Microglia in Alzheimer’s disease: from pathogenic mechanisms to therapeutic targeting
5 affiliations
- 1Department of Laboratory Medicine, Shifang People’s Hospital
- 2Chongqing Key Laboratory of Sichuan-Chongqing Co-Construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, College of Medical Technology, Chengdu University of Traditional Chinese Medicine
- 3Department of Orthopedics, People’s Hospital of Deyang City
- 4Department of Anesthesiology, Chengdu Shangjin Nanfu Hospital
- 5Yan’an Medical College, Yan’an University
Abstract
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder driven by β-amyloid (Aβ) deposition, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, vascular injury, and metabolic dysregulation. Recent advances in single-cell, spatial, and multi-omics transcriptomics have substantially reshaped our understanding of microglia, shifting the field from the classical M1/M2-like polarization dichotomy toward a model of state-dependent functional heterogeneity. Distinct subpopulations-including disease-associated microglia, lipid-associated microglia, interferon-responsive microglia, and senescence-associated microglia are now mechanistically linked to Aβ clearance, tau propagation, complement-mediated synaptic pruning, NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, and immunometabolic reprogramming. Central to this regulatory network are the TREM2-ApoE axis, complement cascades, NLRP3 inflammasome, mitochondrial dysfunction, and aberrant lipid/iron metabolism, which largely contribute to AD progression. In parallel, the clinical deployment of anti-Aβ monoclonal antibodies such as lecanemab has ushered in the era of disease-modifying therapy; however, limited efficacy and the occurrence of amyloid-related imaging abnormalities underscore that Aβ removal alone is insufficient to halt disease evolution completely. In this review, we systematically synthesize the evolving landscape of microglial states and their pathogenic contributions, and we further evaluate current therapeutic avenues, including microglia-targeted strategies, anti-Aβ antibody combination regimens, non-pharmacological interventions, and peripheral immunomodulation. We also compare these microglial mechanisms with those in multiple sclerosis to highlight shared neuroimmune modules and disease-specific features. Our goal is to provide a valuable updated reference for accurate molecular subtyping and multi-target combination therapy in AD.
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BibTeX
@article{tang2026microglia,
title = {{Microglia in Alzheimer’s disease: from pathogenic mechanisms to therapeutic targeting}},
author = {Ling Tang and Xiao-Yan Li and Zhao Ran and Zhu-Zhu Qin and Shi-Yan Chen and Miao-Miao Zhang and Lin-Ying Zhou and Wen-Jun Wang and Liang Chen},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1952810},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1952810/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Microglia in Alzheimer’s disease: from pathogenic mechanisms to therapeutic targeting
AU - Ling Tang
AU - Xiao-Yan Li
AU - Zhao Ran
AU - Zhu-Zhu Qin
AU - Shi-Yan Chen
AU - Miao-Miao Zhang
AU - Lin-Ying Zhou
AU - Wen-Jun Wang
AU - Liang Chen
PY - 2026
DA - 2026/10/26
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1952810
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1952810/full
AB - Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder driven by β-amyloid (Aβ) deposition, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, vascular injury, and metabolic dysregulation. Recent advances in single-cell, spatial, and multi-omics transcriptomics have substantially reshaped our understanding of microglia, shifting the field from the classical M1/M2-like polarization dichotomy toward a model of state-dependent functional heterogeneity. Distinct subpopulations-including disease-associated microglia, lipid-associated microglia, interferon-responsive microglia, and senescence-associated microglia are now mechanistically linked to Aβ clearance, tau propagation, complement-mediated synaptic pruning, NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, and immunometabolic reprogramming. Central to this regulatory network are the TREM2-ApoE axis, complement cascades, NLRP3 inflammasome, mitochondrial dysfunction, and aberrant lipid/iron metabolism, which largely contribute to AD progression. In parallel, the clinical deployment of anti-Aβ monoclonal antibodies such as lecanemab has ushered in the era of disease-modifying therapy; however, limited efficacy and the occurrence of amyloid-related imaging abnormalities underscore that Aβ removal alone is insufficient to halt disease evolution completely. In this review, we systematically synthesize the evolving landscape of microglial states and their pathogenic contributions, and we further evaluate current therapeutic avenues, including microglia-targeted strategies, anti-Aβ antibody combination regimens, non-pharmacological interventions, and peripheral immunomodulation. We also compare these microglial mechanisms with those in multiple sclerosis to highlight shared neuroimmune modules and disease-specific features. Our goal is to provide a valuable updated reference for accurate molecular subtyping and multi-target combination therapy in AD.
SN - 1664-3224
ER -