Aug 2026· Medicine· Vol 105· 0 citations· 47 references
Medicine
TL;DR
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.
Abstract
Observational studies link psychiatric disorders to Alzheimer disease (AD), but whether these associations are causal remains unclear due to confounding and reverse causality. We aimed to dissect these relationships using genetic evidence. We performed a two-sample Mendelian randomization (MR) study to assess the causal effects of 7 psychiatric and neurodevelopmental disorders on AD and its subtypes. The primary analysis utilized the inverse-variance weighted (IVW) method, supported by comprehensive sensitivity analyses (MR Steiger test, MR-Egger, and MR-PRESSO) and a supplementary analysis excluding single nucleotide polymorphisms (SNPs) associated with potential confounders. Depression showed a significant causal association with late-onset AD (odds ratio [OR] = 1.0736, 95% confidence interval [CI]: 1.0084–1.1431, P = .0264). No significant causal associations were found for other psychiatric disorders (all P > .05). A directionality test conducted by MR Steiger confirmed our estimation of potential causal direction (P < .001). Sensitivity analyses excluding pleiotropic SNPs yielded consistent results. The causal association for depression and late-onset AD remained significant after excluding pleiotropic SNPs linked to confounders (OR = 1.0726, 95% CI: 1.0069–1.1425, P = .03). Our study provides genetic evidence supporting a causal role for depression in the etiology of late-onset AD, a link not observed for other major psychiatric disorders tested. These findings highlight the specific importance of managing depression as a potential strategy for mitigating AD risk and suggest distinct etiological pathways between different mental health conditions and neurodegeneration.
This study aimed to investigate the genetic causality between cataract (senile and other types) and psychiatric disorders using Mendelian randomization (MR). We performed a bidirectional 2-sample MR analysis using genome-wide association studies summary data. Primary analysis employed inverse-variance weighted, MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses included Cochran Q, MR-pleiotropy residual sum and outlier, MR-Egger intercept, and leave-one-out tests to assess heterogeneity and pleiotropy. Forward MR analysis revealed a suggestive causal effect of other cataract on anxiety (inverse-variance weighted odds ratio [OR] = 0.99, 95% confidence interval: 0.98–1.00, P = .043), though unsupported by other methods. MR-Egger and weighted median suggested potential associations between other cataract and bipolar disorder (P < .05). No significant links were found between senile cataract and psychiatric disorders. Reverse MR analysis showed no consistent causal effects, except for anxiety disorder on other cataract (MR-Egger OR = 8.04, P = .040; weighted median OR = 2.99, P = .047). Sensitivity analyses confirmed robustness despite heterogeneity. This study provides evidence of a potential causal relationship between other cataract and anxiety, though findings were method-dependent. No significant associations were observed for senile cataract or most psychiatric disorders.
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.
N. Akbarian, M. Ebrahimi, F. D. Dos Santos et al.· medRxiv· 0 citations
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
Genetic evidence of potential associations between antidepressant use and increased risks of Hashimoto's thyroiditis and hypothyroidism is provided, and support consideration of thyroidfunction monitoring in patients receiving antidepressant treatment, particularly those with pre-existing thyroid risk factors.
Yingxian Ling, Qisong Chen· Actas espanolas de psiquiatr...· 0 citations
Background The relationship between sleep disorders and psychiatric disorders has been extensively studied in epidemiological research. However, whether specific sleep-related traits are associated with psychiatric disorders through potential causal mechanisms remains incompletely understood. Methods This study employed a two-sample Mendelian randomization (MR) analysis method to investigate potential causal associations between six sleep-related traits and eleven psychiatric disorders. MR analyses were performed using inverse variance weighting (IVW), weighted median, and MR-Egger methods. Cochran’s Q test was used to assess heterogeneity, while MR-Egger intercept analysis and MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlie) were applied to evaluate potential horizontal pleiotropy. In addition, a retrospective observational study was conducted using clinical data from the First Affiliated Hospital of Soochow University between November 2023 and December 2025. Logistic regression analysis was performed to assess the association between sleep disorders and psychiatric disorders. Results MR analyses identified potential associations between sleep-related traits and psychiatric disorders. Genetically predicted insomnia was associated with an increased risk of major depressive disorder (OR = 2.22, 95% CI: 1.66–2.97, P < 0.001). In the retrospective clinical cohort, individuals with sleep disorders exhibited a higher prevalence of psychiatric disorders (adjusted OR = 1.71, 95% CI: 1.09–2.69, P = 0.020). The consistency between genetic evidence and clinical observational findings provides complementary support for the clinical relevance of the observed association. Conclusion By integrating MR analyses with retrospective clinical observational data, this study provides genetic and clinical evidence supporting an association between sleep disorders and psychiatric disorders. These findings suggest that sleep disturbances may represent potential modifiable factors associated with mental health outcomes and highlight the importance of sleep-related interventions in psychiatric disease prevention and management.
Xin Wu, Mei Chang, Bingyi Song et al.· Frontiers in Psychiatry· 0 citations
This study aimed to investigate the relationship between cognitive performance and the pathogenesis of osteoarthritis (OA) and rheumatoid arthritis (RA), emphasizing the role of plasma metabolites and proteins. Using National Health and Nutrition Examination Survey 2011 to 2014 data, cognitive functions of participants aged >60 years were evaluated, examining their correlation with OA and RA. Covariates, including demographics and health-related factors, were included. Genetic causality was determined using Mendelian randomization with single-nucleotide polymorphisms from the UK Biobank and other datasets. Linkage disequilibrium score regression and colocalization analyses were performed to validate genetic correlations and identify shared genetic variants. Cognitive performance was assessed in 387 and 237 OA and RA patients, respectively, compared with 1569 controls. OA patients had significantly lower Consortium to Establish a Registry for Alzheimer’s Disease-4 cognitive scores (odds ratio [OR]: 0.962, P = .001), while RA patients had lower digit symbol substitution test scores (OR: 0.980, P = .001). Mendelian randomization revealed a negative causal association between cognitive performance and OA (OR: 0.767, P = .001) and RA (OR: 0.712, P = .006). Plasma components, including bone sialoprotein 2, NKP44, and the metabolite X-11478, were causally linked to cognitive performance. Mediation analysis identified mediators, including FGR and 6CKine. Linkage disequilibrium score regression revealed a genetic correlation between cognitive performance and OA and RA, with colocalization analysis identifying shared genetic factors. GDF5 and TRAIP were associated with OA, and EHMT2 with RA. Cognitive factors, influenced by plasma components, may influence OA and RA onset. This relationship highlights the need for integrated interventions targeting cognitive function and joint health.
Xin Wang, Linfang Deng, Tianyi Wang et al.· Medicine· 0 citations