Growing older may be inevitable, but getting Alzheimer’s disease is not. While we can’t stop our advancing age (which is the biggest risk factor for Alzheimer’s), there are many other factors that can be modified to reduce our risk for the disease.

Determining how these risk factors may differentiate between women and men could help us understand why Alzheimer’s can present, progress, and respond to treatments differently in each sex, providing new therapeutic avenues to explore.

Unfortunately, most studies of Alzheimer’s risk factors look at combined data for women and men and do not analyze data by sex to identify risk factors that are more common or more predictive in women versus men.

In a review paper just published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, I, along with researchers from the Society for Women’s Health Research Interdisciplinary Network on Alzheimer’s Disease call for more research into sex differences in Alzheimer’s disease to improve prevention, diagnosis and treatment.

The paper examines our current knowledge about the differences between women and men in Alzheimer’s, identifies knowledge gaps and recommends priority areas for future research.

There are three types of sex-related risk factors for Alzheimer’s: those that only affect women, those that only affect men and those that impact both sexes.

THE IMPACT OF HORMONES

Hormones play a key role in sex differences in the brain, yet relatively little is known about their influence in Alzheimer’s. Ovaries are the primary source of estrogen for premenopausal women, and surgical removal of a woman’s ovaries before menopause is associated with higher risk of dementia. However, using estrogen therapy after surgery until age 50 negates that risk. This suggests that estrogen may be important and even protective in premenopausal women, but more research is needed to understand why.

On the other hand, there are conflicting studies as to whether androgen deprivation therapy, which is used to treat prostate cancer, increases risk for Alzheimer’s in men. Further investigation is needed into the role of sex hormones, the use of different hormonal treatments, and how they each impact Alzheimer’s risk.

RISK FACTORS FOR BOTH SEXES

Among risk factors that affect both women and men, some are more common in one sex. For example, depression and sleep apnea are both risk factors for dementia, but depression is twice as common in women and sleep apnea is three times more common in men. Similarly, low education or job attainment are Alzheimer’s risk factors, but traditionally women have not had the same access to education and job opportunities as men, putting them at increased risk.

Some risk factors have a stronger effect in one sex, but cannot be changed. The ε4 allele of the APOE gene is the strongest and most common genetic risk factor for Alzheimer’s in both women and men. However, women with APOE ε4 have an increased risk of developing Alzheimer’s compared to women without APOE ε4 and men with and without APOE ε4.

Cardiovascular disease and metabolic issues like type 2 diabetes and obesity are also factors that increase risk for Alzheimer’s, but we don’t yet know whether there are differences in risk between women and men for these factors. However, because we do know that there are sex differences in the development, progression and treatment of cardiovascular disease, it is important that we look at the relationship between sex and the cardiovascular and metabolic risk factors of Alzheimer’s.

Learning how risk factors influence risk over time is also critical. For example, in cardiovascular disease, taking aspirin helps reduce heart attack and stroke risk in women aged 65 years and older. This effect is not seen in younger women. It is possible that certain Alzheimer’s risk factors may be strongest at certain points during our lives, and understanding this is key for prevention and early intervention.

Determining how risk factors differ between women and men can help optimize our management of them and guide Alzheimer’s research moving forward.

PRIORITY AREAS FOR FUTURE RESEARCH

Risk factors are just one of the areas in which we need more research into the differences between the sexes in Alzheimer’s disease. As outlined in the review paper from the Society for Women’s Health Research Interdisciplinary Network on Alzheimer’s Disease, additional research is also needed to examine:

  • Sex and gender differences in racial and ethnic groups
  • Gender differences in caregiving and how the burden of caregiving increases Alzheimer’s risk
  • Differences between women and men in the detection, diagnosis, progression, management, and treatment of Alzheimer’s
  • Differences between women and men in response to current Alzheimer’s therapeutics and those in development

To achieve these research goals, not only do we need funding agencies and scientists on board, we need the support and participation of patients, caregivers and the wider public in clinical trials. When all these groups join together, that’s when true scientific progress is made.