Informal Notes: Additional Research on APOE variants for Increased Risk of Late-Onset Alzheimer's Disease

[this set of notes branched out from this blog post; with 2 similar / partially identical paragraphs] 

I found it hard to find cohorts with individuals greater than 80 years of age in the AlzGene database (and 23andMe was reporting that is the age interval when onset was most likely, and risk was most increased).

To be fair, I also noticed that a recent study by Licher et al. 2019 reported Low-Risk Onset with an average age of 85.5 and High-Risk Onset with an average age of 81.3 (meaning individuals must have been over 80 at some point).  However, they grouped both E3/E4 individuals (like myself) with E4/E4 individuals (who should be at noticeably higher risk) in the "High-Risk" group.  The CDC also provides a short review here.

There is an earlier paper by Corder et al. 1993 reports "mean age at onset decreased from 84 to 68 years," but here were less than a dozen E4/E4 individuals for each gender in that paper (and the maximum risk of 90% seems high compared to other studies).  To be fair, Farrer et al. 1997 also reports an earlier age of onset with more samples (closer to 755 Caucasian E4/E4 individuals from meta-analysis; 14.8% of 5107 cases).  However, with that later study, I would kind of like to see some error bars (and ideally see individual points and/or be able to download an Excel / tab-delimited text / comma-separated text file with APOE genotype, disease status, age of onset, gender, ethnicity, and cohort / batch / family ID).

Myers et al. 1996 report an E4/E4 age of onset closer to 80 years (for 55% of E4/E4 individuals); however, the total percent of individuals developing Alzheimer's Disease is noticeably lower for E3/E4 and E3/E3 (27% and 9%, respectively) as well as having a later onset of closer to 85 years than 80 years.  Unfortunately, I don't have access to that later information, to check additional details.  It also doesn't look like 23andMe directly cites these papers (but I think these are what are discussed in review articles), but they report something more similar to Myers et al. 1996 (and Genin et al. 2011, which I do have access to).

Also, to be fair, my 23andMe Report says "Approximately 40-65% of Alzheimer's patients have one or two copies of the APOE ε4 variant. However, many people with the APOE ε4 variant will not develop late-onset Alzheimer's disease" (citing Alzheimer's Association 2016).  This probably matches the 55% APOE E4/E4 onset (and an indication that E3/E4 individuals like myself are increased risk, but are still more likely not to get the disease).

There are also different genes (such as APP / PSEN1 / PSEN2) which are more associated with early-onset Alzheimer's disease (which I found from this CDC link).

While a slightly different topic, my understanding is that the previous content from the 23andMe forums will be deleted.  So, to copy over some of the main points here, the 23andMe scientific report describes the "General population" risk estimates for individuals over 85 to be 11% for males and 14% from females.  I noticed that the overall risk estimates for individuals over 85 from other sources were numbers like 25%, 50%, and 50%.  Another member of the 23andMe community passed along a link to a PDF of the World Alzheimer Report 2018 from Alzheimer's Disease International; while a bit hard to find that same document, I do see the prevalence values that I mention in this article (which is "3% of people age 65-74, 17% of people age 75-84 and 32% of people age 85 or older have Alzheimer's dementia.").  If you check the reference in this CDC post, then Hebert et al. 2013 indicate previous and projected frequencies of 32% to 37% in Table 1.  I think this leaves some questions unanswered, but I think also the younger age estimates are more similar (and I would guess it is easier to collect data from those younger than 85).  So, I thought the feedback and discussion was helpful.

Change Log:

9/14/2019 - public post date
10/3/2019 - add link for CDC review

8/21/2021 - add overall frequency notes from 23andMe forum