Does the protectiveness of APOE 2 cancel the 4, in a 2/4?

Post by JoannaElizabeth »

Interesting, thank you! And I didn't realize you had answered, my apologies for the delay.

I wish we could get the inside scoop on what's up with that study! What other studies do you have your eye on? I know Dr Bredesen's results are supposed to be out next February... Someone told me Dr Dean Ornish is currently doing some kind of trial with diet and meditation.
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Re: Does the protectiveness of APOE 2 cancel the 4, in a 2/4?

Post by TheresaB »

JoannaElizabeth wrote: Wed Apr 03, 2024 5:23 pm A friend tells me they are APOE 2/4. Does that exist? If so, does their 2 cancel out their 4?

I know 2 is protective, at least when paired with other numbers.
Yes, there is such a thing as a 2/4, but the 2 does not cancel out the 4. According to this paper, Association of APOE e2 genotype with Alzheimer’s and non-Alzheimer’s neurodegenerative pathologies (Terry E. Goldberg et al, Nature 18 Sep 2020), it’s not as simple as that. It appears the 4 is dominant.

The paper's abstract:
The apolipoprotein E (APOE) gene contains both the major common risk variant for late onset Alzheimer’s disease (AD), e4, and the major neuroprotective variant, e2. Here we examine the association of APOE e2 with multiple neurodegenerative pathologies, leveraging the NACC v. 10 database of 1557 brains that included 130 e2 carriers and 679 e4 carriers in order to examine potential neuroprotective effects. For AD-related pathologies of amyloid plaques and Braak stage, e2 had large and highly significant protective effects contrasted with e3/e3 and e4 carriers with odds ratios of about 0.50 for e3 contrasts and 0.10 for e4 contrasts. When we separately examined e2/e4 carriers, risk for AD pathologies was similar to that of e4 carriers, not e2 carriers. For multiple fronto-temporal lobar pathologies and tauopathies, e2 was not significantly associated with pathology. In sum, we found that e2 was associated with large but circumscribed protective effects.
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Re: Does the protectiveness of APOE 2 cancel the 4, in a 2/4?

Post by JoannaElizabeth »

Interesting, thank you SO much for that! I've read the excerpt and I notice they are comparing to "e4 carriers" but not making a distinction between 3/4 and 4/4.

I wonder if the 2/4 folks they examined basically had the same risk as 3/4 folks? It would be shocking if they had the same risk as 4/4, right?

Also, have you heard of the research from Lexeo therapeutics that another user (Shrug) commented about in this thread, where they are trying to maybe mimic APOE2 protection, or insert the gene itself, into the CNS of people with APOE4/4? I found this link on it but I've never heard of them: https://www.lexeotx.com/programs/cns-programs/
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Re: Does the protectiveness of APOE 2 cancel the 4, in a 2/4?

Post by Brian4 »

Welcome Joanna!

From what I've read (a lot on this; but not the last couple years' research), 2/4s have a risk for Alzheimer's that is a wee bit lower (better) than 3/4s, but definitely not as good as 3/3s.

This is why Lexeo is working on a new treatment that involves increasing apoE2 levels and decreasing apoE4 levels. It's still a couple years from being trialed in humans, I believe.

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Brian
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