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Dementia and Cognitive Impairment Research · Journal article
Frontiers in Aging Neuroscience · September 9, 2026
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This cross-sectional study reports that midlife metabolic syndrome is associated with reduced within-network connectivity in the default mode network (DMN), with abdominal obesity and low HDL cholesterol as the primary contributors. Reduced DMN connectivity showed an association with poorer verbal fluency, but effect sizes are small and the study is observational without causal or longitudinal evidence.
Cross-sectional observational study with resting-state fMRI and neuropsychological testing. Cognitively unimpaired, community-dwelling adults aged 40–65 years; 73 with metabolic syndrome, remainder without.. Intervention: Metabolic syndrome status (observed; not experimentally assigned). Compared with: Cognitively unimpaired adults without metabolic syndrome. n = 223.
MetS participants showed reduced within-network connectivity in DMN (adjusted p = 0.038, partial η² = 0.035) Abdominal obesity associated with reduced DMN connectivity (adjusted p = 0.027, partial η² = 0.029) Low HDL cholesterol associated with reduced DMN connectivity (adjusted p = 0.002, partial η² = 0.058)
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Clinicians should recognize that these findings are exploratory associations in a cross-sectional design and do not establish causation or clinical utility. The small effect sizes and lack of hard clinical outcomes mean this work is hypothesis-generating rather than immediately actionable for midlife metabolic syndrome screening or cognitive risk assessment.
Cross-sectional observational study with modest effect sizes (partial η² = 0.035–0.058) and surrogate neuroimaging endpoints; findings are exploratory and require confirmation in prospective designs.
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Clinicians should recognize that these findings are exploratory associations in a cross-sectional design and do not establish causation or clinical utility. The small effect sizes and lack of hard clinical outcomes mean this work is hypothesis-generating rather than immediately actionable for midlife metabolic syndrome screening or cognitive risk assessment.
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Objective Metabolic syndrome (MetS) may amplify neural vulnerability via vascular and inflammatory pathways. Existing literature suggests there are alterations to functional brain network organization in adults with MetS, though the specific patterns and their relation to cognitive vulnerabilities warrant further investigation, particularly in a midlife sample. Method Cognitively unimpaired, community-dwelling adults ( N = 223; ages 40–65; MetS = 73) were included. Resting-state fMRI data were preprocessed with fMRIPrep and analyzed using the Schaefer 400-parcel atlas. Functional connectivity (FC) metrics included within- and between-network connectivity, system segregation, modularity, and global efficiency. Cognitive performance was measured via neuropsychological tests for memory and executive functioning. Generalized linear models (adjusted for age, sex, framewise displacement) were used to examine group differences in FC metrics and associations between FC metrics and cognitive performance. Results MetS participants showed reduced within-network connectivity in the default mode network (DMN; adjusted p = 0.038, partial η 2 = 0.035). Follow-up component-level analyses indicated abdominal obesity and low HDL cholesterol were associated with reduced connectivity in DMN (abdominal obesity: adjusted p = 0.027, partial η 2 = 0.029; cholesterol: adjusted p = 0.002, partial η 2 = 0.058). Reduced DMN connectivity was associated with poorer verbal fluency (adjusted p = 0.026, partial R 2 = 0.037). Exploratory analyses identified age and sex as factors that interacted with MetS group to influence FC metrics ( p ’s < 0.050, partial η 2 ’s = 0.020–0.030). Conclusion Midlife MetS was associated with modest reductions in within-network DMN connectivity, with abdominal obesity and low HDL cholesterol as the primary contributing MetS components. Reduced DMN connectivity was associated with poorer verbal fluency performance. These findings suggest that subtle differences in higher-order functional brain network organization associated with metabolic syndrome can be detected during midlife and are related to cognitive functioning, highlighting the importance of prevention and intervention of cardiometabolic risk in midlife to preserve network integrity and cognitive health.
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