Linking metabolic syndrome, cerebral small vessel disease, and cognitive health: insights from a subclinical population study using TriNetX

Metabolic syndrome (MetS) has been linked to accelerated cognitive decline and Alzheimer’s disease and related dementias (ADRDs) via cerebral small vessel disease (CSVD); however, this relation in MetS without overt cardiometabolic disease comorbidities is unknown and may represent a population amenable to preventative strategies. Our study aimed to determine risk profiles for neurocognitive decline and ADRDs in early-stage MetS with evidence of CSVD using the TriNetX electronic health records (EHR) research network. Patients aged 50 to 80 years old meeting MetS criteria were identified utilizing TriNetX data from 76 healthcare organizations. Propensity score matching controlled for demographic and confounding factors. Cohorts included MetS-only, non-MetS, and a MetS subset with evidence of CSVD (MetS-CSVD) created by clustering relevant ICD-codes for diagnoses, imaging, and lab work. Contingency analyses determined odds of developing neurocognitive decline, ADRDs, and CSVD in MetS vs non-MetS and MetS-CSVD vs. MetS-only, using odd ratios with 95% confidence intervals (p-value < 0.05). After propensity score matching, there were 57,347 men and 52,259 women in each of the MetS and non-MetS cohorts and 2,810 men and 2,862 women in each of the MetS-CSVD and MetS-only cohorts. Compared to non-MetS, the MetS cohort exhibited higher odds of developing neurocognitive decline (men: RR = 1.82, p < 0.001; women: RR = 1.34, p = 0.015) and CSVD (men: RR = 2.83, p < 0.001; women: RR = 2.14, p < 0.001), but only women exhibited significantly higher odds of developing ADRDs (men: RR = 1.13, p = 0.38; women: RR = 1.52, p < 0.001). Compared to MetS-only, the MetS-CSVD showed elevated odds in developing neurocognitive decline (men: RR = 1.81, p = 0.040; women: RR = 1.87, p = 0.018) and ADRDs (men: RR = 2.39, p = 0.009; women: RR = 1.65, p = 0.041). A large, predominantly US, sample of subclinical MetS demonstrated heightened odds for developing neurocognitive decline and ADRDs, with even higher odds when evidence of CSVD was also present. TriNetX facilitated a robust exploration of these associations, and our findings warrant further investigation of interventions that target this subclinical at-risk population.