Mind the Gap

by Women's Brain Health Initiative:Approximately two-thirds of those diagnosed with Alzheimer’s disease (AD) are women. However, research into sex and gender differences in AD is astonishingly limited. Because the greatest risk factor for dementia is age, the discrepancy between the sexes has historically been attributed to the longevity of women.While it is true that women generally live longer than men, we also now know that Alzheimer’s is a disease that begins years, or even decades, before the onset of overt symptoms. A growing body of research suggests that there may be unique biological reasons for these differences, as well as related genetic, lifestyle, and societal factors at play.In recent years, due to the significant shift towards precision medicine, the scientific community has started to look further into why women are more likely to develop AD than men. In contrast to the “one-size-fits-all approach,” precision medicine (also referred to as personalized or individualized medicine) aims to optimize the effectiveness of disease prevention and treatment, and minimize side effects for those less likely to respond to a particular therapeutic, by considering an individual’s specific pattern of genetic variability, environment, and lifestyle factors.The concept that a treatment option might work well in some patients and not as well in others is consistent with an emerging sense that AD may be several different diseases, as well as the idea that genetic factors predispose some individuals to AD while protecting others.Although substantial advances in precision medicine have been made over the past years for some diseases (particularly in cancer care), for most other diseases – including AD – precision medicine is only in its beginning. Part of the customization of precision medicine includes examining the ways in which sex and gender are implicated in disease processes.In the context of AD, progress towards sex and gender integration in research has lagged behind. To improve the diagnosis of the disease, and to accelerate the development of new treatments and interventions, sex and gender differences must be better understood and measured.Since its launch in 2012, Women’s Brain Health Initiative (WBHI) has worked incessantly to help transform the international conversation around dementia, and has quickly become an important, trusted voice across the globe for women’s brain health.WBHI has forged strategic alliances within the scientific and medical communities both in Canada and abroad. For instance, WBHI supports the Canadian Consortium on Neurodegeneration in Aging (CCNA), which includes approximately 340 researchers across the country, where sex and gender considerations are now being taken into account as part of research practice. In 2015, WBHI partnered with other esteemed organizations from the U.S., the U.K., and Canada to form the Global Alliance on Women’s Brain Health, which advocates for gender-sensitive focus and investment.More recently, WBHI was the driving force behind the funding and creation of the world’s first Research Chair in Women’s Brain Health and Aging, awarded to Dr. Gillian Einstein at the University of Toronto. This initiative has helped make Canada a world leader in exploring the sex-gender divide.In the U.S., the Society for Women’s Health Research (SWHR) has similarly worked towards correcting imbalances in health care for women by addressing unmet needs and research gaps in women’s health. In 2016, the SWHR convened an expert panel of clinicians and scientists to review ongoing and published research related to sex and gender differences in AD. The results of that exploration were published in the June 2018 issue of Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association in a groundbreaking paper entitled “Understanding the impact of sex and gender in Alzheimer’s disease: A call to action.”“In the past, sex had initially been adjusted for,” says Dr. Michelle Mielke, an Associate Professor in the Departments of Epidemiology and Neurology at the Mayo Clinic in Rochester, Minnesota, and one of the paper’s authors. In other words, any differences noted in research inquiries were removed from the equation, rather than factored in. “Sex and gender has been seen more as a nuisance or label and people have previously understood that there are differences, but it wasn’t a focus of the research.”Much of what is known to date about sex and gender differences in disease formation has come from those innovative researchers who, as they were conducting analyses, “realized that there were differences in sex, and the more they looked at it, the more differences they saw,” explains Dr. Mielke. Now, though, structural change is beginning to occur. The major Canadian, European, and U.S. funding agencies, since 2010, 2014, and 2015 respectively, have created and implemented policies that require researchers to include sex as a variable in research design and in the reporting of research findings. It is an important step in the long road ahead.One of the most significant sex-based differences that have been discovered is that women with the APOE e4 gene are at greater risk for developing AD than men with that same gene. “Although it’s a genetic risk factor for both sexes, women are more vulnerable to that genetic risk factor than men,” says Dr. Pauline Maki, a Professor of Psychiatry and Psychology and Associate Director of the Center for Research on Women and Gender at the University of Illinois at Chicago, and co-senior author on the paper. “Among persons aged 65 to 75 years with the APOE e3/e4 genotype, the risk of AD dementia is fourfold higher in women than that in men.” Unfortunately, the reasons as to why this is the case remain elusive.Another key sex-based difference between men and women is hormonal. For instance, a woman’s brain undergoes a considerable change in function and structure during menopause and, according to Dr. Maki, researchers are just beginning to examine whether this critical female-specific life event might in some way set up, for at least a portion of women, AD later in life. Women who have their ovaries removed before a natural menopause are at a “70% increased risk in cognitive impairment or dementia,” says Dr. Maki.If women take estrogen until the age of 50, though, that risk factor is eliminated. “That tells us in a fundamental way that estrogen, created from the ovaries, protects our brains,” says Dr. Maki. Of course, while all women go through menopause, not all women develop AD. It is therefore important not to “pathologize what’s normal.” Nevertheless, researchers still need to uncover why for certain women “this reproductive event is the perfect storm,” notes Dr. Maki.A further difference between the sexes is that “women have a lifelong advantage in verbal memory,” says Dr. Rebecca Nebel, Director of Scientific Programs at the SWHR, and one of the paper’s authors. While this advantage may benefit women by delaying verbal memory impairment until more advanced pathology, it may also delay diagnosis and treatment intervention. Many of the tests that are used to diagnose AD depend on verbal memory acuity.Despite having an inherent advantage, women are assessed the same way as men, using the same cutoff score (which is an average of both men and women’s scores).“Consequently, women are often diagnosed with the disease later than men, and it has been hypothesized that this delayed detection could be part of the reason why women decline more rapidly after diagnosis.”In light of this difference between the sexes, researchers need to rethink how AD and other forms of dementia are initially recognized, and perhaps institute different testing mechanisms and/or use sex-specific cutoff scores, says Dr. Nebel.With respect to gender-specific risk factors, it is important to note that while they are unique, they cannot be completely isolated from sex, says Dr. Mielke. These risk factors include exercise (women exercise less than men, and we know exercise is protective) and marital status (men who are not married or are widowed have a greater risk of developing AD, perhaps because single women are more likely to see a health-care provider and to engage in social activities). Women are more likely to be caregivers, which is associated with elevated levels of cortisol and impaired attention and executive functioning. Caregiver spouses may also be at a higher risk of developing dementia. Much more research is needed to understand these gender differences and to fill the knowledge gaps.

• To promote future research, the paper’s authors identified twelve “high-priority areas” that warrant further investigation:
• the extent to which differences in longevity, survival bias, and comorbidities impact sex and gender differences in AD;
• potential risk factors that affect only one sex, such as pregnancy and menopause for women and testosterone loss for men;
• the influence of estrogens and hormone therapy on brain function and disease risk;
• possible sex differences in genetic risk factors, such as in the case of APOE e4 carriers;
• how sex and gender may be differently implicated in AD in risk factors that both sexes experience, including cardiovascular disease, diabetes, education, and depression;
• sex differences in disease progression and change in cognitive function, neuroimaging, cerebrospinal fluid, and biomarkers;
• whether sex differences in brain development impact sex differences in brain aging and disease pathology;
• sex and gender differences in racial and ethnic subgroups;
• societal, political, and geographical changes in estimates of sex differences in AD;
• gender differences in caregiving and how the burden of caregiving influences AD risk for the caregiver;
• variances in the development of therapeutics in preclinical and clinical studies, as well as in designing clinical trials; and
• differences on clinical detection, diagnosis, management, and treatment of AD for men and women.

It is important to remember that focusing the conversation on sex and gender is beneficial for both men and women. “We’re trying to find individualized approaches for both sexes and genders,” says Dr. Mielke. The hope is that the call-to-action paper will motivate the industry, academia, and the government to change the ways in which research is conducted and, specifically, improve the integration of sex and gender at all stages of the research process.Source: MIND OVER MATTER V8