Invited Commentary: Examining Sex/Gender Differences in Risk of Alzheimer Disease and Related Dementias—Challenges and Future Directions

Abstract

The majority of people living with Alzheimer disease (AD) and related dementias are women. Longer life expectancy is one factor thought to contribute to this observation, but possible sex-specific biological mechanisms have received considerable attention from the research community. In the current issue of the Journal, Buckley et al. (Am J Epidemiol. 2019;188(7):1213–1223) use death certificate information on all deaths occurring among adults aged ≥60 years in Australia between 2006 and 2014 to evaluate sex/gender differences in rates of death with dementia (all types), AD dementia, and vascular dementia listed on the death certificate. The paper by Buckley et al. highlights several important methodological challenges for research examining sex/gender differences in risk of AD and related dementias, including challenges in measurement, survival bias and competing risks, and selection bias arising from sample selection. The current evidence on possible sex-specific biological risk factors for AD is intriguing, but there are numerous alternative explanations for differences in AD dementia and AD biomarkers between women and men. Triangulation of evidence from study designs with different strengths and weaknesses and transdisciplinary collaboration will be vital to generating conclusive evidence about sex/gender differences in risk of AD and related dementias.

Sex is a defining feature of neuroimaging phenotypes in major brain disorders

“…These findings highlight reliability issues when using death certificates for retroactive disease classification. Greater prevalence of AD in females may also reflect a survival bias, since AD incidence increases with age and females have longer lifespans than males [Mayeda, 2019].…”

“…However, neither of these studies specifically addressed whether participants met criteria for VCI. While many studies report higher stroke prevalence in males [Barker-Collo et al, 2015], females exhibit more atypical cardiac symptoms that result in longer delays to seek treatment and a higher rate of misdiagnosis that may contribute to less frequent stroke recovery in females than males [Mayeda, 2019]. Atypical cardiac characteristics in females include non-obstructive cardiac plaques and coronary microvascular dysfunction.…”

“…Further, females are twice as likely as males to receive a diagnosis of heart failure despite preserved ejection fraction. Clinicians who are unaware of these sex differences, or more typically encounter male patients with classical cardiovascular symptoms, may be less likely to diagnose females with VCI or VaD when significant (yet atypical) cardiovascular morbidities are present [Mayeda, 2019].…”

Interleukin‐12/23 deficiency differentially affects pathology in male and female Alzheimer's disease‐like mice

“…APP23 mice show a much slower rate of Aβ deposition than APPPS1 mice utilised in earlier studies, which recapitulates more closely Aβ pathology of human AD patients with respect to the Aβ accumulation time course and the histopathological Aβ composition consisting of a sound mixture of “soft”/”diffuse” and “core” Aβ plaques. Similar to effects described in human AD patient populations , gender differences in plaque deposition have been described in this mouse model, although these have not been characterised thoroughly to the best of our knowledge . To address the latter, we assessed gender‐specific properties of Aβ deposition as well as Aβ processing, surrogate markers of neuritic dystrophy and glial activation in male and female APP23 mice lacking or harbouring the IL‐12/IL‐23 signalling pathway.…”

Using Cross-Cultural Studies to Improve Evidence on Dementia Prevention: Lessons from the Special Issue Sponsored by the International Research Network on Dementia Prevention (IRNDP)

“…LIBRA predicted verbal memory decline among women but not men, although given that small differences were observed in only one cognitive outcome, Deckers et al [29] summarized the evidence as roughly similar associations by education and gender. The possibility of gender differences in ADRD incidence has received substantial research attention, but recent work also highlights the many reasons that small differences may reflect methodological artefacts [30]. The careful sensitivity analyses evaluating the role of cardiovascular disease and baseline differences in cognitive test scores help allay concerns that their these factors may have contributed to their findings [29].…”