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Abstract The complement system, a critical arm of innate immunity, has emerged as a key contributor to the pathogenesis of Alzheimer’s disease (AD). While complement-mediated synaptic pruning is essential during brain development, its reactivation in the aging and diseased brain can promote neurodegeneration. In AD and cerebral amyloid angiopathy (CAA), aberrant complement activity contributes to amyloid-β (Aβ) accumulation, synapse loss, neuroinflammation, vascular dysfunction and blood-brain barrier (BBB) disruption. This review traces the evolving understanding of complement dysregulation in AD, from foundational findings in human studies to mechanistic discoveries in animal models and emerging induced pluripotent stem cell (iPSC)-derived cellular systems. It describes how genetic and epigenetic factors, including risk variants, chromatin modifications, and microRNAs, modulate complement pathways in the AD brain. Systemic influences, such as gut-brain axis disruption, are also considered for their potential to exacerbate complement-mediated neuroinflammation in AD. We further highlight efforts to identify biomarkers of complement activation and review the therapeutic potential of targeting complement components and regulators. By integrating molecular, experimental, and translational perspectives, this review outlines the multifaceted involvement of complement in AD and discusses key directions for future research and therapeutic interventions.
Papavergi et al. (Mon,) studied this question.