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Abstract
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 β-amyloid, tau-related neuropathology, and the rate of cognitive decline. Effect sizes for PAM measures are substantial, comparable to that of APOE ε4, 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.

Author information

Felsky D1,2, Roostaei T1, Nho K3, Risacher SL3, Bradshaw EM1, Petyuk V4, Schneider JA5,6, Saykin A3, Bennett DA5,6, De Jager PL7,8.
1
Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.
2
Program in Population and Medical Genetics, Broad Institute of MIT and Harvard, 320 Charles Street, Cambridge, MA, 02141, USA.
3
Indiana Alzheimer's Disease Center, Center for Neuroimaging, Department of Radiology and Imaging Sciences, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, 355 West 16th Street, Indianapolis, IN, 46202, USA.
4
Pacific Northwest National Laboratory, Richland, WA, 99354, USA.
5
Department of Neurology, Rush University Medical Center, 1653 West Congress Parkway, Chicago, IL, 60612, USA.
6
Rush Alzheimer's Disease Center, Rush University Medical Center, 1653 West Congress Parkway, Chicago, IL, 60612, USA.
7
Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA. pld2115@cumc.columbia.edu.
8
Program in Population and Medical Genetics, Broad Institute of MIT and Harvard, 320 Charles Street, Cambridge, MA, 02141, USA. pld2115@cumc.columbia.edu.