Brain proteomic analysis implicates actin filament processes and injury response in resilience to Alzheimer’s disease

Zhi Huang, Gennifer E. Merrihew, Eric B. Larson, Jea Park, Deanna Plubell, Edward J. Fox, Kathleen S. Montine, Caitlin S. Latimer, C. Dirk Keene, James Y. Zou (), Michael J. MacCoss () and Thomas J. Montine ()
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Zhi Huang: Stanford University School of Medicine
Gennifer E. Merrihew: University of Washington
Eric B. Larson: University of Washington
Jea Park: University of Washington
Deanna Plubell: University of Washington
Edward J. Fox: Stanford University School of Medicine
Kathleen S. Montine: Stanford University School of Medicine
Caitlin S. Latimer: University of Washington
C. Dirk Keene: University of Washington
James Y. Zou: Stanford University School of Medicine
Michael J. MacCoss: University of Washington
Thomas J. Montine: Stanford University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Resilience to Alzheimer’s disease is an uncommon combination of high disease burden without dementia that offers valuable insights into limiting clinical impact. Here we assessed 43 research participants meeting stringent criteria, 11 healthy controls, 12 resilience to Alzheimer’s disease and 20 Alzheimer’s disease with dementia and analyzed matched isocortical regions, hippocampus, and caudate nucleus by mass spectrometry-based proteomics. Of 7115 differentially expressed soluble proteins, lower isocortical and hippocampal soluble Aβ levels is a significant feature of resilience when compared to healthy control and Alzheimer’s disease dementia groups. Protein co-expression analysis reveals 181 densely-interacting proteins significantly associated with resilience that were enriched for actin filament-based processes, cellular detoxification, and wound healing in isocortex and hippocampus, further supported by four validation cohorts. Our results suggest that lowering soluble Aβ concentration may suppress severe cognitive impairment along the Alzheimer’s disease continuum. The molecular basis of resilience likely holds important therapeutic insights.

Date: 2023
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DOI: 10.1038/s41467-023-38376-x

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