Exploring the triglyceride-glucose index's role in depression and cognitive dysfunction: Evidence from NHANES with machine learning support.
Journal of affective disorders
BACKGROUND:Depression and cognitive impairments are prevalent among older adults, with evidence suggesting potential links to obesity and lipid metabolism disturbances. This study investigates the relationships between the triglyceride-glucose (TyG) index, body mass index (BMI), depression, and cognitive dysfunction in older adults, leveraging data from the NHANES survey and employing machine learning techniques. METHODS:We analysed 1352 participants aged 60-79 from the 2011-2014 NHANES dataset, who underwent cognitive function testing, depression assessments, and TyG index measurements. Multivariate linear regression and subgroup analyses were conducted to examine associations between the TyG index and depression/cognitive impairment. Machine learning models evaluated the importance of predictive factors for depression, while Mendelian randomization (MR) was employed to explore the causal relationship between BMI and depression/cognitive function. RESULTS:The TyG index was negatively associated with cognitive function scores and positively associated with depression scores in adjusted models (p < 0.001). In fully adjusted subgroup analyses, among obese individuals (BMI ≥ 28), a 100-unit increase in the TyG index was linked to a 3.79-point decrease in depression scores. Machine learning models (Xgboost, AUC = 0.960) identified BMI, TyG-BMI, gender, and comorbidities (e.g., asthma, stroke, emphysema) as key determinants of depression. MR analyses revealed a negative association between BMI and depression risk [OR: 0.9934; 95 % CI (0.9901-0.9968), p = 0.0001] and cognitive dysfunction risk [OR: 0.8514; 95 % CI (0.7929-0.9143), p < 0.05]. No evidence of heterogeneity or pleiotropy was detected. LIMITATIONS:Depression and cognitive impairments were self-reported, potentially introducing bias. The observed associations may be influenced by unmeasured confounders, necessitating further research into the underlying mechanisms. CONCLUSIONS:Our findings reveal associations between the TyG index and psychocognitive health in older adults. While these results highlight lipid metabolism as a potential factor in depression and cognitive dysfunction, further studies are needed to validate these findings and explore underlying mechanisms.
10.1016/j.jad.2025.01.051
Insulin resistance: Genetic associations with depression and cognition in population based cohorts.
Experimental neurology
Insulin resistance, broadly defined as the reduced ability of insulin to exert its biological action, has been associated with depression and cognitive dysfunction in observational studies. However, it is unclear whether these associations are causal and whether they might be underpinned by other shared factors. To address this knowledge gap, we capitalized on the stability of genetic biomarkers through the lifetime, and on their unidirectional relationship with depression and cognition. Specifically, we determined the association between quantitative measures of cognitive function and depression and genetic instruments of insulin resistance traits in two large-scale population samples, the Generation Scotland: Scottish Family Health Study (GS: SFHS; N = 19,994) and in the UK Biobank (N = 331,374). In the GS:SFHS, the polygenic risk score (PRS) for fasting insulin was associated with verbal intelligence and depression while the PRS for the homeostasis model assessment of insulin resistance was associated with verbal intelligence. Despite this overlap in genetic architecture, Mendelian randomization analyses in the GS:SFHS and in the UK Biobank samples did not yield evidence for causal associations from insulin resistance traits to either depression or cognition. These findings may be due to weak genetic instruments, limited cognitive measures and insufficient power but they may also indicate the need to identify other biological mechanisms that may mediate the relationship from insulin resistance to depression and cognition.
10.1016/j.expneurol.2019.04.001
The effect of mid-life insulin resistance and type 2 diabetes on older-age cognitive state: the explanatory role of early-life advantage.
Diabetologia
AIMS/HYPOTHESIS:Type 2 diabetes, hyperglycaemia and insulin resistance are associated with cognitive impairment and dementia, but causal inference studies using Mendelian randomisation do not confirm this. We hypothesised that early-life cognition and social/educational advantage may confound the relationship. METHODS:From the population-based British 1946 birth cohort, a maximum number of 1780 participants had metabolic variables (type 2 diabetes, insulin resistance [HOMA2-IR] and HbA) assessed at age 60-64 years, and cognitive state (Addenbrooke's Cognitive Examination III [ACE-III]) and verbal memory assessed at age 69 years. Earlier-life measures included socioeconomic position (SEP), cognition at age 8 years and educational attainment. Polygenic risk scores (PRSs) for type 2 diabetes were calculated. We first used a PRS approach with multivariable linear regression to estimate associations between PRSs and metabolic traits and later-life cognitive state. Second, using a path model approach, we estimated the interrelationships between earlier-life measures, features of mid-life type 2 diabetes and cognitive state at age 69 years. All models were adjusted for sex. RESULTS:The externally weighted PRS for type 2 diabetes was associated with mid-life metabolic traits (e.g. HOMA2-IR β = 0.08 [95% CI 0.02, 0.16]), but not with ACE-III (β = 0.04 [-0.02, 0.90]) or other cognitive outcomes. While there was an association between HOMA2-IR and subsequent ACE-III (β = -0.09 [-0.15, -0.03]), path modelling showed no direct effect (β = -0.01 [-0.06, 0.03]) after accounting for the association between childhood SEP and education with HOMA2-IR. The same pattern was observed for later-life verbal memory. CONCLUSIONS/INTERPRETATION:Associations between type 2 diabetes and mid-life metabolic traits with subsequent cognitive state do not appear causal, and instead they may be explained by SEP in early life, childhood cognition and educational attainment. Therefore, glucose-lowering medication may be unlikely to combat cognitive impairment in older age.
10.1007/s00125-019-4949-3
Association Between Plasma LRG1 and Lower Cognitive Function in Asians With Type 2 Diabetes Mellitus.
The Journal of clinical endocrinology and metabolism
CONTEXT:Leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in the pathogenesis of diabetic complications, but its association with cognitive function remains unclear. OBJECTIVE:Our primary objective is to investigate the longitudinal association between LRG1 and cognitive function in patients with type 2 diabetes mellitus (T2DM). Secondarily, we determine the causal relationship using Mendelian randomization (MR) and the role of arterial stiffness as a potential mediator. METHODS:T2DM patients (n = 1039; age = 64.1 ± 6.4 years) were followed-up for 5.3 ± 1.2 years. Plasma LRG1 was measured at baseline using enzyme-linked immunosorbent assay. Baseline and follow-up cognitive function was assessed using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). One-sample MR was performed with rs4806985 as plasma LRG1-associated single-nucleotide polymorphism. Mediation analysis was performed to examine if pulse wave velocity (PWV), an arterial stiffness index, mediated the association between plasma LRG1 and follow-up cognitive function. RESULTS:Elevated baseline natural log (Ln)-transformed LRG1 was inversely associated with baseline and follow-up RBANS total score with adjusted coefficients -1.38 (95% CI -2.55 to -.21; P = .021) and -1.38 (95% CI -2.70 to -.07; P = .039), respectively. Genetically predicted higher levels of plasma LRG1 was associated with lower follow-up RBANS total score with coefficient -7.44 (95% CI -14.14 to -.74; P = .030) per unit increase in LnLRG1. Higher PWV accounted for 27.7% of the association between LnLRG1 and follow-up RBANS total score. CONCLUSION:Baseline plasma LRG1 was associated with lower cognitive function at follow-up in patients with T2DM, mediated by PWV. MR analysis provided evidence of an association between genetically influenced plasma LRG1 and lower cognitive function at follow-up.
10.1210/clinem/dgad768
Exploring the therapeutic mechanism of Banxia Xiexin Decoction in mild cognitive impairment and diabetes mellitus: a network pharmacology approach.
Metabolic brain disease
The incidence of mild cognitive impairment (MCI) and diabetes mellitus (DM) is increasing year by year. Clinical findings show that Banxia Xiexin Decoction (BXD) can be combined to treat MCI and DM. However, the principle and mechanism of BXD in treating MCI and DM remain unclear. In this study, to explore the common mechanism of BXD in treating MCI and DM by using the method of network pharmacology. Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) was used to screen the main active components of BXD, as well as to predict and screen its potential targets. Using Online Mendelian Inheritance in Man (OMIM), Therapeutic Target Database (TTD), DisGeNET, GeneCards to select the target proteins of two diseases, and intersecting the drug target and the disease target to obtain the common target of drug diseases, which is imported into cytoscape software to draw the network diagram of "drug components-target diseases" and the interaction network diagram between the common target proteins. According to the Database for Annotation, Visualization and Integrated Discovery (DAVID) database, we analyzed the common targets using two methods, gene ontology Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway enrichment analysis and Gene Ontology (GO) function enrichment analysis, as well as studied the interaction mechanism of the two diseases, with the results validated using molecular docking. A total of 267 main active components of BXD were screened, together with the two diseases shared 233 common targets. The top five key targets identified by the topological analysis were TP53, AKT1, STAT3, TNF, and MAPK3. Go enrichment results indicated that it was primarily related to response to drug, extracellular space, enzyme binding, RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding. t KEGG enrichment pathway analysis identified 20 significant pathways, the majority of which are AGE-RAGE signaling pathways in diabetic complications, lipid and atherosclerosis, fluid shear stress and atherosclerosis, IL-17 signaling pathway, TNF signaling pathway, and so on. The results of molecular docking revealed that the key components of BXD, baicalein, licochalcone a, quercetin, and naringenin, had strong binding ability with core targets TP53, AKT1, STAT3, TNF, MAPK3. BXD can treat MCI and DM by multi-targets and multi-channels,and plays a role of "homotherapy for heteropathy" mainly through response to drug, positive regulation of gene expression, extracellular space and enzyme binding and other ways.
10.1007/s11011-023-01270-y
Type 2 Diabetes and Cognitive Status in the Health and Retirement Study: A Mendelian Randomization Approach.
Frontiers in genetics
BACKGROUND:Type 2 diabetes mellitus (T2DM) and dementia are leading causes of mortality and disability in the US. T2DM has been associated with dementia; however, causality has not been clearly established. This study tested inferred causality between T2DM and dementia status using a Mendelian randomization approach. METHODS:Participants (50+ years) from the 2010 wave of the Health and Retirement Study of European or African genetic ancestry were included ( = 10,322). History of T2DM was self-reported. Cognitive status (dementia, cognitive impairment non-dementia, or normal cognition) was defined from clinically validated cognitive assessments. Cumulative genetic risk for T2DM was determined using a polygenic score calculated from a European ancestry T2DM genome-wide association study by Xue et al. (2018). All models were adjusted for age, sex, education, -ε4 carrier status, and genetic principal components. Multivariable logistic regression was used to test the association between cumulative genetic risk for T2DM and cognitive status. To test inferred causality using Mendelian randomization, we used the inverse variance method. RESULTS:Among included participants, 20.9% had T2DM and 20.7% had dementia or cognitive impairment. Among European ancestry participants, T2DM was associated with 1.66 times odds of cognitive impairment non-dementia (95% confidence interval: 1.55-1.77) relative to normal cognition. A one standard deviation increase in cumulative genetic risk for T2DM was associated with 1.30 times higher odds of T2DM (95% confidence interval: 1.10-1.52). Cumulative genetic risk for T2DM was not associated with dementia status or cognitive-impaired non-dementia in either ancestry ( > 0.05); lack of association here is an important assumption of Mendelian randomization. Using Mendelian randomization, we did not observe evidence for an inferred causal association between T2DM and cognitive impairment (odds ratio: 1.04; 95% confidence interval: 0.90-1.21). DISCUSSION:Consistent with prior research, T2DM was associated with cognitive status. Prevention of T2DM and cognitive decline are both critical for public health, however, this study does not provide evidence that T2DM is causally related to impaired cognition. Additional studies in other ancestries, larger sample sizes, and longitudinal studies are needed to confirm these results.
10.3389/fgene.2021.634767
Diabetic Retinopathy and Brain Structure, Cognition Function, and Dementia: A Bidirectional Mendelian Randomization Study.
Journal of Alzheimer's disease : JAD
BACKGROUND:Accumulating evidence has demonstrated that hyperglycemia is a possible risk factor for mild cognitive impairment or Alzheimer's disease. Diabetic retinopathy (DR) has been identified as a risk factor for dementia in patients with diabetes. OBJECTIVE:This study aimed to investigate the causal relationships between DR and brain structure, cognitive function, and dementia. METHODS:We performed bidirectional two-sample Mendelian randomization for DR, brain structure, cognitive function, and dementia using the inverse-variance weighted method. RESULTS:Inverse-variance weighted analysis showed the association of DR with vascular dementia (OR = 1.68, 95% CI: 1.01-2.82), and dementia was significantly associated with the increased risk of non-proliferative DR (NPDR) (OR = 1.76, 95% CI: 1.04-2.98). Furthermore, better cognitive performance was significantly associated with a reduced risk of NPDR (OR = 0.85, 95% CI: 0.74-0.98). No association was observed between DR and brain structure. CONCLUSIONS:These findings suggest that the association of DR with vascular dementia. The reciprocal effect of cognitive performance and dementia on NPDR risk highlights the potential benefits of dementia prevention for reducing the burden of DR.
10.3233/JAD-231022
Type 2 diabetes, glycaemic traits, structural brain capacity and cognitive function: A Mendelian randomization analysis.
Diabetes, obesity & metabolism
AIM:To estimate the causal associations of type 2 diabetes and glycaemic traits with cognitive function, and to determine the potential mediating role of various brain imaging-derived phenotypes (IDPs) using Mendelian randomization (MR) analysis. METHODS:Using publicly available summary data, we performed a series of univariable and multivariable MR analysis to infer causality. Two-step MR analysis was then conducted in turn to evaluate the potential mediating role of each brain IDP. RESULTS:There was no evidence of causal associations between type 2 diabetes and cognitive function outcomes. Each 1-SD unit higher genetically predicted fasting proinsulin was associated with worse cognitive performance, as evidenced by both univariable (beta: -0.022; 95% confidence interval [CI] -0.038, -0.007) and multivariable MR analysis (beta: -0.027; 95% CI -0.048, -0.005). In addition, the univariable MR analysis identified several causal associations between fasting proinsulin and brain IDPs, and between brain IDPs and cognitive performance. The inverse association of genetically predicted fasting proinsulin with cognitive performance did not attenuate after adjusting for each of the brain IDPs in multivariable MR analysis. CONCLUSIONS:The present MR study provided credible evidence for the causal association between genetically predicted fasting proinsulin and cognitive function, informing a potential diagnosis and intervention target for patients with cognitive impairment. No significant brain IDP included in this study was identified as lying on the causal pathway from fasting proinsulin to cognitive performance. Future research involving more specific and granular brain IDP or other brain process is warranted to explore the potential biological mechanism underlying the association.
10.1111/dom.15702
Identification of adipose tissue-derived exosomal microRNA as a novel causal biomarker for cognitive impairment in type 2 diabetes mellitus: Triangulating evidence from Mendelian randomization and multicentre population studies.
Diabetes, obesity & metabolism
AIMS:To explore serum exosomal microRNAs (miRNAs) as risk biomarkers for early detection of cognitive impairment in type 2 diabetes mellitus (T2DM) patients. MATERIALS AND METHODS:This study included two phases: a discovery phase and a validation phase. To detect adipose tissue exosomal biomarkers for T2DM patients, small RNA sequencing was conducted on a discovery population consisting of six T2DM patients and five subjects with normal glucose tolerance. To identify miRNAs with causal effects on cognitive impairment, Mendelian randomization (MR) analysis using publicly available genome wide association studies (GWAS) datasets was performed. Relationships between serum exosomal miRNAs and cognitive impairment were evaluated in a training population of 207 T2DM patients, and further validated in an external population of 101 T2DM patients from multiple centres. RESULTS:In the discovery phase, 13 exosomal miRNAs were significantly upregulated in adipose tissue of T2DM patients. MR analyses identified that increased miR-125a-5p was causally associated with increased Alzheimer's disease (AD) risk (OR = 1.231, 95% CI 1.062-1.426). In the validation phase, higher serum exosomal miR-125a-5p levels were related to increased amnestic mild cognitive impairment (aMCI) risk (OR = 1.066, 95% CI 1.030-1.103) and reduced left hippocampal body volume (r = -0.189, p < 0.05), achieving an area under the curve (AUC) of 0.728 for identifying aMCI in T2DM patients. External validation confirmed a diagnostic AUC of 0.738. CONCLUSIONS:Serum exosomal miR-125a-5p derived from adipose tissue can serve as a causal biomarker for cognitive impairment in T2DM patients.
10.1111/dom.16121