Evaluation of Selective Survival and Sex/Gender Differences in Dementia Incidence Using a Simulation Model

IMPORTANCE 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. OBJECTIVE To assess the role of selective survival in explaining reported sex/gender differences in dementia incidence. DESIGN, SETTING, AND PARTICIPANTS 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 varyingmagnitudes. Data analysis was performed from April 2018 to May 2020. EXPOSURE Sex/gender, conceptualized as the combination of biological sex and social consequences of gender. MAIN OUTCOMES AND MEASURES 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. RESULTS 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 forwomen [IRR, 1.20; 95% CI, 1.08-1.32]) reported in an extant study. Simulations in which biaswas 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). CONCLUSIONS AND RELEVANCE 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.

Automated summary

Selective survival may contribute to observed sex/gender differences in dementia incidence, but sex/gender-specific mechanisms may also play a role in understanding prevention and treatment of dementia. Further research on plausibility of selection characteristics with outcomes and potential contributions of sex/gender-specific mechanisms is needed.