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

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. Caselli, James J. Lah, Nicholas T. Seyfried, Allan I. Levey, Thomas S. Wingo

Research output: Contribution to journalArticlepeer-review

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 novel evidence for increased neuronal mitochondrial activities in cognitive stability regardless of the burden of traditional neuropathologies. Furthermore, we provide additional evidence for increased synaptic activities 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.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Jan 23 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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