Clinical phenotype, atrophy, and small vessel disease in <i>APOE</i>ε2 carriers eth Alzheimer disease

초록

Objective 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 APOE epsilon 2 allele. Methods We included 36 beta-amyloid-positive (by CSF or PET) APOE epsilon 2 carriers (all epsilon 2/epsilon 3) with mild cognitive impairment or dementia due to Alzheimer disease who were matched for age and diagnosis (ratio 1:2) to APOE epsilon 3 homozygotes and APOE epsilon 4 carriers (70% epsilon 3/epsilon 4 and 30% epsilon 4/epsilon 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 epsilon 2 carriers, epsilon 3 homozygotes, and epsilon 4 carriers were assessed using analysis of variance analyses, and Pearson chi(2) tests were used to examine differences in prevalence of microbleeds. Results We found that epsilon 2 carriers performed worse on nonmemory domains compared to both epsilon 3 homozygotes and epsilon 4 carriers but better on memory compared to epsilon 4 carriers. Voxelwise T1-weighted MRI analyses showed asymmetric (left > right) temporoparietal-predominant atrophy with subtly less involvement of medial temporal structures in epsilon 2 carriers compared to epsilon 4 carriers. Finally, epsilon 2 carriers had larger total white matter hyperintensity volumes compared to epsilon 4 carriers (mean 10.4 vs 7.3 mL) and a higher prevalence of microbleeds compared to epsilon 3 homozygotes (37.5% vs 18.3%). Conclusion APOE epsilon 2 carriers who develop Alzheimer disease despite carrying the protective allele display a nonamnestic clinical phenotype with more severe small vessel disease.

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