Neuronal autoantibodies in neurodegenerative dementia: From evidence to clinical framework

Neuronal autoantibodies, including against neuronal surface receptors or intracellular antigens, are established pathogenic mediators and therapeutic targets in autoimmune encephalitis (AIE) and paraneoplastic neurological syndromes (PNS). These antibodies are now increasingly reported in patients with clinically diagnosed neurodegenerative dementia, prompting re-evaluation of a neurodegenerative etiology. Within neurodegenerative trajectories, whether such antibodies act as pathogenic drivers, non-causal markers, or immune modulators remains unresolved, and heterogeneous cohorts, assays, and endpoints limit inference and clinical translation. This review integrates current research at the intersection of autoimmunity and neurodegeneration and highlights accumulating evidence for a biological continuum. This model suggests that antibody-mediated mechanisms may extend beyond acute inflammation, with sustained exposure contributing to time-dependent neurodegeneration. To facilitate clinical translation, we advance a standardized diagnostic workflow comprising three sequential stages: (i) a pretest-probability triage that defines high-risk constellations prompting antibody testing, stratifies patients accordingly; (ii) a specimen-and-assay pathway for standardized testing workflow and structured interpretation of results; and (iii) post-test integrated analysis to adjudicate pathogenic relevance based on phenotype-antibody concordance. By bridging observational research to clinical decision-making, the framework supports identification of an immunologically modulated neurodegenerative subtype with potential for therapeutic intervention, while reducing false positives and avoiding non-essential immunotherapy in low-probability contexts.