A groundbreaking study published in Molecular Psychiatry has identified sex-specific mitochondrial marker deficiencies that are linked to early cognitive dysfunction in Alzheimer’s disease (AD). The findings offer new insights into potential personalized prevention strategies for AD, which has a twofold higher incidence in women than in men. The study specifically focuses on the role of mitochondrial metabolism, particularly acetyl-L-carnitine (LAC) and free-carnitine, in the early stages of cognitive decline and dementia.
Background
Amnestic mild cognitive impairment (aMCI) often precedes the onset of Alzheimer’s disease, and understanding the biological processes behind early cognitive dysfunction remains a challenge. Research has suggested that mitochondrial dysfunction plays a significant role in brain plasticity, with fatty acid metabolism—especially the utilization of acetyl-L-carnitine—being central to these processes. Previous studies have linked LAC deficiency to cognitive decline, but the influence of sex-specific differences on mitochondrial pathways and their association with cognitive impairment had not been fully explored.
The present study aimed to clarify the role of mitochondrial mechanisms in AD and to investigate whether non-invasive plasma-based biomarkers could serve as reliable tools to detect early cognitive dysfunction and slow disease progression.
The Study
The study involved de-identified samples from participants recruited through the University of California Irvine Alzheimer’s Disease Research Center (UCI ADRC) cohort. Ethical approval was granted by several institutions, including the Nathan Kline Institute for Psychiatric Research and the Rockefeller University. The study adhered to international ethical standards, ensuring the confidentiality of participants through anonymized data.
A total of 125 participants were included, consisting of cognitively healthy controls (cHC), individuals with AD, Lewy body dementia (LBD), or aMCI. Clinical and neuropsychological assessments, including cognitive tests and diagnostic evaluations, were conducted. Additionally, cerebrospinal fluid (CSF) biomarkers—such as amyloid-beta 42 (Aβ42), Aβ40, the Aβ42/40 ratio, and total tau (t-Tau)—were measured to assess the progression of neurodegeneration.
The study employed ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to measure plasma levels of LAC and free-carnitine, with isotopically labeled internal standards ensuring high accuracy.
Key Findings
The study found significant sex-specific differences in mitochondrial markers. Women with cognitive impairment (CI), including those with aMCI, AD, or LBD, exhibited markedly lower plasma levels of free-carnitine compared to cognitively healthy women. This difference was not observed in men, suggesting a potential sex-based disparity in mitochondrial function related to cognitive decline.
After adjusting for variables such as age, education, and clinical factors, it was found that in women with CI, free-carnitine levels were strongly correlated with cognitive dysfunction severity, as assessed by the Mini-Mental State Examination (MMSE) and the Wechsler Memory Scale (WMS-IV). In contrast, no such correlation was observed in men.
Moreover, a stepwise decline in free-carnitine levels was observed in women as their cognitive impairment progressed—from cognitively healthy controls to aMCI and AD/LBD, with the lowest levels seen in those with the most severe cognitive impairment. This trend suggests that mitochondrial dysfunction may intensify as the disease progresses in women.
LAC levels showed a consistent decrease in both men and women with AD compared to healthy controls, with intermediate levels observed in individuals with aMCI. However, the decline in LAC levels did not exhibit the same sex-specific pattern as free-carnitine.
Validation and Diagnostic Accuracy
The findings were validated in a replication cohort from the UCI ADRC, where women with cognitive impairment showed a significant inverse relationship between free-carnitine levels and the severity of cognitive dysfunction, as measured by the Clinical Dementia Rating sum-of-boxes (CDR-SB). This correlation persisted after controlling for demographic and clinical factors, including hormone therapy use.
In terms of diagnostic accuracy, the study demonstrated that plasma levels of free-carnitine and LAC were as accurate as CSF biomarkers like Aβ42 and t-Tau in distinguishing between different disease states. The combination of plasma and CSF biomarkers provided even better diagnostic accuracy, enhancing the ability to differentiate between cognitively healthy controls, aMCI, AD, and LBD.
Conclusions
The study concluded that a sex-specific deficiency in free-carnitine levels is strongly associated with cognitive impairment and early dementia in women, correlating with higher levels of amyloid-beta accumulation and elevated tau levels. The research also highlights that plasma markers like free-carnitine and LAC could serve as reliable, non-invasive diagnostic tools for early-stage Alzheimer’s disease and related dementias.
Moreover, the study emphasizes the importance of considering sex-specific mitochondrial dysfunction in the development of personalized treatments and prevention strategies for Alzheimer’s disease. By identifying these mitochondrial biomarkers in plasma, clinicians could potentially detect cognitive impairment earlier, allowing for better-targeted interventions and improving the prognosis for individuals with AD.
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