Regular articleThe effect of increased genetic risk for Alzheimer's disease on hippocampal and amygdala volume
Introduction
The strongest identified genetic risk factor for Alzheimer's disease (AD) is the apolipoprotein E (APOE) ε4 allele (Genin et al., 2011). Large-scale GWASMA (Genome Wide Association Study Meta Analyses) have identified an additional 19 common risk loci with small effects on AD risk (Lambert et al., 2013). A low-frequency missense variant in TREM2 (p.R47H or rs75932628) substantially increases AD risk (Guerreiro et al., 2013). Whether these variants exert an effect on disease-related phenotypes (such as brain atrophy) in the early stages of AD, or before clinical onset is largely unknown.
The earliest histopathological changes in AD are typically seen within the medial temporal lobe, where neurofibrillary tangles and amyloid depositions first form. Beginning in the preclinical phase, these lesions lead to changes in regional brain volumes, in particular, the hippocampus and amygdala (Yang et al., 2012). Brain volume reduction is evident in other disorders (e.g., depression and anxiety) as well as in healthy aging, with the hippocampus being especially vulnerable (Small et al., 2011). Determining how AD risk variants affect hippocampal and amygdala volume directly, and whether this is detectable before clinical manifestations of AD, will provide clues as to how they contribute to disease risk.
An effect of APOE status has been observed on structural brain changes in the elderly. Carriers of ε4 are generally found to have smaller hippocampal and amygdala volumes than homozygous ε3 subjects, but this is not consistently observed before the onset of mild cognitive impairment (MCI) or AD (Hostage et al., 2013, Khan et al., 2014, Liu et al., 2010). Effects have also been identified in young people (O'Dwyer et al., 2012), though findings have also been inconsistent (Khan et al., 2014). In addition, sex differences have been reported, with greater deleterious effect of APOE ε4 on hippocampal pathology in females (Fleisher et al., 2005).
Other common AD genetic risk factors identified though GWAS studies have been investigated in relation to hippocampal and amygdala volume, through the use of polygenic risk scores (PRSs). A PRS allows the identification of phenotypic associations that would not be detectable using single variants with low effect size, as well as allowing a reduction in the number of statistical tests (Wray et al., 2014). A PRS containing the first AD GWAS findings (3 genome-wide associated variants) was found to be associated with clinical diagnosis and reduced hippocampal and amygdala volume in the AD case and/or control cohort Alzheimer's Disease Neuroimaging Initiative (ADNI; Biffi et al., 2010). A proxy for the rare TREM2 risk variant (rs9394721) was also associated with smaller hippocampal volume and increased rate of temporal lobe atrophy in the ADNI cohort (Rajagopalan et al., 2013).
A recent study assessed the effect of 20 AD risk variants combined in a PRS with various magnetic resonance imaging (MRI) markers of brain aging (intracranial volume, total brain volume, hippocampal volume, white matter hyperintensities, and brain infarcts) in nondemented older community persons (Chauhan et al., 2015). The PRS was applied to meta-analysis summary estimates from 10 population-based studies (total N = 11,500). An association was observed with smaller hippocampal volume only, which remained significant after excluding APOE. Here, we extend on this previous work by investigating the effect of AD genetic risk variants on hippocampal volume, and also investigate amygdala volume in our large sample (N > 2000). By accessing the raw genotyping data, as opposed to meta-analysis summary estimates, we are able to test for an effect in distinct diagnostic groups, including AD, MCI, and healthy elderly to examine at which clinical stage effects can be seen. We also tested for any early effects of AD risk factors on hippocampal and amygdala volume in healthy young adults before substantial age-related atrophy. Age and sex interaction effects were also investigated. We used the most recent GWAS findings identified by the International Genomics of Alzheimer's Project (IGAP) GWASMA which included 74,046 individuals (Lambert et al., 2013) to select the 19 genome-wide significant AD risk variants to include in the PRS. We also examine the effect of several additional PRS adding increasing numbers of single nucleotide polymorphisms (SNPs) at different p value thresholds of association. Inclusion of SNPs that do not pass the threshold for genome-wide significance, but include a proportion of truly associated variants will give increased power to detect an association up to an optimal p value cutoff (Wray et al., 2014).
Section snippets
Participants
Five cohorts, including two case-control and 3 population based, were used (Table 1). ADNI (Mueller et al., 2005; Alzheimer's Disease Neuroimaging Initiative, www.adni-info.org) and AddNeuroMed (Westman et al., 2011, Innovative Medicines (InnoMed) in Europe) are comprised of AD cases, MCI, and aged-matched controls (Table 1). All AD cases met criteria for either probable or definite AD with inclusion criteria as previously described (Simmons et al., 2011 and www.adni-info.org). MCI was assessed
AD risk
The AD PRS was associated with AD risk in the AddNeuroMed cohort. The most significantly associated threshold was p < 1 × 10−3 (OR = 1.51; p = 0.011), though this had no more discriminative accuracy than a model with only age and sex covariates. However, APOE ε4 genotype was highly associated with AD risk (OR = 2.41 p = 1.64 × 10−5) with significant improvement in discriminative accuracy over the covariates. In contrast, TREM2 rs9394721 was not associated with AD risk in this small sample (
Discussion
Chauhan et al. (2015) recently showed that an AD PRS constructed from 20 AD risk loci associated with reduced hippocampal volume in a large population-based meta-analysis. Here, we confirm these findings using raw genotype level data using a smaller sample size, but including a larger number of variants in the PRS identified in the largest GWASMA available [IGAP discovery sample: 17,008 cases, 37,154 controls (Lambert et al., 2013)]. We also investigate a variant in TREM2. Through
Disclosure statement
The authors have no conflicts of interest to disclose.
Acknowledgements
The authors would like to acknowledge and thank the Sydney MAS and OATS participants, their supporters, and their research teams. Sydney MAS is supported by the Program Grants 350833 and 568969 from the Australian National Health and Medical Research Council (NHMRC). The NHMRC/Australian Research Council Strategic Award 401162 and NHMRC Project Grant 1045325 support OATS, which was facilitated through access to the Australian Twin Registry (ATR). The ATR is supported by the NHMRC Enabling Grant
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- 1
Data used in preparing this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but (those not listed as authors) did not participate in analysis or writing of this report. A complete listing of ADNI investigators may be found at http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.