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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NRN1 is associated with a slower rate of cognitive decline independent of AD and related dementia pathologies.
“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]
Yu et al. identified associations between cognitive resilience and cortical proteins involved in synaptic, metabolic, and neurogenic functions.
“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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Self-citationNeuropathologic Correlates of Human Cortical Proteins in Alzheimer Disease and Related Dementias
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Self-citationm6A mRNA methylation in human brain is disrupted in Lewy body disorders
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Associations of VGF with Neuropathologies and Cognitive Health in Older Adults
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Differential blood DNA methylation across Lewy body dementias
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Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes
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“49,50 Joint analysis in different cognitive domains also revealed many differentially expressed proteins, with 1976 for episodic memory, 1576 for working memory, 1501 for semantic memory, 461 for perceptual speed, and four for visuospatial ability (Figure S2, Table S7-S11).”
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Self-citationRabphilin-3A Drives Structural Modifications of Dendritic Spines Induced by Long-Term Potentiation
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Association of AK4 Protein From Stem Cell–Derived Neurons With Cognitive Reserve
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Genetic background influences the 5XFAD Alzheimer's disease mouse model brain proteome
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Self-citationInterneuron transcriptomics reveals pathologic markers of Alzheimer's disease progression
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DNA methylation signature of a lifestyle-based resilience index for cognitive health
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Self-citationThe prognostic significance of epoxide hydrolases in colorectal cancer
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Self-citationMitochondrial Respiratory Chain Protein Co-Regulation in the Human Brain
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Self-citationComprehensive analysis of the immune implication of EPHX4 gene in laryngeal squamous cell carcinoma
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Self-citationAssociations of Brain Morphology with Cortical Proteins of Cognitive Resilience
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Exome sequencing identifies genes for socioeconomic status in 350,770 individuals
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Exploring cortical proteins underlying the relation of neuroticism to cognitive resilience
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Cytokine expression profile in the human brain of older adults
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Self-citationNeuropathologic Profiles and Associated Cognitive Trajectories in Community-Living Older Adults
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Self-citationNRN1 as a therapeutic target for Alzheimer's disease
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Strategies for translating proteomics discoveries into drug discovery for dementia
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G-protein coupled estrogen receptor 1, amyloid-β, and tau tangles in older adults
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Self-citationNeurodegeneration risk variants promote lysosomal TMEM106B fibril accumulationPreprint
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- 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
- Health Sciences › Medicine › Physiology › 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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