Causal relationship between feelings and cognitive decline: An univariable and multivariable Mendelian randomization study

ARTICLE HIGHLIGHTS

Research background

The study addresses the escalating concern of cognitive health, particularly in the aging population. With conditions like Mild Cognitive Impairment (MCI) and dementia on the rise, understanding the prevalence, progression, and contributing factors becomes paramount. Globally, millions grapple with cognitive disorders, and the intricate interplay between cognitive decline and neuropsychiatric symptoms poses a significant challenge. The study aims to explore the complex relationship between feelings and cognition, utilizing innovative Mendelian randomization (MR) methodology to assess causal links and overcome common pitfalls associated with observational studies.

Research motivation

The increasing prevalence of cognitive disorders, such as MCI and dementia, poses a critical challenge in understanding the complexities of cognitive decline. With a global aging population, the urgency to address cognitive health issues becomes evident. The study aims to unravel the intricate interplay between cognitive and emotional processes in various health conditions, including neuropsychiatric disorders, and to explore the significant impact of feelings on cognitive function. This investigation is motivated by the need to fill gaps in our understanding of the causal relationship between emotions and cognition, utilizing innovative MR methodology to overcome limitations in observational studies and advance future research in this field.

Research objectives

The primary objectives of this study are to comprehensively investigate the prevalence and progression of MCI and dementia in the aging population, identifying modifiable and non-modifiable risk factors contributing to cognitive decline. Additionally, we aim to elucidate the intricate interplay between cognitive and emotional processes in various neuropsychiatric disorders, such as Alzheimer’s disease, autism, and schizophrenia. Achieving these objectives will not only enhance our understanding of the causal relationship between emotions and cognition but also provide valuable insights for future research in the field of cognitive health.

Research methods

The study employed a two-sample MR approach, utilizing univariable MR (UVMR) and subsequent multivariable MR (MVMR) analyses to comprehensively assess the causal role of feelings in cognition. Data on intelligence and feelings, sourced from publicly available Genome-Wide Association Study data and the UK Biobank, respectively, underwent meticulous selection of valid instrumental variables (IVs). Statistical analyses using R software packages included UVMR analysis employing IVW, weighted median, and MR-Egger approaches, assessing the causal relationship between feelings and intelligence. The study addressed potential correlations among feelings impacting cognition through seven UVMR analyses with a Bonferroni-corrected threshold and employed MVMR methods to assess the independent causal influence of feelings on cognition, ensuring robust investigation into their intricate relationship.

Research results

Following the meticulous elimination of SNPs in linkage disequilibrium, feelings-related SNPs were carefully chosen, meeting the F-statistics threshold for robust instrumental variables. Notably, the analysis of Happiness faced challenges with only one qualifying IV. In the UVMR analysis, fed-up feelings and sensitivity/hurt feelings showed potential impacts on cognitive function (OR 0.64, 95%CI: 0.42-0.97, P = 0.037 and OR 0.63, 95%CI: 0.43-0.92, P = 0.017, respectively). Other feelings had no significant impact, and robustness was ensured by addressing heterogeneity and pleiotropy concerns. The MVMR analysis, excluding worrier/anxious feelings, utilized 36 SNPs. Despite heterogeneity, sensitivity/hurt feelings exhibited a negative direct effect on cognitive function (ORIVW = 0.39, 95%CI: 0.17-0.90, PIVW = 0.027), with consistent results from MR-Egger and median-based analyses. Conversely, fed-up feelings, when considering other factors, showed no significant association with cognitive function. These findings deepen our understanding of the nuanced relationship between specific feelings and cognitive function, offering insights into potential causal links, while challenges in the analysis of Happiness and remaining heterogeneity indicate avenues for further exploration in future research.

Research conclusions

This study introduces a groundbreaking theory by genetically linking sensitivity/hurt feelings to cognitive decline. Employing MR as a method, the research sheds light on the causal relationships between emotions and cognitive function. Notably, it proposes that while hurt feelings have a potential causal effect on cognitive decline, fed-up feelings do not exhibit a direct causal effect after adjusting for genetic influences.

Research perspectives

Several aspects merit further exploration in future studies. Firstly, regarding the potential impact of feelings of fed-upness on cognitive function, despite the absence of a direct causal effect in this study, it is essential to delve deeper into potential moderating mechanisms or interactions with other emotional factors. Secondly, in relation to the potential association between loneliness, social isolation, and cognitive decline, further research with careful design and diverse samples is necessary to elucidate this relationship due to limitations in the current dataset. Additionally, a more in-depth investigation into the role of anxiety and worry in cognitive function is needed to address questions about their potentially bidirectional effects. Lastly, cross-cultural and cross-ethnic studies will contribute to validating the universality of these findings across different populations, providing a more comprehensive understanding of the relationship between emotions and cognition.