Alzheimer’s disease (AD) is traditionally defined by Amyloid-β (Aβ) plaques and tau neurofibrillary tangles, yet these proteinopathies alone fail to explain disease heterogeneity, progression, and cognitive decline. Emerging evidence identifies chronic neuroinflammation as a central integrator that converts molecular pathology into synaptic failure and neurodegeneration. In this context, Aβ acts as a danger-associated molecular pattern that activates microglial and astrocytic immune programs through receptors such as TREM2, TLRs, and RAGE, leading to inflammasome activation, cytokine release, and oxidative stress. These responses pathologically re-engage developmental complement pathways (C1q–C3–CR3), driving excessive synaptic pruning that correlates more closely with cognitive impairment than neuronal loss. Reactive astrocytes further amplify dysfunction by impairing glutamate and potassium homeostasis, promoting excitotoxic and metabolic stress, while inflammatory glia facilitate prion-like tau propagation via extracellular vesicles. Concurrent neurovascular inflammation disrupts blood–brain barrier integrity and cerebral perfusion, reinforcing immune-metabolic failure. Importantly, neuroinflammatory biomarkers (GFAP, sTREM2, YKL-40, cytokines, complement, and TSPO-PET) provide dynamic readouts of disease activity and therapeutic response. Together, these findings position AD as a disorder of failed immune resolution and support precision immunomodulatory and pro-resolving therapies aimed at restoring neuroimmune homeostasis rather than merely removing protein aggregates.
Aranda-Abreu et al. (Fri,) studied this question.