Targeted brain proteomics uncover multiple pathways to Alzheimer's dementia

Objective Previous gene expression analysis identified a network of coexpressed genes that is associated with β‐amyloid neuropathology and cognitive decline in older adults. The current work targeted influential genes in this network with quantitative proteomics to identify potential novel therapeut...

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Bibliographic Details
Published in:Annals of neurology Vol. 84; no. 1; pp. 78 - 88
Main Authors: Yu, Lei, Petyuk, Vladislav A., Gaiteri, Chris, Mostafavi, Sara, Young‐Pearse, Tracy, Shah, Raj C., Buchman, Aron S., Schneider, Julie A., Piehowski, Paul D., Sontag, Ryan L., Fillmore, Thomas L., Shi, Tujin, Smith, Richard D., Jager, Philip L., Bennett, David A.
Format: Journal Article
Language:English
Published: United States Wiley Subscription Services, Inc 01.07.2018
Wiley Blackwell (John Wiley & Sons)
Subjects:
Abundance
Adults
Aging
Alzheimer's disease
Autopsies
Autopsy
Brain
Cognitive ability
Cortex
Death
Dementia
Dementia disorders
Gene expression
Genes
Identification methods
Insulin-like growth factor-binding protein 5
Mortality
Neurodegenerative diseases
Neuropathology
Older people
Proteins
Proteomics
Regression analysis
Target recognition
Therapeutic applications
ISSN:0364-5134, 1531-8249, 1531-8249
Online Access:Get full text
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Summary:Objective Previous gene expression analysis identified a network of coexpressed genes that is associated with β‐amyloid neuropathology and cognitive decline in older adults. The current work targeted influential genes in this network with quantitative proteomics to identify potential novel therapeutic targets. Methods Data came from 834 community‐based older persons who were followed annually, died, and underwent brain autopsy. Uniform structured postmortem evaluations assessed the burden of β‐amyloid and other common age‐related neuropathologies. Selected reaction monitoring quantified cortical protein abundance of 12 genes prioritized from a molecular network of aging human brain that is implicated in Alzheimer's dementia. Regression and linear mixed models examined the protein associations with β‐amyloid load and other neuropathological indices as well as cognitive decline over multiple years preceding death. Results Average age at death was 88.6 years. Overall, 349 participants (41.9%) had Alzheimer's dementia at death. A higher level of PLXNB1 abundance was associated with more β‐amyloid load (p = 1.0 × 10−7) and higher PHFtau tangle density (p = 2.3 × 10−7), and the association of PLXNB1 with cognitive decline is mediated by these known Alzheimer's disease pathologies. On the other hand, higher IGFBP5, HSPB2, and AK4 and lower ITPK1 levels were associated with faster cognitive decline, and, unlike PLXNB1, these associations were not fully explained by common neuropathological indices, suggesting novel mechanisms leading to cognitive decline. Interpretation Using targeted proteomics, this work identified cortical proteins involved in Alzheimer's dementia and begins to dissect two different molecular pathways: one affecting β‐amyloid deposition and another affecting resilience without a known pathological footprint. Ann Neurol 2018;83:78–88
Bibliography:These authors contributed equally.
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DE‐AC05‐76RL0 1830
USDOE
Contributed equally
ISSN:0364-5134
1531-8249
1531-8249
DOI:10.1002/ana.25266