Effects of APOE ε4 and amyloid pathology on longitudinal tau biomarkers, neurodegeneration, and cognitive decline in mild cognitive impairment.

BackgroundMild cognitive impairment (MCI) confers an increased risk of Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for late-onset AD and is strongly associated with amyloid-β (Aβ) pathology. However, whether Aβ burden is associated with APOE ε4-related longitudinal changes in tau pathology, neurodegeneration, and cognitive decline in MCI remains incompletely understood.ObjectiveTo examine whether Aβ burden is associated with APOE ε4-related longitudinal changes in tau pathology, neurodegeneration, and cognition in MCI using ε4 carrier-based and genotype-stratified approaches.MethodsData from 396 individuals with MCI in the Alzheimer's Disease Neuroimaging Initiative were analyzed. Longitudinal changes in cerebrospinal fluid (CSF) tau biomarkers, neurodegeneration, and cognition were quantified using individual-specific slopes and examined in multiple linear regression models in relation to APOE ε4 carrier status and Aβ burden. Mediation analyses were used to quantify the associations between baseline Aβ burden and APOE ε4-related longitudinal changes across ε4 carrier-based and genotype-stratified analyses.ResultsAPOE ε4 carriers showed greater longitudinal increases in CSF tau and more pronounced declines in glucose metabolism, regional brain volumes, and cognition. Baseline Aβ burden showed associations with APOE ε4-related longitudinal changes in CSF tau, cerebral glucose metabolism, brain atrophy, and memory and global cognition. A similar pattern was also observed in genotype-stratified analyses.ConclusionsThese longitudinal findings suggest that Aβ burden is closely associated with APOE ε4-related tau accumulation, neurodegeneration, and cognitive decline in individuals with MCI.