APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's Disease pathology.
APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's Disease pathology.
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APOE 功能丧失变异：与长寿相容，并与对阿尔茨海默病病理学的抵抗力相关。
DOI：
10.1101/2023.07.20.23292771
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Hale
中科院分区：
文献类型：
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作者：
Chemparathy,Augustine;Guen,YannLe;Chen,Sunny;Lee,Eun-Gyung;Leong,Lesley;Gorzynski,John;Xu,Guangxue;Belloy,Michael;Kasireddy,Nandita;Tauber,AndrésPeña;Williams,Kennedy;Stewart,Ilaria;Wingo,Thomas;Lah,James;Jayadev,Suman;Hale
The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Knockdown of ε4 may provide a therapeutic strategy for AD, but the effect ofAPOEloss of function (LoF) on AD pathogenesis is unknown. We searched forAPOELoF variants in a large cohort of controls and patients with AD and identified seven heterozygote carriers ofAPOELoF 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. TwoAPOEε3/ε4 controls carried a stop-gain affecting ε4: 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 ε4 drives AD risk through the gain of abnormal function and support ε4 knockdown as a viable therapeutic option.
