The Major Risk Factors for Alzheimer's Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques.

Summary Gene expression profilesof more than 10,000 individual microglial cellsisolated from cortex and hippocampus of male and female App NL-G-F mice over time demonstrate that progressive amyloid-β accumulation accelerates two main activated microgliastates that are also present during normal aging. Activated response microglia(ARMs) are composed of specialized subgroups overexpressing MHC type II and putative tissue repair genes ( Dkk2 , Gpnmb, and Spp1 ) and are strongly enriched with Alzheimer’s disease (AD) risk genes. Microgliafrom female mice progress faster in this activation trajectory. Similar activated states are also found in a second AD model and in human brain. Apoe , the major genetic risk factor for AD, regulates the ARMs but not the interferon response microglia(IRMs). Thus, the ARMs response is the converging point for aging, sex, and genetic AD risk factors.