Declining blood levels of two of the body’s own molecules are closely linked to the worsening of Alzheimer’s disease, particularly in women. Levels have been found to decline gradually, from women with no signs of memory impairment, disorientation and slowed thinking, to women with early signs of mild cognitive impairment. The decline was more pronounced in women with moderate or severe disease. In men, the decline was only observed in one molecule, indicating a disease-specific difference between the sexes.
Decrease in Acetyl-L-Carnitine and Free Carnitine Closely Linked to the Severity of Alzheimer’s Disease
Led by neuroscientists at NYU Langone Health and in collaboration with other researchers in the U.S. 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 Alzheimer’s disease. Blood levels of free carnitine, the main by-product of acetyl-L-carnitine in reactions important for brain function, decreased steadily in women depending on the severity of their cognitive impairment. In men, a significant decrease was found only for acetyl-L-carnitine, but not for free carnitine. The results of the study, published online in the journal Molecular Psychiatry, suggest that a decline in these two brain chemicals may indicate the presence and severity of Alzheimer’s disease, and that this difference may offer an explanation as to why women are at higher risk of the disease than men.
Additional computer testing showed that blood levels of acetyl-L-carnitine and free carnitine in the study participants were in direct proportion to elevated levels of amyloid beta and tau protein, which have long been considered markers of the progressive severity of Alzheimer’s disease. In fact, the research team’s accuracy in diagnosing the severity of Alzheimer’s disease increased from more than 80% – when using either the amyloid beta and tangled tau protein levels from cerebrospinal fluid or the two blood molecules – to 93% when using both. “Our results are the strongest evidence to date that decreased blood levels of acetyl-L-carnitine and free carnitine could serve as blood biomarkers for identifying Alzheimer’s patients, and possibly for those at higher risk of developing early dementia,” explained lead study author Betty Bigio, PhD. who is an assistant professor in the Department of Psychiatry at NYU Grossman School of Medicine. The findings could also explain the gender differences in Alzheimer’s disease, with more women than men developing dementia. Because the decline in acetyl-L-carnitine and free carnitine is closely related to the severity of Alzheimer’s disease, the molecular pathways involved in their production offer further potential therapeutic targets to address the cause of the disease and potentially intervene before permanent brain damage occurs, according to lead study researcher Carla Nasca, PhD, assistant professor in the Departments of Psychiatry and Neuroscience at NYU Grossman School of Medicine.
A Blood Test Could Help Predict the Effectiveness of Potential New Drug Treatments to Delay or Prevent the Onset of the Disease
The study included data on two separate groups of men and women in Brazil and California, in which the researchers measured blood levels of the two molecules. A total of 93 subjects diagnosed with varying degrees of cognitive impairment participated in the study, as well as 32 cognitively healthy men and women of similar age, weight and education level. The results of the Californian group were used to confirm the results of the Brazilian group. According to Nasca, further research is needed into the origins of acetyl-L-carnitine and the molecular pathways that control its production, as well as tracking the molecule’s effects on brain chemistry as it is contained in the brain’s vesicle stores that are released into the blood. The team’s goal is to define other biomarkers in the brain that are closely linked to the progression of Alzheimer’s disease. If further studies confirm their latest findings, Nasca says the team’s research could be used to develop a blood test for dementia and to track the progression of Alzheimer’s disease more easily and non-invasively.
Currently, looking for biomarkers of disease progression can involve repeated lumbar punctures, which carry the risk of pain and infection. A blood test could also be useful to support or add a more objective, quantitative measure of disease severity than the existing questionnaires that test memory or thinking ability. According to Nasca, a blood test could also be useful in predicting the effectiveness or ineffectiveness of potential new drug treatments to delay or prevent the onset of Alzheimer’s disease. Both acetyl-L-carnitine and free carnitine are essential for healthy brain function and the regulation of cellular energy metabolism. Previous research by Nazca’s team showed that acetyl-L-carnitine also transports molecules from the cell’s powerhouse, the mitochondria, to the controlling nucleus, allowing genes to open and be activated. This shuttling is crucial for the regulation of genes that produce the neurotransmitter glutamate. Glutamate is 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 is where initial damage from Alzheimer’s disease occurs.
Nasca says that excessive glutamate levels have also been linked to mood disorders and major depression in humans, disorders that are closely associated with Alzheimer’s disease. Her team has also found a link between a lack of acetyl-L-carnitine, but not free carnitine, and depression as well as childhood trauma. Further research is planned to find out how the progression from depression to Alzheimer’s can be prevented.