For decades, Alzheimer's research centered almost exclusively on amyloid clearance and tau stabilization — yet the brain's own immune cells may be the missing variable that determines whether those pathological proteins cause damage or are contained. A growing body of neuroimmunology evidence is repositioning microglia not as passive bystanders but as active arbiters of disease trajectory, capable of either slowing or accelerating neurodegeneration depending on their activation state.
This comprehensive review in the Journal of Neuroimmunology synthesizes the rapidly expanding literature on microglial biology in Alzheimer's disease, with particular attention to disease-associated microglia (DAM) — a transcriptionally distinct subpopulation identified through single-cell genomic profiling that emerges specifically in response to amyloid-β accumulation. The review maps the functional consequences of key microglial receptors, notably TREM2 and APOE, which modulate phagocytic clearance of amyloid plaques, and extends the analysis to neurotransmitter receptors — cholinergic, glutamatergic, and cannabinoid — whose microglial expression links immune activation to synaptic excitotoxicity. Metabolic reprogramming of microglia during aging, which impairs their homeostatic surveillance functions, is identified as a critical and underappreciated disease accelerant. Therapeutic avenues reviewed include pharmacological targeting of neuroinflammatory cascades, metabolic restoration strategies, and experimental microglial cell transplantation.
The field's pivot toward microglia reflects a broader maturation of neuroinflammation research. Genome-wide association studies have repeatedly flagged immune-related genes — including TREM2 variants — as significant Alzheimer's risk loci, lending genetic credibility to the microglial hypothesis. However, this review is a synthesis of existing data rather than new clinical trial evidence, and several barriers to translation remain formidable: the dual neuroprotective and neurotoxic capacity of microglia means that non-selective immune suppression risks worsening outcomes, while the optimal timing of intervention across disease stages is poorly defined. Single-cell genomics offers resolution to the heterogeneity problem, but converting transcriptomic signatures into druggable targets is still an early-stage endeavor. This is a confirmatory, field-consolidating review — valuable as a strategic orientation but not itself a clinical breakthrough.