White matter microstructure is altered in cognitively normal middle-aged APOE-\u03b54 homozygotes

For The Alfa Study ,Grégory Operto,José Luis Molinuevo,Nuria Bargalló,Sebastián Morán,Manel Esteller,Rubén Ramos,Pablo Ródenas,Raffaele Cacciaglia,Oriol Grau-Rivera,Carles Falcon,Juan Domingo Gispert,Anna Brugulat-Serrat

doi:10.1186/s13195-018-0375-x

Abstract

BackgroundThe ε4 allele of the apolipoprotein E gene (APOE-ε4) is the strongest genetic factor for late-onset Alzheimer’s disease. During middle age, cognitively healthy APOE-ε4 carriers already show several brain alterations that resemble those of Alzheimer's disease (AD), but to a subtler degree. These include microstructural white matter (WM) changes that have been proposed as one of the earliest structural events in the AD cascade. However, previous studies have focused mainly on comparison of APOE-ε4 carriers vs noncarriers. Therefore, the extent and magnitude of the brain alterations in healthy ε4 homozygotes, who are the individuals at highest risk, remain to be characterized in detail.MethodsWe examined mean, axial, and radial water diffusivity (MD, AxD, and RD, respectively) and fractional anisotropy in the WM as measured by diffusion-weighted imaging in 532 cognitively healthy middle-aged participants from the ALFA study (ALzheimer and FAmilies) cohort, a single-site population-based study enriched for AD risk (68 APOE-ε4 homozygotes, 207 heterozygotes, and 257 noncarriers). We examined the impact of age and APOE genotype on these parameters using tract-based spatial statistics.ResultsHealthy APOE-ε4 homozygotes display increased WM diffusivity in regions known to be affected by AD. The effects in AxD were much smaller than in RD, suggesting a disruption of the myelin sheath rather than pure axonal damage.ConclusionsThese findings could be interpreted as the result of the reduced capacity of the ε4 isoform of the APOE protein to keep cholesterol homeostasis in the brain. Because cerebral lipid metabolism is strongly related to the pathogenesis of AD, our results shed light on the possible mechanisms through which the APOE-ε4 genotype is associated with an increased risk of AD.

Highlights

The ε4 allele of the apolipoprotein E gene (APOE-ε4) is the strongest genetic factor for late-onset Alzheimer’s disease
Water molecules are locally influenced by existing axon fibers [6], and their movements properties can be described by a set of measures generally including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AxD), and radial diffusivity (RD)
Effect of Apolipoprotein E gene (APOE) genotype We found significant main effects of APOE-ε4 on MD, RD, and AxD, whereas no significant effect of the risk variant on FA was detected

Summary

Introduction

The ε4 allele of the apolipoprotein E gene (APOE-ε4) is the strongest genetic factor for late-onset Alzheimer’s disease. Cognitively healthy APOE-ε4 carriers already show several brain alterations that resemble those of Alzheimer's disease (AD), but to a subtler degree These include microstructural white matter (WM) changes that have been proposed as one of the earliest structural events in the AD cascade. Water molecules are locally influenced by existing axon fibers [6], and their movements properties can be described by a set of measures generally including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AxD), and radial diffusivity (RD) Variations in these parameters can capture microstructural changes such as axonal loss, inflammation, Wallerian degeneration [7], demyelination, or fiber damage [8], and their alteration is likely to hinder transfer of information across networks, eventually leading to cognitive impairment [9,10,11,12,13]

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