Investigating the Causal Relationship between Neuroticism and Alzheimer's Disease Using Mendelian Randomization and the Mediating Role of Modifiable Risk Factors
Depression, hypertension, hypertension, and alcohol consumption were identified as significant mediators of the relationship between higher neuroticism and increased AD risk, suggesting that the neuroticism-AD relationship is unlikely to be causal.
Abstract
Neuroticism, a personality trait characterized by the predisposition to experience intense and frequent negative emotions, has been associated with an increased risk of Alzheimer's disease (AD). However, the mechanisms underlying this association remain unclear. Our study investigated two potential pathways: (1) whether the relationship between neuroticism and AD is causal, and (2) whether it is mediated by health and behavioral factors associated with both neuroticism and AD risk. To assess causality, a two-sample Mendelian randomization (MR) was employed using publicly available genome-wide association studies (GWAS) for neuroticism (Nagel et al., 2018) and AD (Bellenguez et al., 2022). Mediation analysis was conducted in a subset of UK Biobank participants aged 60 and older, including 121,825 controls (mean age = 63.9 {+/-} 2.81; 61,993 females or 50.9%) and 1,277 individuals with AD (mean age = 65.6 {+/-} 2.71; 628 females or 49.2%). All participants had complete data on neuroticism and the potential mediators. MR analysis suggested that the neuroticism-AD relationship is unlikely to be causal. However, depression ({beta}=0.048, p=3x10-4), hypertension ({beta}=0.005, p=2x10-4), and alcohol consumption ({beta}=0.001, p=1x10-5) were identified as significant mediators of the relationship between higher neuroticism and increased AD risk. Overall, the association between neuroticism and AD may be largely explained by modifiable health and behavioral factors rather than a direct causal effect. A better understanding of these mediating pathways may inform targeted prevention and therapeutic strategies to reduce AD risk.
Genetic evidence supporting a causal role for depression in the etiology of late-onset AD is provided, a link not observed for other major psychiatric disorders tested and highlighted the specific importance of managing depression as a potential strategy for mitigating AD risk.
INTRODUCTION/BACKGROUND
Recent studies show that depression often occurs years before Alzheimer's disease onset in many older adults. However, it is unclear whether this link reflects a causal relationship.
MATERIALS AND METHODS
Summary statistics from Genome-Wide Association Studies (GWAS) of depression and Alzheimer's disease were utilized. Data associated with broad depression included up to 407,746 Europeans, and data associated with major depression disorder included up to 480,359 Europeans; the corresponding Alzheimer's disease associations from consortia included up to 488,285 European participants in the UK Biobank. Two-sample Mendelian randomization analyses served as our primary approach, with additional three-sample analyses performed to validate the findings.
RESULTS
In the sample of 407,746 participants, genetically predicted levels of broad depression showed no significant association with Alzheimer's disease risk (odds ratio, 1.00007; p = 0.908). As for the sample of 480,359 participants associated with major depressive disorder, the result was consistent (odds ratio, 0.99918, p = 0.138) with findings from broad depression. Secondary analyses present consistent results with primary findings. Statistically significant bias from pleiotropy or genetic confounding was not detected in sensitivity analyses.
DISCUSSION
The study's findings do not support a causal role of depression in AD and are more consistent with depression reflecting early disease processes or shared mechanisms.
CONCLUSION
This study's Mendelian randomization approach revealed no causal relationship between depression and Alzheimer's disease, consistent with depression reflecting early disease manifestations rather than a direct causal factor, and hinting at possible shared pathological processes in both conditions.
Chongyang Liu, Bao-Peng Liu, F. Pan et al.· Current Alzheimer Research· 0 citations
BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder resulting from a complex interplay of multiple factors. Recent hypotheses suggest a potential role of selenium and selenoproteins in AD pathogenesis. However, the causality relationship between them remains to be elucidated.ObjectiveThis study investigates the causal link between selenoproteins and AD risk.MethodsWe analyzed the data by leveraging genome-wide association studies from European cohorts (90,338 AD patients and 1,036,225 controls) and expression quantitative trait loci (eQTLs) from eQTLGen (31,684 individuals) and GTEx v8 (838 individuals). Mendelian randomization and summary data-based Mendelian randomization were applied to assess the potential causal associations between selenoproteins and AD. To further confirm these genetic associations at the clinical level, we conducted a case-control study to evaluate the levels of four differentially expressed selenoproteins in peripheral blood in individuals with AD and cognitively normal controls.ResultsOur analysis revealed that four selenoproteins, including selenoprotein S (SEPH2) and selenoprotein M (SELENOM), glutathione peroxidase 4 (GPX4) and thioredoxin reductase 2 (TXNRD2), were correlated with a decreased risk of AD. The levels of GPX4, SELENOM, and TXNRD2 were found to be significantly downregulated in AD patients compared to controls in the case-control validation study, supporting the change identified in our genetic analysis.ConclusionsThis study provides genetic and clinical evidence that specific selenoproteins are associated with a decreased risk of AD. The findings highlight the potential role of these proteins in AD pathophysiology and suggest their promise as biomarkers or therapeutic targets, warranting further investigation.
Peixin Jiang, Sibo Peng, Yanling Huang et al.· Journal of Alzheimer's Disea...· 0 citations