A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer's disease

被引：346

作者：

Mostafavi, Sara ^{[1
,2
]}

Gaiteri, Chris ^{[3
]}

Sullivan, Sarah E. ^{[4
]}

White, Charles C. ^{[5
]}

Tasaki, Shinya ^{[3
]}

Xu, Jishu ^{[5
]}

Taga, Mariko ^{[5
,6
]}

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

Patrick, Ellis ^{[7
]}

Komashko, Vitalina ^{[3
]}

McCabe, Cristin ^{[5
]}

Smith, Robert ^{[4
]}

Bradshaw, Elizabeth M. ^{[5
,6
]}

Root, David E. ^{[5
]}

Regev, Aviv ^{[5
]}

Yu, Lei ^{[3
]}

Chibnik, Lori B. ^{[5
,8
,9
]}

Schneider, Julie A. ^{[3
]}

Young-Pearse, Tracy L. ^{[4
,8
]}

Bennett, David A. ^{[3
]}

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

机构：

[1] Univ British Columbia, Dept Med Genet, Dept Stat, Vancouver, BC, Canada

[2] Canadian Inst Adv Res, Toronto, ON, Canada

[3] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA

[4] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA

[5] Broad Inst, Cambridge, MA 02142 USA

[6] Columbia Univ, Dept Neurol, Med Ctr, Ctr Translat & Computat Neuroimmunol, New York, NY 10027 USA

[7] Univ Sydney, Sydney, NSW, Australia

[8] Harvard Med Sch, Boston, MA USA

[9] Harvard TH Chan Sch Publ Hlth, Boston, MA USA

来源：

NATURE NEUROSCIENCE | 2018年 / 21卷 / 06期

关键词：

GENE-EXPRESSION; NEURONS; NEUROPATHOLOGY; DEMENTIA; MEMORY; MOUSE; IMPAIRMENT; ALIGNMENT; DATABASE; VARIANTS;

D O I：

10.1038/s41593-018-0154-9

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

There is a need for new therapeutic targets with which to prevent Alzheimer's disease (AD), a major contributor to aging-related cognitive decline. Here we report the construction and validation of a molecular network of the aging human frontal cortex. Using RNA sequence data from 478 individuals, we first build a molecular network using modules of coexpressed genes and then relate these modules to AD and its neuropathologic and cognitive endophenotypes. We confirm these associations in two independent AD datasets. We also illustrate the use of the network in prioritizing amyloid-and cognition- associated genes for in vitro validation in human neurons and astrocytes. These analyses based on unique cohorts enable us to resolve the role of distinct cortical modules that have a direct effect on the accumulation of AD pathology from those that have a direct effect on cognitive decline, exemplifying a network approach to complex diseases.

引用

页码：811 / +

页数：13

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