History and Future Outlook of V236E and R251G Missense Variants in Alzheimer disease: Yann Le Guen, PhD


The assistant director of computational biology at Stanford University discussed the knowns and unknowns of 2 rare missense variants and their associations with decreased Alzheimer disease risk. [WATCH TIME: 4 minutes]

WATCH TIME: 4 minutes

"What was nice is that we know that this [R251G] variant may have an impact on the risk that’s associated with ε4. The ε4 risk of Alzheimer disease is unseen, actually. It is decreased due to an alteration of amino acid that probably changed the structure of APOE and made it, apparently, less likely to oligomerize, improve lipid binding, and reduce insoluble [amyloid-ß]."

In a recently published genome-wide association study, investigators found that 2 missense variants, V236E and R251G, are each associated with a more than 2-fold reduction in Alzheimer disease (AD) risk. Because they have a frequency of less than 0.1% on gnomAD version 3.1, they had not been identified in prior studies. R251G, carried on the same haplotype as apolipoprotein (APOE) ε4, is the first APOE variant found to mitigate the AD risk attributable to the ε4 isoform of the APOE protein. Notably, the findings also showed that having R251G in association with APOE ε4 resulted in a risk estimate similar to APOE ε2.

Led by Yann Le Guen, PhD, the research was reportedly the largest available sample to date for APOE ε3 (V236E) and APOE ε4 (R251G). The protective mechanism of R251G remains unexplored but finding a single amino acid substitution that renders the APOE -ε4 allele protective supports the idea that APOE ε4-specific treatments are worth exploring, the study investigators concluded. Le Guen, a postdoctoral researcher in transition to become the assistant director of computational biology at Stanford University, sat down with NeurologyLive® to discuss the previous literature on these 2 missense variants, along with how he plans to expand on the data going forward.

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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