PuSH - Publication Server of Helmholtz Zentrum München

Amin, N.* ; Liu, J.* ; Sproviero, W.* ; Arnold, M. ; Batra, R.* ; Bonnechere, B.* ; Chiou, Y.J.* ; Fernandes, M.* ; Krumsiek, J.* ; Newby, D.* ; Nho, K.* ; Kim, J.P.* ; Saykin, A.J.* ; Shi, L.* ; Winchester, L.M.* ; Yang, Y.* ; Nevado-Holgado, A.J.* ; Kastenmüller, G. ; Kaddurah-Daouk, R.* ; van Duijn, C.M.*

Interplay between age, APOE Ɛ4 and the metabolome in plasma and brain in Alzheimer's disease.

Transl. Psychiatry 15:460 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Age and the ε4 variant of the apolipoprotein E gene (APOE ε4) are two major drivers of Alzheimer's disease (AD). APOE is also the major determinant of longevity. How age and APOE interact in the development of AD is largely unknown. In this study we integrate metabolomics (N = 274,259) and proteomics (N = 54,219) data in plasma from the UK Biobank with the metabolomics (N = 514) and proteomics (N = 618) data in brain from the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP) to understand the interplay of age, APOE ε4 and metabolome in the development of AD. We find that levels of β-hydroxybutyrate (BHBA) and branch-chained amino acids (BCAAs) are dysregulated in plasma and brains of AD patients. APOE ε4 carriers manifest significantly higher plasma concentration of BHBA that is detectable as early as 37 years of age and remains high throughout the studied age range of 37-73 whereas the plasma concentrations of BCAAs decline in APOE ε44 carriers after the age of 58 years. Proteomic signatures of APOE ε4, BHBA and BCAAs suggest downregulation of lysosome, immune and insulin-like growth factor (IGF1) transport/uptake pathways in plasma, and downregulation of the tricarboxylic acid (TCA) cycle, neurexins/neuroligins and clathrin-mediated endocytosis pathways in brain. Our data identifies two major shifts in metabolism occurring decades apart over the age course in AD in APOE ε4 carriers. These include early ketogenesis that manifests around late 30 s and gluconeogenesis, which manifests around the age of 60 years.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Keywords Metabolome ; Apolipoprotein E; Chain Amino-acids; Body-mass Index; Circulating Metabolites; Dementia; Risk; Institute; Beta
ISSN (print) / ISBN 2158-3188
e-ISSN 2158-3188
Journal Translational Psychiatry
Quellenangaben Volume: 15, Issue: 1, Pages: , Article Number: 460 Supplement: ,
Publisher Springer
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
Grants
Oxford NIHR BRC
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago
NIA
Illinois Department of Public Health (ROSMAP)
Translational Genomics Research Institute
National Institute of Aging of the National Institutes of Health
Alzheimer's association award
Wellcome Trust Core Award
National Institute on Aging
Alzheimer's Disease Metabolomics Consortium
FNIH
NIH
National Institute on Aging (NIH)
Oxford-GSK Institute of Molecular and Computational Medicine (IMCM)
US National Institute on Aging (NIH)
NovoNordisk
Centre of Artificial Intelligence for Precision Medicines (CAIPM) of the University of Oxford
Alzheimer Research UK (ARUK), UK National Institute for Health and Care Research (NIHR) Oxford Research Center (BRC)
ZonMW (Delta Dementie)
Alzheimer Nederland