Researchers at the University of Toronto and the University of Alberta have found that women who carry a particular gene variant and have had their ovaries surgically removed before the age of 50 are at high risk for Alzheimer's disease later in life, although hormone therapy can mitigate this risk.
The team of researchers, led by Gillian Einstein, an adjunct scientist at Baycrest Hospital and a professor in the department of psychology in U of T's Faculty of Arts & Science, aimed to investigate risk and resilience factors for Alzheimer's disease in women with early-life loss of estrogens.
In particular, they looked at a variant of the apolipoprotein gene, the APOE4 allele, which is a known risk factor for Alzheimer's disease in the general population but presents greater risk in women.
"One of our most important findings was the fact that loss of the naturally occurring hormone (endogenous), estradiol, as a result of surgical removal of both ovaries, might interact with the APOE4 to further increase Alzheimer's disease risk, placing women with early bilateral oophorectomy and APOE4 in a state of double jeopardy," said Einstein, who is the Wilfred and Joyce Posluns Chair in Women's Brain Health and Aging.
By 2050, Alzheimer's disease is projected to affect 12.7 million individuals aged 65 and older, two-thirds of whom are women. While it is still unclear why Alzheimer's disease is more prevalent in women than in men, researchers think it may have to do with ovary removal surgery (oophorectomy) earlier in life.
The researchers analyzed a cohort of 34,603 women from the UK Biobank, a large dataset, and found that women who had both ovaries surgically removed (bilateral oophorectomy) around the age of 43 showed four times the odds of developing Alzheimer's disease when compared to women who entered natural menopause at a mean age of 54.
The paper was published online in the Journal of Alzheimer's Disease .
Resilience factors
The study also identified resilience factors associated with the risk of Alzheimer's disease for these women.
For example, a high level of education was linked to a nine per cent lower likelihood of developing Alzheimer's disease in women with menopause caused by either ovary removal or aging, supporting previous research showing education as a form of cognitive resilience.
Surprisingly, there was also a modest relationship between body mass index (BMI) and Alzheimer's disease risk - but only for women with early bilateral oophorectomy. Each additional unit of BMI was associated with a seven per cent lower risk of developing Alzheimer's disease.
"Higher BMI might be associated with decreased Alzheimer's disease risk in women with ovary removal surgery because adipose tissue produces estrone (one of the three endogenous estrogens), which, in the absence of estradiol due to oophorectomy, may help maintain cognitive function in early middle age," said first author Noelia Calvo, a postdoctoral researcher in Einstein's U of T lab.
Importantly, among women with early bilateral oophorectomy, hormone therapy was associated with less than half the odds of developing Alzheimer's disease.
"This finding highlights the importance of estrogen-based therapies in decreasing Alzheimer's disease risk for women who have had their ovaries surgically removed before the age of 50," said co-author Esme Fuller-Thomson, a professor in U of T's Factor-Inwentash Faculty of Social Work and director of the Institute for Life Course & Aging . "However, it is interesting to note that hormone therapy was not associated with a lower risk of Alzheimer's disease among those who went through natural menopause at age 51 or older."
The researchers considered possible reasons for this discrepancy.
"It may be due to the fact that women with ovarian removal had a loss of estradiol in their early lives when demand for this hormone may be greatest since their age of menopause was an average of 11 years earlier than those who had gone through natural menopause," said Calvo.
Taken together, the results extend previous findings indicating that women with early bilateral oophorectomy are at high risk for Alzheimer's disease due to a link between APOE4 and estradiol loss in this cohort.
"The study suggests one important early-life reason why more women than men have [Alzheimer's] and also provides a better understanding of resilience factors that might fortify women with oophorectomy," Einstein said.
