Exploring Cortical Proteins Underlying the Relation of Neuroticism to Cognitive Resilience.

• Type of Material: Article
• Authors: Francine Grodstein, Rush Alzheimer's Disease Center, Chicago, IL, 60612, USA.; Lei Yu, Rush Alzheimer's Disease Center, Chicago, IL, 60612, USA.; Philip L de Jager, Center for Translational and Computational Neuroimmunology, Department of Neurology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, NY, NY, 10032, USA.; Allan Levey, Emory University; Nicholas Seyfried, Emory University; David A Bennett, Rush Alzheimer's Disease Center, Chicago, IL, 60612, USA.
• Language: English
• Date: 2022
• Publisher: Elsevier Inc
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Author(s)
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.nbas.2022.100031
• Title of Journal or Parent Work: Aging Brain
• Volume: 2
• Grant/Funding Information: This work was supported by the Accelerating Medicine Partnership NIH grants for AD (U01AG046161 and U01AG061357), and by grants U01AG61356, P30AG10161, R01AG17917, R01AG15819.
• Keywords: cognitive resilience; aging; cortical proteins
• Research Categories: Chemistry, Biochemistry

Abstract

Some individuals maintain cognitive health despite neuropathology. Targets impacting "cognitive resilience" may provide interventions for preventing dementia without decreasing neuropathology. Neuroticism represents the tendency to experience negative emotions, and is related to worse cognitive resilience. Exploring proteins associated with cognitive resilience risk factors, such as neuroticism, could yield new protein targets. We used 355 postmortem prefrontal cortex from two cohorts to measure 8356 proteins. We identified (i) proteins associated with both neuroticism and cognitive resilience, and (ii) proteins statistically mediating relations of neuroticism to cognitive resilience. We found two proteins, 40S ribosomal proteinS3 (RPS3) and branched chain keto acid dehydrogenase E1, subunit beta (BCKDHB), ranked in the top 1% of smallest p-values in parallel linear regression models of neuroticism to protein levels, and protein levels to cognitive decline resilience. In mediation models, RPS3 and BCKDHB accounted for 25% (p=0.005) of the relation of neuroticism to cognitive resilience. Our sample size is modest, thus results may be due to chance (p-values did not meet Bonferroni significance) and will require further confirmation; however, investigating biologic mediators of associations of risk factors to cognitive resilience may help discover targets to promote cognitive resilience and reduce dementia.