Notice: Users may be experiencing issues with displaying some pages on stanfordhealthcare.org. We are working closely with our technical teams to resolve the issue as quickly as possible. Thank you for your patience.
 

Learn about the flu shot, COVID-19 vaccine, and our masking policy »

Stanford Health Care

APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's Disease pathology. medRxiv : the preprint server for health sciences Chemparathy, A., Guen, Y. L., Chen, S., Lee, E. G., Leong, L., Gorzynski, J., Xu, G., Belloy, M., Kasireddy, N., Tauber, A. P., Williams, K., Stewart, I., Wingo, T., Lah, J., Jayadev, S., Hales, C., Peskind, E., Child, D. D., Keene, C. D., Cong, L., Ashley, E., Yu, C. E., Greicius, M. D. 2023

Abstract

The e4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's Disease (AD). Knockdown of this allele may provide a therapeutic strategy for AD, but the effect of APOE loss-of-function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of older controls and patients with AD and identified six heterozygote carriers of APOE LoF variants. Five carriers were controls (ages 71-90) and one was an AD case with an unremarkable age-at-onset between 75-79. Two APOE e3/e4 controls (Subjects 1 and 2) carried a stop-gain affecting the e4 allele. Subject 1 was cognitively normal at 90+ and had no neuritic plaques at autopsy. Subject 2 was cognitively healthy within the age range 75-79 and underwent lumbar puncture at between ages 75-79 with normal levels of amyloid. The results provide the strongest human genetics evidence yet available suggesting that e4 drives AD risk through a gain of abnormal function and support knockdown of APOE e4 or its protein product as a viable therapeutic option.

View details for DOI 10.1101/2023.07.20.23292771

View details for PubMedID 37547016

View details for PubMedCentralID PMC10402217