Researchers say that women are twice as likely to develop Alzheimer’s disease as men. However, despite recent advances in treatments for the condition, historical biases in clinical trial recruitment have failed to account for this epidemiological pattern.
Recently, the complex mechanisms underpinning observed sex differences have come into sharper focus, uncovering an interconnected web of societal and biological factors. For example, the influence of hormonal disruption during menopause has emerged as a central determinant, yet characterising its effect on an individual patient level remains challenging.
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Some of this research has emerged from the Phase III CLARITY AD trial (NCT03887455) with Biogen and Eisai’s Alzheimer’s drug Leqembi (lecanemab), which suggested a weaker treatment effect in women versus men. Earlier this year, simulation-based analyses on supplementary data from the Phase III trial determined that this difference is likely due to a real sex effect rather than chance.
Sex differences will become increasingly important in drug development in the coming years, says Dr. Paul Newhouse, director of the Center for Cognitive Medicine at Vanderbilt University Medical Center, Nashville, Tennessee. Robust subgroup reporting and historical patient data collection is essential, though some barriers like cost stymie implementation efforts.
The role of hormone replacement therapies
A common thread throughout hypothesised sex-specific disease mechanisms is the role of oestrogen. A growing body of evidence indicates that the decline of oestrogen during menopause plays a crucial role in female susceptibility for Alzheimer’s disease. Indeed, early menopause and surgical removal of the ovaries have been found to substantially increase risk, notes Dr. Antonella Santuccione Chadha, neurologist and co-founder and CEO of the nonprofit Women’s Brain Foundation.
Research in this area has become increasingly pertinent as the FDA recently removed boxed warnings for breast cancer and cardiovascular disease from labels of hormone replacement therapies (HRTs), citing a reduced risk of Alzheimer’s disease by up to 35%.
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By GlobalDataHowever, experts say there are several nuances to consider. “It’s not a one-size-fits-all approach,” says Chadha. She says that while HRT has positive effects for women experiencing difficult menopausal symptoms, its ability to prevent Alzheimer’s is not yet proven, and she cautions against inappropriate marketing.
Symptomatically, women tend to present with depressive symptoms in early Alzheimer’s disease, which are often dismissed or misdiagnosed by doctors, says Chadha, whereas men may be more likely to shows signs of aggression, she adds. It has also been widely observed that for the same level of symptoms, women generally exhibit more severe pathology, note Chadha and Newhouse. This effect is particularly pronounced in tau aggregation, adds Chloe Lopez-Lee, PhD and postdoctoral associate at the Icahn School of Medicine at Mount Sinai, New York.
The biological mechanisms underpinning differences between sexes with Alzheimer’s disease are yet to be fully elucidated, but published literature suggests the involvement of several pathways related to inflammation, microglial function, mitochondrial metabolism and oxidative stress, protein clearance, and epigenetic regulation alongside genetic risk factors. For example, female carriers of the apolipoprotein E4 (APOE4) gene are at significantly greater risk of developing Alzheimer’s than males with the same mutation. A cohort study analysis also suggested APOE4-positive women receiving HRT exhibit improved cognition and larger brain volumes compared with non-APOE4 carriers.
Beyond biology, there is also evidence of societal and gender-based influences. Chadha notes that 80% of the worldwide caregiver population is female, a role that can lead to social isolation and depression—both key risk factors for dementia. The number of pregnancies a women experiences may have biological impact as well as behavioural changes, adds Chadha, due to potential for poorer sleep quality and its association with beta-amyloid and tau clearance.
Why might disease-modifying Alzheimer’s treatments be less effective in women?
The FDA approved Leqembi to treat Alzheimer’s disease in 2023 based on results from the CLARITY AD study. As per subgroup data published in the supplementary material, Leqembi was 31% less effective in females compared with males. A subsequent simulation study showed that only 12 of 10,000 simulated trials had a subgroup difference of at least 31%, signifying a 0.0012 probability of the observed variance being due to chance rather than a genuine sex difference. The authors postulated that the clinical efficacy of the drug may relate to a sex-dependent mechanism of amyloid clearance, but the lack of sex-stratified positron emission topography (PET) data prohibited conclusive analysis.
A meta-analysis is soon to be published showing a similar lesser effect of disease-modifying Alzheimer’s therapies, including Biogen’s Aduhelm (aducanumab), Roche’s gantenerumab, and Eli Lilly’s Kisunla (donanemab), in women versus men, Chadha tells this news service.
Meanwhile, women may exhibit better verbal and memory skills at baseline despite having more severe disease, meaning progression is more difficult to stall and potentially leading to a skewed comparison, says Newhouse.
What needs to change in clinical trials and Alzheimer’s management?
The first step is powering studies sufficiently to statistically analyse sex differences and highlighting these findings as they are often “buried in supplementary data,” says Lopez-Lee.
The scales to assess disease progression need to be updated to account for differences between men and women, says Chadha. Another important aspect to incorporate into clinical trials is menopausal history, adds Newhouse. He says exposure to HRT, contraceptive use, and reproductive history are not routinely collected in clinical trials as detailed questionnaires may be difficult to administer on a large scale. Nonetheless, he argues that analysing such data may be key to understanding treatment differences and informing drug development. Though implementation of such processes may initially increase spending, cultivating targeted treatment approaches will ultimately be cost-effective, says Chadha.
The idea that sex-specific treatment differences may lead to restricted indications needs reframing; the goal is understanding the degree to which patients can benefit, Newhouse adds.
Additionally, clinical trial cohorts should reflect real-world prevalence and in the case of Alzheimer’s have a greater proportion of women, says Chadha. This rhetoric is already trickling through to some biotechs in the space. “Just by virtue of the law of the numbers, we’re likely to recruit more women than men into those clinical studies, and we want our recruitment to reflect the general population,” says Isaac Stoner, CEO of the neuroinflammation-focused preclinical biotech MindImmune Therapeutics, which is headquartered in Kingston, Rhode Island.
The onus is also on basic and translational scientists to investigate sex-dependent biology that can guide drug discovery, says Lopez-Lee.
The future of Alzheimer’s drug discovery
Research is increasingly moving beyond traditional amyloid-targeting therapies. One area growing in traction is the role of microglia in modulating neuroinflammation and subsequent synaptic damage. Microglia also phagocytose and degrade amyloid plaques in a process affected by oestrogen and genes expressed on sex chromosomes, says Lopez-Lee.
Women are at significantly greater risk of autoimmune diseases, notes Newhouse. Moreover, Stoner says sex ratios observed in autoimmune disorders like multiple sclerosis and lupus are similar to Alzheimer’s, which supports the hypothesis that Alzheimer’s has a major immunological component. Hence, as Alzheimer’s treatments are explored in the inflammation space, sex differences may become increasingly important, adds Newhouse.
In terms of early detection, the Cognitive Health After Menopause (CHAMP) study is trying to uncover predictors of selective vulnerability in women, by identifying markers for increased risk of cognitive decline in post-menopausal women. Newhouse says blood-based biomarker analyses in this study will take place in the coming months.
Advancements in AI could be leveraged in Alzheimer’s management, while technologies like augmented reality could also be used in detection. Tools based on these technologies could further recognise undetected nuances between men and women, says Chadha.
