Protein misfolding in the gastrointestinal tract predicts and prognosticates neurodegenerative disease years before symptom onset

BackgroundDisease-modifying therapies for neurodegenerative disorders are unlikely to succeed once symptoms emerge, as significant neuronal loss has already occurred. Accessible biomarkers that predict disease years in advance, and that can serve as target-engagement readouts for prevention trials, are urgently needed. MethodsWe analysed archival gastrointestinal (GI) biopsies from 196 individuals with unexplained GI symptoms and 13-15 years of follow-up. Using sensitive histopathological staining, we assessed misfolded TDP-43, tau, and -synuclein to test whether peripheral proteinopathies can serve as predictive biomarkers for neurodegeneration. ResultsProtein misfolding enteropathy was detected in 60% of cases. Individuals with GI proteinopathy were significantly more likely to develop non-Alzheimers dementia or -synucleinopathies, with >80% sensitivity. The presence of two 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 pathological changes were present 6.9 years before neurological symptoms emerged. InterpretationOur 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. FundingTarget ALS, LifeArc, NHS Grampian 45 Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/25337884v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@12d9bcorg.highwire.dtl.DTLVardef@194e059org.highwire.dtl.DTLVardef@11514b2org.highwire.dtl.DTLVardef@101bcee_HPS_FORMAT_FIGEXP M_FIG C_FIG What is already known on this topicNeurodegenerative diseases are typically diagnosed after symptoms emerge, by which time extensive and irreversible neuronal loss has occurred. Reliable biomarkers that can identify individuals at risk many years earlier are lacking, and current strategies for early detection and monitoring of disease-modifying therapies remain limited. What this study adds?This study shows that protein misfolding enteropathy, detectable in routine gastrointestinal biopsies, predicts the later development of non-Alzheimers dementia and -synucleinopathies with high sensitivity. Pathological protein deposits were present more than a decade before neurological symptoms, and the presence of multiple proteinopathy markers correlated with reduced survival. How this study might affect research, practice or policyThese findings establish gastrointestinal proteinopathy as a practical, scalable biomarker for early detection and prognosis in neurodegenerative disorders. This approach could enable earlier intervention, improve risk stratification, and provide target-engagement readouts for clinical trials, opening new avenues for disease interception strategies.