Abstract
Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Individuals with one copy of APOE4 exhibit greater amyloid-beta (Aβ) deposition compared to noncarriers, an effect that is even more pronounced in APOE4 homozygotes. Interestingly, APOE4 carriers not only show more AD pathology but also experience more rapid cognitive decline, particularly in episodic memory. The underlying mechanisms driving this domain-specific vulnerability, however, remain unclear. In this study, we examined whether the accelerated decline in episodic memory among APOE4 carriers is due to increased Aβ deposition or heightened susceptibility to Aβ-related effects. Using data from the Alzheimer's Disease Research Initiative, we modeled amyloid duration, the estimated number of years an individual has been amyloid-positive, and its impact on cognitive trajectories. Our findings reveal that APOE4 is associated with more rapid episodic memory decline as a function of amyloid duration. This decline was dose-dependent, with APOE4 homozygotes declining more rapidly than heterozygotes, and it was consistently observed across multiple episodic memory tasks and measures. Importantly, this pattern was not observed in other cognitive domains, such as processing speed, executive function, visuospatial skills, language, or crystallized intelligence. These results suggest that cognitive trajectories in AD differ by APOE genotype, with APOE4 conferring increased vulnerability to hippocampal dysfunction early in the disease course. Future research should investigate whether these cognitive differences stem from distinct pathological cascades in APOE4 carriers.