Associations between metabolic syndrome and markers of brain pathology: the role of sex- differences

Abstract

Introduction: Cardiovascular and metabolic disorders rarely occur alone in old age but often cluster together in the so-called metabolic syndrome (MetS). While individual components of MetS, such as obesity, hypertension, and diabetes, have been linked to dementia and brain atrophy, their combined impact on cognitive and brain aging remains poorly explored. Our current study aims to investigate the relationship between MetS and markers of neurodegenerative and cerebrovascular pathologies while also considering potential differences between sexes. Methods: We included 741 cognitively intact septuagenarians from the Gothenburg H70-Birth cohort 1944 with available brain MRI (286 had cerebrospinal fluid [CSF] sampling). MetS was defined by standard criteria (at least three among adiposity, raised blood pressure, blood glucose, reduced HDL-cholesterol, elevated triglycerides). MRI markers of brain pathology included overall (mean cortical thickness) and Alzheimer's disease (AD; average cortical thickness in signature areas) neurodegeneration, cerebral small vessel disease (SVD; markers such as white matter hyperintensity, lacunes, microbleeds, and perivascular spaces, and SVD score) and DTI's white- matter microstructural changes (fractional anisotropy). CSF biomarkers included t-tau, neurofilament light, neurogranin (overall neurodegeneration), Aβ42 and p-tau (AD), and CSF/serum albumin ratio (blood-brain barrier integrity). Analyses included regression models and stratification by sex. Results: Overall, 410 participants (53%, n=196 women) had MetS. MetS was associated with increased odds of overall (OR=2.0, 95%CI 1.4–2.9) and AD-related (OR=1.8, 95%CI 1.4–2.6) neurodegeneration, high SVD burden (presence of ≥3 SVD compared to none: OR=2.1, 95%CI 1.1–4.3), and white-matter microstructural changes. Within the SVD markers, MetS was particularly related to white matter hyperintensities, lacunes, and perivascular spaces in basal ganglia. Furthermore, MetS was associated with alterations of blood-brain barrier integrity in the CSF subsample. Sex differences showed increased SVD burden in men with MetS, especially enlarged perivascular spaces (OR=2.9, 95%CI 1.7–5.0), while no differences were observed in women. No associations were detected with amyloid and tau. Discussion: MetS in late life is linked to neurodegenerative and cerebrovascular pathologies, with SVD more prominent in men with MetS, but not in women.