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Cortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons
Open accessAbstract
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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“consistent with prior studies indicating its association with a slower rate of cognitive decline independent of AD and related dementia pathologies.”
From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [49]
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“Yu et al. paralleled these network results, identifying associations between cognitive resilience and cortical proteins involved in synaptic, metabolic, and neurogenic functions [142].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [142]
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Metadata
- Authors
- Yu, L., Tasaki, S., Schneider, J. A., Arfanakis, K., Duong, D. M., Wingo, A. P., Wingo, T. S., Kearns, N., Thatcher, G. R. J., Seyfried, N. T., Levey, A. I., De Jager, P. L., & Bennett, D. A.
- Affiliations
- Rush University Medical Center (US)
- Emory University (US)
- University of Illinois Chicago (US)
- Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, New York
- Corresponding author
- Yu, Lei
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2020-11-01
- Volume
- 77
- Issue
- 11
- Pages
- 1172
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC7330835
- OpenAlex
- W3039778201
- Cited by
- 127
- References
- 42
- Citations by year
- 2026: 13 · 2025: 27 · 2024: 28 · 2023: 19 · 2022: 24 · 2021: 13 · 2020: 2
- FWCI
- 10.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01AG017917, R01AG056533, R01AG015819, P30AG010161, P50AG025688)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- cognitive resilience, dorsolateral prefrontal cortex, proteome-wide association study, Alzheimer's disease, dementia, cognitive decline, community-dwelling older adults, NRN1, ACTN4, VGLUT1, SLC17A9
- MeSH terms
- Rabphilin-3A, Actinin, Adaptation, Psychological, Aged, Aged, 80 and over, Epoxide Hydrolases, Female, Humans, Male, Nerve Tissue Proteins, Neuropeptides, Proteins, Molecular Chaperones, Vesicular Transport Proteins, Adaptor Proteins, Vesicular Transport, Ubiquitin-Activating Enzymes, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Independent Living, GPI-Linked Proteins, Cognitive Dysfunction
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