Anatomically-distinct genetic associations of APOE ɛ4 allele load with regional cortical atrophy in Alzheimer's disease
Introduction
The APOE ɛ4 allele (APOE4) is the strongest genetic risk factor for sporadic early (Okuizumi et al., 1994) and late onset (Corder et al., 1993) Alzheimer's disease (AD) and also is associated with a higher risk of developing age-related cognitive impairment among the healthy elderly (Small et al., 2000, Deary et al., 2002).
Brain imaging studies allow brain or brain tissue volumes to be used as quantitative traits in genetic association studies (Hariri and Weinberger, 2003). To date, most studies on APOE4 have focused on testing for effects on medial temporal lobe (MTL) structures using a region-of-interest (ROI) approach. These have confirmed that MTL structures are vulnerable to effects related to increasing APOE4 load (Lehtovirta et al., 1995, Lehtovirta et al., 1996, Tanaka et al., 1998, Geroldi et al., 1999, Hashimoto et al., 2001), just as increasing APOE ɛ4 allele load is associated with earlier age of onset (Corder et al., 1993). However, disease progression of patients with 2 alleles is not faster than in patients with only 1 allele (Hoyt et al., 2005). This suggests that there may be a regionally variable relation between allele load and brain neuropathology.
Here we have used voxel-based-morphometry (VBM) as a voxel-wise test for associations between APOE4 single nucleotide polymorphism (SNP) variation and regional grey matter volume (GMV). Using a large mild AD population, we tested both additive and genotypic APOE4 load models. Our primary hypothesis was that we could define regional anatomical patterns for more than a single type of association, supporting the hypothesis that APOE4 may influence disease susceptibility and disease progression in different ways.
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Patients
This study was carried out with the approval of the local ethical committees. 100 patients with a diagnosis of AD according to the NINCDS-ADRDA criteria were recruited in an imaging sub-study in the larger genetic association study cohort described previously (Li et al., 2007). After independent quality control (blinded with respect genotype) for imaging datasets and for genotyping (blinded with respect to imaging data), satisfactory data was available on 83 (15 ɛ4/ɛ4, 39 ɛ4/− and 29−/−) AD
Results
An APOE4 additive model showed GMV reduction in MTL structures bilaterally, including the amygdala, the hippocampus, the parahippocampal gyrus and the temporal fusiform cortex, as well as in the orbitofrontal cortex (Fig. 1). The T maximum for the cluster in the left hemisphere was located in the temporal fusiform cortex [p-FWE = 0.001, corrected; z score = 4.35; cluster of 1614 voxels; peak coordinates (x,y,z): − 42, − 14, − 24], while the T maximum for the cluster in the right hemisphere was located
Discussion
The study population described here allowed full, formal testing of an additive model for APOE4 effects on relative brain atrophy for the first time to our knowledge. The observation that MTL and orbitofrontal GMV are correlated with APOE4 allele load confirms and extends an earlier, small VBM study (Boccardi et al., 2004). Both reports are consistent with ROI studies showing smaller amygdala, hippocampal and entorhinal cortex volumes (Lehtovirta et al., 1995, Lehtovirta et al., 1996, Tanaka et
Acknowledgments
I (Paul M Matthews) declare to have had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. We are grateful to Michael C. Irizarry MD, M.P.H. (GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina, 27709, USA), Natalie Coletta MBiotech (GlaxoSmithKline Inc., Mississauga, ON, Canada), Allen D. Roses MD (GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina, 27709, USA),
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