Falling blood levels of two molecules that occur naturally in the body are closely linked to the worsening of Alzheimer’s disease, especially in women. It was found that levels gradually decreased, from women with no signs of memory, disorientation and slowed thinking to women with early signs of mild cognitive impairment. The decreases were more prominent in women with moderate or severe stages of the disease. The decline in men was evident in only one molecule, revealing a disease-specific difference between the sexes.
It is currently estimated that six million Americans, most over 65 years of age and mostly women, have some form of Alzheimer’s disease.
Led by neuroscientists at NYU Langone Health, in collaboration with other researchers in the United States and Brazil, the new study showed that blood levels of the protein acetyl-L-carnitine were lower in both women and men with mild cognitive impairment and the Alzheimer’s disease. Blood levels of free carnitine, the main byproduct of acetyl-L-carnitine in reactions essential for brain function, fell steadily in women in amounts related to the severity of their cognitive decline. In men, a significant decrease was only observed in acetyl-L-carnitine, and not in free carnitine.
Published in the magazine Molecular psychiatry online on January 7, the study results suggest that a decrease in these two chemicals in the brain could indicate the presence and extent of Alzheimer’s disease, and that this difference could provide an explanation as to why women are at higher risk for the disease than men.
Additional computer testing showed that blood levels of acetyl-L-carnitine and free carnitine in study participants were in direct proportion to elevated levels of amyloid beta and tangled tau proteins, long considered markers of progressive severity in diabetes. Alzheimer’s. The research team’s accuracy in diagnosing the severity of Alzheimer’s disease increased from more than 80 percent – using amyloid beta and tangled tau protein levels collected from cerebrospinal fluid or the two blood molecules – to 93 percent using both .
Our findings provide the strongest evidence to date that reduced blood levels of acetyl-L-carnitine and free carnitine could act as blood biomarkers for identifying people who have Alzheimer’s disease, and possibly those at greater risk of developing it. of early dementia.”
Betty Bigio, PhD, principal investigator of the study
“The results could also explain gender differences in Alzheimer’s disease, with more women than men having dementia,” says Dr. Bigio, research assistant professor in the Department of Psychiatry at NYU Grossman School of Medicine. She is also affiliated with the Nathan Kline Institute for Psychiatric Research.
“Because the decrease in acetyl-L-carnitine and free carnitine is closely associated with the severity of Alzheimer’s disease, the molecular pathways involved in its production offer other possible therapeutic targets to determine the cause of the disease and possibly in before permanent brain damage occurs. ,” says senior researcher Carla Nasca, PhD. She is an assistant professor in the Department of Psychiatry and the Department of Neuroscience and Physiology at NYU Grossman School of Medicine. She is also affiliated with the Nathan Kline Institute for Psychiatric Research.
The study involved data on two separate groups of men and women in Brazil and California, where the researchers measured blood levels of the two molecules. It involved a total of 93 study volunteers with varying degrees of cognitive impairment, along with 32 cognitively healthy men and women of similar age, weight and education. Results in the Californian group were used to confirm what was found in the Brazilian group.
In the future, Dr. Nasca that more research is needed into the sources of acetyl-L-carnitine and the molecular pathways that control its production, and into monitoring how the molecule affects brain chemistry as it is contained in the stores of brain vesicles that are released into the blood. . The team’s goal is to define other biomarkers in the brain that can more accurately track the progression of Alzheimer’s disease.
Dr. Nasca says that if further studies confirm their latest findings, the team’s research could be used to develop a blood test for dementia and monitor the progression of Alzheimer’s disease in a more convenient and non-invasive way. Currently, the search for biomarkers of disease progression may involve serial spinal punctures that carry risks of pain and infection. A blood test may also be useful to support or add a more objective, quantitative measure of disease severity than existing questionnaires that test memory or thinking ability.
A blood test, says Dr. Nasca, could also help predict the effectiveness, or lack thereof, of potential new drug treatments designed to slow or prevent the onset of Alzheimer’s disease.
Both acetyl-L-carnitine and free carnitine are essential for healthy brain function and regulating cell energy metabolism. Previous research by Dr.’s team Nasca has shown that acetyl-L-carnitine also transports molecules from a cell’s mitochondria to the controlling nucleus of a cell, allowing genes to open and activate. This shuttling action is critical in regulating genes that produce the neurotransmitter glutamate, another chemical involved in most brain activities, including nerve cell repair (plasticity). This is important in the hippocampus region of the brain, which helps regulate memory and where initial damage from Alzheimer’s disease is known to occur.
Dr. Nasca says excessive levels of glutamate have also been linked to mood disorders and severe cases of depression in people, conditions closely linked to Alzheimer’s disease. Her team has also linked deficiencies of acetyl-L-carnitine, but not free carnitine, to depression and childhood trauma. Future studies are planned on how to prevent the progression of depression to Alzheimer’s disease.
Funding support for the study was provided by National Institutes of Health grants R24AG06517, P50AG16573, and P30AG066519. Additional financial support came from the Robertson Therapeutic Development Fund, D’Or Institute for Research and Education, Rede D’Or Sao Luiz Hospital Network, International Society for Neurochemistry, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Serrapilheira Institute and the Alzheimer’s Association grant AARG-D-61541.
In addition to Dr. Bigio and Dr. Nasca, other NYU Langone researchers involved in the study include co-investigators Aryeh Korman and Drew R. Jones, PhD. Other co-investigators on the study are Ricardo Lima-Filho, Felipe Sudo, Claudia Drummond, Naima Assuncao, Bart Vanderborght, Sergio Ferreira, Paulo Mattos, Fernanda Tovar-Moll, Fernanda De Felice and Mychael Lourenco, at the Federal University of Rio de Janeiro. and the D’Or Institute for Research and Education, also in Brazil; Olivia Barnhill, at Rockefeller University in New York City; James Beasley and Sarah Young, at Duke University in Durham, North Carolina; and David Sultzer and Elizabeth Head, at the University of California, Irvine.
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Magazine reference:
Bigio, B., et al. (2025). Gender differences in mitochondrial free carnitine levels in patients at risk and with Alzheimer’s disease in two independent study cohorts. Molecular psychiatry. doi.org/10.1038/s41380-024-02862-5.