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Blog | What happens if you lose the Y chromosome?

Alzheimer's is a disease that affects more women than men in the world. Today, it is estimated that approximately two thirds of Alzheimer's cases are women. However, the scientific community still does not agree on the causes of this imbalance.

It would be easy to say that women have a higher biological risk of Alzheimer's disease than men. However, there are a multitude of socioeconomic, cultural and geographical factors that could explain the differences observed between the two sexes. Even so, we can say that sex is an important source of heterogeneity in the processes that occur in Alzheimer's disease. Therefore, studying and learning more about sex-specific risk profiles may be crucial for a better understanding of the disease.

Sex chromosomes

When we think of genetics, the first major difference between men and women that comes to mind is the sex chromosomes. Women have one pair of X chromosomes (XX), while men have one copy of an X chromosome and one copy of a Y chromosome (XY). In other words, if we inherit the Y chromosome from our father, our sex will be male, while if we inherit the X it will be female.

The human being is naturally programmed to produce a female. So what is it that causes men to be born? Inheriting the Y chromosome from the father means inheriting the SRY gene with it. This gene is responsible for determining the sex of the individual by activating, as if it were a switch, a series of biological mechanisms that lead to the formation of the primary male sexual characteristics. Later, once the testes are formed, they will be responsible for producing hormones, such as testosterone, which will cause the differentiation of secondary sexual characteristics during puberty.

Mosaic loss of the Y chromosome

The Y chromosome is important because it allows the differentiation of the two sexes (male and female). But is it useful for anything else?

This chromosome is much smaller than the X chromosome and has far fewer genes (63 protein-coding genes compared to 800 on the X chromosome). Moreover, it is the only chromosome that is not necessary for life. Hence, it has been considered a "genetic dumping ground" for many years. However, this conception is gradually changing.

In 1963, a group of scientists observing the blood cells of a group of elderly men noticed that some of them were missing the Y chromosome. This phenomenon was named mosaic loss of the Y chromosome (mLOY) and is highly common among men (about 7% in men aged 65, and 20% in men over 85). However, this loss of the Y chromosome was not given more importance, considering it a harmless phenomenon associated with aging. Today we know that, apart from age, there are mainly 2 factors that increase the risk of mLOY: genetic predisposition and tobacco, the latter multiplying the probability of losing the Y chromosome by four.

Can the Y chromosome protect us against disease?

It was not until the 2010s that scientists began to discover that the loss of the Y chromosome increases the risk of general mortality and, specifically, of contracting various diseases, such as Alzheimer's, cancer or cardiovascular disease.

In 2016, a study found that the loss of the Y chromosome increased, according to the authors, three times the risk of Alzheimer's as well as the speed of progression of the disease. Further on, in a study conducted at Ace Alzheimer Center Barcelona, we have observed that genetic predisposition to mLOY acts as an accelerator of the disease specifically in men. In other words, we observed that the set of genes that increase the chances of losing the Y chromosome is associated with a faster progression of Alzheimer's exclusively if you are male (and have a Y chromosome to lose). These findings challenge the notion that the Y chromosome is a "genetic dumping ground" and evidence its importance beyond sex determination.

If we scientists are able to find protective genes on the Y chromosome, we may be able to design therapies to rebuild or recreate these protective effects in those with the disease. Even more excitingly, these therapies could be applied not only to men, but also to women.

These therapies do not exist at the moment, but if you are a man and you are worried about losing your Y chromosome, quitting smoking has been shown to reduce mLOY compared to continued smokers. You will be taking care of your health, protecting your memory and keeping your Y chromosome!

PABLO GARCÍA GONZÁLEZ

Predoctoral researcher at Ace Alzheimer Center Barcelona

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