Amyloid-β modulates APOE ε4 effects on cognition but not on targeted structural or functional connectivity measures over 2 years in pre-dementia adults

Abstract

Background The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), yet emerging evidence suggests its cognitive effects may be age- and pathology-dependent. Whether and how amyloid-β (Aβ) pathology modifies the longitudinal cognitive trajectory associated with APOE ε4 in the pre-dementia stage remains unclear. Methods We conducted a 2-year longitudinal study in 70 pre-dementia adults from the Alzheimer’s disease Neuroimaging Initiative (ADNI), assessing APOE genotype, Aβ status via positron emission tomography (PET), multi-domain cognition, structural magnetic resonance imaging (MRI) volumes, and resting-state functional connectivity of a predefined hippocampus-auditory network. Linear mixed-effects models evaluated the three-way interaction of time, APOE ε4 carrier status, and Aβ status on longitudinal trajectories. Sensitivity and exploratory mediation analyses were performed. Results A significant three-way interaction (Time × APOE ε4 × Aβ status) was observed for global cognitive decline (ADAS13: β = −4.54, p = 0.001, P_FDR = 0.003), indicating that Aβ pathology moderates the effect of APOE ε4 on cognitive trajectories. Post-hoc analyses revealed that among Aβ-positive individuals, APOE ε4 carriers exhibited a slower rate of cognitive decline compared to non-carriers, whereas no such difference was evident in Aβ-negative individuals. This moderating effect was robust to sensitivity analyses and was consistently observed across multiple cognitive domains (MMSE, CDRSB, FAQ, MoCA; all P_FDR < 0.01). However, no significant three-way interactions survived multiple comparison correction for regional brain volumes or hippocampus-auditory functional connectivity, though nominally significant trends were observed in middle temporal gyrus volume and specific temporal lobe connections. Longitudinal hippocampal atrophy did not mediate the observed association. Conclusion Aβ pathology modifies the longitudinal cognitive trajectory associated with APOE ε4 in pre-dementia adults over a 2-year period. While consistent with the antagonistic pleiotropy framework, this observation requires independent replication, and alternative explanations including cognitive reserve and survivor bias warrant careful consideration.