Elsevier

Neurobiology of Aging

Volume 32, Issue 11, November 2011, Pages 2106.e7-2106.e11
Neurobiology of Aging

Genetic reports abstract
CR1 genotype is associated with entorhinal cortex volume in young healthy adults

https://doi.org/10.1016/j.neurobiolaging.2011.05.017Get rights and content

Abstract

Gene-brain structure associations of 3 recently discovered risk genes for Alzheimer's disease, CLU (rs11136000C>T), CR1 (rs6656401G>A), and PICALM (rs3851179G>A), were investigated in 2 independent cohorts of young healthy adults (n = 430 and n = 492, respectively). We assessed structural differences in 2 core structures of Alzheimer pathology, entorhinal cortex and hippocampus, by voxel-based morphometry using high-resolution magnetic resonance imaging (MRI) data. For CLU and PICALM no significant genotype-related differences in local gray matter volume were found. CR1 risk allele (A) carriers showed smaller local gray matter volume in the entorhinal cortex, as confirmed in both cohorts. This association, apparent in young healthy adults, might mediate susceptibility for Alzheimer's disease later in life.

Introduction

Late-onset Alzheimer's disease (AD) is a genetically complex disorder (Bertram et al., 2007). APOE contributes strongly to the heritability of AD (Corder et al., 1993), but the search for other genes has been difficult because of the small individual effect sizes of presumed risk genes. Recently, 2 large genome-wide association studies (GWAS) succeeded in identifying 3 new genes associated with AD: CLU, CR1, and PICALM (Harold et al., 2009, Lambert et al., 2009). However, the mechanisms behind the increase in AD susceptibility caused by these risk genes remain to be explored.

AD is associated with structural changes in the brain starting with anterior medial temporal lobe atrophy centered in entorhinal cortex and hippocampus (Braak and Braak, 1991, Hyman et al., 1984). For APOE, associations have been found between risk genotype and entorhinal and hippocampal volume in AD patients (Geroldi et al., 1999) as well as in healthy individuals (Shaw et al., 2007, Wishart et al., 2006). To investigate whether these AD-related brain regions also mediate the effects of the CLU, CR1, and PICALM risk alleles, we studied brain structure in 2 cohorts of young healthy adults. Structural differences in anterior medial temporal lobe regions, observed as early as in young adulthood, may contribute to the increased susceptibility for AD later in life.

Section snippets

Methods

Detailed description of the methods can be found in the Supplementary methods section. This study is part of the Brain Imaging Genetics (BIG) project running at the Radboud University Nijmegen (Medical Centre). Saliva and structural magnetic resonance imaging (MRI) data were collected from 922 healthy, highly educated (bachelor student level or higher) adults of Caucasian origin between 18 and 36 years of age, with no self-reported neurological or psychiatric history (for demographics see Table

Results

The participant demographics and genotype distributions are shown in Table 1. All genotypes were in Hardy-Weinberg Equilibrium (p > 0.05). Genotyping was successful in 100%, 97.9%, 98.3%, and 98.7% of the samples for CLU, CR1, PICALM, and APOE respectively.

VBM analysis of local gray matter volume in the entorhinal cortex and the hippocampus showed significant differences between genotypes. In the discovery cohort associations between CR1 genotype and local gray matter volume were found in the

Discussion

In this study we investigated associations of 3 recently identified AD risk genes, CLU, CR1, and PICALM with AD-related brain regions in young healthy adults. Whereas for CLU and PICALM no significant associations with local brain volume were found, carriers of the AD risk allele in CR1 showed smaller local gray matter volume in the entorhinal cortex. This finding was confirmed in a second, independent cohort. Dose effect analysis showed significant results, suggesting a possible additive

Disclosure statement

The authors report no conflicts of interest.

All participants gave written informed consent and the study was approved by the local ethics committee.

Acknowledgements

The authors thank all participants who took part in the study. The authors thank R. Makkinje and S. Kooijman for their support in genotyping and recruitment of participants. This project was partly funded by a grant from the Hersenstichting Nederland.

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      The synonymous SNP rs4844600 (E60E) is located on exon 2, the IGAP SNP rs6656401 is located between exons 4 and 5, and the nonsynonymous SNP rs2296160, which causes an alanine-to-threonine amino acid substitution at codon position 2419 (A2419T), is located on exon 44. The SNP rs1408077 in CR1, which is in strong LD with the IGAP SNP rs6656401, was reported to be associated with loss of EC thickness (Biffi et al., 2010), and carriers of the IGAP SNP rs6656401_A had smaller local gray matter volume in the EC in young health adults, which may lead to or reflect increased risk of late-onset AD (Bralten et al., 2011). These results may indicate a causal relationship between CR1 SNPs and AD development.

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      Genetic differences were found for the SNP rs6656401 (related to gene CR1) and the SNP rs6733839 (related to gene BIN1). Genetic variations at CR1 have been associated with the risk of cerebral amyloid angiopathy and decreased entorhinal cortex volume (Biffi et al., 2012; Bralten et al., 2011). Increased expression of the BIN1 gene has been recently implicated with modulating tau pathology (Chapuis et al., 2013), while BIN1 has also been associated with entorhinal and temporal pole cortex thickness (Biffi et al., 2012).

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      BIN1 was also linked to smaller entorhinal cortex and temporal pole volume in a structural imaging study (34). CR1 has been shown in several studies to be associated with smaller entorhinal cortex volume in younger and older healthy adult subjects (34,37). Finally, a PET study found that there was a relationship between amyloid deposition and polymorphisms in ABCA7 and EPHA1 such that carrying the risk variant of ABCA7 increases the likelihood of amyloid positivity, whereas the low-risk polymorphism of EPHA1 decreases the likelihood of amyloid positivity (38).

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      Further, the population significance of an association is greater if it is associated not just with a greater risk of AD but with lower function in the larger sample of all older adults. Associations of the CLU, CR1, BIN1, PICALM, ABCA7, and CD2AP risk variants have been reported with an earlier age at onset (Thambisetty, An, & Tanaka, 2013, Thambisetty, Beason-Held, et al. 2013), greater burden of AD brain pathology (Biffi et al., 2012; Chibnik et al., 2011; Kok et al., 2011; Shulman et al., 2013), more abnormal levels of cerebrospinal fluid biomarkers (Elias-Sonnenschein et al., 2013; Kauwe et al., 2011; Schjeide et al., 2011; Schott & A. D. N. I. Investigators, 2012), changes in total brain volume and white matter hyperintensities on brain MRI (Biffi et al., 2010; Bralten et al., 2011; Braskie et al., 2011; Erk et al., 2011; Furney et al., 2011; Green et al., 2014; Lancaster et al., 2011; Melville et al., 2012), EEG (Ponomareva et al., 2013), and lower cognitive function (Barral et al., 2012; Chibnik et al., 2011; Engelman et al., 2013; Erk et al., 2011; Green et al., 2014; Lancaster et al., 2011; Mengel-From, Christensen, McGue, & Christiansen, 2011, Mengel-From et al., 2013; Pedraza et al., 2014; Schmidt, Wolff, Ahsen, & Zerr, 2012; Sweet et al., 2012; Thambisetty, Beason-Held, et al., 2013). A large GWAS of hippocampal volumes on over 20,000 persons identified several putative genes associated with apoptosis (HRK), transforming growth factor antagonism (LEMD3), neuronal migration (ASTN2), oxidative stress (MSRB3), brain development (WIF1), the ubiquitin pathway (FBXW8), and a gene (DPP4) encoding an enzyme, which is the target of the incretin class of antidiabetic medications such as sitagliptin (Bis et al., 2012).

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      Significant association of PICALM with MRI-derived hippocampal volume and entorhinal cortex thickness, and that of CR1 on entorhinal cortex thickness have been recently reported (Biffi et al., 2010). Another study found an association of CR1 with entorhinal cortex volume in young, healthy adults (Bralten et al., 2011). Although the association of our 3-SNP risk score with the average atrophy rate across the temporal lobe fell short of significance, our results provide a voxelwise complement to these studies, as we found spatially significant effects in temporal lobe regions that are in agreement with their findings.

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