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Original Investigation
July 1, 2020

Cortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons

Author Affiliations
  • 1Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois
  • 2Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois
  • 3Department of Pathology, Rush University Medical Center, Chicago, Illinois
  • 4Department of Diagnostic Radiology and Nuclear Medicine, Rush University Medical Center, Chicago, Illinois
  • 5Department of Biomedical Engineering, Illinois Institute of Technology, Chicago
  • 6Department of Biochemistry, Emory University, Atlanta, Georgia
  • 7Division of Mental Health, Atlanta Veterans Affairs Medical Center, Decatur, Georgia
  • 8Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia
  • 9Department of Neurology, Emory University, Atlanta, Georgia
  • 10Department of Human Genetics, Emory University, Atlanta, Georgia
  • 11Department of Pharmaceutical Sciences, University of Illinois College of Pharmacy, Chicago
  • 12Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, New York
  • 13Cell Circuits Program, Broad Institute, Cambridge, Massachusetts
JAMA Psychiatry. Published online July 1, 2020. doi:10.1001/jamapsychiatry.2020.1807
Key Points

Question  What cortical proteins are associated with cognitive resilience among community-dwelling older persons?

Finding  This study leveraged data from 391 community-dwelling older persons to conduct a proteome-wide association analysis of the human dorsolateral prefrontal cortex. Eight cortical proteins were identified in association with cognitive resilience, of which a higher level of NRN1, ACTN4, EPHX4, RPH3A, SGTB, CPLX1, and SH3GL1 and a lower level of UBA1 were associated with greater resilience.

Meaning  Identifying these cortical proteins provides a complementary approach to developing novel therapeutics for the treatment and prevention of Alzheimer disease and related dementias.

Abstract

Importance  Identifying genes and proteins for cognitive resilience (ie, targets that may be associated with slowing or preventing cognitive decline regardless of the presence, number, or combination of common neuropathologic conditions) provides a complementary approach to developing novel therapeutics for the treatment and prevention of Alzheimer disease and related dementias.

Objective  To identify proteins associated with cognitive resilience via a proteome-wide association study of the human dorsolateral prefrontal cortex.

Design, Setting, and Participants  This study used data from 391 community-dwelling older persons who participated in the Religious Orders Study and the Rush Memory and Aging Project. The Religious Orders Study began enrollment January 1, 1994, and the Rush Memory and Aging Project began enrollment September 1, 1997, and data were collected and analyzed through October 23, 2019.

Exposures  Participants had undergone annual detailed clinical examinations, postmortem evaluations, and tandem mass tag proteomics analyses.

Main Outcomes and Measures  The outcome of cognitive resilience was defined as a longitudinal change in cognition over time after controlling for common age-related neuropathologic indices, including Alzheimer disease, Lewy bodies, transactive response DNA-binding protein 43, hippocampal sclerosis, infarcts, and vessel diseases. More than 8000 high abundance proteins were quantified from frozen dorsolateral prefrontal cortex tissue using tandem mass tag and liquid chromatography-mass spectrometry.

Results  There were 391 participants (273 women); their mean (SD) age was 79.7 (6.7) years at baseline and 89.2 (6.5) years at death. Eight cortical proteins were identified in association with cognitive resilience: a higher level of NRN1 (estimate, 0.140; SE, 0.024; P = 7.35 × 10−9), ACTN4 (estimate, 0.321; SE, 0.065; P = 9.94 × 10−7), EPHX4 (estimate, 0.198; SE, 0.042; P = 2.13 × 10−6), RPH3A (estimate, 0.148; SE, 0.031; P = 2.58 × 10−6), SGTB (estimate, 0.211; SE, 0.045; P = 3.28 × 10−6), CPLX1 (estimate, 0.136; SE, 0.029; P = 4.06 × 10−6), and SH3GL1 (estimate, 0.179; SE, 0.039; P = 4.21 × 10−6) and a lower level of UBA1 (estimate, −0.366; SE, 0.076; P = 1.43 × 10−6) were associated with greater resilience.

Conclusions and Relevance  These protein signals may represent novel targets for the maintenance of cognition in old age.

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