Toward Inclusive Dementia Studies
RECENT ADVANCES IN ADDRESSING SEX & DIVERSITY GAPS.
In 2024, two Canadian scientists led meetings to advance our understanding of dementia and Alzheimer’s disease (AD). The first meeting summarized what we know about sex and gender differences in AD, gaps in that knowledge, and where we are going with what we currently know; the second asked what is known about risk and resilience factors in underrepresented groups in AD research. Both symposia aimed to draw attention to these inequities and map a path for future research.
SEX, GENDER, & DEMENTIA MEETING
At the first meeting, organized by the Canadian Consortium on Neurodegeneration in Aging’s Women, Sex, Gender, and Dementia cross-cutting Program (CCNA-WSGD) – held in March in Montreal and tied to the Science and Partner’s Day – sex and gender took centre stage. The mandate of the WSGD is to foster sex and gender in aging and dementia research.
The consensus conference/workshop Sex and Gender in Cognitive Aging: Where Are We and What’s Next? was planned and organized by the Sex and Gender Champions of the CCNA, led by Dr. Gillian Einstein, WSGD Lead, professor of psychology, and the Wilfred and Joyce Posluns Chair in Women’s Brain Health and Aging at the University of Toronto. It was supported by the Canadian Institutes of Health Research (CIHR) Institute of Gender and Health,, Brain Canada, and Women’s Brain Health Initiative.
“It was planned as a consensus meeting, because there are a lot of data – although not enough – and there was a previous meeting sponsored by the Alzheimer’s Association about ten years ago, and things have really changed since then, both in the amount of research focusing on women, and our thinking on sex and gender,” said Dr. Einstein.
“We see AD as a spectrum co-incident with other dementias, and we’re much less binary in our thinking about sex and gender, as well as thinking more expansively about their role in both the etiology and potential treatments of dementia.”
The objective of the consensus workshop was to bring together a small group of international experts, including CCNA members, to discuss the current state of sex and gender research in cognitive aging and to lay the groundwork for new research, diagnosis, and treatment directions.
“At the workshop, gender was viewed as not solely gender identity, but also gendered life experiences, including social constructs linked with being a woman or man in society (e.g., the expectation that women shoulder most of the burden of unpaid care).”
Invitees came from a variety of different disciplines and backgrounds. “We had very wide representation, including a strong presence of people with lived experience, our Indigenous colleagues, and two spirit individuals,” Dr. Einstein said.
The conference opened on a unique note. “Because I really wanted to push people to think differently, there was a heavy emphasis on the arts and art-based methods,” Dr. Einstein explained. This included an exhibition of an arts-based qualitative method called body mapping storytelling by women studied in Dr. Einstein’s lab who have subjective cognitive decline in their early 40s, likely due to early life ovarian removal.
SKETCHING THE PRESENT LANDSCAPE
The scientific portion of the meeting began with “talks that were really outstanding, especially keynotes from Victor Henderson and Roger Dixon laying the groundwork for what is known and quantitative methods for understanding individual variation that is inherent in including gender,” Dr. Einstein said.
A few established sex and gender differences were covered:
· the high-risk ApoE4 Alzheimer’s gene appears to have a stronger impact in women than men;
· some forms of exercise are better for midlife females than males. Importantly, women benefit more from strength training because it wards off frailty, which is a big risk factor for females;
· since cognitive tests are verbally heavy, and women have better verbal skills on average, they tend to be diagnosed with dementia at a later stage in the disease than men; and
· the risk of early life ovarian removal for late-life Alzheimer’s.
Panels included experts on sensory loss, Indigenous health and wellness, brain and cognitive reserve, and lifestyle behaviours, including sleep. Evidence was also presented that negative social and structural determinants of health, which women experience more than men, such as lower socioeconomic status and less access to health care, might explain some of the sex differences seen in AD. The Reproductive Life Course panel addressed how sex-specific biology, such as menstrual cycling and pregnancy, interact with age and other known risk factors for dementia.
BRIDGING GAPS IN KNOWLEDGE
Conference attendees also discussed current gaps in our knowledge, and how to address them in future research.
“There’s a lot of territory that hasn’t covered with respect to sex and gender,” Dr. Einstein observed. “For example, there’s been an enormous amount of work done in olfaction (which is the sense of smell) as a potential early sign of AD, but there’s been almost no sex differences work done there. The same with other sensory phenomena – hearing, vision, and balance.”
As with research that looks at diverse communities, going forward, sex and gender research will require designing studies in a way that will provide samples of smaller population subsets large enough to generate meaningful data.
“When you start getting away from the binary of sex and gender, the numbers start getting smaller,” said Dr. Einstein, “and you start getting into the issue of what kinds of methods are available for understanding the subtleties of variation. With any underrepresented group, it’s important to not just include a few in a sea of white, Western participants.
The data from the former will be completely swamped by the latter, and we will learn nothing about these groups. As we begin to understand the range of people in the categories of male and female, as well as those who do not fit into those categories, we are going to need to be able to acquire meaningful data with small participant numbers.”
A key point that arose at the WSGD conference was the lack of sex-based analysis in new drug trials. Take the example of the latest drugs for treating early-stage AD. “Some trials included sex-based analysis in their secondary/sub analyses, but weren’t including it in their primary analysis,” Dr. Einstein explained.
“The secondary analyses revealed that these antibodies against plaques are not as effective in females as in males. But decisions to release them to market were made on the basis of the primary analyses. This really highlighted an area of concern going forward.”
“We’re still encountering people who say the reason we didn’t report on sex difference is that it wasn’t a point of our study,” she said. “How can you design a study for a condition that affects twice as many women as men and not think about that?”
KEY MESSAGES FOR RESEARCH
“The key messages to come out of the conference were strongly that it’s no longer sufficient to do a clinical trial and control for sex. It’s no longer sufficient to do a large database study and not consider gender influences. And it’s no longer sufficient not to take into account the range of lives that inhabit the categories,” across sex and gender spectrums, Dr. Einstein stressed.
“Alzheimer’s disease is multifactorial, and part of multifactorialism is individual differences.”
Said Dr. Einstein, “One of the most encouraging things that happened was that some of the people who are not looking at sex differences said that our meeting had changed the way they look at their research. I’m hoping we see some sex and gender research coming out of their lab in the near future.”
BRAIN RESILIENCE, AGING, & DIVERSITY
The question that motivated the Brain Resilience and Aging Knowledge Synthesis Symposium,, held in May in Montreal was, “Why are there different trajectories in aging across different sociodemographic groups?”
For example, in North America, we know that Black and Hispanic people as well as those from other communities that experienced historical marginalization have a higher risk of AD and other dementias, noted meeting chair Dr. M. Natasha Rajah, Canada Research Chair, Tier 1, Sex and Gender Research in Brain Health, Memory, and Aging, and professor of psychology at Toronto Metropolitan University.
“Why is this health inequity prevalent in our society, and what are the social and structural determinants of health that might be contributing to these inequities?”
“The other rationale for this meeting is that we know so little in Canada because there’s been such little investment and research into how communities that have been historically excluded from research are affected by brain changes associated with aging,” Dr. Rajah added.
“Since Canada has a history of being colour-blind in some ways, we didn’t start collecting data on these demographic and social determinants of health variables in our health systems until recently.”
Consequently, when the authors of the CIHR Dementia Research Strategy approached the topic of health equity and how dementia affects different communities, such as Indigenous peoples, “they basically said they don’t know, because we don’t have the data,” Dr. Rajah explained.
The meeting was really a conversation among scientists who have done work in, or are interested in the area of sex, gender, social determinants of health, race, ethnicity, and diversity – all within the context of neuroscience. “The key idea is that we are trying to understand what brain resilience is from a diversity perspective.”
BRAIN RESILIENCE DEFINED
Brain resilience is part of a broader concept of brain health in aging. “Historically, we’ve defined brain resilience as being related to the concepts of cognitive reserve and brain maintenance.
Cognitive reserve refers to an individual’s ability to maintain higher levels of cognitive function than would be expected from the level of neurodegeneration and/or Alzheimer’s-related brain pathology – that is, amyloid plaques – present in the brain,” said Dr. Rajah. (These abnormal amyloid deposits are one hallmark of Alzheimer’s disease.)
Brain resilience is thought to be related to higher cognitive reserve and more positive life experiences. Such factors, including higher education, better diet, better physical health due to exercise, and less social isolation, have been linked to having cognitive reserve.
“But there’s also this other side – brain maintenance,” Dr. Rajah added. “That idea refers to how well you are able to resist age and neurodegenerative diseases. Somehow, some individuals are able to maintain a youthful mind and brain, and don’t get plaque and/or don’t show neurodegeneration with age.”
These two components each comprise half of a larger whole, Dr. Rajah explained. “That’s the core of what brain resilience is – how do cognitive reserve and brain maintenance interact to provide brain resilience? How does someone’s experience of stress, and positive and negative experiences across their lifetime shape their brain as they age?”
In the U.S., for example, “there’s research showing that racism is a stressor and has effects on the brain,” Dr. Rajah noted, citing the work of Dr. Indira Turney, a former student of Dr. Rajah’s collaborator Dr. Nancy Dennis.
Dr. Turney, now a neuroscientist at Columbia University, “is looking at how stress and racism affect brain volume. And she’s seeing effects. Age-related volume declines are steeper in individuals who experience higher amounts of stress.”
“Then there’s the possible interaction with the environment in which you’re living,” Dr. Rajah said. “When you have a stress reaction, what do go and eat? Do you live in an environment with spaces to go for a walk, where you feel safe? Or is that a stressor for you as well?”
RELATIONSHIP-BUILDING IN RESEARCH
The second day of the meeting was devoted to exploring how to make research on aging and dementia more equitable. One theme that emerged was the importance of engagement and building relationships.
“Our research teams need to include people with lived experience, community leaders from historically underserved communities, and also policy users and knowledge users,” Dr. Rajah explained.
“There is a lot of research that the public can contribute to, and for that type of research, you really need to make sure that when you reach out to these communities, the communities feel safe.”
“To build that relationship, you need to show the respect of including them as a team member – to actually have them in the meeting, get their ideas about how to connect with their community, and establish an agreement on what is mutually beneficial in this relationship,” Dr. Rajah continued.
“So, it’s not just scientists saying come into my lab, let me take all this data from you, and goodbye. Instead, we need to establish meaningful and authentic relationships. Yes, participate in our research, let us know what research questions you think we should be pursuing, and then let us work with your community to show you what we found. And let’s continue the relationship.”
STEPS TOWARD IMPROVING INCLUSIVITY, REPRESENTATION
Dr. Rajah stressed that researchers don’t set out to be exclusionary, but some routine practices exert that effect unintentionally. Take the example of running an ad in a magazine or newspaper focused on a specific cultural group.
“Some communities find it respectful to advertise in their own language,” Dr. Rajah explained. “Even if someone needs a level of English or French to participate (in testing), you’re showing you care enough to approach them in a culturally respectful manner.”
The fact that most testing is verbally based is another barrier to inclusivity.
Attendees also discussed how to structure studies in a way that ensures we have adequate representation of the communities we want to include.
For instance, to qualify for National Institutes of Health funding in the U.S., studies have to match the demographics of their environment. “That may mean including just one Indigenous person in the study statistically,” she said. But that isn’t going to make the research reflective of diverse populations, she noted.
“We need to get to a space of intersectionality,” said Dr. Rajah. “To do that type of research you need really large sample sizes. If you don’t have proper data, you’re going to come up with all sorts of models of the world and healthcare recommendations that aren’t accurate.”
For instance, she said, we need data to understand things like why the average age of menopause in India is 46 versus 51 or 52 in North America. “Are these differences cultural or societal? Is there a biological component to it? We have these models of aging within the sexes that are very much oriented toward the West right now, and we don’t understand how everyone else ages.
RETHINKING RESEARCH DESIGN
Other discussions centred on breaking away from traditional methods of looking at variables like race. “When you study health inequities in communities that have been historically marginalized, you don’t want to ‘other’ them even further by comparing them to each other or to Western standards,” Dr. Rajah explained. “So, how do we move away from that?”
One alternative is to consider an array of social and structural determinants of health, such as income and access to green space. “Everyone has social and structural determinants of health and environment,” said Dr. Rajah.
“So instead of saying Black and white, look at that as part of a continuous variable within the person. Then you’re thinking a bit more deeply about what’s going on. You can study a social factor across everybody instead of clumping them into groups.”
“We have to be careful as scientists about how we communicate any differences we observe because we live in a society where this kind of information can be used in an unintended way.”
Both meetings emphasized the need for big data – including much larger Canadian longitudinal studies, similar in scale to the UK Biobank – as well as recruitment methods and analytic methodologies that can take into account individual differences.
FORGING A PATH TOWARD THE FUTURE
The teams behind both conferences plan to publish their recommendations over the coming months. Drs. Einstein and Rajah hope that the recommendations will stimulate thought and help steer cognitive aging research in animals and humans in a direction that truly reflects our population.
Drs. Einstein and Rajah are committed to bringing sex and gender as well as the diversity lens to aging and dementia research; in fact, they participated in each other’s meetings.
“It’s a very exciting time in neuroscience,” said Dr. Rajah, because “we’re now getting to a level of maturity that we could ask questions that are societally relevant.”
Source: Mind Over Matter V19