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

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 trajec...

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Published inNature communications Vol. 10; no. 1; pp. 1619 - 14
Main Authors Wingo, Aliza P., Dammer, Eric B., Breen, Michael S., Logsdon, Benjamin A., Duong, Duc M., Troncosco, Juan C., Thambisetty, Madhav, Beach, Thomas G., Serrano, Geidy E., Reiman, Eric M., Caselli, Richard J., Lah, James J., Seyfried, Nicholas T., Levey, Allan I., Wingo, Thomas S.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 08.04.2019
Nature Publishing Group
Nature Portfolio
Subjects
631/337/475
631/378/1689/1283
631/378/1689/364
631/378/2612
82/58
82/81
Aged
Aged, 80 and over
Aging - physiology
Alzheimer Disease - pathology
Apoptosis
Biological Variation, Population - physiology
Brain
Brain - metabolism
Brain - pathology
Cognition - physiology
Cognitive ability
Healthy Volunteers
Humanities and Social Sciences
Humans
Middle Aged
Mitochondria
multidisciplinary
Parkinson Disease - pathology
Proteins
Proteome - metabolism
Proteomes
Proteomics - methods
Science
Science (multidisciplinary)
Stability
Trajectory analysis
Online AccessGet full text
ISSN2041-1723
2041-1723
DOI10.1038/s41467-019-09613-z

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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. Cognitive abilities tend to decline over time in advanced age, yet some individuals experience stable abilities or rapid decline. Here the authors present a proteome-wide association study of cognitive trajectory, and identify 38 proteins associated with cognitive resilience.
AbstractList 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.Cognitive abilities tend to decline over time in advanced age, yet some individuals experience stable abilities or rapid decline. Here the authors present a proteome-wide association study of cognitive trajectory, and identify 38 proteins associated with cognitive resilience.
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.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.
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.
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.
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. Cognitive abilities tend to decline over time in advanced age, yet some individuals experience stable abilities or rapid decline. Here the authors present a proteome-wide association study of cognitive trajectory, and identify 38 proteins associated with cognitive resilience.
Cognitive abilities tend to decline over time in advanced age, yet some individuals experience stable abilities or rapid decline. Here the authors present a proteome-wide association study of cognitive trajectory, and identify 38 proteins associated with cognitive resilience.
ArticleNumber 1619
Author Lah, James J.
Dammer, Eric B.
Seyfried, Nicholas T.
Breen, Michael S.
Logsdon, Benjamin A.
Troncosco, Juan C.
Thambisetty, Madhav
Wingo, Aliza P.
Serrano, Geidy E.
Reiman, Eric M.
Wingo, Thomas S.
Duong, Duc M.
Beach, Thomas G.
Levey, Allan I.
Caselli, Richard J.
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  surname: Breen
  fullname: Breen, Michael S.
  organization: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai
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  organization: Johns Hopkins School of Medicine
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  surname: Beach
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  organization: Banner Sun Health Research Institute
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  organization: Banner Alzheimer’s Institute, Arizona State University and University of Arizona
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  organization: Department of Neurology, Mayo Clinic
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  givenname: James J.
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  orcidid: 0000-0002-4507-624X
  surname: Seyfried
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  organization: Department of Biochemistry, Emory University School of Medicine
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  surname: Levey
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/30962425$$D View this record in MEDLINE/PubMed
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Copyright_xml – notice: The Author(s) 2019
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  ident: 9613_CR34
  publication-title: Alzheimers Dement.
  doi: 10.1016/j.jalz.2016.09.003
SSID ssj0000391844
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Snippet In advanced age, some individuals maintain a stable cognitive trajectory while others experience a rapid decline. Such variation in cognitive trajectory is...
Cognitive abilities tend to decline over time in advanced age, yet some individuals experience stable abilities or rapid decline. Here the authors present a...
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SubjectTerms 631/337/475
631/378/1689/1283
631/378/1689/364
631/378/2612
82/58
82/81
Aged
Aged, 80 and over
Aging - physiology
Alzheimer Disease - pathology
Apoptosis
Biological Variation, Population - physiology
Brain
Brain - metabolism
Brain - pathology
Cognition - physiology
Cognitive ability
Healthy Volunteers
Humanities and Social Sciences
Humans
Middle Aged
Mitochondria
multidisciplinary
Parkinson Disease - pathology
Proteins
Proteome - metabolism
Proteomes
Proteomics - methods
Science
Science (multidisciplinary)
Stability
Trajectory analysis
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Title Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age
URI https://link.springer.com/article/10.1038/s41467-019-09613-z
https://www.ncbi.nlm.nih.gov/pubmed/30962425
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https://pubmed.ncbi.nlm.nih.gov/PMC6453881
https://doaj.org/article/9b58a9346e234b21a9e82096eeb3d508
Volume 10
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