Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss, cognitive decline, and structural brain changes.

While amyloid-beta plaques and neurofibrillary tangles have long dominated the focus of AD research, recent advances have spotlighted microglia—the brain's resident immune cells as central modulators of the disease process.

Their role extends beyond phagocytosis; they actively shape neuronal function, synaptic pruning, and inflammatory signaling. Disruption in these homeostatic activities can shift microglia from protective to pathogenic, contributing to neurodegeneration.

Microglial Surveillance and Homeostasis in the Healthy Brain

In the healthy central nervous system (CNS), microglia maintain surveillance using dynamically motile processes that scan the micro-environment. These cells express receptors like TREM2 (Triggering Receptor Expressed on Myeloid cells 2), which modulate response to neuronal injury and debris. TREM2's engagement with lipids and apoptotic cell membranes facilitates microglial survival, proliferation, and phagocytic efficiency.

Dr. Beth Stevens, a neuroscientist at Boston Children's Hospital, has emphasized that "microglia are not passive cleaners—they are architects of brain circuits." They regulate synaptic pruning during development and in response to injury, a role now suspected to contribute to synaptic loss in AD.

Transition from Homeostasis to Pathology

As Alzheimer's pathology progresses, microglia shift into a disease-associated microglial (DAM) state. This phenotype is marked by upregulation of genes like ApoE, CST7, and Spp1, and downregulation of homeostatic genes such as P2ry12 and Cx3cr1. While the DAM profile initially facilitates amyloid clearance, prolonged activation promotes chronic inflammation and neuronal damage.

This duality is driven by environmental cues within the CNS, particularly in regions of amyloid deposition. As microglia surround plaques, their secretory profile becomes proinflammatory, including release of IL-1β, TNF-α, and reactive oxygen species (ROS). These molecules exacerbate tau hyperphosphorylation and neuronal death, reinforcing a feedforward loop of degeneration.

TREM2: Genetic Insight into Microglial Function in AD

The discovery of TREM2 mutations as genetic risk factors for AD was a watershed moment in neuroimmunology. Individuals with TREM2 variants (e.g., R47H) exhibit impaired microglial clustering around amyloid plaques and reduced phagocytic activity. This results in diffuse, poorly contained plaques with higher neurotoxicity.

Recent single-cell RNA sequencing studies have confirmed that TREM2 signaling is essential for transitioning microglia into the DAM phenotype. Without it, microglia remain in a quiescent state, unable to mount an effective response to amyloid accumulation. Therapeutic approaches aiming to boost TREM2 activity or downstream signaling pathways such as DAP12-SYK are under clinical exploration.

Microglia and Tau Pathology: A Complex Relationship

Although initial AD research emphasized amyloid-beta, tau pathology correlates more closely with clinical decline. Microglia contribute to tau propagation by internalizing tau aggregates and releasing them through exosomes or dying cell remnants. Additionally, inflammatory cytokines from activated microglia can promote tau hyperphosphorylation in nearby neurons.

A 2023 study in Nature Neuroscience demonstrated that inhibiting CSF1R, a receptor essential for microglial survival, reduced tau pathology in transgenic mice. However, complete microglial depletion also led to worsened synaptic loss, indicating that a nuanced approach is required—suppressing pathological activity without compromising their protective roles.

Therapeutic Strategies Targeting Microglial Pathways

1. TREM2 Agonists

Antibodies and small molecules that activate TREM2 signaling are being tested in clinical trials. The goal is to enhance microglial phagocytosis while preserving anti-inflammatory properties. Early-stage trials using AL002 (developed by Alector and AbbVie) show promise in modulating microglial function without excessive immune activation.

2. NLRP3 Inflammasome Inhibition

Microglial inflammasome activation, particularly via NLRP3, contributes to chronic neuroinflammation. Inhibitors like MCC950 have shown efficacy in reducing IL-1β production and neuronal loss in preclinical AD models. These findings suggest a potential for inflammasome-targeted therapeutics in modulating disease progression.

3. Colony-Stimulating Factor 1 Receptor (CSF1R) Blockade

Selective CSF1R inhibitors can temporarily deplete microglia or modulate their proliferation. While early results indicate benefit in tau models, the challenge lies in timing and reversibility. Prolonged depletion may impair brain repair and immune surveillance.

Beyond Neuroinflammation: Metabolic Reprogramming of Microglia

Emerging data suggest that microglial metabolism—particularly glycolysis versus oxidative phosphorylation—dictates their functional phenotype. Activated microglia exhibit a glycolytic shift, a metabolic state linked to proinflammatory output. Reversing this metabolic programming may restore microglia to a neuroprotective state. Nicotinamide adenine dinucleotide boosters, such as NR and NMN, are being investigated for their role in enhancing mitochondrial health and reducing microglial-driven neurotoxicity.

Microglia are no longer viewed as secondary responders in Alzheimer's disease—they are now recognized as key players in both its initiation and progression. Ongoing research is unraveling the mechanisms by which microglial phenotypes evolve and influence the neuronal environment. Therapeutic strategies aimed at harnessing their regenerative and phagocytic capabilities, while curbing detrimental inflammation, are rapidly advancing toward clinical application.