Large-scale proteomic analysis of human brain 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 and Thomas S. Wingo ()
Additional contact information
Aliza P. Wingo: Atlanta VA Medical Center
Eric B. Dammer: Emory University School of Medicine
Michael S. Breen: 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

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09613-z

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