Fecal Aβ and Tau aggregates reveal a peripheral dimension of Alzheimer’s disease proteinopathy
A recent collaborative study investigated whether disease-associated amyloid-β (Aβ) and tau aggregates can be detected in human stool and whether these peripheral aggregate signals are associated with cognitive impairment and established cerebrospinal fluid biomarkers.
Using sFIDA, attyloid’s single-particle assay designed for the selective quantification of aggregated protein species, fecal Aβ and tau aggregates were measured in a cohort of 206 participants, including 101 individuals with cognitive impairment and 105 cognitively healthy controls. The study extends earlier proof-of-concept work showing the presence of Aβ aggregates in stool by demonstrating that tau aggregates are also detectable in fecal samples.
Both fecal Aβ and tau aggregate concentrations were significantly elevated in participants with cognitive impairment. Importantly, these differences remained significant after adjustment for age and sex and were preserved in analyses restricted to older control subjects, indicating that the observed group differences were not explained by demographic imbalance alone.
Fecal tau showed the stronger discriminatory performance of the two aggregate markers. In stratified five-fold cross-validation, fecal tau achieved an AUC of 0.80 ± 0.05, compared with 0.68 ± 0.04 for fecal Aβ. A combined Aβ and tau model reached an AUC of 0.83 ± 0.05. When fecal aggregate measurements were integrated with age and sex, classification performance increased to an AUC of 0.91 ± 0.06.
Beyond classification performance, the study provides an interesting biological perspective on the relationship between central and peripheral protein aggregation. Fecal aggregate elevations were also observed in cognitively impaired individuals who were negative for both amyloid and tau according to the CSF-defined AT classification. This suggests that fecal aggregate levels may not simply mirror canonical CNS biomarker status, but could reflect an additional dimension of systemic proteopathic biology.
A further notable observation was the inverse association between fecal Aβ aggregate concentrations and CSF tau biomarkers, including p-tau181, total tau and the p-tau181/Aβ1–42 ratio. Although these associations were moderate, they remained significant after adjustment for demographic factors and diagnosis, supporting the possibility that fecal aggregate signals reflect biological processes that are not redundant with established CSF biomarkers.
One possible framework for interpreting these findings is peripheral aggregate handling and clearance. Aβ clearance involves several interconnected pathways, including glymphatic drainage, blood–brain barrier transport and peripheral elimination. Hepatobiliary clearance has been proposed as one route by which circulating Aβ may be taken up by the liver and subsequently enter the intestinal compartment. At the same time, local processes within the enteric nervous system could also contribute to fecal aggregate levels. The current study does not establish the origin of the detected aggregates, and these mechanisms therefore remain hypotheses to be addressed in future work.
The findings therefore fit into a broader view of Alzheimer’s disease in which pathological protein aggregation is not considered exclusively within the CNS, but as part of a more complex interaction between central and peripheral compartments. In this context, stool-based aggregate measurements may represent a complementary, minimally invasive biomarker approach rather than a direct surrogate for established CSF or imaging biomarkers.
The work was led by Pelin Özdüzenciler and Gültekin Tamgüney together with collaborators from Forschungszentrum Jülich, University Hospital Cologne, Heinrich Heine University Düsseldorf and attyloid GmbH.