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Genome-wide association studies (GWAS) have identified over 20 Alzheimer’s disease (AD) risk genes. The mechanism through which these genes exert their effect remains unknown. Here we report a comprehensive analysis of the effects of the top 20 genes on brain atrophy.
Our sample consisted of 305 cognitively normal (CN), 474 mild cognitive impairment (MCI) and 150 AD subjects from the Alzheimer’s disease Neuroimaging Initiative (ADNI-GO/2) cohort. 795 subjects received 3T and the remainder 1.5T MRI. We focused on the variants of the top 20 AD genes discovered and validated in large GWAS studies. When linkage disequilibrium (LD) was present one variant from each LD block was chosen by yielding a total of 27 variants. We ran multivariate stepwise linear regression models with hippocampal volume, entorhinal, medial temporal and lateral parietal thickness obtained with Freesurfer v5.1 as outcome variables and all 27 variants as predictors while controlling for age, gender, APOE4 status and magnetic field strength in the pooled sample. Variants retained in the regression models, age, gender, APOE4 and magnetic field strength were included as predictors in 3D voxel-wise multiple linear regression models in SPM8 with a cluster threshold of 50 voxels.
Results are shown in the Figure. ABCA7 rs3752246 and rs3764650, CASS4 rs7274581 and CD33 rs3865444 showed strong associations with brain atrophy across most disease stages (results shown are for the pooled sample). SLC24A4/RIN3 rs10498633 and SORL1 rs112118343 showed associations with neurodegeneration in the NC stage only, while PICALM rs3851179 demonstrated effects in both the NC (see Figure) and to some extent also the MCI stage (not shown). NME8 rs2718058 showed an association with neurodegeneration restricted to the MCI stage, while CR1 rs3818361, MEF2C rs190982, PTK2B rs28834970 and SORL1 rs1131497 showed associations in the dementia stage only.
While ABCA7, CASS4, CD33, CR1, MEF2C, NME8, PICALM, PTK2B SLC24A4/RIN3 and SORL1 all show significant independent associations with brain atrophy, these associations are often confined to specific disease stage. Time- and stage-constrained genetic influences on AD pathology might be one of the reasons for the missing heritability in AD and need to be subject of further exploration.