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GENOME-WIDE POLYGENIC RISK FOR ALZHEIMER’S DISEASE IS ASSOCIATED WITH RATE OF METABOLIC DECLINE BUT NOT WITH RATE OF AMYLOID DEPOSITION

      Background

      Genome-wide polygenic scores (GPS) summarize a person’s genetic risk for a disease or trait in a single score. While there is strong evidence for an association of the GPS for Alzheimer’s disease (AD) with AD diagnosis, little is known about the effect of polygenic risk on AD biomarkers. In this work we investigated the link between the AD-GPS and brain metabolism and amyloid deposition using fluorodeoxyglucose (FDG) positron emission tomography (PET) and florbetapir (AV45) PET, respectively.

      Methods

      For computing the AD-GPS we relied on the results of the International Genomics of Alzheimer’s Project (IGAP) genome wide association study (GWAS) comprising 54,162 subjects. We computed the AD-GPS for white, non-Hispanic subjects from the AD Neuroimaging Initiative (ADNI) database, who did not contribute to the IGAP GWAS. To include single nucleotide polymorphisms (SNPs) into the score we applied different P-value cutoffs ranging from 1e-5 to 0.95. SNPs in the extended APOE locus were excluded from the GPS. We obtained longitudinal measures for FDG PET in five ROIs (posterior cingulate cortex; left and right temporal pole; left and right angular gyrus) for 831 subjects and longitudinal measures for AV45 PET in a whole brain ROI for 742 subjects from the ADNI website. Linear mixed effects models were used to model the effect of the AD-GPS on longitudinal changes in both biomarkers. Models were corrected for age, sex, baseline diagnosis (healthy control [HC]; mild cognitive impairment [MCI]; AD) and APOE4 status.

      Results

      There was no association between AD-GPS and rate of amyloid deposition (P>0.05; Figure 1), while APOE4 status was highly significant (P=6.06e-8). Decline in glucose metabolism was significantly associated with AD-GPS (minimal P=1.99e-10). The overall effect was carried by the MCI group (Figure 2; minimal P=7.38e-11) and limited in the other two diagnostic groups (HC: minimal P=0.0037; AD: minimal P=0.085). The left temporal pole ROI showed the strongest association with AD-GPS.

      Conclusions

      The AD-GPS, which excluded APOE, is strongly associated with rate of metabolic decline but not with rate of amyloid deposition. Thus, the polygenic risk may act on pathways independent of the amyloid pathology.
      Figure thumbnail fx1
      Figure 1Association strength for different genome-wide polygenic scores and both PET modalities. The x-axis depicts the number of SNPs included in the score, i.e., lower P-value cutoffs lead to more SNPs, the y-axis shows the -log10 of the P-value for the GPS in the model. Top row: glucose metabolism in five ROIs using FDG PET. Bottom row: amyloid deposition using florbetapir PET. The first column shows the results for all subjects; column two only in APOE4 carriers; column three only in APOE4 non-carriers.
      Figure thumbnail fx2
      Figure 2Association strength by diagnosis group. Same as Figure 1 but grouped by diagnosis. HC: healthy control; MCI: mild cognitive impairment; AD: Alzheimer's disease.