Effects of <i>APOE</i> 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 (<i>APOE</i>) 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 <i>APOE</i> ε4-related longitudinal changes in tau pathology, neurodegeneration, and cognitive decline in MCI remains incompletely understood.ObjectiveTo examine whether Aβ burden is associated with <i>APOE</i> 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 <i>APOE</i> ε4 carrier status and Aβ burden. Mediation analyses were used to quantify the associations between baseline Aβ burden and <i>APOE</i> ε4-related longitudinal changes across ε4 carrier-based and genotype-stratified analyses.Results<i>APOE</i> 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 <i>APOE</i> 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 <i>APOE</i> ε4-related tau accumulation, neurodegeneration, and cognitive decline in individuals with MCI.