Study identifies plasma free-carnitine deficiency in women with aMCI and early-AD, highlighting mitochondrial metabolism as a target for individualized preventive treatments.
Study: Sex differences in mitochondrial free-carnitine levels in subjects at-risk and with Alzheimer’s disease in two independent study cohorts. Image Credit: Doitforfun/Shutterstock.com
In a recent study published in Molecular Psychiatry, a group of researchers explored sex-specific mitochondrial marker changes in plasma linked to early cognitive dysfunction and Alzheimer’s disease(AD), guiding personalized prevention strategies.
Background
AD has a twofold higher incidence in women, with amnestic mild cognitive impairment (aMCI) often preceding its onset. Early biological processes underlying aMCI and AD remain poorly understood, hindering the development of effective diagnostics and therapeutics.
Mitochondrial metabolism, particularly acetyl-L-carnitine (LAC), plays a crucial role in brain plasticity, with sex differences in fatty acid utilization influencing its pathways. LAC deficiency has been linked to cognitive decline in both preclinical and clinical studies.
Further research is needed to clarify sex-specific mitochondrial mechanisms and develop non-invasive plasma-based biomarkers to target early cognitive dysfunction and slow AD progression.
About the study
De-identified samples from prior recruitment efforts and the University of California Irvine Alzheimer’s Disease Research Center (UCI ADRC) cohort were used to investigate sex differences in mitochondrial pathways and their associations with cerebrospinal fluid (CSF) biomarkers.
The study followed international ethical standards, with approvals from the Nathan Kline Institute for Psychiatric Research, Rockefeller University, and the D’Or Institute of Research and Education in Brazil. Anonymized data ensured participant confidentiality.
Levels of LAC and free-carnitine were measured in plasma using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) with isotopically labeled internal standards.
Samples were processed uniformly, and investigators were blinded to group assignments.
A total of 125 participants from two cohorts were included, comprising cognitively healthy controls and individuals with AD, Lewy body dementia (LBD), or aMCI.
Participants underwent clinical and neuropsychological assessments, including cognitive tests and diagnostic evaluations. CSF biomarkers such as amyloid-beta 42 (Aβ42), Aβ40, Aβ42/40 ratio, and total tau (t-Tau) were measured using enzyme-linked immunosorbent assays.
Statistical analyses evaluated demographic differences, sex-specific free-carnitine levels, and associations with cognitive dysfunction and CSF biomarkers. Receiver operating characteristic (ROC) analyses assessed the diagnostic accuracy of plasma and CSF markers, providing insights into mitochondrial pathways as diagnostic and therapeutic targets.
Study results
In the primary cohort, subjects with cognitive impairment (CI) exhibited lower CSF levels of Aβ42, a decreased Aβ42/40 ratio, and increased t-Tau levels compared to cognitively healthy controls (cHC). These findings align with established biomarkers of AD.
Plasma levels of LAC and free-carnitine were measured using UPLC-MS/MS. Women with CI, including aMCI, AD, or LBD, showed significantly lower free-carnitine levels than cHC women, whereas no such differences were observed in men.
This sex-specific relationship was held after adjusting for age, education, and other clinical variables. Furthermore, in women with CI, free-carnitine levels correlated strongly with cognitive dysfunction severity, as assessed by the Mini-Mental State Examination (MMSE) and Wechsler Memory Scale (WMS-IV). No such correlation was found in men.
A stepwise decrease in free-carnitine levels was observed in women across cHC, aMCI, and AD or LBD, with the lowest levels in those with the most severe cognitive impairment.
LAC levels, on the other hand, showed a sex-independent decrease in AD compared to cHC, with intermediate levels in aMCI. These findings were consistent after controlling for body mass index, depressive symptoms, and age.
In the replication cohort from the UCI ADRC, the findings of sex-specific free-carnitine deficiency were validated. Women with CI showed a significant inverse relationship between free-carnitine levels and cognitive impairment severity, as measured by the Clinical Dementia Rating sum-of-boxes (CDR-SB). This relationship persisted after adjusting for demographic and clinical factors, including the use of hormone therapy.
Computational analyses demonstrated that plasma levels of free-carnitine and LAC were as accurate as CSF markers (Aβ42 and t-Tau) in distinguishing disease status.
A combined model integrating plasma and CSF markers provided superior diagnostic accuracy for differentiating cHC, aMCI, AD, and LBD. These results highlight the potential of plasma mitochondrial markers as non-invasive tools for identifying cognitive impairment and support further investigation into sex-specific mechanisms underlying AD.
Conclusions
To summarize, this study reveals a sex-specific decrease in free-carnitine levels in women, but not men, with cognitive impairment or early dementia, correlating with cognitive dysfunction severity, higher Aβ accumulation, and elevated tau levels.
Plasma free-carnitine and LAC were as accurate as CSF biomarkers for disease classification. Women exhibited a stepwise decline in free-carnitine levels across healthy controls, aMCI, and AD/LBD, suggesting heightened mitochondrial dysfunction.
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