Bedford, Logan M.Tutrow, Kaylee D.Hooper, KarlyMessenger, Evan J.Hernandez, MelodyLamb, Bruce T.Meyer, Jason S.Richardson, Timothy I.Bissel, Stephanie J.2025-11-032025-11-032025Bedford LM, Tutrow KD, Hooper K, et al. Alzheimer's disease-associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell-derived microglia-like cells. Alzheimers Dement. 2025;21(10):e70772. doi:10.1002/alz.70772https://hdl.handle.net/1805/52007Introduction: Variants of phospholipase C gamma 2 (PLCG2), a key microglial immune signaling protein, are genetically linked to Alzheimer's disease (AD) risk. Understanding how PLCG2 variants alter microglial function is critical for identifying mechanisms that drive neurodegeneration or resiliency in AD. Methods: Induced pluripotent stem cell (iPSC) -derived microglia carrying the protective PLCG2P522R or risk-conferring PLCG2M28L variants, or loss of PLCG2, were generated to ascertain the impact on microglial transcriptome and function. Results: Protective PLCG2P522R microglia showed significant transcriptomic similarity to isogenic controls. In contrast, risk-conferring PLCG2M28L microglia shared similarities with PLCG2KO microglia, with functionally reduced TREM2 expression, blunted inflammatory responses, and increased proliferation and cell death. Uniquely, PLCG2P522R microglia showed elevated cytokine secretion after lipopolysaccharide (LPS) stimulation and were protected from apoptosis. Discussion: These findings demonstrate that PLCG2 variants drive distinct microglia transcriptomes that influence microglial functional responses that could contribute to AD risk and protection. Targeting PLCG2-mediated signaling may represent a powerful therapeutic strategy to modulate neuroinflammation. Highlights: The impact of Alzheimer's disease protective- and risk-associated variants of phospholipase C gamma 2 (PLCG2) on the transcriptome and function of induced pluripotent stem cell (iPSC) -derived microglia was investigated. PLCG2 risk variant microglia exhibited a basal transcriptional profile similar to PLCG2-deficient microglia but significantly different from isotype control and the transcriptionally similar PLCG2 protective variant microglia. PLCG2 risk variant and PLCG2-deficient microglia show decreased levels of triggering receptor expressed on myeloid cells 2 (TREM2). The differential transcriptional pathways of protective and risk-associated PLCG2 variant microglia functionally affect proliferation, apoptosis, and immune response. Protective PLCG2 microglia show resilience to apoptosis and increased cytokine/chemokine secretion upon exposure to lipopolysaccharide (LPS).en-USAttribution-NonCommercial 4.0 InternationalAlzheimer's diseaseMicrogliaInduced pluripotent stem cellsGenetic variantsGenetic predisposition to diseaseApoptosisCell deathCell proliferationPhenotypeArticle