Background: Genome-wide association studies (GWAS) have identified many risk genes for Alzheimer's disease (AD). The precise mechanism through which many of these genes exert their effect on AD remains unknown.
      Methods: We downloaded the top 10 AD gene single nucleotide polymorphism, baseline clinical and MR volumetric data (hippocampal, ventricular, fusiform and entorhinal volumes) of 33 ADNI-2/GO cognitively normal and 126 mild cognitive impairment subjects. The corresponding AV45 images were downloaded and processed with the FDA-approved AmyQ software. For each individual AmyQ derived the mean SUVR in 46 ROIs across the brain with whole cerebellum as a reference. We employed ANOVA with Bonferroni correction for multiple comparisons to investigate the effect of minor allele dosage on cognitive and functional performance, neurodegeneration and brain amyloidosis.
      Results: CR1 rs6691117 and BIN1 rs749008 had significant effects on multiple measures. The minor allele of CR1 rs6691117 showed significant association with functional decline at 6, 12 and 24 months as measured with the Functional Activity Questionnaire (FAQ). The minor allele of CR1 rs6691117 also associated with lower entorhinal and fusiform volumes as well as with greater brain amyloidosis in the lateral temporal, parietal and occipital association cortices at baseline. The minor allele of BIN1 showed a negative association with ventricular size and amyloid load in the frontal association, sensorimotor, posterior cingulate, medial temporal cortices, the pons, the midbrain and the lentiform nuclei.
      Conclusions: Both CR1 rs6691117 and BIN1 rs749008 demonstrate significant associations with brain amyloidosis and neurodegeneration providing further support for the relevance of these two genes to AD pathophysiology. The minor allele of CR1 rs6691117 appears to have a disease-promoting effect while the minor allele of BIN1 rs749008 seems to convey a disease-protective effect. The associations differed significantly in terms of localization in the brain.