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Meta-Analysis
. 2019 Apr 8;10(1):1619.
doi: 10.1038/s41467-019-09613-z.

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

Aliza P Wingo  1   2 , Eric B Dammer  3 , Michael S Breen  4   5   6 , Benjamin A Logsdon  7 , Duc M Duong  3 , Juan C Troncosco  8 , Madhav Thambisetty  9 , Thomas G Beach  10 , Geidy E Serrano  10 , Eric M Reiman  11 , Richard J Caselli  12 , James J Lah  13 , Nicholas T Seyfried  14 , Allan I Levey  13 , Thomas S Wingo  13   15   16
Affiliations
Meta-Analysis

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

Aliza P Wingo et al. Nat Commun. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Overview of the study design and results. The samples used in this study were from participants in two large prospective studies of aging in the United States who donated their brains upon death. Each subject in the present study were initially cognitively normal and had antecedent cognitive data used to estimate personal cognitive trajectories. Whole brain proteomic analysis of dorsolateral prefrontal cortex was used to estimate protein abundance for each participant. Proteome-wide association study of cognitive trajectory and protein co-expression network analysis revealed that individuals with cognitive stability (i.e., relatively little decline in cognition over time) have decreased abundance of the proteins involved in inflammation and apoptosis but increased abundance of the proteins involved in mitochondrial activities and synaptic function. Promising protein targets for further study are presented
Fig. 2
Fig. 2
Person-specific cognitive trajectory. This figure summarizes cognitive trajectory for each individual with colors indicating clinical diagnosis and Braak stage. Individual cognitive trajectory in the Banner cohort by a last clinical diagnosis (AD or control) prior to death and b Braak stage. Individual cognitive trajectory in the BLSA cohort by c clinical diagnosis; d Braak stage. A positive slope or small negative slope reflects cognitive stability. A larger negative slope reflects faster cognitive decline. The underlying data are available through the Synapse platform (protein abundance, https://www.synapse.org/#!Synapse:syn7170616 and https://www.synapse.org/#!Synapse:syn3606086) and Supplementary Data 1
Fig. 3
Fig. 3
Differential protein expression in cognitive trajectory. This figure summarizes the meta-analysis of the proteome-wide association study of cognitive trajectory in the discovery (Banner) and replication (BLSA) cohort. a Volcano plot for the meta-analysis of the proteome-wide association studies of cognitive trajectory in the discovery and replication cohorts. A total of 579 proteins were associated with cognitive trajectory at FDR < 0.05. Among these, 350 proteins had increased abundance and 229 had decreased abundance in cognitive stability. The underlying data are available as Supplementary Data 2. In b, c, protein abundance vs. slope of cognitive trajectory is plotted with the best-fit regression line drawn in blue and the 95% confidence interval for the regression line shaded in gray. b Higher VGF protein level was associated with cognitive stability. Of note, for cognitive trajectory, a small negative slope reflects slow decline and a large negative slope reflects fast decline. Cognitive stability is reflected by a positive slope or very small negative slope of the cognitive trajectory. c Lower MAPT protein level was associated with cognitive stability. The data underlying b, c are available through the Synapse platform (protein abundance, https://www.synapse.org/#!Synapse:syn7170616 and https://www.synapse.org/#!Synapse:syn3606086) and Supplementary Data 1 (cognitive trajectories)
Fig. 4
Fig. 4
Protein co-expression network. This figure shows the WGCNA cluster dendogram and 20 distinct protein co-expressed modules defined by dendogram branch cutting in the Banner cohort. Each module is given in a box with the module number and a functional summary of the proteins in the module derived by gene ontology enrichment. The underlying data are provided as a Supplementary Data 7
Fig. 5
Fig. 5
Modules enriched for cognitive trajectory-associated proteins. This figure summarizes the protein co-expression modules that are enriched for cognitive trajectory-associated proteins for each cohort with and without adjustment for neuropathologies. Enrichment was determined by Fisher’s exact test and reported p-values are adjusted for FDR. There are 579 cognitive trajectory-associated proteins in Banner and BLSA cohorts, which were divided into lower-abundance proteins in cognitive stability (229 proteins, colored in salmon) and higher-abundance proteins in cognitive stability (350 proteins, colored in turquoise), respectively. a Banner protein module enrichment; b BLSA protein module enrichment. After adjusting for β-amyloid plaques and neurofibrillary tangles, there were 232 cognitive trajectory-associated proteins, and enrichment was performed separately for lower-abundance proteins in cognitive stability (81 proteins, colored in salmon) and higher-abundance proteins in cognitive stability (151 proteins, colored in turquoise), respectively. c Banner protein module enrichment; d BLSA protein module enrichment. Source data are provided as a Source Data file
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