Browsing by Author "Peterson, Ronald C."

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    APOE effect on Alzheimer's disease biomarkers in older adults with significant memory concern
    (Elsevier, 2015-12) Risacher, Shannon L.; Kim, Sungeun; Nho, Kwangsik; Foroud, Tatiana; Shen, Li; Peterson, Ronald C.; Jack Jr, Clifford R.; Beckett, Laurel A.; Aisen, Paul S.; Koeppe, Robert A.; Jagust, William J.; Shaw, Leslie M.; Trojanowski, John Q.; Department of Radiology and Imaging Sciences, IU School of Medicine
    INTRODUCTION: This study assessed apolipoprotein E (APOE) ε4 carrier status effects on Alzheimer's disease imaging and cerebrospinal fluid (CSF) biomarkers in cognitively normal older adults with significant memory concerns (SMC). METHODS: Cognitively normal, SMC, and early mild cognitive impairment participants from Alzheimer's Disease Neuroimaging Initiative were divided by APOE ε4 carrier status. Diagnostic and APOE effects were evaluated with emphasis on SMC. Additional analyses in SMC evaluated the effect of the interaction between APOE and [(18)F]Florbetapir amyloid positivity on CSF biomarkers. RESULTS: SMC ε4+ showed greater amyloid deposition than SMC ε4-, but no hypometabolism or medial temporal lobe (MTL) atrophy. SMC ε4+ showed lower amyloid beta 1-42 and higher tau/p-tau than ε4-, which was most abnormal in APOE ε4+ and cerebral amyloid positive SMC. DISCUSSION: SMC APOE ε4+ show abnormal changes in amyloid and tau biomarkers, but no hypometabolism or MTL neurodegeneration, reflecting the at-risk nature of the SMC group and the importance of APOE in mediating this risk.
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    Integration of bioinformatics and imaging informatics for identifying rare PSEN1 variants in Alzheimer's disease
    (BioMed Central, 2016-08-12) Nho, Kwangsik; Horgusluoglu, Emrin; Kim, Sungeun; Risacher, Shannon L.; Kim, Dokyoon; Foroud, Tatiana; Aisen, Paul S.; Peterson, Ronald C.; Jack Jr., Clifford R.; Shaw, Leslie M.; Trojanowski, John Q.; Weiner, Michael W.; Green, Robert C.; Toga, Arthur W.; Saykin, Andrew J.; Department of Radiology and Imaging Sciences, IU School of Medicine
    BACKGROUND: Pathogenic mutations in PSEN1 are known to cause familial early-onset Alzheimer's disease (EOAD) but common variants in PSEN1 have not been found to strongly influence late-onset AD (LOAD). The association of rare variants in PSEN1 with LOAD-related endophenotypes has received little attention. In this study, we performed a rare variant association analysis of PSEN1 with quantitative biomarkers of LOAD using whole genome sequencing (WGS) by integrating bioinformatics and imaging informatics. METHODS: A WGS data set (N = 815) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort was used in this analysis. 757 non-Hispanic Caucasian participants underwent WGS from a blood sample and high resolution T1-weighted structural MRI at baseline. An automated MRI analysis technique (FreeSurfer) was used to measure cortical thickness and volume of neuroanatomical structures. We assessed imaging and cerebrospinal fluid (CSF) biomarkers as LOAD-related quantitative endophenotypes. Single variant analyses were performed using PLINK and gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). RESULTS: A total of 839 rare variants (MAF < 1/√(2 N) = 0.0257) were found within a region of ±10 kb from PSEN1. Among them, six exonic (three non-synonymous) variants were observed. A single variant association analysis showed that the PSEN1 p. E318G variant increases the risk of LOAD only in participants carrying APOE ε4 allele where individuals carrying the minor allele of this PSEN1 risk variant have lower CSF Aβ1-42 and higher CSF tau. A gene-based analysis resulted in a significant association of rare but not common (MAF ≥ 0.0257) PSEN1 variants with bilateral entorhinal cortical thickness. CONCLUSIONS: This is the first study to show that PSEN1 rare variants collectively show a significant association with the brain atrophy in regions preferentially affected by LOAD, providing further support for a role of PSEN1 in LOAD. The PSEN1 p. E318G variant increases the risk of LOAD only in APOE ε4 carriers. Integrating bioinformatics with imaging informatics for identification of rare variants could help explain the missing heritability in LOAD.
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    Targeted neurogenesis pathway-based gene analysis identifies ADORA2A associated with hippocampal volume in mild cognitive impairment and Alzheimer's disease
    (Elsevier, 2017-12) Horgusluoglu-Moloch, Emrin; Nho, Kwangsik; Risacher, Shannon L.; Kim, Sungeun; Foroud, Tatiana; Shaw, Leslie M.; Trojanowski, John Q.; Aisen, Paul S.; Peterson, Ronald C.; Jack, Clifford R., Jr.; Lovestone, Simon; Simmons, Andrew; Weiner, Michael W.; Saykin, Andrew J.; Medical and Molecular Genetics, School of Medicine
    Alzheimer's disease (AD) patients display hippocampal atrophy, memory impairment, and cognitive decline. New neurons are generated throughout adulthood in 2 regions of the brain implicated in AD, the dentate gyrus of the hippocampus and the subventricular zone of the olfactory bulb. Disruption of this process contributes to neurodegenerative diseases including AD, and many of the molecular players in AD are also modulators of adult neurogenesis. However, the genetic mechanisms underlying adult neurogenesis in AD have been underexplored. To address this gap, we performed a gene-based association analysis in cognitively normal and impaired participants using neurogenesis pathway-related candidate genes curated from existing databases, literature mining, and large-scale genome-wide association study findings. A gene-based association analysis identified adenosine A2a receptor (ADORA2A) as significantly associated with hippocampal volume and the association between rs9608282 within ADORA2A and hippocampal volume was replicated in the meta-analysis after multiple comparison adjustments (p = 7.88 × 10-6). The minor allele of rs9608282 in ADORA2A is associated with larger hippocampal volumes and better memory.