Individual bioenergetic capacity as a potential source of resilience to Alzheimer’s disease
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.
Authors
- Vilmundur Guðnason (ORCID: https://orcid.org/0000-0001-5696-0084)
- David Alan Bennett (ORCID: https://orcid.org/0000-0003-3689-554X)
- Mustafa Büyüközkan (ORCID: https://orcid.org/0000-0001-5027-5078)
- Lenore J. Launer (ORCID: https://orcid.org/0000-0002-3238-7612)
- Jan Krumsiek (ORCID: https://orcid.org/0000-0003-4734-3791)
- Rima F Kaddurah-Daouk (ORCID: https://orcid.org/0000-0003-1858-5732)
- Andrew J. Saykin (ORCID: https://orcid.org/0000-0002-1376-8532)
- Tong Wu (ORCID: https://orcid.org/0000-0002-2296-3380)
- Karsten Suhre (ORCID: https://orcid.org/0000-0001-9638-3912)
- Philip L. De Jager (ORCID: https://orcid.org/0000-0002-8057-2505)
- Jerzy Adamski (ORCID: https://orcid.org/0000-0001-9259-0199)
- Gabi Kastenmüller (ORCID: https://orcid.org/0000-0002-2368-7322)
- Rui Wang‐Sattler (ORCID: https://orcid.org/0000-0002-8794-8229)
- Matthias Arnold (ORCID: https://orcid.org/0000-0002-4666-0923)
- Nilüfer Ertekin‐Taner (ORCID: https://orcid.org/0000-0003-4436-8889)
- Kwangsik Nho (ORCID: https://orcid.org/0000-0002-7624-3872)
- Annette Peters (ORCID: https://orcid.org/0000-0001-6645-0985)
- P. Murali Doraiswamy (ORCID: https://orcid.org/0000-0003-0697-3893)
Institutions
- Rush University Medical Center (US)
- NewYork–Presbyterian Hospital (US)
- University of Ljubljana (SI)
- University of Iceland (IS)
- National University of Singapore (SG)
- Duke University (US)
- Cornell University (US)
- New York Hospital Queens (US)
- Helmholtz Zentrum München (DE)
- German Centre for Cardiovascular Research (DE)
- National Institute on Aging (US)
- Mayo Clinic in Florida (US)
- Deutsches Diabetes-Zentrum e.V. (DE)
- Weill Cornell Medical College in Qatar (QA)
- Icelandic Heart Association (IS)
- German Center for Diabetes Research (DE)
- Weill Cornell Medicine (US)
- Indiana University School of Medicine
- Heinrich Heine University Düsseldorf (DE)
- Indiana University – Purdue University Indianapolis (US)
- Columbia University (US)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-24
- DOI
- https://doi.org/10.1038/s41467-025-57032-0
- Citations
- 14
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 11.28
Funders
- U.S. Department of Defense
- Alzheimer's Association
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- Biogen
- University of Southern California
- Mayo Foundation for Medical Education and Research
- Meso Scale Diagnostics
- Alzheimer's Disease Neuroimaging Initiative
- BioClinica
- Novartis Pharmaceuticals Corporation
- CurePSP
- Rush University
- Northern California Institute for Research and Education
- Bundesministerium für Bildung und Forschung
- Eisai
- Servier
- Hjartavernd
- H. Lundbeck A/S
- IXICO
- National Institutes of Health
- Genentech
- Canadian Institutes of Health Research
- Helmholtz Zentrum München
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke