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

Author

Listed:
  • Aliza P. Wingo

    (Atlanta VA Medical Center
    Emory University School of Medicine)

  • Eric B. Dammer

    (Emory University School of Medicine)

  • Michael S. Breen

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Benjamin A. Logsdon

    (Sage Bionetworks)

  • Duc M. Duong

    (Emory University School of Medicine)

  • Juan C. Troncosco

    (Johns Hopkins School of Medicine)

  • Madhav Thambisetty

    (National Institutes of Health)

  • Thomas G. Beach

    (Banner Sun Health Research Institute)

  • Geidy E. Serrano

    (Banner Sun Health Research Institute)

  • Eric M. Reiman

    (Arizona State University and University of Arizona)

  • Richard J. Caselli

    (Mayo Clinic)

  • James J. Lah

    (Emory University School of Medicine)

  • Nicholas T. Seyfried

    (Emory University School of Medicine)

  • Allan I. Levey

    (Emory University School of Medicine)

  • Thomas S. Wingo

    (Emory University School of Medicine
    Atlanta VA Medical Center
    Emory University School of Medicine)

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.

Suggested Citation

  • Aliza P. Wingo & Eric B. Dammer & Michael S. Breen & Benjamin A. Logsdon & Duc M. Duong & Juan C. Troncosco & Madhav Thambisetty & Thomas G. Beach & Geidy E. Serrano & Eric M. Reiman & Richard J. Case, 2019. "Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09613-z
    DOI: 10.1038/s41467-019-09613-z
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