GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer's disease implicates microglial activation gene IL1RAP

Abstract

Brain amyloid deposition is thought to be a seminal event in Alzheimer's disease. To identify genes influencing Alzheimer's disease pathogenesis, we performed a genome-wide association study of longitudinal change in brain amyloid burden measured by (18)F-florbetapir PET. A novel association with higher rates of amyloid accumulation independent from APOE (apolipoprotein E) ε4 status was identified in IL1RAP (interleukin-1 receptor accessory protein; rs12053868-G; P = 1.38 × 10(-9)) and was validated by deep sequencing. IL1RAP rs12053868-G carriers were more likely to progress from mild cognitive impairment to Alzheimer's disease and exhibited greater longitudinal temporal cortex atrophy on MRI. In independent cohorts rs12053868-G was associated with accelerated cognitive decline and lower cortical (11)C-PBR28 PET signal, a marker of microglial activation. These results suggest a crucial role of activated microglia in limiting amyloid accumulation and nominate the IL-1/IL1RAP pathway as a potential target for modulating this process.

Keywords: Alzheimer’s disease; amyloid; genetics; interleukin-1; microglia.

In a genome-wide study, Ramanan et al. discover an association between the microglial activation gene IL1RAP and higher rates of amyloid plaque accumulation as measured by PET in prodromal Alzheimer’s disease. Activated microglia may be crucial in amyloid clearance, and targeting the interleukin-1/IL1RAP pathway may be a potential therapeutic approach.

Figure 1

Effect of the APOE locus on 2-year change in cortical amyloid PET burden. Mean annualized per cent change in global cortical ¹⁸F-florbetapir SUVR (adjusted for age and gender) ± standard errors are displayed based on (A) APOE ε4 status and (B) APOE ε2/ε3/ε4 status. (A) APOE ε4 carriers exhibited larger increases in brain amyloid PET burden compared to non-carriers (P = 9.00 × 10⁻⁶). (B) APOE ε2/ε3 participants displayed lower rates of amyloid accumulation compared to ε3/ε3 (P = 0.01), ε3/ε4 (P = 1.42 × 10⁻⁵), and ε4/ε4 (P = 1.57 × 10⁻⁴) participants.

Figure 2

Manhattan plot for the GWAS of longitudinal change in cortical amyloid PET burden. Observed −log₁₀ P-values (y-axis) are displayed for all tested SNPs on each autosomal chromosome (x-axis). A genome-wide significant association (P < 5 × 10⁻⁸; red line) with longitudinal change in global cortical amyloid burden measured by ¹⁸F-florbetapir PET was identified on chromosome 3 within IL1RAP. Suggestive associations (P < 5 × 10⁻⁶; blue line) were identified on additional chromosomes.

Figure 3

Association and effect of IL1RAP rs12053868-G on longitudinal change in cortical amyloid PET burden. (A) All SNPs within 250 kb of rs12053868 are plotted based on their GWAS −log₁₀ P-values, NCBI build 37 genomic position, and recombination rates calculated from the 1000 Genomes Project reference data. The colour scale of r² values is used to label SNPs based on their degree of linkage disequilibrium with rs12053868. Genes in the region are labelled with arrows denoting 5’-to-3’ orientation. (B) Mean annualized per cent change in global cortical ¹⁸F-florbetapir SUVR (adjusted for age and gender) ± standard errors are displayed based on rs12053868 genotype. The minor allele (G) of rs12053868 was associated with a 0.8% increase per allele copy per year in cortical amyloid PET burden. The association of rs12053868 was genome-wide significant under additive (P = 1.38 × 10⁻⁹) and dominant (P = 5.26 × 10⁻⁹) genetic models. (C) Selected cross-sectional slices (top) and surface renderings (bottom) from voxel-wise analysis of the effect of rs12053868 on longitudinal amyloid accumulation measured by ¹⁸F-florbetapir PET. The colour scale indicates regions where the rs12053868-G allele was associated with higher rates of amyloid accumulation (GG > GA > AA). All comparisons are displayed at a voxel-wise threshold of P < 0.001 (uncorrected) with minimum cluster size (k) = 175 voxels (approximately corresponding to a cluster-wise threshold of FDR-corrected P < 0.05). Where applicable, the left and right cerebral hemispheres are labelled for orientation. As displayed, the most significant clusters (identifying regions where rs12053868-G exhibited the greatest effect on rates of amyloid accumulation) were observed in the bilateral frontal lobes, medial parietal lobes, lateral parietal lobes, lateral temporal lobes, and the anterior and posterior cingulate cortex.