APOE in subjective cognitive decline: a systematic review and meta-analysis

Abstract

Alzheimer’s disease (AD) is increasingly conceptualised as a biological and clinical continuum that includes Subjective cognitive decline (SCD), mild cognitive impairment (MCI), and overt dementia. We conducted a systematic review and meta-analysis to assess the prevalence of APOE ε4 allele in individuals with SCD. Main databases were searched to identify studies published up to 15 April 2026, plus citation checking. Eligible studies included participants with SCD defined according to standardized criteria, with available APOE genotype data. Application of SCD-plus criteria was also recorded. Of 474 screened records, 49 studies were included in the quantitative synthesis. The pooled prevalence of APOE ε4 allele carriers was 28.3% (95% CI 25.1–31.8%) in SCD, 41.0% (95% CI 35.3–46.8%) in MCI, and 22.0% (95% CI 18.6–25.9%) in cognitively normal (CN) individuals. Multivariate analysis showed that the odds of being an APOE ε4 allele carrier were significantly higher in SCD compared to HC (OR = 1.28, 95% CI 1.12–1.46, p <0.001) and higher in MCI compared to SCD (OR = 1.48, 95% CI 1.23–1.76, p <0.0001). Meta-regression analyses indicated that age and education contributed to heterogeneity in SCD cohorts, while sex distribution did not. Sensitivity analyses restricted to SCD-plus studies confirmed the robustness of these findings. The prevalence of APOE ε4 allele in SCD falls between that observed in CN and MCI populations, supporting its role as an intermediate stage in the AD continuum. However, substantial heterogeneity persists, highlighting the need for more accurate stratification approaches integrating genetic and clinical markers.