@article{1b03adb0730344249b4508201c5ffb62,
title = "Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age",
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.",
author = "Wingo, {Aliza P.} and Dammer, {Eric B.} and Breen, {Michael S.} and Logsdon, {Benjamin A.} and Duong, {Duc M.} and Troncosco, {Juan C.} and Madhav Thambisetty and Beach, {Thomas G.} and Serrano, {Geidy E.} and Reiman, {Eric M.} and Caselli, {Richard J.} and Lah, {James J.} and Seyfried, {Nicholas T.} and Levey, {Allan I.} and Wingo, {Thomas S.}",
note = "Funding Information: Support was provided by R01 AG056533, R01 AG053960, the Accelerating Medicine Partnership for AD (U01AG046161; U01 AG061357), the Emory Alzheimer{\textquoteright}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{\textquoteright}s Association, Alzheimer{\textquoteright}s Research UK, The Michael J. Fox Foundation for Parkinson{\textquoteright}s Research, the Weston Brain Institute Biomarkers Across Neurodegenerative Diseases Grant (11060), R01 AG061800, and R01 AG057911. 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. 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{\textquoteright}s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer{\textquoteright}s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer{\textquoteright}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{\textquoteright}s Research. We are grateful to participants in BLSA for their invaluable contribution. We acknowledge Mesa Schumacher for her contribution to Fig. 1. Publisher Copyright: {\textcopyright} 2019, The Author(s).",
year = "2019",
month = dec,
day = "1",
doi = "10.1038/s41467-019-09613-z",
language = "English (US)",
volume = "10",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}