Mitochondrial Molecules Linking to Alzheimer Disease Disparities in Gender: Betty Bigio, PhD; Carla Nasca, PhD

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"These findings should motivate new research into the sources of acetyl-L-carnitine and free carnitine, the molecular players that regulate their production, and the ways these molecules affect brain chemistry."

A major challenge in Alzheimer disease (AD) research is identifying molecular mechanisms linked to specific disease features. Notably, AD occurs twice as often in women as in men and has a prolonged prodromal phase marked by amnestic mild cognitive impairment (aMCI), suggesting early biological processes may increase AD risk. In a recent study, investigators analyzed plasma levels of 2 essential mitochondrial markers, acetyl-L-carnitine (LAC) and free carnitine, in a sample of 125 participants across 2 cohorts. In the study, researchers aimed to explore mitochondrial metabolism, as previous rodent models indicated that targeting LAC metabolism could improve cognitive function and gene expression mechanisms.

The findings revealed a sex-specific deficiency in free carnitine in women with aMCI and early AD compared with healthy controls, with no change observed in men. Additionally, both sexes showed decreased LAC levels, which corroborated earlier findings. The severity of cognitive dysfunction in women was directly related to the degree of free carnitine deficiency. Plasma free carnitine levels also correlated with increased β-amyloid and tau levels in cerebrospinal fluid (CSF). Computational analyses indicated that plasma mitochondrial markers were as accurate as CSF markers in classifying disease status. These results provide a foundation for developing individualized treatments targeting early sex-specific mitochondrial changes to prevent AD progression.

In a recent interview with NeurologyLive^®, lead author Betty Bigio, PhD, research assistant professor of psychiatry, and senior author Carla Nasca, PhD, assistant professor of psychiatry and neuroscience, both from NYU Grossman School of Medicine, further explored the significance of mitochondrial molecules like LAC and free carnitine in AD. They discussed how these molecules contribute to brain health, the implications of their deficiency in early disease progression, and the molecular pathways that regulate their production. Additionally, they highlighted the potential for combining blood and CSF markers to enhance diagnostic accuracy for Alzheimer, shedding light on how these insights could inform future therapeutic strategies.

REFERENCES
1. Bigio B, Lima-Filho RAS, 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. Published online January 7, 2025. doi:10.1038/s41380-024-02862-5
2. Study Advances Possible Blood Test for Early-Stage Alzheimer’s Disease. News Release. NYU Langone Health. Published January 8, 2024. Accessed January 10, 2024. https://nyulangone.org/news/study-advances-possible-blood-test-early-stage-alzheimers-disease