Authors
Ahmed M Abdelaziz, Fatma S Eltyar
Published in
Clinical immunology (Orlando, Fla.). Pages 110777. Aug 28, 2026. Epub Aug 28, 2026.
Abstract
Anti-amyloid-β monoclonal antibodies have established immunotherapy as a viable approach for Alzheimer's disease, yet all α-synuclein and tau antibodies tested to date have failed clinically. These setbacks offer invaluable immunology lessons reshaping next-generation therapeutic development. Four key lessons emerge: epitope specificity determines outcomes, with mid-domain and microtubule-binding region antibodies showing promise over failed N-terminal approaches; biomarker-driven stratification using p-tau217 and AI algorithms can unmask efficacy in rapid progressors; most patients harbor mixed proteinopathies, rendering monotherapy insufficient and mandating combination immunotherapy; and neuroinflammation, particularly NLRP3 activation and microglial dysfunction, represents a convergent pathway targetable independently of upstream triggers. Emerging approaches include conformation-specific antibodies, protein-protein interaction inhibitors, and immune checkpoint targeting, such as anti-SIGLEC-10, to restore phagocytosis. These insights inform biomarker-enriched trials and combination regimens, although clinical evidence for specific combinations remains limited and requires validation. The systems framework targeting aggregation, neuroinflammation, and immunity offers a promising paradigm yet awaits empirical testing.
PMID:
42665238
Bibliographic data and abstract were imported from PubMed on 29 Aug 2026.
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