Fecal Aβ and tau aggregates are elevated in cognitive impairment and reveal peripheral proteopathic alterations

Abstract Background Aggregation of amyloid-β (Aβ) and tau is central to Alzheimer’s disease (AD) pathogenesis and forms the basis of established cerebrospinal fluid (CSF) and imaging biomarkers. However, increasing evidence suggests that AD involves systemic processes beyond the central nervous system. We previously demonstrated the presence of fecal Aβ aggregates. Here, we assessed the detectability of tau aggregates in human feces and examined the diagnostic value of combined fecal Aβ and tau quantification in cognitive impairment. Methods Using surface-based fluorescence intensity distribution analysis (sFIDA), a single-particle assay selective for aggregated species, we quantified fecal Aβ and tau aggregates in individuals with cognitive impairment (dementia, MCI, SCD) and cognitively normal controls. Associations with CSF biomarkers were assessed, and classification performance was evaluated using cross-validated logistic regression models. Results Tau aggregates were detectable in fecal samples. Both fecal Aβ and tau aggregate concentrations were significantly elevated in cognitively impaired individuals and remained independently associated with patient status after adjustment for age and sex. Fecal Aβ aggregates showed inverse associations with CSF tau biomarkers, particularly phosphorylated tau. In cross-validated models, fecal tau aggregates achieved stronger classification performance than fecal Aβ (AUC ~ 0.80 vs. ~ 0.68), and integration of fecal aggregates with demographic predictors improved discrimination to an AUC of 0.90. Conclusions Detection of fecal tau aggregates extends previous observations on fecal Aβ and supports the concept that stool-based aggregate measurements capture systemic aspects of proteopathic biology associated with cognitive impairment. These findings suggest that fecal aggregate quantification may provide a minimally invasive biomarker approach that complements established CNS-based biomarkers and may be useful for patient stratification and monitoring in neurodegenerative disease.