| Summary: | Introduction: Memory impairment is a hallmark feature of Alzheimer's disease (AD) and may emerge years before clinical diagnosis. However, the temporal sequence and acceleration patterns of decline across specific memory domains during the preclinical stage remain incompletely understood. This study aimed to characterize the longitudinal dynamics of four distinct memory processes in individuals progressing to clinical AD, and to identify the temporal sequence of continually accelerated decline. Methods: We analyzed longitudinal data from 382 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) who converted from cognitively normal or mild cognitive impairment to AD. Generalized additive mixed models (GAMMs) were employed to characterize the nonlinear trajectories of four Rey Auditory Verbal Learning Test (RAVLT) derived scores over time prior to AD diagnosis, adjusting for key demographics and genetic factors. The finite difference method was applied to identify time points of continually accelerated decline from the fitted curves. Sensitivity analyses additionally adjusted for stroke and emotional incontinence, replicating all steps. Results: Our analysis revealed distinct nonlinear progression patterns across memory domains. All trajectories significantly deviated from linearity (Edf > 1, p < 0.001). Learning memory demonstrated the earliest continually accelerated decline, beginning 8.5 years before AD onset. APOE-ε4 allele carriage exhibited a dose-dependent effect, significantly associated with RAVLT_learning (β = −0.389 for one allele, −0.530 for two alleles) and RAVLT_forgetting (β = −0.449 for one allele, −0.508 for two alleles), but not with RAVLT_immediate performance. Females exhibited better immediate memory function than males, which was positively associated with years of education. Conclusion: The decline in four memory tests among individuals with preclinical AD followed nonlinear trajectories, with learning memory exhibiting the earliest continuously accelerated decline. Higher education was associated with better immediate memory performance, while the APOE-ε4 genotype specifically exacerbated impairments in learning memory and retention loss.
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