Investigating Sex Differences in Risk and Protective Factors in the Progression of Mild Cognitive Impairment to Dementia: A Systematic Review

Background: Developing effective strategies for reducing dementia risk requires a detailed understanding of the risk and protective factors associated with the progression of mild cognitive impairment (MCI) to dementia. Objective: We aimed to systematically review the evidence for sex differences in these factors. Methods: Five online databases (PubMed/CINAHL/EMBASE/PsycINFO/Cochrane) were searched from inception until 17 October 2022 for cohort studies that focused on sex differences in risk and protective factors in the progression of MCI to dementia. Results: Atotal of 2,972 studies were identified, of which 12 studies from five countries were included in the systematic review. There was substantial variability in study designs, study populations and outcome measures. Sex differences were present in the associations of sociodemographic, health, psychological factors, genetic and other biomarkers with the progression of MCI to dementia. APOE epsilon 4 status and depression appeared to increase the risk of progression for females, whereas history of stroke, MRI markers and cerebrospinal fluid biomarkers appeared to increase the risk of progression for males. APOE epsilon 2 status and marital status (unmarried) were observed to reduce risk of progression in males and females, respectively. Conclusions: The ability of studies to accurately detail risk factors for dementia are likely limited when solely controlling for the effects of sex. Although the heterogeneity and underpowered nature of the studies made it difficult to synthesize the findings for each risk factor, this study highlights the apparent need for further research examining risk factors for dementia in males and females with MCI separately.