title: APOE ε4 status is associated with white matter hyperintensities volume accumulation rate independent of AD diagnosis.
abstract: To assess the relationship between carriage of APOE ε4 allele and evolution of white matter hyperintensities (WMHs) volume, we longitudinally studied 339 subjects from the Alzheimer's Disease Neuroimaging Initiative cohort with diagnoses ranging from normal controls to probable Alzheimer's disease (AD). A purpose-built longitudinal automatic method was used to segment WMH using constraints derived from an atlas-based model selection applied to a time-averaged image. Linear mixed models were used to evaluate the differences in rate of change across diagnosis and genetic groups. After adjustment for covariates (age, sex, and total intracranial volume), homozygous APOE ε4ε4 subjects had a significantly higher rate of WMH accumulation (22.5% per year 95% CI [14.4, 31.2] for a standardized population having typical values of covariates) compared with the heterozygous (ε4ε3) subjects (10.0% per year [6.7, 13.4]) and homozygous ε3ε3 (6.6% per year [4.1, 9.3]) subjects. Rates of accumulation increased with diagnostic severity; controls accumulated 5.8% per year 95% CI: [2.2, 9.6] for the standardized population, early mild cognitive impairment 6.6% per year [3.9, 9.4], late mild cognitive impairment 12.5% per year [8.2, 17.0] and AD subjects 14.7% per year [6.0, 24.0]. Following adjustment for APOE status, these differences became nonstatistically significant suggesting that APOE ε4 genotype is the major driver of accumulation of WMH volume rather than diagnosis of AD.
authors.affiliation: Translational Imaging Group, Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London, Malet Place Engineering Building, London, UK; Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK. Electronic address: carole.sudre.12@ucl.ac.uk.
authors.forename: Carole H
authors.initials: CH
authors.lastname: Sudre
authors.affiliation: Translational Imaging Group, Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London, Malet Place Engineering Building, London, UK; Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK.
authors.forename: M Jorge
authors.initials: MJ
authors.lastname: Cardoso
authors.affiliation: Department of Medical Statistics, London School of Hygiene and Tropical Medicine, Faculty of Epidemiology and Medical Health, University College London, London, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Frost
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Josephine
authors.initials: J
authors.lastname: Barnes
authors.affiliation: Translational Imaging Group, Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London, Malet Place Engineering Building, London, UK; Department of Radiology & Nuclear Medicine, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Fox
authors.affiliation: Translational Imaging Group, Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London, Malet Place Engineering Building, London, UK; Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Ourselin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D053327:Apolipoprotein E4 / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D059906:Neuroimaging; D012720:Severity of Illness Index; D066127:White Matter / Q000000981:diagnostic imaging* / Q000473:pathology*
chemical_list: D053327:Apolipoprotein E4
keywords: APOE; Alzheimer's disease; Longitudinal; White matter hyperintensities