title: Multimodal Brain Imaging Reveals Structural Differences in Alzheimer's Disease Polygenic Risk Carriers: A Study in Healthy Young Adults.
abstract: Recent genome-wide association studies have identified genetic loci that jointly make a considerable contribution to risk of developing Alzheimer's disease (AD). Because neuropathological features of AD can be present several decades before disease onset, we investigated whether effects of polygenic risk are detectable by neuroimaging in young adults. We hypothesized that higher polygenic risk scores (PRSs) for AD would be associated with reduced volume of the hippocampus and other limbic and paralimbic areas. We further hypothesized that AD PRSs would affect the microstructure of fiber tracts connecting the hippocampus with other brain areas.
  
  
  
  We analyzed the association between AD PRSs and brain imaging parameters using T1-weighted structural (n = 272) and diffusion-weighted scans (n = 197).
  
  
  
  We found a significant association between AD PRSs and left hippocampal volume, with higher risk associated with lower left hippocampal volume (p = .001). This effect remained when the APOE gene was excluded (p = .031), suggesting that the relationship between hippocampal volume and AD is the result of multiple genetic factors and not exclusively variability in the APOE gene. The diffusion tensor imaging analysis revealed that fractional anisotropy of the right cingulum was inversely correlated with AD PRSs (p = .009). We thus show that polygenic effects of AD risk variants on brain structure can already be detected in young adults.
  
  
  
  This finding paves the way for further investigation of the effects of AD risk variants and may become useful for efforts to combine genotypic and phenotypic data for risk prediction and to enrich future prevention trials of AD.
authors.affiliation: Cardiff University Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Wales, United Kingdom; Cardiff University Brain Research Imaging Centre, School of Psychology, Wales, United Kingdom; Central Biotechnology Services, TIME Institute, Wales, United Kingdom. Electronic address: foleys2@cardiff.ac.uk.
authors.forename: Sonya F
authors.initials: SF
authors.lastname: Foley
authors.affiliation: Cardiff University Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Wales, United Kingdom; Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, Faculty of Medicine & Dentistry, University of Bristol, Bristol, United Kingdom.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Tansey
authors.affiliation: Cardiff University Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Wales, United Kingdom; Cardiff University Brain Research Imaging Centre, School of Psychology, Wales, United Kingdom.
authors.forename: Xavier
authors.initials: X
authors.lastname: Caseras
authors.affiliation: Cardiff University Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Wales, United Kingdom; Cardiff University Brain Research Imaging Centre, School of Psychology, Wales, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lancaster
authors.affiliation: Cardiff University Brain Research Imaging Centre, School of Psychology, Wales, United Kingdom.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bracht
authors.affiliation: Cardiff University Brain Research Imaging Centre, School of Psychology, Wales, United Kingdom.
authors.forename: Greg
authors.initials: G
authors.lastname: Parker
authors.affiliation: Cardiff University Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Wales, United Kingdom; Neuroscience and Mental Health Research Institute, Wales, United Kingdom.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hall
authors.affiliation: Cardiff University Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Wales, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.affiliation: Cardiff University Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Wales, United Kingdom; Cardiff University Brain Research Imaging Centre, School of Psychology, Wales, United Kingdom.
authors.forename: David E J
authors.initials: DE
authors.lastname: Linden
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics; D056324:Diffusion Tensor Imaging; D018728:Entorhinal Cortex / Q000000981:diagnostic imaging / Q000473:pathology; D005260:Female; D020712:Fornix, Brain / Q000000981:diagnostic imaging / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging / Q000473:pathology; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020412:Multifactorial Inheritance; D064847:Multimodal Imaging; D020534:Parahippocampal Gyrus / Q000000981:diagnostic imaging / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C000612345:ApoE protein, human; D001057:Apolipoproteins E
keywords: Alzheimer’s disease; Cingulum; Fornix; Hippocampus; Imaging; Polygenic risk