The neuroimmune network in Alzheimer’s and Parkinson’s diseases: from mechanistic insights to biomarker-guided immunotherapies and clinical translation

Abstract

Neurodegenerative disorders such as Alzheimer’s (AD) and Parkinson’s (PD) have traditionally been examined from the perspectives of neurons or microglia, resulting in constrained therapeutic achievements. Recent findings endorse a cohesive neuroimmune framework in which central nervous system (CNS)-resident microglia, border-associated macrophages, clonally proliferated CD8+ T cells, and peripheral signaling centers (IL-20 family, gut-brain axis) perpetuate chronic maladaptive inflammation via feed-forward mechanisms. This review critically examines investigational immunotherapies aimed at this network: the CNS‑penetrant NLRP3 inhibitor NT-0796 (Phase 1b/2a) demonstrated preliminary biomarker reductions in axonal damage and T-cell activation in PD but remains unapproved and necessitates further confirmatory trials; the anti‑SIGLEC10 antibody ONC-841 improved microglial phagocytosis of Aβ and tau in preclinical studies but has yet to commence human trials; and CAR‑based platforms (CAR-T/NK) remain in the nascent preclinical phase, facing significant delivery and toxicity challenges. A three-part biomarker framework, encompassing target engagement (CSF IL-1β, caspase-1), pharmacodynamic responses (neurofilament light chain, ASC specks), and predictive endotyping (T-cell clonality, complement profiles), is proposed to facilitate patient stratification by neuroimmune endotype. None of these agents have received regulatory approval for neurodegenerative conditions; all findings are preliminary. Effective immunotherapy may ultimately necessitate multi-node, network-aware combinations (e.g., inflammasome inhibition coupled with Treg augmentation) rather than single-target suppression. Embracing this complexity offers a roadmap for future disease-modifying therapies, though rigorous clinical validation remains essential. Neuroimmune networks, not microglia alone, drive chronic neuroinflammation in neurodegeneration. Clonally expanded CD8+ T cells actively contribute to neuronal damage in neurodegeneration. First-in-class CNS-penetrant inhibitor NT-0796 of the NLRP3 protein shows biomarker responses in Parkinson’s disease. Peripheral IL-20 family and gut-brain axis offer accessible targets for neuroimmune modulation. Biomarker-guided stratification and multi-node combinations are essential for neuroimmune therapy success. Neuroimmune networks, not microglia alone, drive chronic neuroinflammation in neurodegeneration. Clonally expanded CD8+ T cells actively contribute to neuronal damage in neurodegeneration. First-in-class CNS-penetrant inhibitor NT-0796 of the NLRP3 protein shows biomarker responses in Parkinson’s disease. Peripheral IL-20 family and gut-brain axis offer accessible targets for neuroimmune modulation. Biomarker-guided stratification and multi-node combinations are essential for neuroimmune therapy success.