1. This protein-wide association study found that eight specific proteins were associated with cognitive resilience in older adults, pointing toward targets for novel therapies.
Evidence Rating Level: 2 (Good)
Many primary causes of dementia occur among older adults present without commonly recognized neuropathological signatures. Proteomics can be useful in identifying proteins that are associated with cognitive decline, resulting in novel drug targets to curb this decline in the absence of neuropathological signatures. This proteome-wide association study of the human dorsolateral prefrontal cortex (DLPFC) aimed to identify proteins associated with cognitive decline using data from the Religious Orders Study and Rush Memory and Aging Project. These studies began enrollment in January 1994 and September 1997, respectively, with data collected and analyzed through October 2019. Data included annual clinical examinations, postmortem evaluations, and tandem mass tag proteomic analyses. Cognitive resilience was defined by this study as longitudinal change in cognition after controlling for age-related neuropathology, including Lewy bodies, Alzheimer’s disease (AD), transactive response DNA-binding protein 43, infarcts, hippocampal sclerosis, and vessel diseases. More than 8,000 high-abundance proteins were quantified from DLPFC tissue using tandem mass tag and liquid chromatography-mass spectrometry. A total of 391 participants were included in the analyses (mean [SD] age = 79.7 [6.7] years at baseline; 89.2 [6.5] years at death). A total of 59.6% of participants had a pathologic diagnosis of AD at autopsy, as well as cerebrovascular diseases such as macroscopic infarcts (32.0%). Cognitive resilience was associated with eight cortical proteins, including higher levels of SH3GL1 (estimate 0.179, SE 0.039, p = 4.21×10-6), CPLX1 (estimate 0.136, SE 0.029, p = 4.06×10-6), SGTB (estimate 0.211, SE 0.045, p = 3.28×10-6), RPH3A (estimate 0.148, SE 0.031, p = 2.58×10-6), EPHX4 (estimate 0.198, 0.042, p = 2.13×10-6), ACTN4 (estimate 0.321, SE 0.065, p = 9.94×10-7), and NRN1 (estimate 0.140, SE 0.024, p = 7.35×10-9), along with lower levels of UBA1 (estimate -0.366, SE 0.076, p = 1.43×10-6). Overall, this study suggests that maintenance of these proteins may improve cognitive resilience in later life, particularly in the context of NRN1, due to neuritin’s role in axonal regeneration, extension, and neuritic arborization.
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