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Realistic Views for Developing APOE-Targeted Gene Therapies for Alzheimer Disease: Yann Le Guen, PhD

The assistant director of computational biology at Stanford University discussed where the Alzheimer disease community stands on gene therapies that target APOE, and whether missense variants will play a role. [WATCH TIME: 4 minutes]

WATCH TIME: 4 minutes

"You want to have an impact on the population level. If you have a drug that modulates a peripheral risk, then you are likely to have a strong impact on the population, because that’s the main risk modifier for Alzheimer disease, and most individuals with this [disease] carry this allele."

Most of the common identified single-nucleotide variants contribute a small amount to an individual’s risk of Alzheimer disease (AD), with the exception of apolipoprotein (APOE) ε2 and ε4 missense variants that are associated with substantially decreased and increased AD risk, respectively. A recently published study combined case-control, family-based, population-based, and longitudinal AD-related cohorts to determine whether rare missense variants on APOE are associated with AD risk.

Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). In stages 2 and 3, across multiple replication cohorts, 2 missense variants, V236E on APOE ε4 and R251G on APOE ε3, were associated with a 2- and 3-fold decreased AD risk (V236E: odds ratio [OR], 0.37 [95% CI, 0.25-0.56]; P = 1.9 x 10-6; R251G: OR, 0.44 [95% CI, 0.33-0.59]; P = 4.7 x 10-8). As these variants have an allele frequency of less than 0.1%, they had not been previously studied.

With the number of failed AD therapeutics in recent years, the findings beg to question whether directly targeting APOE using gene therapy is a viable option. To learn more about this phenomenon and the realistic future of it, NeurologyLive® sat down with lead investigator Yann Le Guen, PhD. Le Guen, assistant director of computational biology at Stanford University, provided background on the ins and outs of APOE-targeted gene therapy, how the community views it, and the ongoing efforts being done.

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.