Detectan alteraciones cerebrales en personas sanas con riesgo de sufrir enfermedad de Alzheimer

Effects of APOE-ε4 allele load on brain morphology in a cohort of middle-aged healthy individuals with enriched genetic risk for Alzheimer's disease

Abstract

Introduction

Apolipoprotein E (APOE)-ε4 is the major genetic risk factor for Alzheimer's disease. However, the dose-dependent impact of this allele on brain morphology of healthy individuals remains unclear.

Methods

We analyzed gray matter volumes (GMvs) in a sample of 533 healthy middle-aged individuals with a substantial representation of ε4-carriers (207 heterozygotes and 65 homozygotes).

Results

We found APOE-ε4 additive GMv reductions in the right hippocampus, caudate, precentral gyrus, and cerebellar crus. In these regions, the APOE genotype interacted with age, with homozygotes displaying lower GMv after the fifth decade of life. APOE-ε4 was also associated to greater GMv in the right thalamus, left occipital gyrus, and right frontal cortex.

Discussion

Our data indicate that APOE-ε4 exerts additive effects on GMv in regions relevant for Alzheimer's disease pathophysiology already in healthy individuals. These findings elucidate the mechanisms underlying the increased Alzheimer's disease risk in ε4-carriers, suggesting a dose-dependent disease vulnerability on the brain structure level.

Keywords

Alzheimer's disease

APOE-ε4

Healthy individuals

Voxel-based morphometry

Gray matter volumes

Aging

Background

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder characterized by progressive cognitive impairment and a characteristic pattern of regional brain atrophy that starts in the hippocampus and medial temporal regions and then spreads to other cortical areas [1]. The two major neuropathologic features of AD are extracellular fibrillary amyloid β (Aβ) plaques and intracellular neurofibrillary tau tangles. AD pathology develops slowly with a protracted preclinical phase characterized by abnormal cerebral Aβ deposition in cognitively intact individuals [2]. The apolipoprotein E (APOE)-ε4 represents the major genetic risk factor for late-onset AD, with increasing copies of the ε4 allele being associated to greater AD risk and younger age of disease onset [3,4]. Three common polymorphic alleles referred as ε2, ε3, and ε4 code, respectively, three distinct apoeE isoforms, which differ among each other by a single amino acid, and depending on the allele pairs, they result in six possible diploid haplotypes. In the brain, apoE mediates neuronal delivery of cholesterol, which is an essential component for axonal growth, synaptic formation, and remodeling, and has an important role in Aβ metabolism. The apoE4 isoform (coded by the APOE-ε4 allele) has been shown to be less efficient in Aβ clearance and cholesterol transport than the other isoforms (apoE2 > apoE3 > apoE4) [4]. APOE-ε4-homozygous (HO) individuals are therefore an interesting population for studying the long-term effects of the lack of expression of the more efficient apoE isoform. Regarding the pathogenesis of AD, the mechanisms through which APOE-ε4 increases risk can be regarded as conferring a loss of neuroprotective function, gain of neurotoxic function, or both [4]. APOE-ε4 allele dose effects on memory decline have been reported in cognitively healthy individuals [5], and a dose-dependent hippocampal gray matter (GM) degeneration has been observed in AD patients [6,7]. However, only a few reports have assessed the impact of APOE-ε4 homozygosity on the brain morphology of healthy middle-aged subjects. One cross-sectional studyfound significantly reduced hippocampal volume in healthy APOE-ε4 homozygotes, as compared to ε4-heterozygotes and noncarriers (NC), without however reporting any ε4 dose-dependent effects [8]. In the follow-up of this study, an age-related hippocampal volume loss was found only in homozygotes, again not supporting for APOE-ε4 additive effects in this region [9]. On the other hand, Chen et al. [10]reported a significant correlation between APOE-ε4 gene dose and higher annualized rates of whole-brain atrophy in healthy individuals.

Aside from these reports, most of the studies in the literature pooled together APOE-ε4 homozygotes and heterozygotes into a single APOE-ε4 carrier category. Although longitudinal studies reported significantly faster decays of regional gray matter volume (GMv) in healthy carriers compared to NC [11,12], most cross-sectional studies which determined volumes in a priori–defined AD-sensitive cerebral regions did not find significant group differences [13–15]. Similarly, null findings were reported in studies using voxelwise techniques, such as voxel-based morphometry (VBM) [16–18]. By contrast, two studies using VBM reported GMv differences in brain regions including the hippocampus, lingual gyrus, and precuneus, when comparing carriers to NC [19,20]. More recently, Ten Kate et al. [21] reported decreased volume in the precuneus and insula in healthy middle-aged carriers of the risk allele as well as an interaction between APOE status and age in determining GMv in temporal and occipital regions. Discrepancies among studies might be in part due to the volumetric technique adopted and the difference in the samples' age, where studies including relatively older individuals tend to report significant differences compared to those including younger samples.

In the present study, we sought to determine the effects of APOE-ε4 allele load on brain morphology to better characterize the mechanisms through which APOE-ε4 confers an increased risk to develop AD in the healthy population. To this end, we used VBM in a cohort of healthy middle-aged individuals enriched for this genetic risk for AD (261 NC, 207 APOE-ε4 heterozygotes, and 65 APOE-ε4 homozygotes). We also sought to determine potential interactions between APOE status and age in determining GMv variability.