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

Matthias Arnold (), Mustafa Buyukozkan, P. Murali Doraiswamy, Kwangsik Nho, Tong Wu, Vilmundur Gudnason, Lenore J. Launer, Rui Wang-Sattler, Jerzy Adamski, Philip L. Jager, Nilüfer Ertekin-Taner, David A. Bennett, Andrew J. Saykin, Annette Peters, Karsten Suhre, Rima Kaddurah-Daouk, Gabi Kastenmüller and Jan Krumsiek ()
Additional contact information
Matthias Arnold: Duke University
Mustafa Buyukozkan: Weill Cornell Medicine
P. Murali Doraiswamy: Duke University
Kwangsik Nho: Indiana University School of Medicine
Tong Wu: Helmholtz Zentrum München, German Research Center for Environmental Health
Vilmundur Gudnason: University of Iceland
Lenore J. Launer: National Institute on Aging
Rui Wang-Sattler: Helmholtz Zentrum München, German Research Center for Environmental Health
Jerzy Adamski: Helmholtz Zentrum München, German Research Center for Environmental Health
Philip L. Jager: New York Presbyterian Hospital
Nilüfer Ertekin-Taner: Mayo Clinic
David A. Bennett: Rush University Medical Center
Andrew J. Saykin: Indiana University School of Medicine
Annette Peters: Helmholtz Zentrum München, German Research Center for Environmental Health
Karsten Suhre: Weill Cornell Medicine-Qatar, Education City
Rima Kaddurah-Daouk: Duke University
Gabi Kastenmüller: Helmholtz Zentrum München, German Research Center for Environmental Health
Jan Krumsiek: Weill Cornell Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Impaired glucose uptake in the brain is an early presymptomatic manifestation of Alzheimer’s disease (AD), with symptom-free periods of varying duration that likely reflect individual differences in metabolic resilience. We propose a systemic “bioenergetic capacity”, the individual ability to maintain energy homeostasis under pathological conditions. Using fasting serum acylcarnitine profiles from the AD Neuroimaging Initiative as a blood-based readout for this capacity, we identified subgroups with distinct clinical and biomarker presentations of AD. Our data suggests that improving beta-oxidation efficiency can decelerate bioenergetic aging and disease progression. The estimated treatment effects of targeting the bioenergetic capacity were comparable to those of recently approved anti-amyloid therapies, particularly in individuals with specific mitochondrial genotypes linked to succinylcarnitine metabolism. Taken together, our findings provide evidence that therapeutically enhancing bioenergetic health may reduce the risk of symptomatic AD. Furthermore, monitoring the bioenergetic capacity via blood acylcarnitine measurements can be achieved using existing clinical assays.

Date: 2025
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DOI: 10.1038/s41467-025-57032-0

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