EFFECT OF APOE-ε2 ON REGIONAL GRAY MATTER ATROPHY AND CLINICAL PHENOTYPE IN ALZHEIMER’S DISEASE

Abstract

The APOE ε2 allele is considered a protective factor against developing Alzheimer's disease (AD). Consequently, the proportion of APOE ε2 carriers among AD patients is low (3–5%), but a small number of individuals do develop AD despite ε2 carriership. In this study, we characterized the neuropsychological profile and distribution of gray matter atrophy of ε2 carriers with MCI or dementia -due-to-AD. 38 ε2 carriers (all ε2/ε3) with a clinical diagnosis of MCI or dementia -due-to-AD based on positive amyloid PET and/or CSF amyloid-beta1–42 were included. This group was matched for age, sex and education with an amyloid-negative cognitively normal ε3/ε3 (NC) group, and groups of amyloid-positive ε3/ε3, ε3/ε4, and ε4/ε4 AD patients (Table 1). Neuropsychological test scores were converted into Z-scores using the mean and standard deviation of the NC group and then categorized into 4 cognitive domains (i.e. memory, attention, executive functioning and language). ANCOVA analyses adjusted for age, sex, education and disease-stage (MCI/ dementia) were used to compare cognition between AD groups. Voxel-based morphometry was conducted in statistical parametric mapping 12 to assess voxelwise differences in gray matter atrophy between AD groups and controls. The models included age, sex, scanner-type and total intracranial volume as covariates. ε2 carriers had more impaired language function compared to all other AD groups (F(3)=6.29, p<.01; Figure 1), while memory was relatively preserved in ε2 carriers compared to ε4/ε4 carriers (F(3)=2.67, p=.05). Voxelwise contrasts against controls revealed relative sparing of the medial temporal lobe in ε2 compared to ε4 carriers (p<.05, family-wise error corrected; Figure 2). Similar analyses using a less stringent threshold (p<.001, uncorrected; Figure 3) revealed that ε2 carriers displayed i) an atrophy pattern that was mostly restricted to temporoparietal regions compared to wider neocortical involvement in other groups, and ii) left>right asymmetry. The observed atrophy pattern in ε2 carriers (i.e. left>right asymmetry and relatively spared medial temporal lobes) matches their neuropsychological profile with prominent language deficits and relatively preserved memory performance. These results help to elucidate differences in regional vulnerability across APOE genotypes and better understand clinical heterogeneity in AD. Neuropsychological performance of all amyloid-positive groups across cognitive domains Z-scores, calculated based on the mean and standard deviation of the normal control group indicate better memory performance of ε2 compared to ε4/ε4 and worse language performance of ε2 compared to all groups. * significant contrast with ε2 carriers at α=.05, adjusted for age, sex, education and disease stage. Voxelwise contrasts between normal controls and amyloid-beta positive ε2, ε3/ε3, ε3/ε4 and ε4/ε4 AD patients, family-wise error corrected (p<0.05) Colored areas indicate regions where AD groups have significantly lower gray matter volume than normal controls. Voxelwise contrasts between normal controls and amyloid-beta positive ε2, ε3/ε3, ε3/ε4 and ε4/ε4 AD patients, (p<0.001, uncorrected for multiple comparisons) Colored areas indicate regions where AD groups have significantly lower gray matter volume than normal controls.