Glial Dysfunction in Alzheimer's Disease: Contributions to Disease Progression, Pathomechanism and Therapeutic Opportunities.

Abstract

Abstract
Alzheimer's disease (AD), the most common cause of dementia, remains a major neurodegenerative disorder with an incompletely understood etiology despite decades of research. While beta-amyloid (A?) plaques and neurofibrillary tau tangles represent the defining pathological hallmarks of AD, growing evidence indicates that the disease's progression is profoundly influenced by chronic neuroinflammation. Microglia and astrocytes, which are essential for maintaining neuronal homeostasis, clear A? plaques, support vascular and synaptic function, and undergo a pathological shift in AD from protective regulators to dysfunctional, pro-inflammatory mediators. This transition is characterized by impaired A? phagocytosis, excessive cytokine release, oxidative stress, and blood-brain-barrier (BBB) disruption, all of which contribute to synaptic loss and neurodegeneration. However, the mechanisms driving glial failure remain poorly defined, leaving unresolved questions about whether neuroinflammation in AD acts as an amplifier of existing pathology or a downstream consequence. This literature review examines recent evidence on microglial and astrocytic dysfunction in AD, evaluates proposed cellular and molecular mechanisms underlying their pathological transformation, and explores the potential for glial-targeted interventions. Emerging research suggests that restoring glial function, rather than solely targeting A? plaques or tau tangles, may offer a promising strategy to slow or delay AD progression by enhancing A? clearance, maintaining metabolic and vascular stability, and reducing inflammatory neurotoxicity.