Neuroinflammation across neurodegenerative diseases: an aging-conditioned convergence–divergence framework for precision neuroimmunology

Abstract

Neuroinflammation is increasingly recognized as a disease-shaping component of neurodegeneration rather than a secondary response to neuronal injury. This review integrates mechanistic and translational evidence across Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis/frontotemporal dementia, Huntington’s disease, and progressive multiple sclerosis to advance an aging-conditioned convergence–divergence framework. In this model, aging and inflammaging establish a susceptible neuroimmune ground state through microglial priming, cellular senescence, mitochondrial and lysosomal dysfunction, impaired inflammatory resolution, blood–brain barrier deterioration, and increased peripheral–central immune coupling. Distinct initiating lesions subsequently converge on a restricted immune–glial architecture involving NLRP3 inflammasome activation, cGAS–STING and interferon signaling, NF-κB/JAK–STAT/MAPK networks, complement-mediated synaptic vulnerability, TREM2-dependent microglial programs, and immunometabolic dysfunction. However, the cellular source, anatomical distribution, timing, intensity, and functional consequences of these shared pathways diverge according to disease type, stage, genotype, regional vulnerability, and systemic context. Convergence therefore defines the common mechanistic architecture, whereas conditional divergence explains disease-specific inflammatory signatures and supports precision neuroimmunology. Therapeutic evidence further indicates that molecular selectivity alone is insufficient; effective intervention requires confirmation of causal pathway activity, central nervous system exposure, target engagement, appropriate timing, and biomarker-defined patient selection. Neuroimmune therapies should therefore prioritize restoration of homeostatic and pro-resolving functions over indiscriminate suppression and be evaluated within defined inflammatory endotypes using mechanistically aligned biomarkers and testable hypotheses.

Keywords: Neuroinflammation, neurodegenerative diseases, microglia, astrocyte reactivity, inflammasome signaling, precision neuroimmunology