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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