Examining the Association of APOE Missense Variants and the Risk of Alzheimer Disease: Yann Le Guen, PhD


The assistant director of computational biology at Stanford University provided background on recent findings of two rare APOE missense variants and reduced risk of Alzheimer disease associated with them. [WATCH TIME: 4 minutes]

WATCH TIME: 4 minutes

"The goal of our study was to study missense variants on APOE. Why missense variants and not synonymous variants? Because until recently, it’s been thought that missense variants are more likely to have a functional impact on the protein itself."

To date, literature has revealed that the apolipoprotein (APOE) ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). Using the Alzheimer’s Disease Sequencing Project whole-genome sequencing and whole-exome sequencing data, a newly published study aimed to identify missense variants in addition to those 2 that could provide critical new insights on the protein’s role in AD pathogenesis.

Among a cohort of 544,384 participants, two missense variants, R251G in APOE ε4 (odds ratio [OR], 0.44; 95% CI, 0.33-0.59; P = 4.7 x 10-8) and V236E in APOE ε3 (OR, 0.37; 95% CI, 0.25-0.56; P = 1.9 x 10-6) were associated with a 2- and 3-fold decreased AD risk, respectively. These variants have an allele frequency of less than 0.1% in gnomAD version 3.1, even when restricting this frequency estimate to individuals of European ancestry. Because of their rarity and link-age disequilibrium with the common APOE ε3 and ε4 alleles, they have not been identified in prior genome-wide association studies.

To learn more about these new findings, NeurologyLive® sat down with lead investigator, Yann Le Guen, PhD, a postdoctoral researcher at Stanford University. Le Guen, in transition to become the assistant director of computational biology, provided context on the findings, the most notable take-home points clinicians should be aware of, and the importance of gathering large-scale genomic research to understand differences in AD risk.

1. Guen YL, Bellow ME, Grenier-Boley B, et al. Association of rare APOE missense variants V236E and R251G with risk of Alzheimer disease. JAMA Neurol. 2022;79(7):652-663. doi:10.1001/jamaneurol.2022.1166.
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