APOE ε4, white matter hyperintensities, and cognition in Alzheimer and Lewy body dementia
Saira Saeed Mirza1, Usman Saeed2, Jo Knight2
1From the Division of Neurology, Department of Medicine (S.S.M., D.T.S., S.E.B., M.M.), Hurvitz Brain Sciences Research Program (S.S.M., J.R., D.T.S., D.Y., W.S., S.E.B., M.M.) and LC Campbell Cognitive Neurology Research Unit (U.S., J.R., S.M.N., D.Y., W.S., S.E.B., M.M.), Sunnybrook Research Institute, Institute of Medical Science (U.S., S.E.B., M.M.), Rehabilitation Sciences Institute (D.T.S., S.E.B.), and Department of Psychiatry (S.M.N.), Faculty of Medicine, Heart and Stroke Foundation Canadian Partnership for Stroke Recovery (J.R., D.Y., W.S., S.E.B.) and Department of Anatomic Pathology (J.K.), Sunnybrook Health Sciences Centre, Department of Psychology, Faculty of Arts and Science (D.T.S.), Department of Pharmacology & Toxicity (D.Y., W.S.), Tanz Centre for Research in Neurodegenerative Diseases (E.R., P.S.G.H.), and Institute of Biomaterials and Biomedical Engineering (S.E.B.), University of Toronto, Canada; Data Science Institute and Medical School (J.K.), Lancaster University, Lancaster; and Cambridge Institute for Medical Research (P.S.G.H.), Department of Clinical Neuroscience, University of Cambridge, UK. saira.mirza@sunnybrook.ca.
Objective:
To determine if APOE ε4 influences the association between white matter hyperintensities (WMH) and cognitive impairment in Alzheimer disease (AD) and dementia with Lewy bodies (DLB).
Methods:
A total of 289 patients (AD = 239; DLB = 50) underwent volumetric MRI, neuropsychological testing, and APOE 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 APOE ε4 in the full sample, we tested associations of WMH with factor scores using linear regression models in APOE ε4 carriers (n = 167) and noncarriers (n = 122). We hypothesized that greater WMH volume would relate to worse cognition more strongly in APOE 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.
Results:
A significant interaction was observed between WMH and APOE ε4 for language, but not for memory or executive functions. Separate analyses in APOE ε4 carriers and noncarriers showed that greater WMH volume was associated with worse attention/executive functions, learning/memory, and language in APOE ε4 carriers only. In ADNI-I, greater WMH burden was associated with worse attention/executive functions and language in APOE 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 APOE ε4 carriers only.
Conclusion:
APOE ε4 may influence the association between WMH and cognitive performance in AD and DLB.
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