A Call to Action to Address Sex Differences in Alzheimer Disease Clinical Trials

Historically, scientific findings from male in vitro and in vivo models have formed the standard of medical knowledge. This approach, exacerbated by low female representation in medical research and a dearth of studies investigating sex differences, has led to substantial public health, clinical, and humanitarian implications, as well as economic consequences. A cardinal example from the field of cardiology was the discovery of critical sex-specific treatment effects through ad hoc observational analyses, years after the results of clinical trials had been published. There is a pressing need to study and report sex differences across the field of medicine but most crucially now in Alzheimer disease (AD).

With decades of AD drug research failing to show efficacy and even induced excess toxic effects, the headline findings from the CLARITY-AD clinical trial¹ with lecanemab offered some optimism. The ability of lecanemab to clear large soluble protofibrils of beta-amyloid (Aβ)in the brain and moderately slow the progression of cognitive decline¹ was hailed by Alzheimer Research UK as a momentous finding. The US Food and Drug Administration subsequently authorized its use via the accelerated approval pathway. This came after the controversial approval of aducanumab based on a retrospective reanalysis result from the EMERGE and ENGAGE trials.² Not only does uncertainty exist around the clinical efficacy of both drugs, but also substantial financial costs associated with treatment could pose an immense burden on patients, families, and health care systems.

All 3 recent clinical trials with antiamyloid agents (CLARITY-AD, EMERGE, ENGAGE) had a balanced representation of female enrollment (52.3%, 51.5%, and 52.4%, respectively). Disappointingly, sex-disaggregated analyses were not expanded in the main reporting of the trial results, particularly when examining sex by treatment interactions, despite indications of meaningful differences. On closer inspection of the CLARITY-AD reporting, subgroup analyses in the supplementary material revealed noteworthy sex differences. Specifically, the cognitive benefits of the drug (in primary end point tests of the Clinical Dementia Rating scale Sum of Boxes [CDR-SB] and Alzheimer Disease Assessment Scale-Cognitive Subscale [ADAS-COG]) were evident primarily in men.¹ This was similarly observed in the EMERGE trial,² in which reduced cognitive decline (again in CDR-SB and ADAS-COG) was evident in men but not in women. These preliminary findings support mounting evidence that drug efficacy, including pharmacokinetics and pharmacodynamics, can be affected by biologic sex. However, currently there is a dearth of published clinical and biomarker data on sex differences in AD trials, since sex stratification and evidence of interactions are not considered.

Several potential rationales exist for the possible sex differences in these trials. One well-documented finding is that women exhibit higher tau burden relative to men,^3,4 and the synergistic effect of sex with APOE genotype has consistently revealed that female APOE ε4 carriers exhibit higher tau burden and risk for progression to dementia.⁵ Moreover, transcriptomes associated with the X chromosome have also been implicated in AD pathogenesis in a sex-specific manner.⁶ While the picture surrounding sex differences in incidence rates for AD remains somewhat convoluted, with a dependence on other intersectional factors such as age, race and ethnicity, socioeconomic status, geographic regions, and gender-related comorbidities, it is increasingly clear that women have a greater lifetime risk of dementia due to greater longevity, and a disproportionate contribution from female-specific reproductive factors to elevated dementia risk and neuropathology.³ The role of pathology in clinical outcomes also differs by sex, with women expressing cognitive resilience in the face of pathologic load in preclinical AD,⁷ but these compensatory mechanisms are lost with increasing cognitive impairment.⁸ It is possible that any or all of these factors are playing a role in therapeutic sex differences. Understanding potential bases of the differences in therapeutic effects will require further exploration of the clinical trial data, as well as targeted efforts to examine sex-specific treatment effects in future trials.

If the potential benefits of this new generation of AD drugs are specific to men, this is likely to further widen the gap that already exists in a multitude of health conditions between women and men. Without a careful interpretation of the sex differences in AD treatment effects, and subsequently accounting for these differences in clinical practice, inequities in health care can occur. For instance, women with early signs of cognitive decline might continue to accumulate adverse neuropathologic burden and experience decline in cognition and function, but with the perception of being prescribed the most appropriate guideline-based care. This situation echoes that from cardiovascular medicine, in which women were historically overlooked when it came to receiving optimized cardiovascular therapeutics.⁹

The recent reporting of AD trials still perpetuates the recurring pattern of research studies failing to report outcomes disaggregated by sex (or gender), in such a way as to judge the effect of sex on treatment outcomes. A study found that only 8 of 118 identified dementia trials reported sex-disaggregated outcomes.¹⁰ This is despite women representing approximately 60% of all patients with AD dementia, and publication guidelines such as the Sex and Gender Equity in Research policy, and government funding bodies (eg, National Institutes of Health) requiring sex-balanced study designs and sex-disaggregated analyses. As such, these data collection and reporting standards should be continuously recommended or even mandated.

It is crucial to note that the lack of sex-disaggregated data reporting in clinical trials is not unique to AD research but is a pervasive issue across many areas of medicine. Given the unique complexities of AD pathophysiology and the disproportionate burden of AD on women, it is especially important for AD research to adopt rigorous standards for sex-disaggregated analyses, starting with increasing the representation of women to better reflect clinical populations.¹⁰ Therefore, we call for comprehensive investigations into sex differences associated with treatments in existing AD (and related dementia) clinical trials and integrating these considerations into future trials. This includes taking baseline AD biomarker and genetic burden by sex into consideration, the inclusion of sex disaggregated results as a routine standard, and even the initiation of powered trials that can include sex disaggregated results as a primary end point. Routine examination and reporting of reproductive characteristics of women and men in clinical trials should be considered to augment the biomarker information. Reporting of sex differences in drug to lerability and adverse events, and exploring potential sex-specific mechanisms of therapeutic response are warranted. Prespecification of these analyses prior to trial commencement can help establish robust evidence for sex differences, leading to sex-specific recommendations for dosingand drug applicability.

As we anticipate more AD drugs to be approved and enter the market, it is imperative to ensure that sex differences in treatment effects are well understood before they are prescribed to patients. Without considering sex (and gender) differences, dementia researchers are poorly serving clinicians and their patients.