Valine modulates Alzheimer’s disease risk in APOE ε4 carriers: evidence from two cohorts

Introduction The apolipoprotein E ε4 ( APOE ε4) allele confers the greatest genetic risk for sporadic Alzheimer’s disease (AD). Objectives To identify APOE ε4-associated metabolic factors related to AD risk and to provide preliminary insights into their biological and nutritional context. Methods We leveraged multi-omics analyses across two independent cohorts to characterize biomarkers associated with AD. The effects of metabolite × APOE ε4 interactions were tested on incident AD and the ε4-specific metabolic signatures were pinpointed. Multimodal analyses were used to test the underlying mechanisms, including neuroimaging, cerebrospinal fluid (CSF), and PET biomarkers within the A/T/N framework, as well as plasma proteomics combined with bioinformatics enrichment analyses. Results Across both cohorts, valine emerged as the only metabolite associated with a reduced risk of incident AD specifically among APOE ε4 carriers ( P < 0.005). Significant interaction effects between valine and APOE ε4 were detected in both cohorts ( P for meta -analyses < 0.005). Higher levels of valine were associated with greater total white matter and posterior cingulate cortex volumes, as well as with lower levels of CSF tau proteins. Higher valine levels also predicted a slower decline in FDG-PET metabolism. No association was found between valine and Aβ. Mediation analyses of plasma proteomic data suggested statistically significant mediation effects involving GFAP, NEFL, and APOE ( P < 2 × 10 -16 ). Conclusion Valine is a metabolite associated with lower AD risk in APOE ε4 carriers, with potential associations with tau pathology, neurodegeneration, and neuroinflammation-related processes. As this was an observational study, causality cannot be inferred.