Abstract
BACKGROUND AND OBJECTIVES: APOE4 is the strongest genetic risk factor of sporadic Alzheimer disease (AD), associated with greater β-amyloid (Aβ) deposition and accelerated cognitive decline, especially in episodic memory. However, it remains unclear whether this decline is driven by increased Aβ burden in APOE4 carriers or by greater susceptibility to Aβ-related effects. 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. METHODS: We analyzed data from individuals in the Alzheimer's Disease Neuroimaging Initiative who underwent neuropsychological assessments, Aβ PET imaging, and APOE genotyping. Using sampled iterative local approximation, we estimated Aβ duration, defined as the number of years each individual was amyloid positive (Aβ+). Using these estimates, we examined its impact on cognitive trajectories across multiple domains, including episodic memory, executive function, processing speed, visuospatial abilities, semantic memory, and crystallized intelligence. RESULTS: We analyzed data from 1,542 participants (mean age = 72.2 years, SD = 7.2; 50.8% female; mean education = 16.3 years, SD = 2.6) and found that APOE4 was associated with steeper declines in episodic memory as a function of Aβ duration. Homozygous APOE4 carriers (4/4) exhibited the most pronounced decline, followed by heterozygotes (3/4), with noncarriers (3/3) showing the slowest decline. This genotype-dependent pattern was specific to episodic memory; no consistent or meaningful differences were observed across other cognitive domains. In all genotype groups, episodic memory was the first domain to show impairment. However, the lag between memory decline and subsequent nonmemory decline was substantially longer in APOE homozygote individuals compared with the other groups, suggesting a more domain-specific vulnerability early in the disease process. DISCUSSION: These findings suggest that APOE4 carriers, particularly homozygotes, exhibit reduced cognitive resilience to Aβ accumulation, but that this effect is largely specific to episodic memory. These findings indicate that cognitive trajectories in AD differ by APOE genotype, highlighting the importance of examining clinical symptoms in the context of APOE status. Future research should investigate whether these differences are driven by distinct pathologic mechanisms in APOE4 carriers.