TY - JOUR
T1 - Interplay between age, APOE Ɛ4 and the metabolome in plasma and brain in Alzheimer’s disease
AU - Amin, Najaf
AU - Liu, Jun
AU - Sproviero, William
AU - Arnold, Matthias
AU - Batra, Richa
AU - Bonnechere, Bruno
AU - Chiou, Yu-Jie
AU - Fernandes, Marco
AU - Krumsiek, Jan
AU - Newby, Danielle
AU - Nho, Kwangsik
AU - Kim, Jun Pyo
AU - Saykin, Andrew J.
AU - Shi, Liu
AU - Winchester, Laura M.
AU - Yang, Yang
AU - Nevado-Holgado, Alejo J.
AU - Kastenmüller, Gabi
AU - Kaddurah-Daouk, Rima
AU - van Duijn, Cornelia M.
N1 - Funding: The computational aspects of this research were supported by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z and the Oxford NIHR BRC.
PY - 2025/12
Y1 - 2025/12
N2 - 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.
AB - 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.
U2 - 10.1038/s41398-025-03625-8
DO - 10.1038/s41398-025-03625-8
M3 - Article
C2 - 41173821
AN - SCOPUS:105020639874
SN - 2158-3188
VL - 15
SP - 1
EP - 15
JO - Translational Psychiatry
JF - Translational Psychiatry
M1 - 460
ER -
