Alzheimer’s disease affects men and women very differently, experts find

An international team of experts, led by the Barcelona Institute for Global Health (ISGlobal) and supported by the “la Caixa” Foundation under the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment, has issued a consensus statement on the disparities in resilience to Alzheimer's disease between sexes and genders. This research, published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, emphasizes the importance of incorporating these differences into future studies.

Women account for the majority of Alzheimer's cases and face twice the lifetime risk compared to men. The prevalence of protective and risk factors, as well as the burden of Alzheimer’s-related conditions like cerebrovascular disease, differ by sex and gender due to both biological (e.g., genetic risk) and social factors (e.g., education and lifestyle).

"Assessing how sex and gender interact is crucial to understanding the mechanisms that maintain cognitive function and reduce the accumulation of pathologies in ageing and Alzheimer's disease," says Eider Arenaza-Urquijo, ISGlobal researcher, first author of the study, and President of the Reserve, Resilience and Protective Factors Group of the Alzheimer's Association.

Through extensive literature review, the team highlighted significant gaps in understanding specific risk and resilience pathways for dementia. Women generally have an initial cognitive advantage but experience faster decline than men as Alzheimer's progresses. This could be due to differences in the development of Alzheimer’s pathologies (resistance) or in maintaining normal cognitive function over time despite the presence of pathology (resilience).

Initially, women show greater resilience, better coping with brain pathology and atrophy while maintaining cognitive function. Animal studies suggest the X-Chromosome may play a protective role in Alzheimer’s (females have two X chromosomes, males one). However, this resilience diminishes as women progress to mild cognitive impairment and Alzheimer’s, showing greater vulnerability. Research indicates women are more likely to have abnormal tau protein accumulation and higher vascular pathologies, particularly post-menopause.

The authors propose that the differences in risk and resilience between sexes may be influenced by higher prevalence of physical inactivity and affective disorders in women, alongside biological factors. Genetic evidence indicates that resilience might be associated with immune pathways in females and cardiovascular pathways in males.

Research has often focused on individual behavior without considering how social and cultural factors, such as gender, influence behavior and, consequently, risk and resilience. However, differences in cognitive function between men and women may be decreasing as gender inequalities reduce, providing more opportunities in education, workforce participation, and economic status for women.

"Protective factors, such as education, may have different effects in men and women. We need to understand the complexity of interactions between biological and social factors to understand resilience to Alzheimer’s disease," argues Arenaza-Urquijo.

The authors advocate for a sex- and gender-sensitive approach to studying resilience, to better understand the interplay of biological and social determinants. "Focusing more on the differential effects of modifiable factors will help to determine whether a particular factor has a greater impact on cognitive or brain resilience in men or women," remarks Arenaza-Urquijo.

To enhance understanding of how sex and gender affect cognitive resilience to ageing and Alzheimer's, the researchers recommend several future research directions. They emphasize exploring the interaction of sex and gender factors across different cultures, considering demographic, genetic, social, and clinical differences that influence dementia risk.

Additionally, they highlight that sex/gender differences in brain characteristics, like brain connectivity, remain understudied as potential resilience factors for Alzheimer’s. Publishing negative results is crucial to avoid bias, and all studies should include sex-disaggregated results. Moreover, it's important to consider sex and gender in a non-binary way and to include LGTBIQ+ populations, who are often underrepresented and face a higher burden of chronic disease.

Incorporating these recommendations can lead to a more nuanced understanding of Alzheimer's resilience, potentially leading to more effective and personalized interventions.

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