Abstract
BACKGROUND: Apolipoprotein E (ApoE) ε 4 has been identified as the strongest genetic risk factor for Alzheimer's disease (AD). However, the importance of ApoE ε 4 on clinical and biological heterogeneity of AD is still to be determined, particularly at the prodromal stage. Here, we evaluate the association of ApoE ε 4 with clinical cognition and neuroimaging regions in mild cognitive impairment (MCI) participants based on the AT (N) system, which is increasingly essential for developing a precise assessment of AD. METHODS: We stratified 178 A+T+MCI participants (prodromal AD) into ApoE ε 4 (+) and ApoE ε 4 (-) according to ApoE genotype from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We determined Aβ-positivity (A+) by the standardized uptake values ratios (SUVR) means of florbetapir-PET-AV45 (the cut-off value of 1.1) and fibrillar tau-positivity (T+) by cerebrospinal fluid (CSF) phosphorylated-tau at threonine 181 position (p-Tau) (cut-off value of 23 pg/mL). We evaluated the effect of ApoE ε 4 status on cognitive conditions and brain atrophy from structural magnetic resonance imaging (MRI) scans. A multivariate analysis of variance was used to compare the differences of cognitive scores and brain atrophy from structural MRI regions of interest (ROIs) between both groups. Furthermore, we performed a linear regression model to assess the correlation between signature ROIs of structural MRI and cognitive scores in the prodromal AD participants. RESULTS: ApoE ε 4 (+) prodromal AD participants had lower levels of CSF Aβ 1-42, higher levels of t-Tau, more memory and global cognitive impairment, and faster decline of global cognition, compared to ApoE ε 4 (-) prodromal AD. ApoE ε 4 (+) prodromal AD participants had a thinner cortical thickness of bilateral entorhinal, smaller subcortical volume of the left amygdala, bilateral hippocampus, and left ventral diencephalon (DC) relative to ApoE ε 4 (-) prodromal AD. Furthermore, the cortical thickness average of bilateral entorhinal was highly correlated with memory and global cognition. CONCLUSIONS: ApoE ε 4 status in prodromal AD participants has an important effect on clinical cognitive domains. After ascertaining the ApoE ε 4 status, specific MRI regions can be correlated to the cognitive domain and will be helpful for precise assessment in prodromal AD.