Research has found a close correlation between the decreasing blood levels of two naturally occurring molecules and the progression of Alzheimer’s disease, especially in women. The study observed a gradual decline in these levels, starting from women who show no memory issues or disorientation, to those displaying early signs of mild cognitive impairment. This decline became more pronounced in women experiencing moderate or severe stages of the illness. Conversely, in men, notable reductions were observed only in one of the molecules, highlighting a difference in the disease’s impact between the genders.
Currently, around six million Americans, predominantly women over 65, are estimated to live with some form of Alzheimer’s disease.
Conducted by neuroscientists at NYU Langone Health alongside other researchers from the U.S. and Brazil, the study revealed that levels of the protein acetyl-L-carnitine were lower in both women and men with mild cognitive impairment and Alzheimer’s. Additionally, the blood concentration of free carnitine— a key byproduct of acetyl-L-carnitine and crucial for brain function— steadily decreased in women in relation to the severity of their cognitive decline. In men, a significant drop occurred only in acetyl-L-carnitine levels, not in free carnitine.
The findings, published on January 7 in the journal Molecular Psychiatry, indicate that reductions in these two brain chemicals may serve as indicators of the presence and severity of Alzheimer’s disease. This disparity might help explain why women are at a greater risk for the disease than men.
Furthermore, computer analysis demonstrated that blood concentrations of acetyl-L-carnitine and free carnitine corresponded directly with increased levels of amyloid beta and tangled tau proteins, which are recognized markers of Alzheimer’s disease progression. The research team’s accuracy in diagnosing the severity of the disease improved from over 80% to 93% when utilizing both the molecules and amyloid beta and tau protein levels collected from cerebrospinal fluid.
“Our study provides compelling evidence that reduced blood levels of acetyl-L-carnitine and free carnitine could serve as blood biomarkers for the identification of those with Alzheimer’s disease and those who may be at higher risk for early dementia,” said lead investigator Betty Bigio, PhD. “These findings also suggest possible reasons for the sex differences noticed in Alzheimer’s prevalence,” added Bigio, who is a research assistant professor in the Department of Psychiatry at NYU Grossman School of Medicine and affiliated with the Nathan Kline Institute for Psychiatric Research.
“As the declines in acetyl-L-carnitine and free carnitine closely matched the severity of Alzheimer’s disease, exploring the molecular pathways involved in their production could unveil new therapeutic targets to address the disease’s root causes and possibly intervene before irreversible brain damage occurs,” stated senior investigator Carla Nasca, PhD, an assistant professor in the Departments of Psychiatry and Neuroscience at NYU Grossman School of Medicine, also affiliated with the Nathan Kline Institute for Psychiatric Research.
The study utilized data from two separate cohorts of men and women across Brazil and California, where the researchers assessed blood levels of the two molecules. A total of 93 participants with varying degrees of cognitive impairment were involved, alongside 32 cognitively healthy individuals of comparable age, weight, and education level. The Californian group’s results were used to validate the findings from the Brazilian cohort.
Looking ahead, Nasca indicates that further research is necessary to explore the origins of acetyl-L-carnitine, the molecular pathways regulating its production, and how it affects brain chemistry when stored in brain vesicles and released into the bloodstream. The research team aims to identify other biomarkers in the brain closely associated with Alzheimer’s disease progression.
If their recent findings are confirmed through additional studies, Nasca believes that they could develop a blood test for dementia, facilitating the tracking of Alzheimer’s disease progression in a simpler and non-invasive manner. Currently, identifying biomarkers for disease progression often necessitates multiple spinal taps, which carry risks of pain and infection. A blood test would not only provide a more objective and quantitative measure of disease severity than existing memory or cognitive assessments but could also aid in predicting the effectiveness of new potential drug treatments aimed at delaying or preventing Alzheimer’s disease onset.
Both acetyl-L-carnitine and free carnitine are critical for maintaining healthy brain function and regulating cell energy metabolism. Previous studies by Nasca’s team have shown that acetyl-L-carnitine transports molecules from a cell’s energy-producing mitochondria to its nucleus, activating essential genes. This transportation is crucial for regulating the genes responsible for producing glutamate, a neurotransmitter involved in many brain functions, including nerve cell repair (neuroplasticity). This process is particularly important in the hippocampus, the brain region associated with memory, where initial damage from Alzheimer’s disease often manifests.
Nasca has noted that excess glutamate levels may also be linked to mood disorders and severe depression in humans, conditions that closely associate with Alzheimer’s disease. Her team has previously found links between low acetyl-L-carnitine levels (but not free carnitine) and depression, as well as childhood trauma. Future research will focus on how to halt the transition from depression to Alzheimer’s disease.
This study was funded by the National Institutes of Health grants R24AG06517, P50AG16573, and P30AG066519, alongside support from the Robertson Therapeutic Development Fund, D’Or Institute for Research and Education, Rede D’Or Sao Luiz Hospital Network, International Society for Neurochemistry, Fundacao Carlos Chagas Filho de Ampara a Pesquisa do Estado do Rio Janeiro, Serrapilheira Institute, and Alzheimer’s Association grant AARG-D-61541.
In addition to Bigio and Nasca, co-investigators from NYU Langone included Aryeh Korman and Drew Jones. Other collaborators were Ricardo Lima-Filho, Felipe Sudo, Claudia Drummond, Naima Assuncao, Bart Vanderborght, Sergio Ferreira, Paulo Mattos, Fernanda Tovar-Moll, Fernanda De Felice, and Mychael Lourenco from the Federal University of Rio de Janeiro and the D’Or Institute for Research and Education in Brazil; Olivia Barnhill from Rockefeller University in New York City; James Beasley and Sarah Young from Duke University in Durham, N.C.; and David Sultzer and Elizabeth Head from the University of California Irvine.
