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- W2897338060 abstract "In recent years, genome-wide association studies (GWAS) have identified several genetic variants associated with increased risk for Alzheimer's disease (AD); however, little is known about how and if these risk variants modulate the severity of AD pathology. To address this question, we first aimed to test the association of known AD genetic risk variants with AD disease burden and severity of comorbid pathologies in a cohort of autopsy confirmed AD cases, and second to perform a GWAS analysis on our pathology endophenotypes. An autopsy cohort of 207 cases with moderate to severe AD pathology from the University of Pittsburgh ADRC was included. Quantitative immunohistochemical analyses using whole slide scanning and digital area fraction measurements were performed in the dorsolateral prefrontal cortex for beta-amyloid and p-Tau burden, microglial density using Iba1 and microglial activation using HLA-DR antibodies. Cerebral amyloid angiopathy was rated as none, mild, moderate or severe. For alpha-synuclein and pTDP-43 pathologies, staging systems were used based on extent and distribution of pathologic inclusions in standardized sections. Genotype information was obtained using Illumina Omni1-quad SNP arrays. All pre-defined AD risk genes showed nominally significant associations with at least one but often several of the pathology endophenotypes, with several of the associations remaining significant after correction for multiple comparisons. HLA-DR area fraction was strongly associated with multiple SNPs in the HLA-DRB1 gene region at genome-wide significance level (p=1.86E-14), with minor allele homozygotes showing the highest protein expression. GWAS analysis for pathology endophenotypes revealed a genome-wide significant signal in SCYL3 for severity of TDP-43 pathology (p=3.61E-08). For all pathology endophenotypes, several additional candidate markers at suggestive significance levels of p<1E-05 were identified. Amyloid and tau burden and comorbid pathologies are variably associated with AD risk genotypes, with many AD risk genes affecting multiple pathologies, suggesting that these genes not only increase AD risk but also modulate disease burden. The findings from this study increase our understanding of how AD risk genes affect AD pathogenesis." @default.
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- W2897338060 date "2018-07-01" @default.
- W2897338060 modified "2023-10-16" @default.
- W2897338060 title "P4‐239: ASSOCIATION OF ALZHEIMER'S DISEASE GENETIC RISK VARIANTS WITH PATHOLOGY ENDOPHENOTYPES" @default.
- W2897338060 doi "https://doi.org/10.1016/j.jalz.2018.07.060" @default.
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