Apoe4 /4 a new genetic variant of Alzheimer’s ??

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LondonGirl
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Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by LondonGirl »

https://www.nature.com/articles/s41591-024-02931-w


This article claims that apoe4 homozygosity repreeenrs a distinct form of the disease. It also claims that onset averages at age 65 and almost all homozygotes will suffer from it.

Does anyone have any response ?
Fiver
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by Fiver »

The article just hit the news:

https://www.nytimes.com/2024/05/06/heal ... apoe4.html

Thank goodness the field in general is finally starting to "get it".

We have the technology to address apoe4 as a gene. In fact, gene silencing and therapy options are already coming online for a variety of other diseases, including some neuro-degenerative diseases. Maybe this will accelerate research in this direction for apoe4.

(Reading the Nature article gave me some of the same feelings I had when I first got my test results. Even though this is more a re-classification than new information it's going to take a while to absorb.)

Update: to link this to another current discussion thread here is a conclusion from a recent article:
Alzheimer’s Disease: Novel Targets and Investigational Drugs for Disease Modification

“Some processes critical to AD have few or no candidate therapies in the pipeline. APOE4 is one of the most important risk factors for AD and is present in 65%–70% of patients. There is only one agent, the gene therapy LEX 1001, in the pipeline targeting APOE4. In this trial, a viral vector carrying the APOE2 gene is being given to antagonize the effects of APOE4.”

I’m not 100% sure this is true. But nonetheless, it’s hard to understand how there aren’t many apoe4 focused candidate therapies in the pipeline.
Last edited by Fiver on Mon May 06, 2024 12:48 pm, edited 5 times in total.
rufus4me
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by rufus4me »

Have just read this too ..has made me very upset, hopefully someone will be along with a positive comment.
Fiver
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by Fiver »

rufus4me wrote: Mon May 06, 2024 11:48 am Have just read this too ..has made me very upset, hopefully someone will be along with a positive comment.
Hi R4me. Same here. I guess we should remember that this data isn’t really new stuff - we knew this - it’s more of a re-classification of terms. And it will probably focus attention on apoe4, which is a good thing.

Does that count as a “positive” comment?
chronophylos
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by chronophylos »

If the medical community adopts this re-interpretation, we could be diagnosed with AD just on the basis of our genes, and I imagine most of the implications are health-insurance related in the US at least. In terms of risk, we're still seeing the "close to full penetrance" which is what was always there in the literature, 10% risk of AD for 4/4 in our 60s, 33% in our 70s, 50% in our 80s. This is about the same genetic risk that carriers of the BRCA1 mutation have. High enough to warrant radical double mastectomies in otherwise healthy women.
I have always been very frustrated with the lumping of Apoe4/4 and Apoe4/3 data in most scientific studies, so the one positive could be that papers discussing Apoe are forced by reviewers to break down the data into "carriers" and homozygotes.
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by buttercup »

The key to understanding this study is, I think, to recognize that the results are based on a "biomarker" definition of Alzheimer disease. This is what the "nearly full penetrance" is referring to: that nearly all folks with Apoe4/4 have higher levels of amyloid beta in their cerebrospinal fluid at at 65, and many have higher levels of amyloid that show up on PET scans. In other words, most people with Apoe4/4 will have amyloid beta in their brain/spinal fluid.

What this is NOT saying is that everyone with Apoe4/4 will get Alzheimer disease dementia. Having amyloid beta in your brain is a risk factor for developing symptoms of cognitive impairment and dementia, but doesn't guarantee that a person will develop dementia. Some people with amyloid beta go on to develop Alzheimer disease symptoms (what we as the public consider to be Alzheimer disease); some don't. It's kind of confusing how they convey this in the study, and is a product of the recent (and controversial) shift in the research field to define Alzheimer disease based wholly on biomarkers rather than symptoms.

One thing I'm unclear on: what proportion of people in the study who were Apoe4/4 had clinical symptoms of dementia. I know they talk about the average age of clinical symptoms starting at 65 years, but I haven't been able to easily find what proportion of people with Apoe4/4 had dementia. (I don't think it's all of them, given that other studies suggest the lifetime prevalence of dementia among folks with Apoe4/4 is ~60% by age 85.)
Last edited by buttercup on Mon May 06, 2024 3:18 pm, edited 3 times in total.
LondonGirl
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by LondonGirl »

Can someone give me more information on the LEX1001 therapy? Is there a trial or something?
Fiver
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by Fiver »

LondonGirl wrote: Mon May 06, 2024 2:39 pm Can someone give me more information on the LEX1001 therapy? Is there a trial or something?
Hi. This is a small gene therapy trial - 15 participants, all with MCI, I think - that get adenovirus particles carrying apoe2 infused into their brains. The idea is that some of the cells will take the apoe2 genes into their genomes and that this would be sufficient to counteract the effects of the remaining apoe4s. The procedure is relatively standard gene therapy but getting it into the brain is a technological hurdle. This approach works well to counteract the negative effects in apoe4 cells in cell culture and in mice. I’ve heard positive things about the trial, indirectly. Lexeo is the company that uses the technology. But it’s been slow going. Others here know much more about it.
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Re: Apoe4 /4 a new genetic variant of Alzheimer’s ??

Post by NF52 »

Fiver wrote:
chronophylos wrote:
rufus4me wrote: Mon May 06, 2024 11:48 am Have just read this too ..has made me very upset, hopefully someone will be along with a positive comment.
I posted a longer version of this here in reply to
LondonGirl wrote:
It does seem like scientists like to scare the heck out of us on a fairly routine basis, without noting some important caveats, or "limitations to this research" in the coverage or abstract. At 72, I have not led a perfect life (and have yet to do so) but am still scoring just fine on cognitive tests, EKGs and MRIs given in the AHEAD-45 trial, as do ChicagoGirl and Nevada who have posted on the forum about being in that study, and others not in studies on our forum in their 70's and 80's. I have met and talked at length with a judge in their late 70's with AD family history and ApoE4/4 who is doing just fine with a full caseload (not in NYC in case you're wondering!)

Here's the link from Nature with the title added:
APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease.

Here's what seems like a useful summary with expert commentary from CNN: Genes known to increase the risk of Alzheimer’s may actually be an inherited form of the disorder, researchers say

This quote from the CNN article isn't surprising to me, given my personal family history. But it applies to the generation before us Baby Boomers, who had a whole different level of toxins, education options, access to preventive cardiology and overall health care and knowledge of diet and exercise benefits :
Familial forms, caused by mutations in any of three genes, tend to strike earlier and are known to be rare, accounting for about 2% of all Alzheimer’s diagnoses, or about 1 in 50 cases. Under the new paradigm, 1 in 6 cases of Alzheimer’s would be considered to be inherited, or familial.
Note the wording in this statement:
Nearly 95% of the people in the studies with two copies of the APOE4 gene had the biology of Alzheimer’s disease by the time they were 82 years old.
It refers to biomarkers of amyloid or tau, the "biology" of Alzheimer's, NOT a diagnosis of MCI or dementia. A PET scan at age 65 told me I had elevated amyloid, even though I had gone back to grad school in a tough program at age 57 and worked in challenging positions until retiring at age 62. In fact, having high levels of cognitive and social engagement might have been an unexpected gift I gave my brain in my 50's and 60's.

But having heard one of the authors, Dr. Reisa Sperling, director of the center for Alzheimer’s Research and Treatment at Brigham and Women’s Hospital, speak several times in conferences, she has a clear message, which includes focus on lifestyle as a given:

She noted that
it would be important to do research to see whether it might be possible to find safer dosing or safer treatments for this patient group. “For me, this just means we need to treat them earlier,” Sperling said, “and this research really suggests that we should be treating them quite early, at a younger age, and at an early stage of pathology because we know they are very, very likely to progress to impairment quickly.”
Note that she is referring to starting prevention for people with ApoE 4/4 in their 60's--most people screened for the AHEAD trial between ages 55-60 did NOT have even "intermediate" levels of amyloid on PET scans, as two of our members found out during screenings. NONE of the 229 people screened at my AHEAD site who were below age 60 were found to have concerning levels of amyloid--and only about 7% qualified for the study--I don't know how many had ApoE 4/4, but some of those folks were likely doing fine!

This seems long overdue--and good news for those of us with ApoE 4/4:
Dr. Sterling Johnson, a study author who leads the Wisconsin Registry for Alzheimer’s Prevention at the University of Wisconsin, said it would be very important for clinical trials to start to take participants’ APOE4 status into account. “We may need to start treating these as a separate group in our research papers so that we can really understand the relationship between amyloid and tau and symptoms” in people with two copies of the APOE4 gene, in a way that we kind of have not been able to before, Johnson said in the news briefing.
One of the limitations of generalizing from this study is that it is NOT a population-based study: National Alzheimer’s Coordinating Center (NACC) skews MUCH more towards people with AD history than do population-based studies. Here's a quote from a well-regarded 2017 study that looked at diagnosis in both a NACC cohort and the Framingham Heart study, a SALSA study of AD in a Hispanic population and a Rotterdam population cohort in The Netherlands: [/quote] APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts
The four cohorts also differed markedly...NACC also had a 58.3% fraction with a family history of dementia, compared to 18.6% in the Rotterdam Study, the only other site that assessed it....Similarly, viewing the cumulative incidence for APOE-e4/e4 genotype across the three age strata, cumulative incidence ranged from 5.60% to 20.58% in the three population-based cohorts versus from 23.06% to 38.34% in NACC...The difference between the population-based cohort studies and NACC, on the other hand, is striking... Individuals join this cohort for a variety of reasons, but concerns about family history and their own memory are likely to play a role. This probably contributes to the relatively high APOE-e4 allele frequency and reported family history of dementia in this cohort seen in Table 1, although some of the difference in family history likely represents measurement issues (see below).
Here's what I was told at an academic research center in 2017 when I joined the Generation Study for people with ApoE 4/4:
The Generation Study elected to disclose the following “lifetime” risks of MCI or dementia to its potential participants: 30%–55% for individuals with APOE-e4/e4; 20%–25% for individuals with APOE-e3/e4 and -e2/e4 (with a note that risk might be lower for those with APOE-e2/e4); and 10%–15% for individuals with APOE-e3/e3, -e3/e2, and -e2/e2 (with a note that risk might be lower for those with APOE-e2/e3 and -e2/e2). These values are consistent with our findings, but use round numbers for intelligibility, and broader ranges to reflect statistical and other sources of uncertainty.
Nancy
4/4 and still an optimist!
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