Journal Article

DZNE-2026-00405

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Immune-proteo-metabolomic changes link to Aβ and tau pathology in Alzheimer disease.

Wang, M. ; Buthut, M.DZNE* ; Meinhardt, J. ; Otto, C. ; Gallaccio, G. ; Fernández-Zapata, C. ; Teves, M. ; Samol, C. ; Dettmer, K. ; Heckscher, S. ; Kamboj, S. ; Bahar, Y. ; Conrad, C. ; Böttcher, C. ; Kunkel, D. ; Ruprecht, K. ; Paul, F. ; Oefner, P. J. ; Radbruch, H. ; Gronwald, W. ; Prüß, H.DZNE* ; Böttcher, C.

2026
Wiley Hoboken, NJ

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Please use a persistent id in citations: doi:10.1002/alz.71359

Abstract: 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.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).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.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.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).

Keyword(s): Humans (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: cerebrospinal fluid (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Alzheimer Disease: immunology (MeSH) ; tau Proteins: cerebrospinal fluid (MeSH) ; tau Proteins: metabolism (MeSH) ; Female (MeSH) ; Male (MeSH) ; Amyloid beta-Peptides: cerebrospinal fluid (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Aged (MeSH) ; Tryptophan: metabolism (MeSH) ; Metabolomics (MeSH) ; Proteomics (MeSH) ; Brain: metabolism (MeSH) ; Biomarkers: cerebrospinal fluid (MeSH) ; Alzheimer's disease ; amyloid‐beta ; aryl hydrocarbon receptor ; mass cytometry ; tau pathology ; tryptophan ; tau Proteins ; Amyloid beta-Peptides ; Tryptophan ; Biomarkers

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Contributing Institute(s):

1. Autoimmune Encephalopathies (AG Prüß)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DEAL Wiley ; Essential Science Indicators ; IF >= 10 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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