Physical activity relates to reduced dementia risk, but the cellular and molecular mechanisms are unknown. We translated animal and in vitro studies demonstrating a causal link between physical activity and microglial homeostasis into humans. Decedents from Rush Memory and Aging Project completed actigraphy monitoring (average daily activity) and cognitive evaluation in life, and neuropathological examination at autopsy. Brain tissue was analyzed for microglial activation via immunohistochemistry (anti-human HLA-DP-DQ-DR) and morphology (% Stage I, II, or III), and synaptic protein levels (SNAP-25, synaptophysin, complexin-I, VAMP, syntaxin, synaptotagmin-1). Proportion of morphologically activated microglia (PAM) was estimated in ventromedial caudate, posterior putamen, inferior temporal (IT), and middle frontal gyrus. The 167 decedents averaged 90 years at death, two-thirds were nondemented, and 60% evidenced pathologic Alzheimer's disease (AD). Adjusting for age, sex, education, and motor performances, greater physical activity associated with lower PAM in the ventromedial caudate and IT. Relationships between physical activity and PAM in the ventromedial caudate or IT were particularly prominent in adults evidencing microinfarcts or AD pathology, respectively. Mediational analyses indicated that PAM IT mediated ∼30% of the relationships between (1) physical activity and synaptic protein in IT, and (2) physical activity and global cognition, in separate models. However, the size of the mediation depended on AD pathology ranging from >40% in adults with high AD burden, but <10% in adults with low AD burden. Lower microglial activation may be a pathway linking physical activity to age-related brain health in humans. Physical activity may promote AD-related synaptic and cognitive resilience through reduction of pro-inflammatory microglial states.SIGNIFICANCE STATEMENT Physical activity relates to better cognitive aging and reduced risk of neurodegenerative disease, yet the cellular and molecular pathways linking behavior-to-brain in humans are unknown. Animal studies indicate that increasing physical activity leads to decreased microglial activation and corresponding increases in synaptogenesis and neurogenesis. We objectively monitored physical activity (accelerometer-based actigraphy) and cognitive performances in life, and quantified microglial activation and synaptic markers in brain tissue at death in older adults. These are the first data supporting microglial activation as a physiological pathway by which physical activity relates to brain heath in humans. Although more interventional work is needed, we suggest that physical activity may be a modifiable behavior leveraged to reduce pro-inflammatory microglial states in humans.
Keywords: Alzheimer's disease; HLA; exercise; major histocompatibility complex II.
Copyright © 2022 the authors.