APOE ε4 is associated with disproportionate progressive hippocampal atrophy in AD.

Emily N Manning,Josephine Barnes,Sebastien Ourselin,David M Cash,Nick C Fox,Kelvin K Leung,Jonathan W Bartlett,Christopher Mark Norris

doi:10.1371/journal.pone.0097608

Abstract

ObjectivesTo investigate whether APOE ε4 carriers have higher hippocampal atrophy rates than non-carriers in Alzheimer's disease (AD), mild cognitive impairment (MCI) and controls, and if so, whether higher hippocampal atrophy rates are still observed after adjusting for concurrent whole-brain atrophy rates.MethodsMRI scans from all available visits in ADNI (148 AD, 307 MCI, 167 controls) were used. MCI subjects were divided into “progressors” (MCI-P) if diagnosed with AD within 36 months or “stable” (MCI-S) if a diagnosis of MCI was maintained. A joint multi-level mixed-effect linear regression model was used to analyse the effect of ε4 carrier-status on hippocampal and whole-brain atrophy rates, adjusting for age, gender, MMSE and brain-to-intracranial volume ratio. The difference in hippocampal rates between ε4 carriers and non-carriers after adjustment for concurrent whole-brain atrophy rate was then calculated.ResultsMean adjusted hippocampal atrophy rates in ε4 carriers were significantly higher in AD, MCI-P and MCI-S (p≤0.011, all tests) compared with ε4 non-carriers. After adjustment for whole-brain atrophy rate, the difference in mean adjusted hippocampal atrophy rate between ε4 carriers and non-carriers was reduced but remained statistically significant in AD and MCI-P.ConclusionsThese results suggest that the APOE ε4 allele drives atrophy to the medial-temporal lobe region in AD.

Highlights

Hippocampal atrophy rate has been proposed as an imaging biomarker for Alzheimer’s disease (AD) progression [1,2]
As previously shown [31], the AD subjects had smaller mean hippocampal volumes at baseline than mild cognitive impairment (MCI) subjects whose hippocampi were in turn smaller than control subjects (Table 1); the mean hippocampal volume for the AD subjects was,20% smaller than the controls with the MCI subjects were divided into ‘‘progressors’’ (MCI-P) and MCI-S subjects having intermediate volumes
There was no evidence of a difference in mean adjusted baseline hippocampal volume between e4 carriers and non-carriers in MCI-P, MCI-S or controls

Summary

Introduction

Hippocampal atrophy rate has been proposed as an imaging biomarker for Alzheimer’s disease (AD) progression [1,2]. It is essential to understand how factors might affect hippocampal atrophy rates if this biomarker is to be used most effectively in clinical trials. The most important genetic risk factor for sporadic AD is the e4 variant of the APOE gene [3]. Some studies reported elevated hippocampal atrophy rates in e4+ in AD, mild cognitive impairment (MCI) and control groups, it is possible that the greater hippocampal rates observed could have been attributed to higher concurrent whole-brain atrophy rates and faster disease progression

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Discussion

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