Visualizing the impact of APOE4 on ageing

Recently, Luke reported that I am a carrier of the E4 allele at the gene APOE; this gives me approximately double the average risk for late-onset Alzheimer’s disease. I didn’t think too much about this–it’s only double the risk, and in any case I’m 28 years old. But I recently came across the below plot, by Nick Eriksson (I’ve re-plotted it). It shows the frequency of the APOE4 allele plotted against average age in 15 cohorts of “cognitively normal elders” (data from here).

If we assume that these 15 cohorts are all from relatively similar populations, the interpretation of this is that, between the ages of 70 and 85, people with my genotype go from being cognitively normal elders to not (due to Alzheimer’s, another form of dementia, or death) at a rate about twice that of people who don’t carry the E4 allele [1]. This, of course, is exactly what I knew before (that E4 carriers have double the risk of Alzheimer’s), but seeing this visually is quite striking.

[1] Could the drop in APOE4 allele frequency could be mostly due to E4/E4 homozygotes (i.e. people not of my genotype)? If we assume an initial allele frequency of 20% and Hardy-Weinburg equilibrium, then a fifth of the APOE4 alleles are present in homozygotes. So even if all of these individual developed Alzheimer’s, then this would drop the allele frequency from 20% to ~16%. The observed drop in allele frequency is much greater than that.

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12 Responses to “Visualizing the impact of APOE4 on ageing”


  • This, of course, is exactly what I knew before (that E4 carriers have double the risk of Alzheimer’s), but seeing this visually is quite striking.

    hm. with the rise of this sort of genomic information someone should do research using a heuristics & biases framework to see how different people take numerical values vs. visualization of numerical values. my assumption would be that charts are more likely to cause alarm or calm, whether warranted or not.

  • my assumption would be that charts are more likely to cause alarm or calm, whether warranted or not.

    yep, that would be my guess as well. I initially found it hard to believe that the above figure (which gives off a depressing sense of inevitability) could be due to “only” a two-fold increase in risk.

  • yep, that would be my guess as well. I initially found it hard to believe that the above figure (which gives off a depressing sense of inevitability) could be due to “only” a two-fold increase in risk.

    right. i am not in the higher risk category, but the figure creeped me out when i first saw it. i have other risks so it was easy to project.

    hoping that genetic counselors have this all covered? cuz if we’re given mild willies, the public is going to be another issue altogether.

  • Life-threatening predispositions like Alzheimers may inevitably cause anxiety. However, it is known that this response is often short lived and carriers quickly adapt to this information.

    A well-known example is Sergey Brin, who found to be a carrier of the G2019S mutation in the LRRK2 gene; a mutation inherited from his mum, who developed the disease.

    I find very helpful a quote that was written in Sergey’s blog (http://too.blogspot.com/), which perhaps is pertinent to this discussion:

    “I feel fortunate to be in this position. Until the fountain of youth is discovered, all of us will have some conditions in our old age only we don’t know what they will be. I have a better guess than almost anyone else for what ills may be mine — and I have decades to prepare for it.”

  • Yvette Cassidy

    Until the fountain of youth is discovered, all of us will have some conditions in our old age only we don’t know what they will be.

    OR NOT

    Its not about the gene 100 % its about the environment that matches the gene. An if you think you are going to get sick in your old age then you will – if you think you will not then you wont.
    Compression of morbidity is what you want to have. HEALTHY HEALTHY HEALTH HEALTHY DEAD.
    Change you thoughts change your life.
    Remember we are not just physical bodies – we are energetic bodies and spiritual bodies but most of medicine doesn’t recognize these other bodies.

  • @ Razib — There’s a pretty decent literature in the area of cancer risk perceptions, including studies of framing & graphical presentation of information, and how personal experience (often family history of cancer) colors our risk perceptions. In truth, the marketing folks are way ahead of the health care folks in this regard, they’ve been framing risk information for years, convincing us that risky things are really ok to buy while benign stuff requires a purchase to “cure” it :)

    As a genetic counselor, my own approach for presenting risk information involves helping people understand the concepts of penetrance and group data vs personalized data. While patients are typically told “your lifetime risk of disease X is Y%”, the Y figure is usually derived from either a meta-analysis or the largest, least biased studies available that counted up how many people with a particular allele developed the disease by a certain age. When we incorporate personalized risk/protective factors, we can often tweak that Y up or down (sometimes quite a bit, especially if there is a proven intervention available).

    @Yvette– It’s true– human mortality rates are still 100%, and we can all do a better job of taking care of ourselves. But comments suggesting that you can out-think your genes does a disservice to the many families that have been profoundly affected by genetic disease.

  • The decrease in the APOE e4 allele frequency with age that is illustrated above has been well documented for about 25 years in multiple publications, starting with one by Davignon et al in 1987. The decline in e4 frequency with age of subjects is stronger in males than in females. It is there in populations of cognitively normal people as well as in populations sampled through the presence of dementia, and the decline in allele frequency starts before one would expect a substantial impact through developing dementia. The e4 allele is also a strong risk factor for cardiovascular disease, and a plausible explanation is that carriers of the e4 allele have a higher cardiovascular-disease-related mortality, especially in (younger) men.

  • Ellen,

    Thanks, very helpful!

  • For people following this thread, I believe the Davignon et al. study referred to above is this one:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376437/

  • Hey Joe,

    Thanks for the post. I am e3/e4. Could you tell me where I stand with respect to the cohort data you used? Is there any paper you can recommend about this particular allele combination?

    I am quite young, late 20s and feel like I’m pretty much doomed to suffer from Alzheimer throughout my oldie days – granted that I survive the cardiovascular troubles that are too, though less strongly – I presume, linked to e4.

  • Hi Gauzn,

    We’re in the same boat (e3/e4). We’re the people driving the correlation you see in the plot in the post. You might be interested in Luke’s post on Alzheimer’s prediction:
    http://genomesunzipped.org/2011/05/calculating-your-alzheimers-risk.php

    Our chances of getting Alzheimer’s are about double the average–approaching 20% (or 30% if you’re female). So I wouldn’t say you’re “doomed”!

  • Prefer Anonymity

    How to you think I feel? E4/E4 and female. I really am doomed. I am starting to hope I just get cancer in my 70s so I don’t have to get AD. And that assumes I don’t get it in my 60s. Taking fish oil, niacin, running, healthy weight, B12, folate, probably all just pissing in the wind. Or worse, preventing the fatal heart attack that I would prefer to dementia.

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