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Author Notes:

Correspondence and requests for materials should be addressed to N.T.S. (email:nseyfri@emory.edu) or to T.S.W. (email: thomas.wingo@emory.edu)

Author contributions: A.P.W. and T.S.W. conceived and designed the experiments. D.M.D., J.C.T., M.T., T.G.B., G.E.S., E.M.R., R.J.C., J.J.L, N.T.S., and A.I.L. generated the experimental data. A.P.W., E.B.D., M.S.B., B.A.L., and T.S.W. performed the analyses. A.P.W., E.B.D., M.S.B., B.A.L., J.J.L., N.T.S., A.I.L., and T.S.W.

interpreted the results. N.T.S., A.I.L., A.P.W., and T.S.W. acquired the funding.

A.P.W. wrote the first draft of the manuscript.

All authors revised and approved the manuscript.

We are grateful to the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona for the provision of human brain tissue.

Competing interests: The authors declare no competing interests.

Subjects:

Research Funding:

Support was provided by R01 AG056533, R01 AG053960, the Accelerating Medicine Partnership for AD (U01AG046161; U01 AG061357), the Emory Alzheimer’s Disease Research Center (P50 AG025688), and the NINDS Emory Neuroscience Core (P30 NS055077).

This work was supported in part by funding from the intramural program of the National Institute on Aging (NIA). A.P.W. is also supported by U01 MH115484 and I01 BX003853. T.S.W. is also supported by IK2 BX001820 and P50 AG025688.

N.T.S. is also supported by an Alzheimer’s Association, Alzheimer’s Research UK, The Michael J. Fox Foundation for Parkinson’s Research, the Weston Brain Institute Biomarkers Across Neurodegenerative Diseases Grant (11060), R01 AG061800, and R01 AG057911.

The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05–901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • MINI-MENTAL-STATE
  • ALZHEIMERS-DISEASE
  • AMYLOID-BETA
  • EXPRESSION
  • DECLINE
  • MITOCHONDRIA
  • HIPPOCAMPUS
  • VGF
  • METAANALYSIS
  • IMPAIRMENT

Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age

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Journal Title:

Nature Communications

Volume:

Volume 10, Number 1

Publisher:

, Pages 1619-1619

Type of Work:

Article | Final Publisher PDF

Abstract:

In advanced age, some individuals maintain a stable cognitive trajectory while others experience a rapid decline. Such variation in cognitive trajectory is only partially explained by traditional neurodegenerative pathologies. Hence, to identify new processes underlying variation in cognitive trajectory, we perform an unbiased proteome-wide association study of cognitive trajectory in a discovery (n = 104) and replication cohort (n = 39) of initially cognitively unimpaired, longitudinally assessed older-adult brain donors. We find 579 proteins associated with cognitive trajectory after meta-analysis. Notably, we present evidence for increased neuronal mitochondrial activities in cognitive stability regardless of the burden of traditional neuropathologies. Furthermore, we provide additional evidence for increased synaptic abundance and decreased inflammation and apoptosis in cognitive stability. Importantly, we nominate proteins associated with cognitive trajectory, particularly the 38 proteins that act independently of neuropathologies and are also hub proteins of protein co-expression networks, as promising targets for future mechanistic studies of cognitive trajectory.

Copyright information:

© 2019, The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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