Alzheimer’s disease is more common in women, and the fact that age is a risk factor for developing this dementia and that women live longer cannot fully explain it. In fact, and according to the Pasqual Maragall Foundation, two out of every three people who are diagnosed in the United States are women and this data can be extrapolated worldwide.
Although the causes why the female population is more prone to suffering from Alzheimer’s have not been discovered, it seems that there may be a link with menopause due to the decrease in estrogen that occurs at this stage. Now, a new study from the Karolinska Institute suggests that activation of the brain protein CYP46A1 may protect women from developing neurodegenerative diseases such as Alzheimer’s. This protein converts excess brain cholesterol into a cholesterol product called 24S-hydroxycholesterol, 24SOH.
The study was carried out in genetically modified mice of both sexes by increasing the levels of the CYP46A1 protein, which in turn increases the production of 24SOH. In females, the researchers were able to observe healthier neurons, improved memory abilities and greater estrogen activity, both under menopause-like conditions and during aging. These effects were not observed in male mice. The results have been published in Science Advances.
Early menopause, a risk factor for cognitive decline
“Cholesterol turnover and sex hormones are modifiable factors. Our results suggest that they may serve as potential treatment targets for several neurodegenerative diseases in the future,” says Silvia Maioli, associate professor at the Department of Neurobiology, Caring Sciences and Society at the Karolinska Institutet and principal investigator of the study.
Measurements of 24SOH in the cerebrospinal fluid of patients with Alzheimer’s disease showed that higher levels of 24SOH were correlated with lower levels of Alzheimer’s markers such as tau, but only in women.
“We believe that cholesterol metabolism directed by CYP46A1 activators such as Efavirenz may promote estrogen-mediated neuroprotection in women at risk for Alzheimer’s”
Two-thirds of people with Alzheimer’s disease are women, and early menopause is a specific risk factor for cognitive decline. Menopause is characterized by the loss of estrogen, a hormone produced not only in the ovaries but also in the brain, which is essential for keeping neurons healthy and functional. The study shows that activation of CYP46A1 increases estrogen activity in the brains of menopausal and elderly female mice, making CYP46A1 a potential female-specific therapeutic target.
“Previous research has shown that CYP46A1 can be activated pharmacologically with low doses of the anti-HIV drug Efavirenz,” explained Silvia Maioli. “We believe that cholesterol metabolism directed by CYP46A1 activators such as Efavirenz may offer a new approach to promote estrogen-mediated neuroprotection in women at risk for Alzheimer’s disease,” concludes the researcher.
