Early effects of amyloid-β on structural and vascular brain changes in mid-life cognitively unimpaired individuals.

Abstract

The apolipoprotein E (APOE) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). It has been shown that APOE ε4 allele (ε4) relates to early pathological accumulation of cerebral amyloid-β (Aβ), leading to decade earlier age-of-onset of AD. However vascular and anatomical brain changes in the presence of Aβ and ε4 gene have not yet been fully examined in middle age. We aim to investigate how ε4 and Aβ level influence MR neuroimaging biomarkers such as white-matter hyperintensities and hippocampus volume in mid-life (45-65 year old) cognitively unimpaired (CU) individuals. 149 middle age (44 to 66 years of age) CU adults (age 58.2±5.4, 115 Females, years of education 13.5±2.8) underwent 3T MRI and amyloid PET scans using 18 F-Florbetaben as part of the PISA study. Of this ε4 enriched cohort (N=78 ε4 carriers), 12 were classified as Aβ+ (Centiloid≥20). 5 participants with ε2ε4 genotypes were excluded due to the protective effect of the ε2 allele. Multivariable general linear models were implemented to study the association of ε4 and Aβ with structural neuroimaging markers including white-matter hyperintensity volume (WMHV) and Hippocampus volume (HV). Both volumes were normalised using total intracranial volume, and age, gender and years-of-education were used as independent covariates. There was no age difference between ε4+ and ε4- groups (Kruskal-Wallis test, p-value=0.8), but Aβ+ participants were older compared to Aβ- (p-value=0.005). There was no HV differences between ε4+ and ε4- groups when controlling for Centiloid (p-value=0.55). When comparing HV differences between groups based on joint ε4 and Aβ, Aβ+ε4+ had significantly lower HV compared to Aβ-ε4+ (p-value=0.01) and Aβ-ε4- (p-value=0.021) as shown in Figure 1. For WMHV differences, a trend towards significance exists for Aβ+ε4+ when compared to and Aβ+ε4- and Aβ-ε4- (p-value=0.069) as shown in Figure 2. In this study, we found that early signs of hippocampus degeneration may occur in the middle age in the presence of both high Aβ level and APOE ε4 allele. Future studies will investigate the effective age spread for middle-aged preclinical AD population which will be beneficial for participant recruitment for new clinical trials.