Targeted brain proteomics uncover multiple pathways to Alzheimer's dementia

Journal Article · Tue Jul 03 00:00:00 EDT 2018 · Annals of Neurology

DOI:https://doi.org/10.1002/ana.25266· OSTI ID:1458778

Yu, Lei ^[1]; Petyuk, Vladislav A. ^[2]; Gaiteri, Chris ^[1]; Mostafavi, Sara ^[3]; Young‐Pearse, Tracy ^[4]; Shah, Raj C. ^[5]; Buchman, Aron S. ^[1]; Schneider, Julie A. ^[6]; Piehowski, Paul D. ^[2]; Sontag, Ryan L. ^[2]; Fillmore, Thomas L. ^[2]; Shi, Tujin ^[2]; Smith, Richard D. ^[2]; De Jager, Philip L. ^[7]; Bennett, David A. ^[1]

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1. Rush Alzheimer's Disease Center Rush University Medical Center Chicago IL, Department of Neurological Sciences Rush University Medical Center Chicago IL
2. Pacific Northwest National Laboratory Richland WA
3. University of British Columbia Vancouver British Columbia Canada
4. Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry Brigham and Women's Hospital Boston MA, Harvard Medical School Boston MA
5. Rush Alzheimer's Disease Center Rush University Medical Center Chicago IL, Department of Family Medicine Rush University Medical Center Chicago IL
6. Rush Alzheimer's Disease Center Rush University Medical Center Chicago IL, Department of Neurological Sciences Rush University Medical Center Chicago IL, Department of Pathology Rush University Medical Center Chicago IL
7. Center for Translational and Computational Neuroimmunology Columbia University Medical Center New York NY, Cell Circuits Program, Broad Institute Cambridge MA

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

• Sponsoring Organization: USDOE
• Grant/Contract Number: DE‐AC05‐76RL0 1830
• OSTI ID: 1458778
• Journal Information: Annals of Neurology, Journal Name: Annals of Neurology Vol. 84 Journal Issue: 1; ISSN 0364-5134
• Publisher: Wiley Blackwell (John Wiley & Sons)
• Country of Publication: United States
• Language: English