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.
Highlights
Microglia, the resident immune cells of the brain, have important roles in brain health
Stage III microglial density was different between Alzheimer’s disease (AD) and non-AD subjects, though this was only true in cortical regions (midfrontal (MF) p = 1.5 × 10−8, Cohen’s d[95%CI] = 0.80 [0.52,1.08]; inferior temporal (IT) p = 6.4 × 10−9, Cohen’s d[95% CI] = 0.84[0.55,1.12])
A stronger association was observed with the proportion of stage III microglia density relative to total microglia (MF p = 1.8 × 10−10, Cohen’s d[95%CI] = 0.91[0.63,1.19]; IT p = 1.5 × 10−11, Cohen’s d[95%CI] = 0.99[0.70,1.28]), confirming that morphologically activated microglia rather than the total number of microglia is most important for the accumulation of AD-related pathology in aging[6,7]
Summary
The resident immune cells of the brain, have important roles in brain health. We leverage two large cohort studies of cognitive aging that include antemortem longitudinal cognitive assessments and structured postmortem histopathological evaluations to characterize a postmortem measure of microglial activation, directly observed by immunohistochemical staining and light microscopy. This morphological assessment of microglial activation stage represents a clear and robust measurement of neuroinflammation that cannot be captured by a surrogate marker. We first examine how this measure relates to different agingrelated pathologies We follow this with causal mediation analyses aimed at placing microglial activation temporally within the cascade of pathological events leading to AD.
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