Abstract
Dementia research is susceptible to bias arising from selective survival, a process that results in individuals with certain characteristics disproportionately surviving to old age. Spurious associations between risk factors and dementia may be induced when factors associated with longer survival also influence dementia incidence. To assess the role of selective survival in explaining reported sex/gender differences in dementia incidence. This decision analytical model used a simulated cohort of US participants aged 50 years and without dementia at baseline followed up for incident dementia through age 95 years. Selective survival was induced by a selection characteristic (eg, childhood social disadvantage or Alzheimer genetic risk) that influenced both mortality and dementia incidence at varying magnitudes. Data analysis was performed from April 2018 to May 2020. Sex/gender, conceptualized as the combination of biological sex and social consequences of gender. Dementia incidence rate ratios (IRRs) for women compared with men. In all simulations, it was assumed that there would be no true effect of sex/gender on dementia incidence; all observed sex/gender differences were due to selective survival. At baseline, the simulation included 100 000 participants aged 50 years (51 000 [51%] women, mirroring the 1919-1921 US birth cohort of non-Latino White individuals at age 50 years); distributions of the selection characteristic were standard normal (mean [SD], 0.0 [1.0]). Observed sex/gender differences in dementia incidence in individuals aged 85 years or older ranged from insignificant (IRR, 1.00; 95% CI, 0.91-1.11) to consistent with sex/gender differences (20% higher risk for women [IRR, 1.20; 95% CI, 1.08-1.32]) reported in an extant study. Simulations in which bias was large enough to explain prior findings required moderate to large differential effects of selective survival (eg, hazard ratio for selection characteristic on mortality at least 2.0 among men, no effect among women). These results suggest that selective survival may contribute to observed sex/gender differences in dementia incidence but do not preclude potential contributions of sex/gender-specific mechanisms. Further research on plausibility of selection characteristics with outcomes of the magnitude required for selective survival to explain sex/gender differences in dementia incidence and sex/gender-specific mechanisms represent an opportunity to understand prevention and treatment of dementia.
Highlights
Most people living with dementia are women.[1]
Observed sex/gender differences in dementia incidence in individuals aged 85 years or older ranged from insignificant (IRR, 1.00; 95% CI, 0.91-1.11) to consistent with sex/gender differences (20% higher risk for women [incidence rate ratios (IRRs), 1.20; 95% CI, 1.08-1.32]) reported in an extant study
Further research on plausibility of selection characteristics with outcomes of the magnitude required for selective survival to explain sex/gender differences in dementia incidence and sex/gender-specific mechanisms represent an opportunity to understand prevention and treatment of dementia
Summary
Most people living with dementia are women.[1] Excess dementia burden among women compared with men could be explained by women’s longer life expectancy, higher age-specific dementia incidence rates among women, or selective survival bias.[2] Some studies report higher age-specific dementia incidence in women compared with men at older ages (ie, ages Ն85 years),[3,4,5,6,7,8,9] while other studies have not reported differences.[10,11,12] Mechanisms triggered by either biological sex or social consequences of gender could contribute to the difference.[10,13,14,15] Selective survival bias can occur if men (or women) with specific characteristics disproportionately survive to old age and those same characteristics are associated with dementia risk.[16,17,18,19] Subsequently, measures of association among survivors may not represent causal effects and can be exaggerated, attenuated, or reversed compared with the truth.[16] The magnitude of bias is driven by the strength of association between exposure of interest and mortality, strength of association between dementia and mortality, and cumulative mortality.[20,21]
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