Hall-Roberts, H.; Maguire, E.; Shaw, B.; O'Donoghue, R.; Winston, J.; Keat, S.; Capitani, L.; Mahoney, R.; Geary, B.; Faber, K.; Stöberl, N.; Connor-Robson, N.; Bridge, C.; Castillo Morales, A.; Bernado-Harrington, M.; Allen, N. D.; Escott-Price, V.; Webber, C.; Cowley, S. A.; Taylor, P. R.; Holmans, P.; Sims, R.; Williams, J.

Genetic discoveries implicate microglia in late-onset Alzheimer's disease (AD). We modelled AD in a powerful study of 51 human induced pluripotent stem cell (iPSC) microglia derived from high-polygenic risk AD or low-risk cognitively well individuals, sampled from a large cohort. We explored mitochondrial function, cytokine secretion, endocytosis, phagocytosis, lipid accumulation, calcium store release, and chemotaxis under basal conditions and immune challenge. High polygenic risk was independently associated with significant functional deficits in iPSC microglia under immune challenge, in mitochondrial ATP production (p=0.005, -13%), and inflammatory cytokine release (IL-6: p=0.018, -42%; TNF p=0.026, -38.5%). Furthermore, a selective deficit in amyloid-{beta} uptake was identified (p=0.00477, -5.9%). Deficits in inflammatory cytokine release were driven by APOE {epsilon}4. These findings reflect primary changes in AD pathogenesis predating plaque formation and validate a human in vitro platform for late-onset AD to further understand disease mechanisms and screen drug or genetic therapies.