Overview: Why sex differences in dementia risk may not be fixed
Many studies report higher dementia incidence in females, often attributed to longer female life expectancy and biological factors. However, a large national cohort study adds a crucial twist: when researchers adjust for a broad range of underlying medical conditions, the sex differences in incident dementia risk largely disappear. This finding suggests that sex disparities in dementia may reflect differences in medical history and comorbidity, rather than innate sex-specific vulnerability alone.
Study design at a glance
Researchers analyzed 53,224 adults born between 1922 and 1946 who were dementia-free at baseline. The cohort was followed for up to 18 years (2002–2020) within an Israeli nonprofit health system that covers a substantial portion of the population. Dementia diagnoses came from clinical ICD codes recorded by specialists, ensuring standardized outcome ascertainment. The team used Cox regression models, first unadjusted and then adjusting for demographic factors and 33 medical diagnoses grouped into ten medical domains.
Key findings: crude versus adjusted risk estimates
In crude analyses, female sex was linked with a modestly higher risk of developing dementia (hazard ratio [HR] about 1.08). After full adjustment for demographic factors and medical histories across ten domains, the association attenuated to near null (adjusted HR around 1.02). In other words, differences in underlying health conditions largely explain the apparent sex gap in dementia risk observed in crude analyses.
Complementary analyses revealed intriguing nuances: when the models accounted for specific domains such as circulatory, respiratory, metabolic, digestive, or nervous system diseases, females showed higher dementia risk than males. Yet, after adjusting for rheumatic or genitourinary diseases, the sex difference largely vanished. When psychiatric disorders were included, males emerged as having a greater risk, underscoring how specific conditions can shift the balance of risk between sexes.
What medical domains most strongly shape risk by sex?
The strongest, consistent patterns emerged for cardiovascular-related conditions: females tended to have larger effect sizes for circulatory diseases in relation to dementia risk in several models. This aligns with other contemporary research suggesting female cardiovascular health interacts with dementia pathways differently than male cardiovascular health. Conversely, rheumatic and genitourinary diseases tended to reduce the sex difference to null, potentially because these conditions are more prevalent in females and are themselves linked to dementia risk via chronic inflammation and other pathways.
Psychiatric disorders: a notable reversal in some models
A striking finding was that psychiatric disorders, particularly psychosis, altered the sex-dementia relationship in opposite directions depending on sex. When psychiatric disorders were the primary adjustment factor, males showed higher dementia risk than females. This echoes meta-analytic trends that connect psychiatric conditions with later cognitive decline, especially in men, and may reflect sex-specific brain aging trajectories and symptom profiles.
Strengths and limitations to inform interpretation
The study’s strengths include a large, population-based sample with long follow-up, objective clinical diagnoses, and comprehensive adjustment for a wide range of medical conditions. Limitations include potential residual confounding from unmeasured factors such as education, lifestyle behaviors, and genetics. The authors note that dementia subtypes were not separately analyzed, which could mask pattern differences between, for example, vascular versus Alzheimer-type dementia. They also acknowledge the possibility of reverse causation, given the long preclinical phase of dementia.
Implications for research and prevention
These findings advocate for sex-aware dementia research that explicitly accounts for medical history. Prevention strategies should consider how gendered patterns of disease—cardiovascular risk, autoimmune and rheumatic conditions, psychiatric illnesses, and genitourinary health—contribute to cognitive trajectories. By contextualizing sex differences within the broader medical landscape, researchers can better identify high-risk individuals and tailor interventions that address modifiable comorbidities for both sexes.
Take-home message
Sex differences in dementia risk are not fixed two-way probabilities. They evolve with the constellation of underlying medical conditions. When researchers control for these conditions, the sex gap in incident dementia risk often shrinks, highlighting the central role of comorbidity in shaping cognitive aging.
