An international team of researchers led by scientists at Uppsala University in Sweden presented their recently published findings at the annual conference of the European Society of Human Genetics yesterday. The new study found that men with blood cells that do not carry the Y chromosome are at greater risk of being diagnosed with Alzheimer's disease (AD). The loss of the Y chromosome (LOY), which is known to affect up to 20% of men who are aged over 80, is the most common genetic mutation acquired during a man's lifetime.
"Most genetic research today is focused on inherited gene variants—mutations that are inherited by the offspring, but what we're looking at are postzygotic mutations that are acquired during life," stated senior study author Lars Forsberg, Ph.D., a researcher in the department of immunology, genetics, and pathology at Uppsala University.
“The idea for this research project came to me when I was writing our first paper on the relationship between LOY and the development of nonblood cancers," Dr. Forsberg added. "In thinking about the process known as immunosurveillance—the body's ability to fight disease development throughout life—I found that it had been well studied in AD, and hence it occurred to me that LOY might be involved in this disease too."
The investigators examined LOY in over 3200 men with an average age of 73 and an age range of 37–96. Approximately 17% of the participants showed LOY in blood cells, and this increased with age. Moreover, the researchers found that those with an existing diagnosis of AD had a higher degree of LOY and that LOY was also a marker for the likelihood of developing the disease during the follow-up period.
"Using new tools to analyze genetic variations that accumulate with age, we can help explain how sporadic diseases like cancer or Alzheimer's manifest," commented lead study author Jan Dumanski, Ph.D., professor of experimental pathology in the department of immunology, genetics and pathology at Uppsala University.
The findings from this study were published recently in The American Journal of Human Genetics in an article entitled “Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease.”
Interestingly, because women do not carry a Y chromosome, and men have, on average, shorter lives, it is possible that LOY may be related to the earlier death of men. However, the researchers say, the mechanisms and causes for their findings are still not properly understood. They are currently investigating the functional effects of LOY and looking at its role in different groups of men and in other diseases. They hope to understand better which types of cancer are associated with LOY, as well as whether there is a link with early signs of dementia, for example, mild cognitive impairment. Furthermore, how LOY in blood cells can be related to disease in other organs is still unclear.
"The blood cells we studied are involved in the immune system, and the fact that LOY in them is associated with disease in other tissues is striking,” Dr. Forsberg remarked. “We therefore hypothesize that the loss of LOY in blood cells leads them to lose part of their immune function."
The participants for this new analysis came from three long-term studies that could provide regular blood samples. Across the participant’s datasets, those with the highest fraction of blood cells without a Y chromosome were consistently more likely to be diagnosed with Alzheimer's.
"Having loss of Y is not 100% predictive that you will have either cancer or Alzheimer's," Dr. Forsberg noted, adding that there were men in the study who had the mutation and lived with no symptoms well into their 90s. "But in the future, loss of Y in blood cells can become a new biomarker for disease risk and perhaps evaluation can make a difference in detecting and treating problems early."
The researchers are optimistic that in the future it might be possible to use a LOY test to identify men at risk and then carry out oncological or neurological evaluations to try to detect early, mild, symptoms of disease. LOY might also become an important diagnostic tool in combination with other biomarkers that may be used to predict risks for various diseases.
"The addition of LOY testing in the general population could give medical practitioners the possibility of using preventive strategies in men at risk," Dr. Forsberg stated. "For example, in cancer, primary tumors are usually not deadly—it is the metastatic process that is typically responsible for deaths. If we could predict which men have an increased risk of cancer, we could watch them carefully for the development of disease and also use appropriate preventive treatments. In short, the widespread use of LOY testing could radically decrease male mortality rates, and even perhaps eliminate the difference in life expectancy between the sexes."