Individual bioenergetic capacity as a potential source of resilience to Alzheimer’s disease

• DOI: 10.1002/alz.072776
• Publication Date: 2023-12-25T09:32:58Z
• Authors: Matthias Arnold; Mustafa Buyukozkan; P. Murali Doraiswamy; Tong Wu; Kwangsik Nho; Vilmundur Gudnason; Lenore J J. Launer; Rui Wang‐Sattler; Jerzy Adamski; Philip L De Jager; Nilufer Ertekin‐T...; David A. A Bennett; Andrew J. Saykin; Annette Peters; Karsten Suhre; Rima F. Kaddurah‐...; Gabi Kastenmuller; Jan Krumsiek
• Keywords: Bioenergetics; Cognitive Decline

Abstract Background Brain glucose hypometabolism is among the earliest pathogenic changes in Alzheimer’s disease (AD). This metabolic dysfunction points to personal bioenergetic capacity, defined as ability maintain energy homeostasis under all circumstances including deregulated uptake, a potential source of resilience disease. Fasting blood acylcarnitine profiles are central readout for this capacity absence dietary and capture activity efficiency glucose‐independent routes mitochondrial metabolism. Method We used fasting serum 1,531 participants (465 with normal cognition, 762 mild cognitive impairment, 304 clinical AD) from AD Neuroimaging Initiative perform unsupervised subgroup identification using hierarchical clustering. Identified subgroups were investigated differences A/T/N biomarker status. The contributions genetic potentially modifiable factors defining quantified analysis explained variance. influence strongest determining on longitudinal trajectories was estimated linear mixed‐effects models gene‐by‐environment interaction analysis. Result found several bioenergetically distinct significant function. contribution endophenotype seems be specifically linked succinylcarnitine metabolism significantly modulates rate future decline. In contrast, sustainment beta‐oxidation decelerate aging, thus creating reserve that delays progression Using analysis, we demonstrate molecular framework identifies individuals likely benefit personalized therapeutic, or lifestyle interventions tailored increase against disturbances AD. Conclusion Our study reports set markers define level. Longitudinal data suggest targeting fraction might promising strategy slow down specific allelic configurations.