载脂蛋白E
长寿
损失函数
功能(生物学)
医学
阿尔茨海默病
抗性(生态学)
疾病
老年学
病理
遗传学
生物
基因
表型
生态学
作者
Augustine Chemparathy,Yann Le Guen,Sunny Chen,Eun-Gyung Lee,Lesley Leong,John Gorzynski,Guangxue Xu,Michaël E. Belloy,Nandita Kasireddy,Andrés Peña-Tauber,Kennedy Williams,Ilaria Stewart,Thomas S. Wingo,James J. Lah,Suman Jayadev,Chad Hales,Elaine R. Peskind,Daniel D. Child,C. Dirk Keene,Le Cong,Euan A. Ashley,Chang‐En Yu,Michael Greicus
出处
期刊:Cold Spring Harbor Laboratory - medRxiv
日期:2023-07-24
被引量:2
标识
DOI:10.1101/2023.07.20.23292771
摘要
The ε4 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 ε3/ε4 controls (Subjects 1 and 2) carried a stop-gain affecting the ε4 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 ε4 drives AD risk through a gain of abnormal function and support knockdown of APOE ε4 or its protein product as a viable therapeutic option.
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