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Sex differences in mitochondrial free-carnitine levels in subjects at-risk and with Alzheimer’s disease in two independent study cohorts

Molecular Psychiatry volume 30, pages 2573–2583 (2025)Cite this article

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Abstract

A major challenge in the development of more effective therapeutic strategies for Alzheimer’s disease (AD) is the identification of molecular mechanisms linked to specific pathophysiological features of the disease. Importantly AD has a two-fold higher incidence in women than men and a protracted prodromal phase characterized by amnestic mild-cognitive impairment (aMCI) suggesting that biological processes occurring early can initiate vulnerability to AD. Here, we used a sample of 125 subjects from two independent study cohorts to determine the levels in plasma (the most accessible specimen) of two essential mitochondrial markers acetyl-L-carnitine (LAC) and its derivative free-carnitine motivated by a mechanistic model in rodents in which targeting mitochondrial metabolism of LAC leads to the amelioration of cognitive function and boosts epigenetic mechanisms of gene expression. We report a sex-specific deficiency in free-carnitine levels in women with aMCI and early-AD compared to cognitively healthy controls; no change was observed in men. We also replicated the prior finding of decreased LAC levels in both women and men with AD, supporting the robustness of the study samples assayed in our new study. The magnitude of the sex-specific free-carnitine deficiency reflected the severity of cognitive dysfunction and held in two study cohorts. Furthermore, patients with the lower free-carnitine levels showed higher β-amyloid(Aβ) accumulation and t-Tau levels assayed in cerebrospinal fluid (CSF). Computational analyses showed that the mitochondrial markers assayed in plasma are at least as accurate as CSF measures to classify disease status. Together with the mechanistic platform in rodents, these translational findings lay the groundwork to create preventive individualized treatments targeting sex-specific changes in mitochondrial metabolism that may be subtle to early cognitive dysfunction of AD risk.

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Fig. 1: Sex differences in free-carnitine deficiency: the lowest mitochondrial free-carnitine levels are found in women but not men with the worst cognitive dysfunction.
Fig. 2: Validation in a second cohort: the magnitude of free-carnitine deficiency reflects the severity of cognitive impairment.
Fig. 3: Interrelated plasma and CSF markers characterize disease status.
Fig. 4: Directionality of the relationship between plasma and CSF measures.
Fig. 5: Plasma free-carnitine and LAC levels have at least equivalent classification accuracy than CSF measures (Aβ42 and t-Tau).

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All data will be made available upon request to the corresponding author Carla Nasca.

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Acknowledgements

This work was supported by the National Institute on Aging (NIA) through the Early Adversity & Later Life Reversibility Pilot Grant to CN under Award Number R24AG06517, by a grant from the Robertson Therapeutic Development Foundation to CN, by New York University Langone fund to CN and by intramural grants from the D’Or Institute for Research and Education (IDOR) and Rede D’Or São Luiz Hospital Network to FTM. RASLF was supported by a predoctoral fellowship by FAPERJ and was awarded a CAEN 1A grant from the International Society for Neurochemistry and a PROLAB travel award from the American Society for Biochemistry and Molecular Biology. MVL was supported by grants from Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) (202.744/2019 and 010.002421/2019), Serrapilheira Institute (R-2012-37967, and Alzheimer’s Association (AARG-D-615741 and Blas Frangione Early Career Achievement Award). The UCI-ADRC is supported by NIH/NIA P50 AG16573 and P30AG066519. This paper is ad memoriam of Professor Bruce McEwen.

Author information

Authors and Affiliations

  1. Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA

    Benedetta Bigio & Carla Nasca

  2. Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, USA

    Benedetta Bigio & Carla Nasca

  3. Institute of Medical Biochemistry Leopoldo de Meis, Rio de Janeiro, RJ, Brazil

    Ricardo A. S. Lima-Filho, Sergio T. Ferreira, Fernanda G. De Felice & Mychael V. Lourenco

  4. Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA

    Olivia Barnhill & Carla Nasca

  5. D’Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil

    Felipe K. Sudo, Claudia Drummond, Naima Assunção, Bart Vanderborght, Sergio T. Ferreira, Paulo Mattos, Fernanda Tovar-Moll & Fernanda G. De Felice

  6. Department of Speech and Hearing Pathology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

    Claudia Drummond

  7. Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Naima Assunção & Paulo Mattos

  8. Biochemical Genetics Laboratory, Duke University Health System, Durham, NC, USA

    James Beasley & Sarah Young

  9. Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA

    Sarah Young

  10. Metabolomics Laboratory, NYU Grossman School of Medicine, New York, NY, USA

    Aryeh Korman & Drew R. Jones

  11. Department of Psychiatry and Human Behavior, School of Medicine, and Institute for Memory Impairments and Neurological Disorders (UCI MIND), University of California, Irvine, Irvine, CA, USA

    David L. Sultzer

  12. Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Sergio T. Ferreira

  13. Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Paulo Mattos

  14. Institute for Memory Impairments and Neurological Disorders (MIND), University of California Irvine, Irvine, CA, USA

    Elizabeth Head

  15. Department of Pathology and Laboratory Medicine, Department of Neurology, University of California Irvine, Irvine, CA, USA

    Elizabeth Head

  16. Centre for Neurosciences Studies, Departments of Biomedical and Molecular Sciences & Department of Psychiatry, Queen’s University, Kingston, ON, Canada

    Fernanda G. De Felice

  17. Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, NY, USA

    Carla Nasca

Authors
  1. Benedetta Bigio
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  2. Ricardo A. S. Lima-Filho
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  3. Olivia Barnhill
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  4. Felipe K. Sudo
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  11. Drew R. Jones
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  16. Fernanda Tovar-Moll
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  17. Fernanda G. De Felice
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  18. Mychael V. Lourenco
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  19. Carla Nasca
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Contributions

Address correspondence to Carla Nasca (NYU School of Medicine, New York, email: carla.nasca@nyulangone.org) regarding the mechanistic platform, acetyl-L-carnitine (LAC) or free-carnitine and cohort samples; and to Mychael V. Lourenco (Institute of Medical Biochemistry Leopoldo de Meis, Rio de Janeiro, Brazil email: mychael@bioqmed.ufrj.br) regarding cohort samples. BB and CN conceived the mechanistic platform, statistical analyses, and computational approaches, and wrote the manuscript. RL, OB and MVL contributed to statistical analyses, interpretation of the data and manuscript writing. FKS, CD, NA, BV, FT-M, and PM contributed to patient recruitment, diagnosis, sample collection and cohort establishment. STF, BM and FGDF contributed reagents, materials or analysis tools and aided with interpretation of data. EH and DLS provided samples and clinical data from the UCI ADRC. JB, SY, AK, DJ performed LAC and carnitine assessment. BB and OB coordinated all experiments for LAC and carnitine assessment. CN supervised the research. All authors discussed and provided inputs to the research.

Corresponding authors

Correspondence to Mychael V. Lourenco or Carla Nasca.

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Bigio, B., Lima-Filho, R.A.S., Barnhill, O. et al. Sex differences in mitochondrial free-carnitine levels in subjects at-risk and with Alzheimer’s disease in two independent study cohorts. Mol Psychiatry 30, 2573–2583 (2025). https://doi.org/10.1038/s41380-024-02862-5

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