PILRA (paired immunoglobulin-like type 2 receptor alpha) is an inhibitory receptor expressed on myeloid cells, particularly microglia, containing an immunoreceptor tyrosine-based inhibitory motif domain 1. PILRA functions as a ligand for CD8α, maintaining CD8+ T cell quiescence through direct cell-cell interactions in the absence of antigen exposure 2. The receptor shows MHC class I protein binding capacity and associates with extracellular exosomes [GO annotations]. PILRA has emerged as a significant Alzheimer's disease (AD) risk gene identified through genome-wide meta-analysis and fine-mapping studies 3. The gene is differentially expressed in microglia in relation to amyloid-beta and phospho-tau pathology 4. Mechanistically, plasma PILRA abundance associates causally with AD risk 5, and the protein influences caudate nucleus volume 6. Notably, loss of PILRA in microglia rescues ApoE4-mediated immunometabolic deficits, enhances chemotaxis, reduces inflammation, and decreases amyloid pathology in AD mouse models 1. The protective PILRA G78R variant reduces AD risk in APOE4 carriers and is enriched in healthy centenarians 1. Clinically, PILRA represents a pharmacologically tractable therapeutic target, with high-affinity ligand-blocking antibodies phenocopying knockout effects 1. This positions PILRA inhibition as a potential disease-modifying strategy for AD through microglial immunometabolic restoration.