<i>APOE</i> ε4, white matter hyperintensities, and cognition in Alzheimer and Lewy body dementia.

Abstract

To determine if <i>APOE</i> ε4 influences the association between white matter hyperintensities (WMH) and cognitive impairment in Alzheimer disease (AD) and dementia with Lewy bodies (DLB). A total of 289 patients (AD = 239; DLB = 50) underwent volumetric MRI, neuropsychological testing, and <i>APOE</i> ε4 genotyping. Total WMH volumes were quantified. Neuropsychological test scores were included in a confirmatory factor analysis to identify cognitive domains encompassing attention/executive functions, learning/memory, and language, and factor scores for each domain were calculated per participant. After testing interactions between WMH and <i>APOE</i> ε4 in the full sample, we tested associations of WMH with factor scores using linear regression models in <i>APOE</i> ε4 carriers (n = 167) and noncarriers (n = 122). We hypothesized that greater WMH volume would relate to worse cognition more strongly in <i>APOE</i> ε4 carriers. Findings were replicated in 198 patients with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI-I), and estimates from both samples were meta-analyzed. A significant interaction was observed between WMH and <i>APOE</i> ε4 for language, but not for memory or executive functions. Separate analyses in <i>APOE</i> ε4 carriers and noncarriers showed that greater WMH volume was associated with worse attention/executive functions, learning/memory, and language in <i>APOE</i> ε4 carriers only. In ADNI-I, greater WMH burden was associated with worse attention/executive functions and language in <i>APOE</i> ε4 carriers only. No significant associations were observed in noncarriers. Meta-analyses showed that greater WMH volume was associated with worse performance on all cognitive domains in <i>APOE</i> ε4 carriers only. <i>APOE</i> ε4 may influence the association between WMH and cognitive performance in AD and DLB.