Interview with: Michael E. Belloy, PhD Department of Neurology and Neurological Sciences Stanford University, Stanford, California

Alzheimer’s Disease: APOE Status Must Be Interpreted in Light of Race, Ethnicity, Ancestry and Sex Interview with: Interview with:Michael E. Belloy, PhD
Department of Neurology and Neurological Sciences
Stanford University, Stanford, California

Dr. Belloy

Michael E. Belloy, PhD
Department of Neurology and Neurological Sciences
Stanford University, Stanford, California What is the background for this study?

Response: Apolipoprotein E (APOE)*2 and APOE*4 are, respectively, the strongest protective and risk-increasing, genetic variants for late-onset Alzheimer disease. As such, one’s APOE genotype is highly relevant towards clinical trial design and Alzheimer’s disease research. However, most insights so far are focused on the associations of these APOE genotypes with Alzheimer’s disease risk in non-Hispanic white individuals.

One important aspect of our work is that we really increased sample sizes for non-Hispanic Black, Hispanic, and East Asian individuals, so that we now have better understanding of the associations of APOE genotypes with Alzheimer’s disease risk in these groups. In complement, we also did the largest investigation to date on the role of ancestry on the associations of APOE genotypes with Alzheimer’s disease risk. The scale of our study was thus a critical factor in generating novel insights. What are the main findings?

Our primary findings can be summarized in 4 points:

  1. It came out strikingly that the effects of APOE*4 (risk increasing) and APOE*2 (risk decreasing) on Alzheimer’s disease are the least pronounced in Hispanic individuals.
  2. BecauseAPOE*2 is rarer in the population, sample sizes in prior studies were limited to generate robust insights into the association of APOE*2 with Alzheimer’s disease risk in understudied populations. We showed clearly that the effect of APOE*2 is less protective in non-Hispanic Black compared to non-Hispanic White individuals, and there appears to be little to no effect in Hispanic and East Asian individuals.
  3. Compared to non-Hispanic White or European ancestry individuals, we showed that African ancestry was a better indicator of diminished APOE*4 risk for Alzheimer’s disease than non-Hispanic black race. This is important because race is a social construct while ancestry relates more closely to geographical origin and inherent biological variation.
  4. Lastly, it had already been shown in non-Hispanic White individuals that female APOE*34 carriers have greater risk for Alzheimer’s disease compared to their male counterparts. We reproduced this finding with more data, but very importantly also showed that the same observation holds true in non-Hispanic black and Hispanic individuals. What should readers take away from your report?

Response: Our findings have profound implications in multiple areas. When consulting individuals on their genetic risk for Alzheimer’s disease, APOE status is a core variable. Our study shows that race, ethnicity, ancestry, sex, and age all matter to provide an individualized answer. This has important implications on clinical trial design, where subjects may be recruited based on expected risk conferred due to APOE genotypes.

Similarly, our findings have significant bearing on treatment-related decision-making, which is particularly relevant in light of monoclonal antibodies against amyloid-β that now have published phase 3 results and FDA approval for lecanemab.
These drugs have shown potential differences in treatment response according to an individual’s APOE*4 status, but trials were heavily represented by non-Hispanic White individuals. Overall, our risk predictions for APOE may have important bearing on expected drug efficacy for individuals of different race and ethnicity groups, of different ancestral backgrounds, and different sexes. What recommendations do you have for future research as a results of this study?

Response: The novel insights we generated raise questions in broad areas of Alzheimer’s disease research, where some specific lines of research may investigate why the effect APOE genotypes are least pronounced in Hispanic individuals, or may more closely investigate the exact role of ancestry on the effect of APOE on Alzheimer’s disease risk. Future research should also focus on further expanding the sample sizes of historically understudied populations, and additionally investigating the impact of social determinants of health.


Belloy ME, Andrews SJ, Le Guen Y, et al. APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry. JAMA Neurol. Published online November 06, 2023. doi:10.1001/jamaneurol.2023.3599

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Last Updated on November 7, 2023 by Marie Benz