Addressing Female-Specific Factors, Period: Gender Publication Bias in Alzheimer’s Disease Research
Irene Zhang
Imagine trying to complete a puzzle with pieces belonging to an entirely different set. Without the right pieces, the larger picture remains incomplete and elusive.
Alzheimer’s Disease (AD) is a prevalent progressive neurodegenerative disease that impairs cognition and can lead to severe dementia. Worldwide, an estimated 416.4 million people are on the AD continuum, which accounts for nearly 22% of the population aged 50 and over (Gustavsson et al., 2022). However, around two-thirds of the diagnosed are women, marking a dominant female-affected population. The question then arises: why are women more vulnerable?
Historically, mainstream research has attributed women’s greater predisposition to their longer average lifespan. Yet, emerging neuroendocrinology studies suggest that the mechanisms underlying their increased susceptibility are much more complex and multifactorial than the traditional view. One key genetic risk factor is the Apolipoprotein E4 (APOE4) gene, which regulates lipid metabolism and affects brain function. Although APOE4 poses equal Alzheimer’s risk across both sexes, women with the allele face a higher likelihood of developing mild cognitive impairment (MCI) and transitioning to AD (O’Neal, 2024). Further, research suggests that the particular combination of APOE4 and female sex is the most deleterious for AD progression (Balu et al., 2023). Beyond genetics, the key factor differentiating the two sexes is hormonal fluctuations inherent to female reproductive physiology. Lisa Mosconi, author of The XX Brain and The Menopause Brain, explores many of these processes, including Menopause Transition (MT), a female neuroendocrine aging mechanism resulting in reproductive cessation. In a comprehensive study on MT, both peri- and postmenopausal female mice displayed increased amyloid beta deposits with APOE4 and decreased white matter compared to male models (Mosconi et al., 2021). These brain patterns reflect hallmark symptoms of AD, indicating a specific increased risk linked to MT. This may be due to APOE4’s interaction with changing hormone levels during menopause; for instance, estrogen, which has neuroprotective abilities, diminishes, amplifying APOE4’s adverse effects on brain health. Moreover, pregnancy, another biological state unique to females, is strongly correlated with heightened AD vulnerability. Women who underwent five or more pregnancies were found 1.7 times more likely to develop AD when compared to those with one to four (O’Neal, 2024). Taken together, these pronounced genetic and hormonal differences, alongside prevalence and mortality, highlight an urgent need for thorough Alzheimer’s research considering sex-specific variables.
But despite the high prevalence of AD in women, the inclusion of female-specific factors in studies is disproportionately low. A 2021 meta-analysis of 56 randomized large AD clinical trials found that only 14.3% included sex-specific data analysis as a method of investigation (Martinkova et al.). This trend is not limited to Alzheimer’s either. In a study of 3,193 neuroscience and psychiatry papers published from 2009 to 2019, merely 6% treated sex as a discovery variable (Rechlin et al., 2022). As clarified by Emily Jacobs, the central problem is not necessarily representation, as nearly half of neuroimaging study participants on OpenNeuro.org are women, but a systemic publication focus on male models (Jacobs, 2023).
This gender bias exists in both human and animal models. Previously, scientists were reluctant to use female mouse models, worried hormonal fluctuations during estrous cycles would lead to high variance and skewed data. However, recent studies reveal that the estrous state has minimal effects on behavior, with variation nearly equal between females and males (Zeng et al., 2023). These new findings refute the historical dogma and stress the importance of including female subjects in research after decades of exclusion.
Moreover, the neglect of innate differences has led to women’s symptoms often being labelled as “atypical” in scientific literature, while research on female-specific factors is seen as “niche.” As a result, medical knowledge and diagnoses are largely based on research models developed on male populations. This has had pernicious consequences for women’s health. For over 13,000 diseases, women are diagnosed an average of two years later than men (Westergaard et al., 2019). Along the same lines, a study of 86 FDA-approved medications discovered that women experienced negative drug responses nearly twice as frequently as men (Zucker & Prendergast, 2020). These disparities underscore a concerning gender gap in the existing healthcare system from diagnosis to treatment. In the case of AD, the antibody medication Lecanemab has emerged as a promising treatment in reducing amyloid and effectively slowing disease progression. The drug’s proposed benefits have led to its “accelerated approval” by the FDA as a treatment for early Alzheimer’s (Alzheimer’s Association, 2022). However, Lecanemab displays a statistically significant sex-based difference in efficacy. In clinical trials, while males had a 43% mean slowing of cognitive decline, females had a strikingly lower 12% mean slowing (Andrews et al., 2024). Thus, it is critical researchers also consider sex differences when prescribing medications to mitigate potential risks of adverse drug reactions and ineffective treatment outcomes.
While women have been severely underserved, those of minorities face even greater barriers to equal treatment. By 2060, the total number of people living with AD in the US is expected to increase by 128%. But for Hispanic and African American populations, that percentage jumps to 423% and 192%, respectively, due to genetic and environmental influences (Rajan et al., 2021). With diagnoses expected to rise, especially among minorities, addressing not only the male gender bias but also the underlying racial inequities is essential.
Fortunately, there are various strategies that work to improve gender equality in AD studies. One leading initiative is increasing open-access research, which can promote accessibility, transparency, and recognition of women’s health among the larger public. Initiatives such as the Women’s Brain Project exemplify the growing efforts toward gender equality. These networks actively help reshape the data composition of existing medical references, addressing historical gender imbalances in research. By making diverse data more accessible, this approach also supports the development of personalized medicine, such as precision neuroimaging, by accounting for individual sex and genetic variations. Legal policies are also a powerful tool in setting widespread standards, as illustrated by the pivotal shift in 1993 when the NIH policy requiring the inclusion of women in clinical trials became US federal law (National Institutes of Health, 2017). As female authors correlate with a greater likelihood of sex-variable considerations, earlier interventions are an effective course of action (Chhaya et al., 2023). Pipeline programs like Stanford’s virtual Neuroscience Journal Club and Harris Neuroscience Internship encourage young women and minorities to pursue medical careers, fostering a more equitable future for academia. Leaders of these movements are just a few of the many pioneers paving the way forward.
The significant female sex differences in AD pathology, coupled with its limited recognition in research, underscore a critical problem in understanding a disease of global concern. Moreover, women’s delayed diagnoses and disproportionate negative drug reactions emphasize the dangers of this systemic bias in practice. To propel meaningful progress in treating Alzheimer’s Disease, there should be an equal, if not higher, universal integration of female-specific considerations into both research design and application. With expanded efforts and funding for solutions from accessible resources to youth initiatives, neuroscience can bring together all the pieces of the puzzle to accurately represent nearly half the human population. Female sex-specific research is not niche; it is foundational.
About the Author
Irene Zhang ('25) is a student at Elgin Park Secondary School in Surrey, British Columbia.
References
Alzheimer’s Disease (AD) is a prevalent progressive neurodegenerative disease that impairs cognition and can lead to severe dementia. Worldwide, an estimated 416.4 million people are on the AD continuum, which accounts for nearly 22% of the population aged 50 and over (Gustavsson et al., 2022). However, around two-thirds of the diagnosed are women, marking a dominant female-affected population. The question then arises: why are women more vulnerable?
Historically, mainstream research has attributed women’s greater predisposition to their longer average lifespan. Yet, emerging neuroendocrinology studies suggest that the mechanisms underlying their increased susceptibility are much more complex and multifactorial than the traditional view. One key genetic risk factor is the Apolipoprotein E4 (APOE4) gene, which regulates lipid metabolism and affects brain function. Although APOE4 poses equal Alzheimer’s risk across both sexes, women with the allele face a higher likelihood of developing mild cognitive impairment (MCI) and transitioning to AD (O’Neal, 2024). Further, research suggests that the particular combination of APOE4 and female sex is the most deleterious for AD progression (Balu et al., 2023). Beyond genetics, the key factor differentiating the two sexes is hormonal fluctuations inherent to female reproductive physiology. Lisa Mosconi, author of The XX Brain and The Menopause Brain, explores many of these processes, including Menopause Transition (MT), a female neuroendocrine aging mechanism resulting in reproductive cessation. In a comprehensive study on MT, both peri- and postmenopausal female mice displayed increased amyloid beta deposits with APOE4 and decreased white matter compared to male models (Mosconi et al., 2021). These brain patterns reflect hallmark symptoms of AD, indicating a specific increased risk linked to MT. This may be due to APOE4’s interaction with changing hormone levels during menopause; for instance, estrogen, which has neuroprotective abilities, diminishes, amplifying APOE4’s adverse effects on brain health. Moreover, pregnancy, another biological state unique to females, is strongly correlated with heightened AD vulnerability. Women who underwent five or more pregnancies were found 1.7 times more likely to develop AD when compared to those with one to four (O’Neal, 2024). Taken together, these pronounced genetic and hormonal differences, alongside prevalence and mortality, highlight an urgent need for thorough Alzheimer’s research considering sex-specific variables.
But despite the high prevalence of AD in women, the inclusion of female-specific factors in studies is disproportionately low. A 2021 meta-analysis of 56 randomized large AD clinical trials found that only 14.3% included sex-specific data analysis as a method of investigation (Martinkova et al.). This trend is not limited to Alzheimer’s either. In a study of 3,193 neuroscience and psychiatry papers published from 2009 to 2019, merely 6% treated sex as a discovery variable (Rechlin et al., 2022). As clarified by Emily Jacobs, the central problem is not necessarily representation, as nearly half of neuroimaging study participants on OpenNeuro.org are women, but a systemic publication focus on male models (Jacobs, 2023).
This gender bias exists in both human and animal models. Previously, scientists were reluctant to use female mouse models, worried hormonal fluctuations during estrous cycles would lead to high variance and skewed data. However, recent studies reveal that the estrous state has minimal effects on behavior, with variation nearly equal between females and males (Zeng et al., 2023). These new findings refute the historical dogma and stress the importance of including female subjects in research after decades of exclusion.
Moreover, the neglect of innate differences has led to women’s symptoms often being labelled as “atypical” in scientific literature, while research on female-specific factors is seen as “niche.” As a result, medical knowledge and diagnoses are largely based on research models developed on male populations. This has had pernicious consequences for women’s health. For over 13,000 diseases, women are diagnosed an average of two years later than men (Westergaard et al., 2019). Along the same lines, a study of 86 FDA-approved medications discovered that women experienced negative drug responses nearly twice as frequently as men (Zucker & Prendergast, 2020). These disparities underscore a concerning gender gap in the existing healthcare system from diagnosis to treatment. In the case of AD, the antibody medication Lecanemab has emerged as a promising treatment in reducing amyloid and effectively slowing disease progression. The drug’s proposed benefits have led to its “accelerated approval” by the FDA as a treatment for early Alzheimer’s (Alzheimer’s Association, 2022). However, Lecanemab displays a statistically significant sex-based difference in efficacy. In clinical trials, while males had a 43% mean slowing of cognitive decline, females had a strikingly lower 12% mean slowing (Andrews et al., 2024). Thus, it is critical researchers also consider sex differences when prescribing medications to mitigate potential risks of adverse drug reactions and ineffective treatment outcomes.
While women have been severely underserved, those of minorities face even greater barriers to equal treatment. By 2060, the total number of people living with AD in the US is expected to increase by 128%. But for Hispanic and African American populations, that percentage jumps to 423% and 192%, respectively, due to genetic and environmental influences (Rajan et al., 2021). With diagnoses expected to rise, especially among minorities, addressing not only the male gender bias but also the underlying racial inequities is essential.
Fortunately, there are various strategies that work to improve gender equality in AD studies. One leading initiative is increasing open-access research, which can promote accessibility, transparency, and recognition of women’s health among the larger public. Initiatives such as the Women’s Brain Project exemplify the growing efforts toward gender equality. These networks actively help reshape the data composition of existing medical references, addressing historical gender imbalances in research. By making diverse data more accessible, this approach also supports the development of personalized medicine, such as precision neuroimaging, by accounting for individual sex and genetic variations. Legal policies are also a powerful tool in setting widespread standards, as illustrated by the pivotal shift in 1993 when the NIH policy requiring the inclusion of women in clinical trials became US federal law (National Institutes of Health, 2017). As female authors correlate with a greater likelihood of sex-variable considerations, earlier interventions are an effective course of action (Chhaya et al., 2023). Pipeline programs like Stanford’s virtual Neuroscience Journal Club and Harris Neuroscience Internship encourage young women and minorities to pursue medical careers, fostering a more equitable future for academia. Leaders of these movements are just a few of the many pioneers paving the way forward.
The significant female sex differences in AD pathology, coupled with its limited recognition in research, underscore a critical problem in understanding a disease of global concern. Moreover, women’s delayed diagnoses and disproportionate negative drug reactions emphasize the dangers of this systemic bias in practice. To propel meaningful progress in treating Alzheimer’s Disease, there should be an equal, if not higher, universal integration of female-specific considerations into both research design and application. With expanded efforts and funding for solutions from accessible resources to youth initiatives, neuroscience can bring together all the pieces of the puzzle to accurately represent nearly half the human population. Female sex-specific research is not niche; it is foundational.
About the Author
Irene Zhang ('25) is a student at Elgin Park Secondary School in Surrey, British Columbia.
References
- Alzheimer's Association. (2022). Lecanemab Approved for Treatment of Early Alzheimer’s Disease. Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/treatments/lecanemab-leqembi
- Andrews, D., Ducharme, S., Chertkow, H., Maria Pia Sormani, & D. Louis Collins. (2024). The higher benefit of lecanemab in males compared to females in CLARITY AD is probably due to a real sex effect. MedRxiv (Cold Spring Harbor Laboratory). https://doi.org/10.1101/2024.07.11.24310278
- Balu, D., Valencia-Olvera, A. C., Islam, Z., Mielczarek, C., Hansen, A., Perez, T. M., York, J., Mary Jo LaDu, & Tai, L. M. (2023). APOE genotype and sex modulate Alzheimer’s disease pathology in aged EFAD transgenic mice. Frontiers in Aging Neuroscience, 15(1279343). https://doi.org/10.3389/fnagi.2023.1279343
- Chhaya, V. Y., Binion, C. C., Mulles, S. M., Tannhauser, P. A., Aziz, D. Z., Greenwood, J. D., Barlek, M. H., Rouan, J. R., Wyatt, T. G., & Kibbe, M. R. (2023). Gender Bias in Clinical Trial Enrollment: Female Authorship Matters. Annals of Vascular Surgery, 95(0890-5096). https://doi.org/10.1016/j.avsg.2023.03.008
- Gustavsson, A., Norton, N., Fast, T., Frölich, L., Georges, J., Holzapfel, D., Kirabali, T., Krolak-Salmon, P., Rossini, P. M., Ferretti, M. T., Lanman, L., Chadha, A. S., & van der Flier, W. M. (2022). Global estimates on the number of persons across the Alzheimer’s disease continuum. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 19(2), 658–670. https://doi.org/10.1002/alz.12694
- Jacobs, E. G. (2023). Only 0.5% of neuroscience studies look at women’s health. Here’s how to change that. Nature, 623(7988), 667–667. https://doi.org/10.1038/d41586-023-03614-1
- Martinkova, J., Quevenco, F.-C., Karcher, H., Ferrari, A., Sandset, E. C., Szoeke, C., Hort, J., Schmidt, R., Chadha, A. S., & Ferretti, M. T. (2021). Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease. JAMA Network Open, 4(9), e2124124. https://doi.org/10.1001/jamanetworkopen.2021.24124
- Mosconi, L., Berti, V., Dyke, J., Schelbaum, E., Jett, S., Loughlin, L., Jang, G., Rahman, A., Hristov, H., Pahlajani, S., Andrews, R., Matthews, D., Etingin, O., Ganzer, C., de Leon, M., Isaacson, R., & Brinton, R. D. (2021). Menopause impacts human brain structure, connectivity, energy metabolism, and amyloid-beta deposition. Scientific Reports, 11(1), 10867. https://doi.org/10.1038/s41598-021-90084-y
- National Institutes of Health. (2017). History of Women’s Participation in Clinical Research | Office of Research on Women’s Health. Nih.gov. https://orwh.od.nih.gov/toolkit/recruitment/history
- O’Neal, M. A. (2024). Women and the risk of Alzheimer’s disease. Frontiers in Global Women’s Health, 4(1324522). https://doi.org/10.3389/fgwh.2023.1324522
- Rajan, K. B., Weuve, J., Barnes, L. L., McAninch, E. A., Wilson, R. S., & Evans, D. A. (2021). Population estimate of people with clinical Alzheimer’s disease and mild cognitive impairment in the United States (2020–2060). Alzheimer’s & Dementia, 17(12). https://doi.org/10.1002/alz.12362
- Westergaard, D., Moseley, P., Sørup, F. K. H., Baldi, P., & Brunak, S. (2019). Population-wide analysis of differences in disease progression patterns in men and women. Nature Communications, 10(1), 1–14. https://doi.org/10.1038/s41467-019-08475-9
- Zeng, P.-Y., Tsai, Y.-C., Lee, C.-L., Ma, Y.-K., & Kuo, T.-H. (2023). Minimal influence of estrous cycle on studies of female mouse behaviors. Frontiers in Molecular Neuroscience, 16(1146109). https://doi.org/10.3389/fnmol.2023.1146109
- Zucker, I., & Prendergast, B. J. (2020). Sex differences in pharmacokinetics predict adverse drug reactions in women. Biology of Sex Differences, 11(1). https://bsd.biomedcentral.com/articles/10.1186/s13293-020-00308-5