The SORL1 gene and convergent neural risk for Alzheimer's disease across the human lifespan.

TitleThe SORL1 gene and convergent neural risk for Alzheimer's disease across the human lifespan.
Publication TypeJournal Article
Year of Publication2014
AuthorsFelsky D, Szeszko P, Yu L, Honer WG, De Jager PL, Schneider JA, Malhotra AK, Lencz T, Ikuta T, Pipitone J, M Chakravarty M, Lobaugh NJ, Mulsant BH, Pollock BG, Kennedy JL, Bennett DA, Voineskos AN
JournalMol Psychiatry
Volume19
Issue10
Pagination1125-32
Date Published2014 Oct
ISSN1476-5578
KeywordsAdolescent, Adult, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Brain, Child, Child, Preschool, Diffusion Tensor Imaging, Female, Genetic Predisposition to Disease, Humans, Infant, Infant, Newborn, LDL-Receptor Related Proteins, Male, Membrane Transport Proteins, Middle Aged, Polymorphism, Single Nucleotide, RNA, Messenger, Young Adult
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.

DOI10.1038/mp.2013.142
Alternate JournalMol. Psychiatry
PubMed ID24166411
PubMed Central IDPMC4004725
Grant ListP30 AG010161 / AG / NIA NIH HHS / United States
P30AG10161 / AG / NIA NIH HHS / United States
P50 MH080173 / MH / NIMH NIH HHS / United States
P50MH080173 / MH / NIMH NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
R01 MH099167 / MH / NIMH NIH HHS / United States
R01AG15819 / AG / NIA NIH HHS / United States
R01AG17917 / AG / NIA NIH HHS / United States
R01AG30146 / AG / NIA NIH HHS / United States
R01MH099167 / MH / NIMH NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada

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