Alzheimer's disease
Summary
Alzheimer's disease is the most common neurodegenerative disease, characterized by amyloid-beta plaque deposition, neurofibrillary tau tangles, synaptic loss, and progressive cognitive decline. Microglia are centrally implicated through both genetic evidence—with multiple GWAS risk genes expressed primarily in microglia—and functional evidence from human tissue and model systems.
Microglial Relevance
Human genetic studies have established that microglial biology is one of the primary causal axes of Alzheimer's disease risk. Risk loci including TREM2, TYROBP, CD33, APOE, PLCG2, ABI3, INPP5D, BIN1, MS4A4A, and SPI1 are expressed predominantly or specifically in microglia. Microglial states shift from homeostatic to disease-associated in proximity to amyloid plaques, with DAM signatures characterized by upregulation of TREM2, SPP1, CST7, and CLEC7A. Complement-mediated synaptic pruning through C1Q-C3-CR3 contributes to synapse loss. TREM2 supports microglial survival and plaque containment. APOE4 impairs microglial lipid metabolism and amyloid clearance.
Sources
- Microglia in Alzheimer's disease (2018)
- Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. (2019)
Last reviewed: June 1, 2026