Protein Misfolding Enteropathy Predicts and Prognosticates Neurodegenerative Disease Years Before Symptom Onset.

BACKGROUND & AIMS: Neurodegenerative disorders are characterized by progressive, irreversible neuronal loss that often advances silently for years before symptoms appear. Disease-modifying therapies are generally less effective once symptoms emerge, as substantial neuronal damage has already occurred. Consequently, there is an urgent need for accessible biomarkers that can predict disease well in advance and serve as reliable target-engagement measures in prevention trials. METHODS: We analysed archival gastrointestinal (GI) biopsies from 196 individuals with unexplained GI symptoms and 13-15 years of follow-up. Using sensitive histopathologic staining, we assessed misfolded TDP-43, tau, and α-synuclein to test whether peripheral proteinopathies can serve as predictive biomarkers for neurodegeneration. RESULTS: Protein misfolding enteropathy was identified in 60% of cases. Individuals with GI proteinopathy were significantly more likely to develop non-Alzheimer's dementia or α-synucleinopathies, demonstrating >80% sensitivity; however, this performance should be balanced against a low specificity. The presence of 2 or more proteinopathy markers was associated with a dose-dependent reduction in survival, establishing GI proteinopathy as an independent, life-limiting prognostic factor. Importantly, these pathologic changes were present 6.9 years before neurologic symptoms emerged. CONCLUSIONS: Our findings reveal that neurodegeneration-associated proteinopathies are not confined to the central nervous system but can be detected in routine GI biopsies years before clinical onset. This discovery provides a practical and scalable biomarker platform that could transform early diagnosis, risk stratification, and target-engagement monitoring in clinical trials. Protein misfolding enteropathy represents a new frontier for disease interception in neurodegenerative disorders, enabling intervention at a stage when neuronal damage may still be preventable.