Association between APOE e4 and white matter hyperintensity volume, but not total brain volume or white matter integrity

Donald M Lyall,Naveed Sattar,Ian J Deary,Jill P Pell,Jonathan Cavanagh,Simon R Cox,Rona J Strawbridge,Carlos Celis-Morales,Joey Ward,Andrew M Mcintosh,Daniel F Mackay,Daniel J Smith,Laura M Lyall,Breda Cullen

doi:10.1007/s11682-019-00069-9

Abstract

Apolipoprotein (APOE) e4 genotype is an accepted risk factor for accelerated cognitive aging and dementia, though its neurostructural substrates are unclear. The deleterious effects of this genotype on brain structure may increase in magnitude into older age. This study aimed to investigate in UK Biobank the association between APOE e4 allele presence vs. absence and brain imaging variables that have been associated with worse cognitive abilities; and whether this association varies by cross-sectional age. We used brain magnetic resonance imaging (MRI) and genetic data from a general-population cohort: the UK Biobank (N = 8395 after exclusions). We adjusted for the covariates of age in years, sex, Townsend social deprivation scores, smoking history and cardiometabolic diseases. There was a statistically significant association between APOE e4 genotype and increased (i.e. worse) white matter (WM) hyperintensity volumes (standardised beta = 0.088, 95% confidence intervals = 0.036 to 0.139, P = 0.001), a marker of poorer cerebrovascular health. There were no associations with left or right hippocampal, total grey matter (GM) or WM volumes, or WM tract integrity indexed by fractional anisotropy (FA) and mean diffusivity (MD). There were no statistically significant interactions with age. Future research in UK Biobank utilising intermediate phenotypes and longitudinal imaging hold significant promise for this area, particularly pertaining to APOE e4’s potential link with cerebrovascular contributions to cognitive aging.

Highlights

Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Variation at the APOE genetic locus is an established risk factor for Alzheimer’s disease (AD) (Lutz et al 2010), and cognitive decline in domains of memory, information processing speed and overall cognitive function (‘g’) (Wisdom et al 2011)
There were no associations between APOE e4 and general factors of FA (gFA), gMD (Table 2), left/right hippocampal volumes, total grey matter (GM) or total white matter (WM) both normalised for skull size: indicating no meanlevel difference in these brain parameters across the sample
There was a significant association between APOE e4 possession and greater WM hyperintensity volume

Summary

Introduction

Variation at the APOE genetic locus is an established risk factor for Alzheimer’s disease (AD) (Lutz et al 2010), and cognitive decline in domains of memory, information processing speed and overall cognitive function (‘g’) (Wisdom et al 2011). The APOE locus’s main function relates to lipid/ cholesterol metabolism, which is pleiotropic for several biological functions including neuronal migration, axon guidance, and the clearance of amyloid beta plaques – which characterise AD - in the brain (Holtzman et al 2012). There is evidence that the effects of APOE e4 variation on brain functioning increase across the lifespan, i.e. differences between e4 carriers vs non-carriers in terms of cognitive ability become more pronounced with older age regardless of outright dementia (Schiepers et al 2011).

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