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

Background

Disease-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.

Methods

We 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 α-synuclein to test whether peripheral proteinopathies can serve as predictive biomarkers for neurodegeneration.

Results

Protein misfolding enteropathy was detected in 60% of cases. Individuals with GI proteinopathy were significantly more likely to develop non-Alzheimer’s dementia or α-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.

Interpretation

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.

Funding

Target ALS, LifeArc, NHS Grampian 45

Graphical Abstract

What is already known on this topic

Neurodegenerative 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-Alzheimer’s dementia and α-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 policy

These 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.