Neuropathological correlates and genetic architecture of microglial activation in elderly human brain

Felsky, Daniel; Roostaei, Tina; Nho, Kwangsik; Risacher, Shannon L.; Bradshaw, Elizabeth M.; Petyuk, Vlad A.; Schneider, Julie A.; Saykin, Andrew; Bennett, David A.; De Jager, Philip L.

doi:10.1038/s41467-018-08279-3

Title: Neuropathological correlates and genetic architecture of microglial activation in elderly human brain

Journal Article · 23 January 2019 · Nature Communications

DOI: https://doi.org/10.1038/s41467-018-08279-3 · OSTI ID:1591798

Felsky, Daniel ^[1];

^[2]; Nho, Kwangsik ^[3]; Risacher, Shannon L. ^[3]; Bradshaw, Elizabeth M. ^[2];

^[4]; Schneider, Julie A. ^[5];

^[3]; Bennett, David A. ^[5];

^[1]

Columbia Univ. Medical Center, New York, NY (United States); Broad Inst. of MIT and Harvard, Cambridge, MA (United States)
Columbia Univ. Medical Center, New York, NY (United States)
Indiana Univ. School of Medicine, Indianapolis, IN (United States)
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Rush Univ. Medical Center, Chicago, IL (United States)

Microglia, the resident immune cells of the brain, have important roles in brain health. However, little is known about the regulation and consequences of microglial activation in the aging human brain. Here we report that the proportion of morphologically activated microglia (PAM) in postmortem cortical tissue is strongly associated with ß-amyloid, tau-related neuropathology, and the rate of cognitive decline. Effect sizes for PAM measures are substantial, comparable to that of APOE e4, the strongest genetic risk factor for Alzheimer's disease, and mediation models support an upstream role for microglial activation in Alzheimer's disease via accumulation of tau. Further, we identify a common variant (rs2997325) influencing PAM that also affects in vivo microglial activation measured by [¹¹C]-PBR28 PET in an independent cohort. Thus, our analyses begin to uncover pathways regulating resident neuroinflammation and identify overlaps of PAM's genetic architecture with those of Alzheimer's disease and several other traits.

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Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 1591798

Report Number(s):: PNNL-SA--147570

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 10; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Title: Neuropathological correlates and genetic architecture of microglial activation in elderly human brain

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