Interaction of APOE e4 and poor glycemic control predicts white matter hyperintensity growth from 73 to 76

Simon R Cox,Stuart J Ritchie,David Alexander Dickie,Alison Pattie,Natalie A Royle,Janie Corley,Benjamin S Aribisala,Sarah E Harris,Maria Valdés Hernández,Alan J Gow,Susana Muñoz Maniega,John M Starr,Mark E Bastin,Joanna M Wardlaw,Ian J Deary

doi:10.1016/j.neurobiolaging.2017.02.014

Abstract

We examined whether apolipoprotein E (APOE) status interacts with vascular risk factors (VRFs) to predict the progression of white matter hyperintensities (WMHs) on brain MRI scans over a specific period of life in older age when the risk of dementia increases. At age 73 years, baseline VRFs were assessed via self-reported history of diabetes, hypertension, smoking, and hypercholesterolemia, and via objective measures of blood HbA1c, body mass index, diastolic and systolic blood pressure, and blood high-density lipoprotein to total cholesterol (HDL) ratio. APOE e4 allele was coded as either present or absent. WMH progression was measured on MRI over 3 years in 434 older adults, in a same-year-of-birth cohort. APOE e4 carriers with either a self-reported diagnosis of diabetes (β = 0.160, p = 0.002) or higher glycated hemoglobin levels (β = 0.114, p = 0.014) exhibited greater WMH progression, and the former survived correction for multiple testing. All other APOE-VRF interactions were nonsignificant (βinteraction < 0.056, p > 0.228). The results suggest that carrying the APOE “risk” e4 allele increases the risk of greater age-related WMH progression over the early part of the eighth decade of life, when combined with poorer glycemic control. The interaction effect was robust to co-occurring VRFs, suggesting a possible target for mitigating brain and cognitive aging at this age.

Highlights

The present study tested whether apolipoprotein E (APOE) status interacted with important vascular risk factors (VRFs) in contributing to white matter hyperintensities (WMHs) volume change from age 73e76 years in a large group of community-dwelling older adults with a narrow age range
Our novel results suggest that WMH growth was greater in those with diabetes and a higher HbA1c, but only in those who possessed an APOE e4 allele, though only the former interaction survived false discovery rate (FDR) correction
Rather than being an index of the degree to which APOE status relates to accumulated WMH burden up to a specific point of assessment, the current data suggest that carrying the e4 allele continues to influence the degree of WMH progression at this specific age

Summary

Introduction

Brain white matter hyperintensities (WMHs) are a prevalent MRI feature of healthy and pathologic states in older age and are associated with important life outcomes (Debette and Markus, 2010; Kloppenborg et al, 2014; Lee et al, 2016; Longstreth et al, 1996) and vascular risk factors (VRFs) such as hypertension, diabetes, smoking, obesity, and hypercholesterolemia (de Leeuw et al, 2004; Dufouil et al, 2001; Prins and Scheltens, 2015; Wang et al., GeorgeSquare, 2015; Wardlaw et al, 2014). Brain white matter hyperintensities (WMHs) are a prevalent MRI feature of healthy and pathologic states in older age and are associated with important life outcomes (Debette and Markus, 2010; Kloppenborg et al, 2014; Lee et al, 2016; Longstreth et al, 1996) and vascular risk factors (VRFs) such as hypertension, diabetes, smoking, obesity, and hypercholesterolemia Alongside evidence of VRF-WMH associations, WMH heritability is estimated at 55%e80% (Atwood et al, 2004; Carmelli et al, 1998; Turner et al, 2004). Possession of the e4 “risk” allele is associated with more WMHs

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Conclusion