👤 Prarthana Kalerammana Gopalakrishna

Alzheimer’s disease (AD) is increasingly recognized as a disorder of dysregulated neuroimmune connectivity rather than isolated proteinopathy. The immuno-glial connectome, the dynamic interplay between microglia, astrocytes, and peripheral immune systems, constitutes a central driver of disease initiation and progression. Emerging single-cell and spatial transcriptomic studies reveal heterogeneous glial subpopulations with context-dependent transcriptional programs governed by TREM2–APOE, NF-κB, JAK/STAT, and NLRP3 inflammasome signaling. These networks converge to sustain chronic inflammation, impair amyloid-β clearance, and accelerate tau pathology. Complement dysregulation (C1q–C3 axis) further promotes aberrant synaptic pruning, while cytokine feedback loops involving IL-1β, TNF-α, and IFN-γ amplify neurotoxicity. Beyond the brain, peripheral immune cells, monocytes, macrophages, T and B lymphocytes, and neutrophils breach the compromised blood–brain barrier (BBB), perpetuating inflammatory cascades. Parallelly, gut dysbiosis and microbial metabolites modulate microglial reactivity via the gut–brain axis (GBA), linking systemic inflammation to central immune activation. Recent advances in plasma and cerebrospinal biomarkers (GFAP, sTREM2, YKL-40, and neurofilament light chain) enable in vivo tracking of neuroinflammatory dynamics, bridging mechanistic research with clinical translation. Therapeutic strategies targeting the immuno-glial interface, including selective NLRP3 inhibitors, TREM2 agonists, anti-cytokine biologics, and microbiome modulation, are reshaping the therapeutic landscape. Framed through the concept of an immune–glial connectome, this review synthesizes how coordinated interactions among microglia, astrocytes, and peripheral immune cells converge to drive synaptic dysfunction, circuit-level disintegration, and cognitive decline in neurodegenerative disease, particularly in AD. An immuno-glial network in AD, where central glia, peripheral immune cells, and the gut–brain axis interact through cytokines, oxidative stress, and barrier dysfunction. These interrelated pathways amplify inflammation via NF-κB, JAK/STAT, and NLRP3 signaling, linking immune dysregulation to neurodegeneration. [Image: see text] Show less

Despite decades of research, Alzheimer's disease (AD) remains without a curative therapy. While amyloid- and tau-centered approaches have dominated the field, failures of monotherapeutic strategies underscore the need for a broader system-level understanding. Here, this review critically revisits the principal hypotheses of AD pathogenesis, including the amyloid cascade, tauopathy, neuroinflammation, cholinergic dysfunction, oxidative and mitochondrial stress, metal dyshomeostasis, autophagy-lysosomal failure, genetic susceptibility, and infectious triggers. This review synthesizes molecular and cellular evidence from human genetics, neuropathology, and experimental models, correcting common misconceptions and emphasizing interactions between pathways. Neuroinflammation is increasingly recognized as a central hub linking amyloid, tau, and vascular factors, while mitochondrial and lysosomal dysfunctions emerge as amplifiers of proteotoxic stress. Genetic studies highlight apolipoprotein-E ε4 (APOE ε4) as the strongest common risk allele, but also implicate genes involved in endosomal trafficking, lipid metabolism, and immune regulation. Taken together, AD is best understood as a multi-hit disorder in which converging processes, rather than a single driver, dictate disease initiation and progression. This narrative review proposes a systems neurobiology framework that integrates these mechanisms and identifies key points of convergence amenable to therapeutic targeting and biomarker development. Finally, this reappraisal aims to inform future research directions and guide the rational design of multi-target interventions. Show less