Research published by a team of researchers from the University of Toronto in collaboration with colleagues from the University of Alberta has found that women who have had both ovaries surgically removed before the age of 50 and carry a variant of the apolipoprotein gene, the APOE4 allele, are at high risk of late-life Alzheimer disease (AD). The use of hormone therapy mitigates this risk.

By 2050, Alzheimer's disease is projected to affect 12.7 million individuals 65 and older with women comprising two-thirds of that number. It is still unclear why Alzheimer's disease is more prevalent in women than in men, but it may have to do with early life events, such as ovary removal surgery (oophorectomy).

The researchers analysed a cohort of 34,603 women from a large dataset, the UK Biobank, and found that in this cohort, women who had had both ovaries surgically removed (bilateral oophorectomy) at the approximate 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.

The team of researchers, led by Dr Gillian Einstein, Professor of Psychology, the Wilfred and Joyce Posluns Chair in Women's Brain Health and Aging, and adjunct scientist at Baycrest Hospital at the University of Toronto, aimed to investigate risk and resilience factors for Alzheimer's disease in women with early life loss of estrogens.

"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 allele to further increase Alzheimer's disease risk, placing women with early bilateral oophorectomy and APOE4 in a state of double jeopardy," said Dr Einstein. APOE4 is a known risk factor for Alzheimer's disease in the general population but presents a greater risk in women.

The study also identified resilience factors associated with the risk of Alzheimer's disease for these women. A high level of education was linked to a 9% lower likelihood of developing Alzheimer's disease in women with both types of menopause—that caused by ovarian removal and that caused by ageing—supporting previous research showing education as a form of cognitive resilience in both women and men.

Surprisingly, there was also a modest relationship between body mass index (BMI) and Alzheimer's disease risk, but only for the women with early bilateral oophorectomy. Each additional unit of BMI was associated with a 7% lower risk of developing Alzheimer's disease.

"Higher BMI might be associated with a 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 Dr. Noelia Calvo, a postdoctoral researcher in Dr. Einstein's lab at the University of Toronto.

Importantly, among women with early bilateral oophorectomy, ever taking hormone therapy was associated with less than half the odds of Alzheimer's disease compared to those women who had not taken hormone therapy.

"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 Dr Esme Fuller-Thomson, a professor at the Factor-Inwentash Faculty of Social Work at the University of Toronto 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 AD and also provides a better understanding of resilience factors that might fortify women with oophorectomy against AD," said Einstein.