Study identifies plasma free carnitine deficiency in women with aMCI and early AD, highlighting mitochondrial metabolism as a target for individualized preventive treatments.
Study: Gender differences in mitochondrial free carnitine levels in patients at risk and with Alzheimer’s disease in two independent study cohorts. Image credits: Doitforfun/Shutterstock.com
From a recent study published in Molecular psychiatry, a group of researchers examined sex-specific changes in plasma mitochondrial markers associated with early cognitive dysfunction and Alzheimer’s disease (AD), leading to personalized prevention strategies.
Background
AD is twice as common in women, with amnestic mild cognitive impairment (aMCI) often preceding its onset. The early biological processes underlying aMCI and AD remain poorly understood, hindering the development of effective diagnostics and therapies.
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 associated with 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 address early cognitive dysfunction and slow AD progression.
About the study
Deidentified samples from previous recruitment efforts and the University of California Irvine Alzheimer’s Disease Research Center (UCI ADRC) cohort were used to examine 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 guaranteed 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 researchers were blind to group assignments.
A total of 125 participants from two cohorts were included, consisting of cognitively healthy controls and individuals with AD, Lewy body dementia (LBD) or aMCI.
Participants underwent clinical and neuropsychological assessments, including cognitive testing 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 analyzes evaluated demographic differences, gender-specific levels of free carnitine, and associations with cognitive dysfunction and CSF biomarkers. Receiver operating characteristic (ROC) analyzes assessed the diagnostic accuracy of plasma and CSF markers and provided insight into mitochondrial pathways as diagnostic and therapeutic targets.
Study results
In the primary cohort, subjects with cognitive impairment (CI) showed lower CSF levels of Aβ42, a reduced Aβ42/40 ratio, and increased t-Tau levels compared to cognitively healthy controls (cHC). These findings are consistent 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 levels of free carnitine than cHC women, while no such differences were observed in men.
This sex-specific relationship held after adjusting for age, education, and other clinical variables. Furthermore, free carnitine levels in women with CI correlated strongly with the severity of cognitive dysfunction, as assessed by the Mini-Mental State Examination (MMSE) and the Wechsler Memory Scale (WMS-IV). No such association was found in men.
A stepwise decrease in free carnitine levels was observed in women in cHC, aMCI and AD or LBD, with the lowest levels in women with the most severe cognitive impairment.
In contrast, LAC levels 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 UCI ADRC replication cohort, the findings of gender-specific free carnitine deficiencies were validated. Women with CI showed a significant inverse association between free carnitine levels and severity of cognitive impairment 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 analyzes showed 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
In summary, this study reveals a sex-specific decrease in free carnitine levels in women, but not men, with cognitive impairment or early dementia, which correlates with severity of cognitive dysfunction, higher Aβ accumulation, and increased tau levels.
Plasma-free carnitine and LAC were equally accurate as CSF biomarkers for disease classification. Women showed a stepwise decrease in free carnitine levels in healthy controls, aMCI and AD/LBD, indicating increased mitochondrial dysfunction.