APOE ε4 as a predictor of cognitive decline and its interaction with hippocampal volume in Alzheimer’s disease

Background/Introduction The apolipoprotein E (APOE) ε4 allele is the strongest known genetic risk factor for late-onset Alzheimer’s disease, and hippocampal atrophy is among the most reliable structural biomarkers of neurodegeneration. While both are independently associated with cognitive decline, whether APOE ε4 dose modulates the hippocampal volume–cognition relationship longitudinally in sporadic Alzheimer’s disease remains underexplored at adequate statistical power. Methods This study analyzed data from 2,417 Alzheimer’s Disease Neuroimaging Initiative participants with complete APOE genotypes, intracranial volume-adjusted hippocampal volumes, and longitudinal cognitive assessments spanning a mean follow-up of 4.2 years and up to 19.3 years with an average of 4.9 visits per participant. Linear mixed-effects models with random intercepts and slopes per subject estimated cognitive trajectories across the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-SB), and Alzheimer’s Disease Assessment Scale Cognitive Subscale 13 (ADAS-Cog13) as a function of time, APOE ε4 dose, and ICV-adjusted hippocampal volume, including their three-way interaction and adjusting for age, sex, education, baseline diagnosis, and depression. Cox proportional hazards models were used to assess conversion risk. Results A clear APOE ε4 dose–response gradient was observed at baseline across all cognitive and hippocampal measures (all p < 0.001). Linear mixed-effects models revealed a significant three-way interaction of time × APOE ε4 dose × hippocampal volume on MMSE ( β = −0.79, 95% CI [−1.51, −0.08], p = 0.030) and CDR-SB ( β = +0.47, 95% CI [+0.03, +0.91], p = 0.037) trajectories, both significant under Bonferroni correction ( α = 0.017), indicating that APOE ε4 amplifies the association between smaller hippocampal volume and faster cognitive deterioration over time. The time × hippocampal volume interaction was confirmed as highly significant by likelihood ratio test (LR = 3712.99, p < 0.001). Cox proportional hazards analyses of 845 conversion events showed that each additional ε4 allele conferred a 48% increase in conversion risk (HR = 1.48, 95% CI [1.29, 1.71], p < 0.001). Sensitivity analyses across diagnostic strata, after outlier exclusion, and in multi-visit subsamples confirmed the robustness of hippocampal volume effects. Discussion/Conclusion These findings demonstrate that APOE ε4 genotype significantly modulates the longitudinal relationship between hippocampal volume and cognitive decline, supporting the integration of APOE genotype and structural hippocampal imaging for refined individual risk stratification in Alzheimer’s disease.