January 6, 2023
The Gender Data Gap: How Women Are Forgotten in Alzheimer's Research
Lead Clinical Information DesignerTeckro
Throughout this article we refer to women/females and men/males to discuss biological sex differences. Our use of these terms in this context applies to any person assigned female at birth (AFAB) or assigned male at birth (AMAB).
Every 3 seconds, someone in the world develops dementia. According to the World Health Organization (WHO), 55 million people worldwide are living with dementia, where Alzheimer’s disease (AD) accounts for an estimated 60-70% of these cases. A further two-thirds of these cases are women. Given the growing number of Alzheimer’s diagnoses year on year, the medical and scientific community are rejoicing at the potential for new drug Lecanemab to slow cognitive decline in early AD.
Amyloid beta (Aβ) is a protein in the brain that accumulates and aggregates when not formed properly, producing neurotoxic amyloid plaques and impacting the brain’s ability to transmit messages between neurons. The formation of these plaques is believed to trigger AD.
Lecanemab is a monoclonal antibody developed to selectively bind to Aβ protofibrils (one of the building blocks in amyloid plaques), allowing the immune system to neutralize and eliminate them, potentially slowing the progression of the disease. What’s unique about Lecanemab is that it’s one of the first drugs to ever demonstrate a positive result by targeting Aβ.
Not the Whole Story
Results from the Phase III clinical trial indicate that Lecanemab slows cognitive decline by 27% compared with placebo – a modest improvement that inspires hope for future research. Researchers had begun to doubt the role of Aβ due to repeated targeted treatment failures, so the results of this trial mark a critical turning point.
While the majority are touting Lecanemab as a new dawn in Alzheimer’s research, this drug may not be the savior that it appears. The negative press coverage has primarily focused on safety concerns for patients (two patients died from blood clotting events), with some questioning if the safety risks outweigh Lecanemab’s benefits. However, the bigger issue with Lecanemab lies in the concerning gender data gap in the research.
Breaking down the statistics of the trial by gender, Lecanemab demonstrated a much lower improvement rate in women, with a mere 12% showing signs of slowed cognitive impairment. Furthermore, the male improvement was in fact 43% – much greater than the reported overall group estimate of 27%. However, the female subgroup was considered too small to draw any firm statistical conclusions, so a gendered analysis was not performed or reported by the trial.
Perpetuating The Default Male
This is not the first Alzheimer’s drug target to show preferential benefit for males. Previous investigations in mouse models of AD show that mGluR5 inhibitors would exclusively benefit males, as the mGluR5 receptor does not contribute to Aβ build up in females. In fact, it’s not surprising that Lecanemab is showing potential for lower efficacy in women, as there is a growing body of evidence from preclinical trials indicating sex-based differences in Aβ formation in the brain.
In light of these sex differences, why aren’t we focusing more on women in Alzheimer’s research?
The gender data gap has been a historical issue in medicine where many conditions with gendered prevalence and/or presentation have been largely informed by early clinical investigations of mainly male populations, such as autism, depression, and cardiovascular disease. Women were traditionally excluded from trials due to the false belief that female hormone variability would have a negative impact on results, an assumption that has held back gender-specific research for years.
Female inclusion and sex-based analysis was made a requirement in mixed gender studies sponsored by the US National Institute of Health (NIH) in the early 1990s, but these analyses are often not conducted due to low female participation in clinical trials (women represent an estimated 43% of clinical trial participants worldwide). It is only since these guidelines have been issued that clear sex differences in diseases have begun to emerge.
Given that Alzheimer’s disease impacts more women than men, the lack of female focused clinical research is concerning. It’s unclear why women are more susceptible to AD, but it’s thought that poor sleep quality, hormonal changes and increased longevity versus men may play a role. Moreover, genetic factors are largely believed to contribute. Mutations in the ApoE4 gene, which is thought to be involved in Aβ clearance, double the risk of AD in women, but not men.
As such, future clinical research should endeavor to be more inclusive of women living with AD. If women are the primary patients, why are they not our primary targets?