Multiple Effect of APOE Genotype on Clinical and Neuroimaging Biomarkers Across Alzheimer's Disease Spectrum

The apolipoprotein E ε4 (APOE ε4) allele is the most important genetic risk factor for Alzheimer's disease (AD); however, the underlying mechanisms responsible for it remain controversial. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) database to examine the influence of APOE ε4 dose on clinical and neuroimaging biomarkers across the AD spectrum (from cognitive normal to AD patients with severe cognitive impairment). A total of 1718 participants from the ADNI cohort were selected, and we evaluated the impact of ε4 dose on cerebrospinal fluid (CSF) levels' Abeta1-42 (Aβ1-42), tau, and phosphorylated-tau (p-tau); cortical amyloid deposition (Florbetapir-PET-AV45); brain atrophy (MRI); brain metabolism (FDG-PET); hippocampal metabolism; and cognitive declines, through different cognitive subgroups. We found that (1) ε4 was associated with decreased CSF beta-amyloid (Aβ1-42) and increased cerebral Aβ deposition across the AD spectrum; (2) increased CSF tau, P-tau and cerebral hypometabolism, hippocampal atrophy, and cognition decline were all associated with APOE ε4 in prodromal AD stage; (3) increased CSF tau, P-tau and cerebral hypometabolism appear to begin earlier than hippocampal atrophy and cognitive decline. We hypothesized that APOE ε4 increases cerebral amyloid-β (Aβ) deposition in all the stages of AD development, and also influences Aβ-initiated cascade of downstream neurodegenerative effects, thereby increasing the risk of AD.