Microglial Dynamics in Alzheimer's: Genetic Variants and Therapeutic Pathways

Microglia are pivotal players in the neuroinflammatory landscape of Alzheimer’s disease (AD). Accumulating evidence underscores their complex role in modulating amyloid plaque dynamics, neuronal integrity, and synaptic function. Recent genome-wide association and sequencing studies have revealed that the majority of AD risk loci are highly expressed in microglia. Variants in a broad network of microglial genes—including TREM2, ABI3, PLCG2, INPP5D, CD33, SPI1 and the MS4A cluster—can fundamentally alter microglial behavior and reactivity. While activated microglia may drive beneficial amyloid clearance and neuroprotective signaling, they can also contribute to pathological synaptic pruning and chronic neuroinflammation, creating a spectrum of responses that complicates our understanding of their exact role in AD pathogenesis. Innovative technologies, such as spatial transcriptomics and in vivo imaging, are now enabling detailed mapping of microglial states in relation to broader genetic backgrounds and disease progression, highlighting previously unappreciated cellular heterogeneity.This Research Topic seeks to clarify the multifaceted contributions of microglial genetic variants and their functional consequences in Alzheimer’s disease. Our primary aim is to delineate how distinct genetic risk factors (such as variants in TREM2, ABI3, PLCG2, INPP5D, CR1) drive divergent microglial responses to amyloid and tau pathology, ultimately influencing disease outcomes. We encourage the exploration of emerging methods—including advanced transcriptomics, live imaging, and cell-specific manipulation—to uncover the complex signaling networks mediating microglial impacts on synaptic health and neuronal survival. Furthermore, we aim to understand how these mechanistic insights can be translated into targeted therapeutic interventions, with a focus on identifying novel strategies to fine-tune microglial activity for disease modification and neuroprotection in AD.This Research Topic invites articles that probe the breadth of microglial genetics and function in Alzheimer’s disease. Contributions may address, but are not limited to, the following themes:• Effects of microglial risk genes and their specific variants (e.g., TREM2, PLCG2, INPP5D, CD33, MS4A family and others) on AD progression and microglial state transitions.• The dual role of microglia: pathological synaptic pruning and neuroinflammation versus amyloid clearance and neuroprotection.• Mechanistic studies leveraging spatial transcriptomics, single-cell RNA sequencing, and in vivo imaging to map microglial heterogeneity.• Therapeutic approaches targeting microglial activity, neuroimmune signaling networks, or specific gene pathways.• Biomarker discovery for monitoring microglial dynamics.We encourage a wide range of submissions, including original research, methods papers, brief research reports, data reports, systematic reviews, mini reviews and perspectives. Topic editors: Giedre Milinkeviciute, Philippe Léon Louis POINDRON Source: https://www.frontiersin.org/research-topics/80449/microglial-dynamics-in-alzheimers-genetic-variants-and-therapeutic-pathways