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APOE ε4, white matter hyperintensities, and cognition in Alzheimer and Lewy body dementia
Open accessAbstract
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 Alzheimer9s 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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“Notably, previous studies have not combined MRI and histological investigation within the same subjects. 12 , 22 , 26 , 27”
From Apolipoprotein ε4 exacerbates white matter impairment in a mouse model of Aβ amyloidosis by decreasing actively myelinating oligodendrocytes (2025) · cites this paper as [22]
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“Multiple MRI studies have reported that APOE4 isoform is associated with white matter degeneration in patients with dementia. 10 , 11 , 22 , 23”
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Metadata
- Authors
- Mirza, S. S., Saeed, U., Knight, J., Ramirez, J., Stuss, D. T., Keith, J., Nestor, S. M., Yu, D., Swardfager, W., Rogaeva, E., St. George Hyslop, P., Black, S. E., Masellis, M., & Initiative, A. D. N.
- Affiliations
- University of Cambridge (GB)
- From 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...
- Corresponding author
- Mirza, Saira Saeed
- ORCID
- Venue
- Neurology
- Published
- 2019-11-05
- Volume
- 93
- Issue
- 19
- Pages
- e1807-e1819
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC6946485
- OpenAlex
- W2972417083
- Cited by
- 67
- References
- 51
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 10 · 2023: 12 · 2022: 14 · 2021: 11 · 2020: 3
- FWCI
- 5.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Neurology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense (U01 AG024904, W81XWH, W81XWH-12-2-, W81XWH1220012, AG024904)
- Foundation for the National Institutes of Health (W81XWH-12-2-0012, U01AG024904, AG024904)
- Alzheimer's Association (U01 AG024904, AARG501466, W81XWH-12-2-0012)
- Bristol-Myers Squibb (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Eli Lilly and Company (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Pfizer (AG024904, W81XWH-12-2-0012, U01 AG024904)
- Biogen (W81XWH-12-2-0012, U01 AG024904, AG024904)
- University of Southern California (W81XWH-12-2-0012, U01 AG024904)
- F. Hoffmann-La Roche (W81XWH-12-2-0012, AG024904, U01 AG024904)
- Meso Scale Diagnostics (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Alzheimer's Disease Neuroimaging Initiative (W81XWH-12-2–0012, U01AG024904, AG024904, W81XWH-12-2-, Department of Defense award number W81XWH-12-2-0012)
- BioClinica (U01 AG024904, W81XWH-12-2-0012, AG024904)
- Novartis Pharmaceuticals Corporation (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Fondation Brain Canada (AARG501466)
- Northern California Institute for Research and Education (U01 AG024904, W81XWH-12-2-0012)
- Sunnybrook Research Institute
- Ionis Pharmaceuticals
- Alzheimer's Society
- Alzheimer Society
- University of Toronto
- Eisai (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Servier (AG024904, W81XWH-12-2-0012, U01 AG024904)
- H. Lundbeck A/S (U01 AG024904, AG024904, W81XWH-12-2-0012)
- IXICO (AG024904, W81XWH-12-2-0012, U01 AG024904)
- National Institutes of Health (3u01ag024904-10s2, W81XWH, W81XWH-12-2-0012, U01-AG024904, AG024904)
- Genentech (W81XWH-12-2-0012, AG024904, U01 AG024904)
- Canadian Institutes of Health Research (U01 AG024904, W81XWH-12-2-0012, MOP#13129)
- National Institute on Aging (U01-AG-024904, W81XWH-12-2–0012, AG 024904)
- National Institute of Biomedical Imaging and Bioengineering (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Clinical Neurology › Cerebrovascular and genetic disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- APOE ε4, white matter hyperintensities, Alzheimer's disease, dementia with Lewy bodies, cognitive impairment, genetic interactions, language performance, attention and executive function, memory
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Attention, Factor Analysis, Statistical, Female, Humans, Language, Learning, Magnetic Resonance Imaging, Male, Memory, Middle Aged, Neuropsychological Tests, Linear Models, Lewy Body Disease, Apolipoprotein E4, Executive Function, Cognitive Dysfunction, White Matter
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