Immune–proteo–metabolomic changes link to Aβ and tau pathology in Alzheimer disease

Abstract INTRODUCTION Tryptophan metabolism is increasingly implicated in Alzheimer's disease (AD), particularly through aryl hydrocarbon receptor (AhR) ligands that influence neuroinflammation. However, their relationships with core AD pathology—amyloid‐β (A) and tau (T) deposition—and associated immune–proteomic alterations remain unclear. METHODS We performed integrative multi‐omics/high‐dimensional profiling of cerebrospinal fluid (CSF) and peripheral blood from A‐T‐ ( n = 19) and A+T+ ( n = 35) individuals, classified based on CSF Aβ and pTau181 levels. Analyses included targeted metabolomics, mass cytometry, and NULISA‐based proteomics, and inter‐compartmental correlation analysis. Brain‐derived tryptophan catabolism was investigated using single‐nucleus RNA sequencing (snRNA‐seq). RESULTS Thirteen differentially expressed CSF proteins in A+T+ individuals correlated positively with tryptophan metabolites and pyroglutamate, and negatively with regulatory T cells, isobutyrate, and dendritic cells. Similar patterns were observed in blood. snRNA‐seq suggested partial brain origin of metabolites. DISCUSSION Our findings highlight conserved immune–metabolic–proteomic signatures in AD and implicate tryptophan metabolism as a cross‐compartmental factor relevant for biomarker and therapeutic development. Highlights Thirteen cerebrospinal fluid (CSF) proteins involved in metabolism and neuronal function link to Alzheimer's disease (AD) pathology Intergrative analysis reveals shared and compartment‐specific AD signatures Tryptophan‐kynurenine metabolites correlate with AD pathology Indole metabolites show CSF‐plasma coupling in A+T+ individuals Immune signatures diverge across CSF (regulatory T cells Tregs, dendritic cells DCs) and blood (B and myeloid cells)