This study assessed the relationship between the triglyceride-glucose (TyG) index, peripheral inflammatory markers, and cognitive impairment among patients with comorbid major depressive disorder (MDD) and type 2 diabetes mellitus (T2DM). The authors frame the investigation in the context of shared immunometabolic and inflammatory mechanisms that may accelerate cognitive decline in this comorbid population and raise translational implications for Alzheimer's disease risk via neuroinflammatory pathways.
The analysis was conducted in a cross-sectional sample of 256 patients who had both MDD and T2DM. Cognitive impairment was operationalized as a Montreal Cognitive Assessment (MoCA) score below 26. The cross-sectional design means all variables were measured at a single time point; the authors emphasize that causality and temporal direction cannot be established from these data.
Peripheral inflammatory markers quantified in the study included C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). In addition, plasma biomarkers related to Alzheimer's disease pathology were assayed: the Aβ42/40 ratio and phosphorylated tau at threonine 217 (p-tau217). The TyG index was used as a surrogate indicator of insulin resistance, calculated from fasting triglyceride and glucose measurements (detailed calculation parameters were not reported in the abstract).
The authors used multivariable logistic regression and mediation analyses with adjustment for relevant covariates (specific covariates adjusted for were not detailed in the abstract). Key findings included:
Cognitive impairment (MoCA < 26) was present in 59.37% of participants.
Participants with cognitive impairment had significantly higher TyG index values and higher levels of CRP, IL-6, and TNF-α (all P < 0.001).
In multivariable analysis, TyG was independently associated with cognitive impairment (odds ratio 2.87, 95% confidence interval 1.68–4.91).
TyG showed moderate positive correlations with peripheral inflammatory markers (reported correlation coefficients r = 0.35–0.42 for CRP, IL-6, and TNF-α).
Mediation analyses tested whether peripheral inflammation statistically mediated the association between TyG and cognitive impairment. Findings reported in the abstract include:
Peripheral inflammation statistically mediated 28.41% of the TyG–cognition association, indicating that a notable portion of the association could be explained by measured systemic inflammatory markers.
Comparisons of Alzheimer's-related plasma biomarkers showed that impaired patients had lower Aβ42/40 ratios and higher p-tau217 levels (P < 0.001).
A serial mediation model evaluated an indirect pathway from TyG to cognition via inflammation and p-tau217. This serial mediation yielded an indirect effect (β = 0.10, 95% CI 0.03–0.22) and accounted for 12% of the total association between TyG and cognitive impairment.
These analytic results are statistical associations and mediation proportions derived from cross-sectional data; they do not establish causal chains but suggest possible mechanistic links worthy of further study.
The results indicate that higher TyG index, a surrogate of insulin resistance, is associated with increased likelihood of cognitive impairment in people with coexisting MDD and T2DM. The observed correlations between TyG and CRP, IL-6, and TNF-α, together with mediation analyses, support a model in which peripheral inflammation partially accounts for the relationship between metabolic dysfunction and cognition.
The presence of altered plasma Alzheimer's disease biomarkers—lower Aβ42/40 and higher p-tau217—in impaired patients further supports a potential link between metabolic–inflammatory processes and AD-related pathology. The serial mediation result suggests a possible pathway: higher TyG → increased peripheral inflammation → increased p-tau217 → worse cognition, which accounted for a minority (12%) of the total observed association in this sample.
Limitations noted by the authors (as presented in the abstract) include the cross-sectional design, which precludes causal inference and clear directionality. The abstract does not provide full details on participant selection criteria, the full set of covariates used in adjusted models, or the analytical approach for calculating the TyG index and biomarker assays; these details would be available only in the full text.
In this cross-sectional cohort of 256 patients with comorbid MDD and T2DM, a higher TyG index was statistically associated with cognitive impairment, and this association was partly mediated by peripheral inflammatory markers (CRP, IL-6, TNF-α). AD-related plasma biomarkers differed by cognitive status, and a serial mediation model including inflammation and p-tau217 accounted for a portion of the TyG–cognition association.
The authors conclude that TyG may serve as an accessible clinical marker linking metabolic dysfunction to cognitive risk through inflammatory pathways, with translational implications for understanding neuroinflammation in Alzheimer's disease risk among high-risk, comorbid populations. They recommend longitudinal studies to determine causality and temporal relationships between TyG, inflammation, AD-related biomarkers, and cognitive decline.
Note: The abstract provides summary statistics and mediation percentages but does not report full methodological details or the complete list of covariates; readers should consult the full article for complete methods and results.