APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's disease pathology

被引：9

作者：

Chemparathy, Augustine ^{[1
]}

Guen, Yann Le ^{[1
,2
]}

Chen, Sunny ^{[3
]}

Lee, Eun-Gyung ^{[3
]}

Leong, Lesley

Gorzynski, John E. ^{[4
]}

Jensen, Tanner D. ^{[4
]}

Ferrasse, Alexis ^{[4
]}

Xu, Guangxue ^{[4
]}

Xiang, Hong ^{[4
]}

Belloy, Michael E. ^{[1
]}

Kasireddy, Nandita ^{[1
,7
]}

Pena-Tauber, Andres ^{[1
]}

Williams, Kennedy ^{[1
]}

Stewart, Ilaria ^{[1
]}

Talozzi, Lia ^{[1
]}

Wingo, Thomas S. ^{[5
,6
]}

Lah, James J.

Jayadev, Suman ^{[8
]}

Hales, Chadwick M. ^{[7
,8
]}

Peskind, Elaine ^{[9
,10
]}

Child, Daniel D. ^{[11
]}

Roeber, Sigrun ^{[12
]}

Keene, C. Dirk ^{[11
]}

Cong, Le ^{[4
]}

Ashley, Euan A. ^{[4
,13
,14
]}

Yu, Chang -En ^{[3
,15
]}

Greicius, Michael D. ^{[1
]}

机构：

[1] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA

[2] Stanford Univ, Dept Med, Quantitat Sci Unit, Stanford, CA USA

[3] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA

[4] Stanford Univ, Sch Med, Dept Genet, Stanford, CA USA

[5] Emory Univ, Sch Med, Atlanta, GA USA

[6] Emory Univ, Sch Med, Goizueta Alzheimers Dis Ctr, Atlanta, GA USA

[7] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA USA

[8] Univ Washington, Dept Neurol, Seattle, WA USA

[9] Vet Affairs Puget Sound Hlth Care Syst, Vet Affairs Northwest Network, Mental Illness Res Educ & Clin Ctr, Seattle, WA USA

[10] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA USA

[11] Univ Washington, Dept Lab Med & Pathol, Sch Med, Seattle, WA USA

[12] Ludwig Maximilians Univ Munchen, Fac Med, Ctr Neuropathol & Prion Res, Munich, Germany

[13] Stanford Univ, Ctr Inherited Cardiovasc Dis, Stanford, CA USA

[14] Stanford Univ, Dept Med, Div Cardiol, Sch Med, Stanford, CA USA

[15] Univ Washington, Dept Med, Seattle, WA USA

来源：

NEURON | 2024年 / 112卷 / 07期

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

APOLIPOPROTEIN-E; NEUROCOGNITIVE FUNCTION; AGE; MODEL;

D O I：

10.1016/j.neuron.2024.01.008

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

The e 4 allele of apolipoprotein E ( APOE ) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Knockdown of e 4 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 e 3/ e 4 controls carried a stop -gain affecting e 4: 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 e 4 drives AD risk through the gain of abnormal function and support e 4 knockdown as a viable therapeutic option.

引用

页码：1110 / 1116.e5

页数：13

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