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AAIC 2023 | Impact of age, sex, and race on the association between APOE and Alzheimer’s disease
As the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), the impact of APOE4 on disease risk and progression has been widely studied. It is known that the associations between APOE and AD are modulated by biological variables, such as age, sex, race, ethnicity, and ancestry. To better understand the impact these variables have on genetic risk, particularly in understudied non-white individuals, Michael E. Belloy, PhD, Stanford University, Stanford, CA, looked into the associations of APOE genotypes with AD in over 70,000 individuals. The study noted a sex-by-age-specific association of APOE*34 in females aged 60-70, across Non-Hispanic Whites (NHW), Non-Hispanic Blacks (NHB), and Hispanics (HISP). Notably, both APOE4 and APOE2 had the least pronounced impact on AD risk in the HISP population. Dr Belloy is also beginning to look at local ancestry at the APOE locus, which may identify other risk variants that modulate the association of APOE with AD. This interview took place at the Alzheimer’s Association International Conference® (AAIC) 2023 in Amsterdam, Netherlands.
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Transcript (edited for clarity)
The general idea behind a lot of the work I’m doing is really focusing on precision medicine. So we want to understand how genetic risk factors may be modulated by important biological variables such as sex status or race and ethnicity or ancestry. This study really sought to investigate this on a large scale, particularly looking at the APOE genotype, which is a very well-established risk factor for Alzheimer’s disease, particularly the APOE4 allele being very much a risk increasing genetic risk factor and APOE2 being a risk decreasing risk factor...
The general idea behind a lot of the work I’m doing is really focusing on precision medicine. So we want to understand how genetic risk factors may be modulated by important biological variables such as sex status or race and ethnicity or ancestry. This study really sought to investigate this on a large scale, particularly looking at the APOE genotype, which is a very well-established risk factor for Alzheimer’s disease, particularly the APOE4 allele being very much a risk increasing genetic risk factor and APOE2 being a risk decreasing risk factor. But there’s also a lot of evidence that has been gathered in the past showing that these effects are different depending on sex or race and ethnicity.
So we sought to interrogate that in a very, very large scale. So we ended up actually with almost 70,000 individuals, substantially increasing the sample sizes compared to prior work. And some of the very cool things we observed, for instance, is that there is a very specific effect whereby the APOE3/4 heterozygous individuals have a stronger risk for females and particularly at the age of 60-70? And what was nice is that we didn’t just observe this in non-Hispanic white individuals, which is the largest population generally studied, but we also observed it in a in a good sample size individuals of non-Hispanic black and Hispanic origin. In that way, I think that’s a very nice addition to show that something like this APOE3/4 being a risk factor for Alzheimer’s disease specifically in women, that effect is consistent across different populations. So that’s very important when we think about designing research studies centered around APOE and what we think about clinical trial design in terms of how we recruit people and which individuals are at more risk or less risk for Alzheimer’s disease. So I think this is a very important finding. And similarly, we observed that the APOE genotypes, APOE4 and APOE2, have actually the least pronounced effect in Hispanic individuals from all populations that we studied. So also this is generating a lot of tasks and how we investigate it further with downstream research and how we make considerations again for clinical trial design and for dealing with diverse populations within the broader research community.
So some of the work we’re interested in is we also studied the effect of ancestry. But there’s two ways you can study this. So one is where we look across the entire genome what is your global ancestry? And another way is where we can look specifically on the APOE gene or APOE locus at the local ancestry and so that tells us something about haplotype structures there that may explain something about a particular other risk variant in that locus being present in a particular ancestry background that could modulate, for instance, expression levels of APOE and in that way explain differences across populations. So something we’re really interested in is understanding what’s going on in the Hispanic individuals. Do they have particular ancestry haplotypes on APOE that explain these differences and particularly the Amerindian ancestry, which is more prominently present in Hispanic individuals than in any of the other race and ethnicity groups that we studied. So that’s definitely one line of research we want to follow up on.
I’m also very excited to announce that actually on October 1st I’ll be starting my own lab in the NeuroGenomics and Informatics Center in Washington University in Saint Louis. And so essentially I’m going to continuing there my line of research that focuses on personalized genetic medicine, where we look at genetic data, multiomics data, and with a particular focus on understanding sex differences and understanding ancestry differences and so I’m very excited about that and I’m hoping to collaborate with many people and recruit many people to do really exciting research in this field.