title: The SORL1 gene and convergent neural risk for Alzheimer's disease across the human lifespan.
abstract: Prior to intervention trials in individuals genetically at-risk for late-onset Alzheimer's disease, critical first steps are identifying where (neuroanatomic effects), when (timepoint in the lifespan) and how (gene expression and neuropathology) Alzheimer's risk genes impact the brain. We hypothesized that variants in the sortilin-like receptor (SORL1) gene would affect multiple Alzheimer's phenotypes before the clinical onset of symptoms. Four independent samples were analyzed to determine effects of SORL1 genetic risk variants across the lifespan at multiple phenotypic levels: (1) microstructural integrity of white matter using diffusion tensor imaging in two healthy control samples (n=118, age 18-86; n=68, age 8-40); (2) gene expression using the Braincloud postmortem healthy control sample (n=269, age 0-92) and (3) Alzheimer's neuropathology (amyloid plaques and tau tangles) using a postmortem sample of healthy, mild cognitive impairment (MCI) and Alzheimer's individuals (n=710, age 66-108). SORL1 risk variants predicted lower white matter fractional anisotropy in an age-independent manner in fronto-temporal white matter tracts in both samples at 5% family-wise error-corrected thresholds. SORL1 risk variants also predicted decreased SORL1 mRNA expression, most prominently during childhood and adolescence, and significantly predicted increases in amyloid pathology in postmortem brain. Importantly, the effects of SORL1 variation on both white matter microstructure and gene expression were observed during neurodevelopmental phases of the human lifespan. Further, the neuropathological mechanism of risk appears to primarily involve amyloidogenic pathways. Interventions targeted toward the SORL1 amyloid risk pathway may be of greatest value during early phases of the lifespan.
authors.affiliation: 1] Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada [2] Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Felsky
authors.affiliation: 1] Division of Psychiatry Research, Zucker Hillside Hospital, North Shore-LIJ Health System, Glen Oaks, NY, USA [2] Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, NY, USA [3] Departments of Psychiatry and Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Szeszko
authors.affiliation: 1] Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA [2] Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.affiliation: BC Mental Health and Addictions Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: W G
authors.initials: WG
authors.lastname: Honer
authors.affiliation: 1] Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Schneider
authors.affiliation: 1] Division of Psychiatry Research, Zucker Hillside Hospital, North Shore-LIJ Health System, Glen Oaks, NY, USA [2] Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, NY, USA [3] Departments of Psychiatry and Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Malhotra
authors.affiliation: 1] Division of Psychiatry Research, Zucker Hillside Hospital, North Shore-LIJ Health System, Glen Oaks, NY, USA [2] Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, NY, USA [3] Departments of Psychiatry and Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA.
authors.forename: T
authors.initials: T
authors.lastname: Lencz
authors.affiliation: Department of Communication Sciences and Disorders, School of Applied Science, University of Mississippi, Oxford, MS, USA.
authors.forename: T
authors.initials: T
authors.lastname: Ikuta
authors.affiliation: Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Pipitone
authors.affiliation: 1] Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada [2] Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada.
authors.forename: M M
authors.initials: MM
authors.lastname: Chakravarty
authors.affiliation: Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: N J
authors.initials: NJ
authors.lastname: Lobaugh
authors.affiliation: 1] Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada [2] Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: B H
authors.initials: BH
authors.lastname: Mulsant
authors.affiliation: 1] Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada [2] Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: B G
authors.initials: BG
authors.lastname: Pollock
authors.affiliation: 1] Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada [2] Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: J L
authors.initials: JL
authors.lastname: Kennedy
authors.affiliation: 1] Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA [2] Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: 1] Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada [2] Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: A N
authors.initials: AN
authors.lastname: Voineskos
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D056324:Diffusion Tensor Imaging; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D026502:LDL-Receptor Related Proteins / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D055815:Young Adult
chemical_list: D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; C102582:SORL1 protein, human