Blood test could help track Alzheimer's disease progression and severity

Declining blood levels of two molecules that occur naturally in the body track closely with worsening Alzheimer's disease, particularly in women. Levels were found to drop gradually, from women with no signs of memory, disorientation, and slowed thinking to those with early signs of mild cognitive impairment. Decreases were more prominent in women with moderate or severe stages of the disease. Declines in men were evident in only one molecule, revealing a disease-specific difference between the sexes.

Six million Americans, most over the age of 65 and predominantly women, are currently estimated to 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 Alzheimer's disease. Blood levels of free carnitine, the main byproduct of acetyl-L-carnitine in reactions essential to brain function, steadily declined in women in amounts related to the severity of their cognitive decline. In men, significant declines were seen only in acetyl-L-carnitine, not free carnitine.

Published in the journal Molecular Psychiatry online January 7, the study results suggest that declines in these two brain chemicals could indicate the presence and degree of Alzheimer's disease, and that this difference might 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 aligned in direct proportion in study participants to increased amyloid beta and tangled tau protein levels, long been considered markers of progressive severity in Alzheimer's disease. Indeed, the research team's accuracy in diagnosing the severity of Alzheimer's disease rose from more than 80 percent—when using either amyloid beta and tangled tau protein levels collected from cerebrospinal fluid or the two blood molecules—to 93 percent when using both.

Our findings offer the strongest evidence to date that decreased blood levels of acetyl-L-carnitine and free carnitine could act as blood biomarkers for identifying those who have Alzheimer's disease, and potentially those who are at greater risk of developing early dementia."

Betty Bigio, PhD, study lead investigator 

"The results also might explain the differences by sex in Alzheimer's disease, with more women than men having dementia," said Dr. Bigio, a 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 declines in acetyl-L-carnitine and free carnitine tracked closely with the severity of Alzheimer's disease, the molecular pathways involved in their production offer other possible therapeutic targets for getting at the root cause of the disease and potentially intervening before permanent brain damage occurs," said senior study investigator 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, in which the researchers measured blood levels of the two molecules. A total of 93 study volunteers diagnosed with varying degrees of cognitive impairment were involved, 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.

Moving forward, Dr. Nasca says more research is needed into the root sources of acetyl-L-carnitine and the molecular pathways that control its production and into tracking how the molecule affects brain chemistry as it is contained in brain vesicle stores released into the blood. The team's goal is to define other biomarkers in the brain that more precisely track Alzheimer's disease progression.

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 for tracking the progression of Alzheimer's disease in an easier and noninvasive way. Currently, searching for biomarkers of disease progression can involve serial spinal taps that pose risks of pain and infection. A blood test might also be useful to support or add a more objective, quantitative measure of disease severity than existing questionnaires that test memory or thinking skills.

A blood test, Dr. Nasca says, could also help predict the effectiveness, or lack thereof, of potential new drug treatments designed to delay 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. Past research by Dr. Nasca's team showed that acetyl-L-carnitine also shuttles molecules from a cell's powerhouse mitochondria to a cell's controlling nucleus, allowing genes to open and become activated. This shuttling action is key in regulating genes that produce the neurotransmitter glutamate, another chemical involved in most brain activities, including nerve cell repair (plasticity). This matters in the hippocampus region of the brain, which helps regulate memory and where initial damage from Alzheimer's disease is known to appear.

Dr. Nasca says that excessive levels of glutamate have also been tied to mood disorders and severe cases of depression in humans, disorders closely tied to Alzheimer's disease. Her team has also linked deficiencies in acetyl-L-carnitine, but not free carnitine, to depression and childhood trauma. Future investigations are planned about 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 funding 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 Alzheimer's Association grant AARG-D-61541.

Besides Dr. Bigio and Dr. Nasca, other NYU Langone researchers involved in the study are co-investigators Aryeh Korman and Drew R. Jones, PhD. Other study co-investigators 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.