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Risks and benefits of apoe2 vs apoe4 in a 5,000-person neuropathological study

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
Fiver
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Risks and benefits of apoe2 vs apoe4 in a 5,000-person neuropathological study

Postby Fiver » Thu Mar 12, 2020 6:48 pm

Hello everyone, I don't know if this has been posted before. I didn't see it when I checked.

This table:
https://www.nature.com/articles/s41467- ... 8/tables/2

From this recent study:
https://www.nature.com/articles/s41467-019-14279-8

Really brought me down. I guess it's been a while since I read studies of the odds ratios and hazard risks. The authors point is that apoe2s have a really low incidence of AD. But the high risk for 4s seemed to jump off the page. I guess I'm a little stressed about things at the moment. Or maybe I'd just forgotten. But it is a good source of basic risk data, so here it is.

I was interested in the supplemental figures, but can't seen to access them. Maybe there is a broken link.

Published: 03 February 2020
Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study
Eric M. Reiman, Joseph F. Arboleda-Velasquez, […]The Alzheimer’s Disease Genetics Consortium
Nature Communications volume 11, Article number: 667 (2020) Cite this article

Abstract

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.
Concerned, but hopeful. Introverted, but will talk about science.

NF52
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Re: Risks and benefits of apoe2 vs apoe4 in a 5,000-person neuropathological study

Postby NF52 » Fri Mar 13, 2020 12:18 am

Fiver wrote:Hello everyone, I don't know if this has been posted before. I didn't see it when I checked.

This table:
https://www.nature.com/articles/s41467- ... 8/tables/2
...Really brought me down. I guess it's been a while since I read studies of the odds ratios and hazard risks. The authors point is that apoe2s have a really low incidence of AD. But the high risk for 4s seemed to jump off the page. I guess I'm a little stressed about things at the moment....
Hi Fiver,
Yet another example of scientists seeming to view us as fascinating lab rats, (or in this case, donated brains) rather than living people who might care about these conclusions!

Here's a link to those supplementary tables: https://static-content.springer.com/esm/art%3A10.1038%2Fs41467-019-14279-8/MediaObjects/41467_2019_14279_MOESM1_ESM.pdf
Specifically, although the article glosses over this, they studied brains donated to Alzheimer's Research Centers. In other words, NOT from a population-based study. The caption to the table notes that it
provides a summary of all cases with the clinical diagnosis of Alzheimer’s dementia and all cognitively unimpaired controls with APOE genotypes in the ADGC database
. Here are the numbers on Supplementary Table 1 for ApoE 4/4:

Neuropathologically confirmed controls (i.e. people now viewed as having elevated amyloid but no cognitive deficits on testing). This is known and characterized now as a "pre-clinical" stage that can continue for decades and does not necessarily progress to clinical disease: Total: 10 out of 633
Neuropathologically unconfirmed controls (i.e. people who were free of amyloid and cognitive impairment at death) 1,359 out of 1,647.

So my one sentence take-away: People who donate their brains to Alzheimer's research who are ApoE 4/4 and have both a diagnosis of AD and beta amyloid are not the same as those with ApoE 4/4 who have elevated beta amyloid and no cognitive impairment and even more different from 1,359 people with ApoE 4/4 who have neither beta-amyloid or cognitive impairment during their lifetimes.

In their discussion of limitations of this study, they acknowledge the difference between a sample of donated brains studied for correlation (not causation) and a prospective (and maybe population-based) study:
Prospective cohort studies that include persons irrespective of their cognitive stage or neuropathological diagnosis are needed to clarify the absolute lifetime risk of neuropathologically confirmed Alzheimer’s dementia for each APOE genotype... Since the reported prevalence and impact of different APOE genotypes on Alzheimer’s dementia risk depends in part on age, race, ethnicity, geographic location, education, and dementia severity, these estimates are likely to vary in different populations. Based on our selection criteria, this study does not provide information about the percentage of APOE genotypes in cognitively unimpaired persons with neuropathological or biomarker evidence of preclinical AD,
https://www.nature.com/articles/s41467-019-14279-8#Tab2

Here's a recent and much more encouraging study, which I hope to post on its own topic: Genetic Risk of Dementia Mitigated by Cognitive Reserve: A Cohort Study And happy thought from this study of 2600+ people:
When combinations of the reserve indicator and genetic risk were examined, cognitive reserve appeared to override the detrimental effect of genetic predisposition, as the risk of dementia among APOE-ε4 carriers was similar to that of the noncarriers.

Never put yourself in the same category as donated brains from a select group of AD research centers, my friend!
4/4 and still an optimist!

Fiver
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Re: Risks and benefits of apoe2 vs apoe4 in a 5,000-person neuropathological study

Postby Fiver » Mon Mar 16, 2020 1:50 pm

Hi NF52. Thank you!

I've been away from the site for a few days as I shut down my lab and started to transition to teaching online. My mom's memory care facility was locked down a few days ago - she is fine but of course I worry abut how all this will play out in the coming weeks.

You are absolutely right. Not sure why I could not access all of the supplementary information but even without it I should have seen that.

Again, thanks! :)
Concerned, but hopeful. Introverted, but will talk about science.


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