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

Molecular Psychiatry volume 19, pages 1125–1132 (2014)Cite this article

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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.

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Acknowledgements

The BrainCloud postmortem data used for the analysis described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000417.v1.p1. Submission of the data, phs000417.v1.p1 to dbGaP was provided by Drs Barbara Lipska and Joel Kleinman. Collection of the data was through a collaborative study sponsored by the NIMH Intramural Research Program. Initial report on this data set is from Colantuoni et al.33 We would also like to thank all of the study participants and acknowledge the essential contributions of Chaya Gopin and Kimberly Cameron to the recruitment and clinical assessments of those participants. We are indebted to the participants in the Religious Orders Study and the Rush Memory and Aging Project. We thank the staff of the Rush Alzheimer’s Disease Center. Work from Rush was supported in part by grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, the Illinois Department of Public Health and the Translational Genomics Research Institute. Work from Hillside was supported by NIMH grant P50MH080173. Work from CAMH was supported in part by the CAMH Foundation thanks to the Kimel Family, Koerner New Scientist Award, and Paul E Garfinkel New Investigator Catalyst Award, as well as the Canadian Institutes of Health Research, Ontario Mental Health Foundation, the Alzheimer’s Society of Canada, and NIMH grant R01MH099167.

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No sponsor or funder had any role in the design and conduct of the study, collection, management, analysis and interpretation of the data, and preparation, review or approval of the manuscript.

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Authors and Affiliations

  1. Department of Psychiatry, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada

    D Felsky, J Pipitone, M M Chakravarty, N J Lobaugh, B H Mulsant, B G Pollock, J L Kennedy & A N Voineskos

  2. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    D Felsky, B H Mulsant, B G Pollock, J L Kennedy & A N Voineskos

  3. Division of Psychiatry Research, Zucker Hillside Hospital, North Shore-LIJ Health System, Glen Oaks, NY, USA

    P Szeszko, A K Malhotra & T Lencz

  4. Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, NY, USA

    P Szeszko, A K Malhotra & T Lencz

  5. Departments of Psychiatry and Molecular Medicine, Hofstra North Shore—LIJ School of Medicine, Hempstead, NY, USA

    P Szeszko, A K Malhotra & T Lencz

  6. Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

    L Yu & D A Bennett

  7. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA

    L Yu, J A Schneider & D A Bennett

  8. BC Mental Health and Addictions Research Institute, University of British Columbia, Vancouver, BC, Canada

    W G Honer

  9. Department of Neurology, Program in Translational NeuroPsychiatric Genomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    P L De Jager

  10. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA

    P L De Jager

  11. Department of Communication Sciences and Disorders, School of Applied Science, University of Mississippi, Oxford, MS, USA

    T Ikuta

  12. Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada

    M M Chakravarty

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  1. D Felsky
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Correspondence to A N Voineskos.

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Competing interests

Within the past 5 years, BGP has been a member of the advisory board of Lundbeck Canada (final meeting was May 2009) and Forest Laboratories (final meeting was March 2008). He has also served one time as a consultant for Wyeth (October 2008) and Takeda (July 2007) and was a faculty member of the Lundbeck International Neuroscience Foundation (LINF) (final meeting was April 2010). JLK has been a consultant to GlaxoSmithKline, Sanofi-Aventis and Dianippon-Sumitomo. BHM has received travel support from Roche. AKM has served as a consultant for Genomind Inc. All other authors declare no conflict of interest. ANV had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Felsky, D., Szeszko, P., Yu, L. et al. The SORL1 gene and convergent neural risk for Alzheimer’s disease across the human lifespan. Mol Psychiatry 19, 1125–1132 (2014). https://doi.org/10.1038/mp.2013.142

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