Sex and gender factors in Alzheimer’s disease — are the models wrong?

In so many fields of neuroscience, scientists have produced models and theories to help explain the conditions and factors that contribute to the risk of developing neurological diseases. However, so many fail to acknowledge major sex and gender factors that can alter the course of a disease. I wanted to take a closer look at the brain and cognitive reserve theory in Alzheimer’s disease, and how sex and gender factors can have a huge impact on how people experience this devastating neurological condition.

Picture by Eberhart Grossgasteiger, Pixaby

Last week, I hosted a talk with Maria Teresa Ferretti, one of the co-founders of the Women’s Brain Project, a not-for-profit organisation that advocates for the better study of sex and gender factors in brain disease and mental health. In the talk, we discussed the many sex- and gender-related factors that influence neuroscience research, for example how we study mental health and neurological conditions in both clinical and animal studies. While I was aware that problems afflicting women are typically understudied, I was shocked by the extent of the ever-present, systematic lack of acknowledgment of the impact that sex and gender can have on research and how these factors can affect a patient’s experience or diagnosis with a condition.

So, this got me thinking. As a neuroscientist, I’ve spent years learning about diseases, models, and theories so established in the literature that I’ve never questioned their validity. Yet, as this talk highlighted, many of these core concepts do not consider sex and gender as important variables. To exemplify this issue, I wanted to take a look at a core concept in the field of Alzheimer’s disease, and using a recent review, pick apart an established model of the risks of developing Alzheimer’s by looking at it through a sex and gender lens.

As a note before we begin, the authors of the review highlight the difficulty in differentiating between factors related to a person’s sex and those related to a person’s gender, as many key risk factors are affected by both. For ease, the review and the following article refer to these influences together as ‘sex/gender factors’, although both I and the authors are clear to note that they are not one and the same.

An established concept: cognitive and brain reserve in Alzheimer’s disease

Two of the key theories behind an individual’s risk of developing Alzheimer’s disease (AD) are cognitive and brain reserve. In the context of AD, “reserve” refers to the “gradual accumulation of neurocognitive resources” over the span of a person’s life, which can help to protect cognitive function as a person ages or develops a neurodegenerative condition. Specifically, “brain reserve” refers to the physical connections in the brain, such as the number of neurons or junctions between neurons, called synapses. “Cognitive reserve” therefore refers to the effect of this lifetime of accumulation on brain function and cognitive performance [1]. Simply put, the greater your reserve, the more connections or cognitive ability you have, and thus have to lose before you pass a certain threshold and start to experience symptoms of cognitive decline, such as confusion or memory loss.

This theory, first suggested by American neuroscientist Yaakov Stern, has changed the way many people look at the risk factors for AD. The theory suggests that people with a higher reserve can sustain a greater degree of neurodegeneration before clinical symptoms appear. However, the model also suggests that because of this greater level of degeneration, the rate of cognitive decline is faster in people with higher reserve [2], as shown by the steeper decline in the high-reserve group in the graph below.

Graph taken from Stern (2009) [2] representing low- and high-reserve individuals and their correlation between cognitive test scores, hence cognitive ability, and the degree of neuropathology at that time point. The dotted line indicates the threshold at which symptoms of neurodegeneration appear.

This model has also proved important in other ways. Typical research on AD emphasises the negative factors that can increase your risk of developing AD — however, Stern’s model raises the possibility that there could also be positive influences on cognitive reserve that reduce the risk of AD. These include any influence that could increase your cognitive ability or number of brain connections as a healthy adult, including environmental factors such as higher educational attainment, occupational complexity, IQ and socioeconomic status, as well as bilingualism, physical activity, and social support.

But what this list lacks is the acknowledgments of the second greatest risk factor for AD, sex. Approximately two-thirds of cases of AD occur in women, and women with AD tend to experience a faster rate of cognitive decline. Ovarian hormone exposure has also been identified as a key contributor to the risk of developing AD in women [3]. Clearly, then, there are major sex/gender differences in the underlying pathology of the condition that could be leading to greater rates of AD in women. Moreover, this model of reserve in AD is based on mixed-sex research and therefore does not take into account sex/gender factors that may be critical in determining the relationship between these supposed positive influences on cognitive reserve and the actual risk of developing AD

Sex/gender differences in reserve

And this what Subramaniapillai and colleagues set out to investigate in their recent review [1]. Specifically, they wanted to assess how influences on reserve differentially affect the risk of men and women developing AD. The authors conducted a systematic literature search to identify papers that looked at this core concept, but that also investigated the sex/gender factors in the variation in levels of reserve.

Shockingly, despite hundreds of papers initially identified as pertaining to reserve in AD, only 16 papers directly investigated sex/gender factors. Despite this limited pool of research, there were clear sex/gender factors in reserve and how these affected the risk of AD. For example, the negative effects of amyloid-beta, the molecule thought to underlie neurodegeneration at the onset of Alzheimer’s disease, are worse for women than men [4]. Men are also thought to have a greater brain reserve than women, as one study found they could sustain cognitive performance with greater reductions in brain activity, as measured by decreased glucose metabolism [5]. Moreover, the brain regions most affected at the point of first detecting AD in women and men were different, suggesting both different disease trajectories and sources of reserve.

There are also environmental factors that affect reserve. It has been suggested that occupational complexity can affect reserve, with greater complexity conferring greater protection against AD. However, the authors could not find any research addressing sex/gender differences in occupational complexity. What they did find, however, is that the environment a job is associated with made a greater difference to reserve than its complexity. For example, farmers were found to have the greatest reserve, particularly compared to inner-city blue-collar workers [6, 7], potentially due to the lower levels of pollution in the countryside and better access to nutrition. Therefore, this research suggests that improving the living conditions of men and women will increase reserve and hence reduce the risk of developing AD.

Bilingualism has also been shown to increase cognitive reserve, with people speaking multiple languages being diagnosed on average 4 to 5 years later than monolingual people [8]. Interestingly, bilingual people are more likely to have lower educational attainment and be immigrants than monolingual people, although there is no overall difference in cognitive performance at the point of diagnosis of dementia, suggesting that speaking two languages fluently is itself increasing reserve. However, in this case, sex/gender factors did not significantly alter the positive benefit of bilingualism on the risk of AD.

There was, of course, variability in the results of these studies — for example, two papers reported that higher educational attainment correlates with reduced risk of AD but only in women, whereas two other studies suggest there was no differential correlation [1]. Similarly, higher IQ and adolescent educational attainment were also shown to increase reserve, but to the same extent in men and women [9]. However, this research is complicated by the fact that women still tend to have lower levels of education than men, demonstrating the huge impact that social norms and gender differences can make on your life and thus on your risk of future degenerative illness. This research highlights that, especially for women, even small amounts of education can be hugely beneficial in reducing your future risk of AD, thus education equality should be promoted wherever possible. Furthermore, if women received on average the same amount of education as men, maybe there would not be such an imbalance in the number of women being diagnosed with AD [1].

But all this is not to say that the studies that included sex/gender factors in their research, and even the review itself, are not without their assumptions and flaws. A key issue with a lot of the current research is that sex and gender cannot be differentiated, mainly due to the highly gendered nature of the variables studied. Levels of education and the number of women in senior jobs are still lower than men, and thus any results will be swayed by this bias. Moreover, many studies fail to acknowledge this, with older studies often pedaling sexist assumptions. For example, one paper defined a category of work as “farm wife”, stating that it was of a lower complexity than “farmer”, despite the complex planning and administrative tasks this job can involve [7]. Astonishingly, one paper from 2001 even grouped “housewives” and “inactive”, meaning people without a fixed occupation, in the same category [6], hugely diminishing the critical and often complex role many women, and importantly also men, play in caring for families. Finally, this research fails to address more than binary sex/gender factors, and hence the impact of being transgender or non-binary on brain reserve is unknown, but it is also likely to have a complex relationship with environmental factors such as socioeconomic status or occupation.

The sheer lack of studies on the impact of sex/gender on what is a huge part of the AD field is astounding and demonstrates the clear need for more directed research on the impact of sex/gender on the risk of developing AD. Moreover, this review highlights the incorrect assumption that factors that increase brain reserve apply equally to men and women, as well as demonstrating how vital social changes could greatly impact the incidence of the disease and benefit so many people around the world.

Revisiting old assumptions

Brain reserve in AD is just one example of how women, or even the acknowledgment of sex/gender factors in research, have long been neglected. In 1973, in the wake of the thalidomide tragedy, the FDA banned the study of women in clinical trials of novel drugs, due to the potential unknown risks to babies during pregnancy. Although well-intentioned, this move paved the way for decades of neglect for women in clinical studies and led many drug companies to simply assume that drugs tested on men are also safe for women. However, this has had disastrous consequences. It has been estimated that of all the drugs withdrawn from the market due to concerns around their safety, eight out of ten of them caused more harm to women than men [10].

In the case of AD, and in the study of mental health and brain diseases more generally, women are generally underrepresented in clinical trials, with astonishingly few preclinical studies even using female animals. We need more focus on sex/gender as factors in disease research, as well as a shift towards precision medicine to better diagnose, treatment and care for all patients, not just those in the majority or that history dictates we study.

And this is the message of the Women’s Brain Project. If you’d like to learn more about sex/gender factors in neuroscience research, I can highly recommend their website, it’s full of helpful information and peer-reviewed research on the impact of sex/gender on a range of mental health and neurological conditions. Moreover, please do follow the link to a recording of last week’s talk, where we also answer audience questions on this fascinating topic!

Review article: Subramaniapillai et al., Frontiers in Neuroendocrinology, 2021: 60: p. 100879.

1. Subramaniapillai, S., et al., Sex and gender differences in cognitive and brain reserve: Implications for Alzheimer’s disease in women. Frontiers in Neuroendocrinology, 2021. 60: p. 100879.

2. Stern, Y., Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol, 2012. 11(11): p. 1006–12.

3. Fox, M., C. Berzuini, and L.A. Knapp, Cumulative estrogen exposure, number of menstrual cycles, and Alzheimer’s risk in a cohort of British women. Psychoneuroendocrinology, 2013. 38(12): p. 2973–2982.

4. Koran, M.E.I., et al., Sex differences in the association between AD biomarkers and cognitive decline. Brain Imaging and Behavior, 2017. 11(1): p. 205–213.

5. Perneczky, R., et al., Gender differences in brain reserve. Journal of Neurology, 2007. 254(10): p. 1395.

6. Helmer, C., et al., Occupation during life and risk of dementia in French elderly community residents. Journal of Neurology, Neurosurgery & Psychiatry, 2001. 71(3): p. 303–309.

7. Santabárbara, J., et al., The effect of occupation type on risk of Alzheimer’s disease in men and women. Maturitas, 2019. 126: p. 61–68.

8. Craik, F.I.M., E. Bialystok, and M. Freedman, Delaying the onset of Alzheimer disease. Bilingualism as a form of cognitive reserve, 2010. 75(19): p. 1726–1729.

9. Huang, A.R., et al., Adolescent Cognitive Aptitudes and Later-in-Life Alzheimer Disease and Related Disorders. JAMA Network Open, 2018. 1(5): p. e181726-e181726.

10. Heinrich, J., Most drugs withdrawn in recent years had greater health risks for women. Gen Account Off-01–286R, 2001.

DPhil Student in Neuroscience at the University of Oxford 🔬 Science 🧠 Neuroscience 🎓 University Life