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APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's disease pathology. Neuron Chemparathy, A., Le Guen, Y., Chen, S., Lee, E. G., Leong, L., Gorzynski, J. E., Jensen, T. D., Ferrasse, A., Xu, G., Xiang, H., Belloy, M. E., Kasireddy, N., Peña-Tauber, A., Williams, K., Stewart, I., Talozzi, L., Wingo, T. S., Lah, J. J., Jayadev, S., Hales, C. M., Peskind, E., Child, D. D., Roeber, S., Keene, C. D., Cong, L., Ashley, E. A., Yu, C. E., Greicius, M. D. 2024

Abstract

The e4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Knockdown of e4 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 controls and patients with AD and identified seven heterozygote carriers of APOE LoF variants. Five carriers were controls (aged 71-90 years), one carrier was affected by progressive supranuclear palsy, and one carrier was affected by AD with an unremarkable age at onset of 75 years. Two APOE e3/e4 controls carried a stop-gain affecting e4: one was cognitively normal at 90 years and had no neuritic plaques at autopsy; the other was cognitively healthy at 79 years, and lumbar puncture at 76 years showed normal levels of amyloid. These results suggest that e4 drives AD risk through the gain of abnormal function and support e4 knockdown as a viable therapeutic option.

View details for DOI 10.1016/j.neuron.2024.01.008

View details for PubMedID 38301647