The APOE gene has three alleles: ε2, ε3 and ε4. These alleles confer a different risk for developing Alzheimer disease (AD), mainly by affecting the accumulation of cerebral amyloid-β. Compared to the APOEε3 allele, which doesn’t appear to influence the risk for AD, the APOEε4 allele increases the risk for AD. In contrast, the APOEε2 reduces the risk of developing AD by about half. Unfortunately, the APOEε2 allele is the rarest allele, with a prevalence of only 8% in the general population. This prevalence is even lower (5%) among AD patients. Consequently, relatively little is known about the effects of APOEε2 on the clinical expression and biological features of AD in patients who develop the disease despite carrying the protective allele. With this study, we aim to provide a comprehensive phenotypical characterization of these patients. The APOEε2-carriers in this study all had PET findings or cerebrospinal fluid molecular profiles consistent with AD and underwent neuropsychological assessments of memory, attention, executive function, and language functions. Furthermore, gray matter atrophy, white matter hyperintensities and microbleeds were assessed using MRI. We found that the APOEε2-carriers display a nonamnestic clinical phenotype, asymmetric temporoparietal-predominant atrophy, and relatively severe small vessel disease, reflected in greater white matter hyperintensity volumes and more microbleeds. Thus, our results indicate that APOEε2 effects the clinical and biological phenotype of AD. Taking into account the atypical presentation of AD in APOEε2-carriers may increase diagnostic accuracy for these patients. Furthermore, these insights into the effects of APOEε2 may increase understanding of APOE-related mechanisms underlying regional vulnerability in AD and aid in drug development aimed at APOE-mediated pathways.
Colin Groot, MSc, Carole H. Sudre, PhD, Frederik Barkhof, MD, PhD, et al.; Clinical phenotype, atrophy and small vessel disease in APOE«2 carriers with Alzheimer disease. Neurology® 2018;91:1. doi:10.1212/WNL.0000000000006503