Mechanisms, Biomarkers and Therapeutic Implications of Neuroinflammation in Alzheimer's Disease
TL;DR
The dual and stage‐dependent roles of microglia and astrocytes are explored, discussion of blood–brain barrier dysfunction and peripheral immune infiltration as underappreciated pathogenic contributors are expanded, and emerging evidence linking neuroinflammation specifically to tau pathology is integrated.
Abstract
Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder worldwide, affecting millions of individuals and imposing substantial socioeconomic burdens. While traditional research has focused on amyloid‐β (Aβ) plaques and neurofibrillary tangles as primary pathological hallmarks, mounting evidence implicates neuroinflammation as a critical third pillar in AD pathogenesis. This review critically evaluates current understanding of neuroinflammatory mechanisms in AD, examining the complex interplay between cellular mediators, molecular pathways and environmental triggers across a temporal disease‐stage framework. We explore the dual and stage‐dependent roles of microglia and astrocytes, expand discussion of blood–brain barrier (BBB) dysfunction and peripheral immune infiltration as underappreciated pathogenic contributors, and integrate emerging evidence linking neuroinflammation specifically to tau pathology and its stereotyped propagation through the brain. Diagnostic biomarkers, including translocator protein–positron emission tomography (TSPO‐PET) and plasma glial fibrillary acidic protein (GFAP), are evaluated with explicit attention to clinical utility, technical limitations, and their relationship to established AD biomarkers. Therapeutic strategies are critically assessed with careful distinction between preclinical proof‐of‐concept data and available clinical evidence, and key translational challenges are highlighted throughout. The review emphasizes the need for stage‐appropriate intervention windows, patient stratification by neuroinflammatory endotype, and biologically rational combination strategies. Understanding neuroinflammation's temporal and spatial dynamics offers promising but as yet insufficiently realized avenues for early intervention and disease modification in AD.