To examine the clinical phenotype, gray matter atrophy patterns, and small vessel disease in patients who developed prodromal or probable Alzheimer disease dementia, despite carrying the protective APOE2 allele.
We included 36 β-amyloid-positive (by CSF or PET) APOE2 carriers (all 2/3) with mild cognitive impairment or dementia due to Alzheimer disease who were matched for age and diagnosis (ratio 1:2) to APOE3 homozygotes and APOE4 carriers (70% 3/4 and 30% 4/4). We assessed neuropsychological performance across 4 cognitive domains (memory, attention, executive, and language functions), performed voxelwise and region of interest analyses of gray matter atrophy on T1-weighted MRI, used fluid-attenuated inversion recovery images to automatically quantify white matter hyperintensity volumes, and assessed T2*-weighted images to identify microbleeds. Differences in cognitive domain scores, atrophy, and white matter hyperintensities between 2 carriers, 3 homozygotes, and 4 carriers were assessed using analysis of variance analyses, and Pearson 2 tests were used to examine differences in prevalence of microbleeds.
We found that 2 carriers performed worse on nonmemory domains compared to both 3 homozygotes and 4 carriers but better on memory compared to 4 carriers. Voxelwise T1-weighted MRI analyses showed asymmetric (left > right) temporoparietal-predominant atrophy with subtly less involvement of medial–temporal structures in 2 carriers compared to 4 carriers. Finally, 2 carriers had larger total white matter hyperintensity volumes compared to 4 carriers (mean 10.4 vs 7.3 mL) and a higher prevalence of microbleeds compared to 3 homozygotes (37.5% vs 18.3%).
APOE2 carriers who develop Alzheimer disease despite carrying the protective allele display a nonamnestic clinical phenotype with more severe small vessel disease.