The use of interventions targeting cognitive resilience motor proteins may have the ability to offset the effects of multiple pathologies. In fact, thousands of proteins in the dorsolateral prefrontal cortex (DLPFC) may contribute to cognitive resilience. These are the conclusions of an analysis published in Neurology.
Cognitive resilience is a well-known concept. However, knowledge gaps regarding its underlying mechanisms have created difficulties in designing instruments that identify older adults with high or low resilience. The researchers decided to test whether aggregating cortical peptides related to cognitive resilience into an index could help identify these older people.
For the present study, they used a novel analytical approach to identify a parsimonious set of multifunctional cortical proteins that may provide cognitive resilience and resistance to Alzheimer’s disease and related dementia pathologies (ADRD) in a population of people. elderly.
Clinical and post-mortem data of a total of 1192 deceased elderly people with a mean of 8.7 ± 4.5 years of follow-up were included in the study. Data derived from 2 independent longitudinal cohorts – the Religious Orders Study and the Rush Memory and Aging Project – were used, including annual clinical tests, ADRD disease indices and 226 proteotypic peptides that were measured in the DLPFC.
Linear mixed-effects models were used to identify peptides associated with cognitive resilience, that is, cognitive decline unexplained by ADRD pathologies. Expression levels of these resilience peptides were aggregated into a person-specific index of cognitive resilience, to explore its relationship to clinical and pathological AD phenotypes.
A total of 226 separate linear mixed-effects models, adjusted for sex, age at death, and education, were examined. Of these, 110 peptides were associated with cognitive decline rate (false discovery rate [FDR] P <.05 overall of the peptides remained associated with cognitive decline after controlling for pathology. these a higher index was significantly slower>P <.001 and slower motor decline>P <.001 a majority of the resilience peptides were specific for cognitive decline although also provided motor decline.>
A higher index was associated with a significantly lower burden of AD pathologies (odds ratio [OR]0.41; P <.001 and altered the relationship between ad pathology cognition with a higher index modifying negative effects of on dementia near death>P =.010). Up to 90% of cognitive resilience peptides were associated with pathological AD phenotypes.
Following an examination of the functions of the 52 proteins identified, the majority of functions were mitochondrial and synaptic plasticity.
A major limitation of the current study is that the results require replication in more diverse patient populations. Although the datasets leveraged in this analysis are large, the effects of individual genes and proteins can be quite small, demonstrating the utility of aggregating multiple proteins into a summary risk score.
“Resilience proteins may be valuable therapeutic targets for drug discovery of interventions that maintain brain health in aging adults via multiple pathways,” the researchers concluded.
Further experiments in model organisms or human cell modeling will be essential to characterize the causal mechanisms and pathways that link these resilience proteins to various AD clinical phenotypes, including cognitive or motor decline, as well as pathological phenotypes. such as AD.
Disclosure: One of the study authors declared affiliations with biotechnology, pharmaceutical and/or device companies. Please see the original citation for a full list of author disclosures.
Zammit AR, Yu L, Petyuk V, et al. Cortical proteins and individual differences in cognitive resilience in the elderly. Neurology. Published online March 3, 2022. doi:10.1212/WNL.0000000000200017