Cell-type-specific Alzheimer's disease polygenic risk scores are associated with distinct disease processes in Alzheimer's disease

被引：14

作者：

Yang, Hyun-Sik ^{[1
,2
,3
,4
]}

Teng, Ling ^{[1
,4
]}

Kang, Daniel ^{[2
]}

Menon, Vilas ^{[5
,6
,7
]}

Ge, Tian ^{[3
,4
,8
,9
]}

Finucane, Hilary K. ^{[3
,4
,10
]}

Schultz, Aaron P. ^{[2
,3
]}

Properzi, Michael ^{[2
]}

Klein, Hans-Ulrich ^{[5
,6
,7
]}

Chibnik, Lori B. ^{[2
,4
,11
]}

Schneider, Julie A. ^{[12
]}

Bennett, David A. ^{[12
]}

Hohman, Timothy J. ^{[13
]}

Mayeux, Richard P. ^{[6
,7
]}

Johnson, Keith A. ^{[1
,2
,3
,14
]}

De Jager, Philip L. ^{[5
,6
,7
]}

Sperling, Reisa A. ^{[1
,2
,3
]}

机构：

[1] Brigham & Womens Hosp, Ctr Alzheimer Res & Treatment, Dept Neurol, Boston, MA 02115 USA

[2] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[3] Harvard Med Sch, Boston, MA 02115 USA

[4] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[5] Columbia Univ, Irving Med Ctr, Ctr Translat & Computat NeuroImmunol, Dept Neurol, New York, NY USA

[6] Columbia Univ, Irving Med Ctr, Dept Neurol, New York, NY USA

[7] Columbia Univ, Irving Med Ctr, Taub Inst Study Alzheimers Dis & Aging Brain, New York, NY USA

[8] Massachusetts Gen Hosp, Ctr Genom Med, Psychiat & Neurodev Genet Unit, Boston, MA USA

[9] Massachusetts Gen Hosp, Ctr Precis Psychiat, Dept Psychiat, Boston, MA USA

[10] Massachusetts Gen Hosp, Dept Med, Boston, MA USA

[11] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[12] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL USA

[13] Vanderbilt Univ, Med Ctr, Dept Neurol, Nashville, TN USA

[14] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

基金：

美国国家卫生研究院;

关键词：

PATHOLOGY; VARIANTS; IMMUNITY; COMMON; GENES; LOCI; TAU;

D O I：

10.1038/s41467-023-43132-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Many of the Alzheimer's disease (AD) risk genes are specifically expressed in microglia and astrocytes, but how and when the genetic risk localizing to these cell types contributes to AD pathophysiology remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets and uncover the impact of cell-type-specific genetic risk on AD endophenotypes. In an autopsy dataset spanning all stages of AD (n = 1457), the astrocytic ADPRS affected diffuse and neuritic plaques (amyloid-beta), while microglial ADPRS affected neuritic plaques, microglial activation, neurofibrillary tangles (tau), and cognitive decline. In an independent neuroimaging dataset of cognitively unimpaired elderly (n = 2921), astrocytic ADPRS was associated with amyloid-beta, and microglial ADPRS was associated with amyloid-beta and tau, connecting cell-type-specific genetic risk with AD pathology even before symptom onset. Together, our study provides human genetic evidence implicating multiple glial cell types in AD pathophysiology, starting from the preclinical stage. Alzheimer's disease genetic risk is enriched in glial genes. Here, the authors derive cell-type-specific polygenic risk scores and link astrocytic genes with A beta, and microglial genes with A beta, tau, microglial activation, and cognitive decline.

引用

页数：13

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