Women tend to get Alzheimer's disease at a significantly higher rate than men; in the US, about two-thirds of people with the neurodegenerative disorder are women. Why that happens has been unclear. Women tend to live longer lives than men, which could be one explanation. However, women do not get non-Alzheimer's dementia at higher rates than men. There are some other theories too. For example, women also get autoimmune diseases more often than men, which may causing more aberrant plaques to form in the female brain. Genetic factors may also be involved.
Scientists have now assessed brain tissue from Alzheimer's patients and a mouse model to show that an enzyme called USP11 (ubiquitin-specific peptidase 11) tends to accumulate at much higher levels in female brains compared to male brains. This causes more abnormal tau protein to build up; tau accumulation has been associate with the development of Alzheimer's disease.
The cell can remove unwanted proteins by tagging them with a molecule called ubiquitin. Tau gets 'ubiquitinated' for removal from the cell, and there are various mechanisms that ensure that the right amount of tau is getting ubiquitinated. But that process can also go awry, and if too much ubiquitin is removed from tau, it may start to accumulate abnormally.
This study showed that women express more USP11, an X-linked gene, than men. Women also have a higher tau burden in Alzheimer's. USP11 expression was strongly connected to tau accumulation in both women and female mice in a mouse model. When USP11 was genetically eliminated from the mouse model, the female mice were protected from tau pathology as well as cognitive impairment. The findings have been reported in Cell.
The authors noted that while this study provides new insight into Alzheimer's risk in women, it may not fully explain why women get the disease more often.
“In terms of implications, the good news is that USP11 is an enzyme, and enzymes can traditionally be inhibited pharmacologically,” said co-senior study author David Kang of Case Western Reserve University. “Our hope is to develop a medicine that works in this way, in order to protect women from the higher risk of developing Alzheimer’s disease.”
In another recent, unrelated study, researchers assessed Alzheimer's patients, all of whom were women from an isolated population with a relatively small gene pool. The work revealed that variants in a gene called MGMT were associated with a significantly higher risk of Alzheimer's disease. None of these people carried the most common Alzheimer's risk variant we now know of, a change in the APOE gene referred to as APOE4.
MGMT encodes for a protein that is involved in DNA damage repair. It was linked to the development of Alzheimer's hallmarks, amyloid-β and tau, particularly in women. This research was reported in Alzheimer’s Disease & Dementia: The Journal of the Alzheimer’s Association.
Sources: Cell Press, Cell, Boston University School of Medicine, Alzheimer’s Disease & Dementia: The Journal of the Alzheimer’s Association
