Associations between metabolic syndrome and markers of brain pathologies: the role of sex‐differences

Abstract

AbstractBackgroundIn old age, cardiovascular and metabolic disorders rarely occur in isolation, but rather cluster together, in the so‐called metabolic syndrome (MetS). Although individual MetS components (obesity, hypertension, diabetes, and dyslipidemia) have been linked to dementia, their combined effect on cognition remains poorly explored. We recently showed that MetS was associated with clinically relevant cognitive decrements in otherwise cognitively healthy septuagenarians. However, the mechanistic underpinnings are unknown. This study investigates the association between MetS and markers of neurodegenerative and cerebrovascular pathologies, considering sex‐differences.MethodWithin the Gothenburg H70‐Birth cohort 1944, we included 741 cognitively intact septuagenarians with available brain MRI (n = 286 with cerebrospinal fluid [CSF] samples). MetS was identified according to standard criteria as the presence of at least three conditions: central obesity, raised blood pressure, raised blood glucose, reduced HDL‐cholesterol, or elevated triglycerides. MRI markers of brain pathology included overall (mean cortical thickness) and Alzheimer’s disease (AD; average cortical thickness in signature areas) neurodegeneration as well as cerebrovascular pathology including small vessel disease (SVD) and DTI’s microstructural white‐matter changes. CSF biomarkers included t‐tau, neurofilament light, and neurogranin (overall neurodegeneration), Aβ42 and p‐tau (AD), and CSF/serum albumin ration (blood‐brain barrier integrity). Analyses included linear, quantile, and logistic regression models as well as interaction and stratification by sex.ResultOverall, 410 participants (53%) had MetS; 196 were women. In multi‐adjusted regressions (by sex, education, heart disease, and APOE‐ɛ4 allele), MetS was associated with increased likelihood of neurodegeneration (OR = 2.0, 95%CI 1.4–2.9) and AD (OR = 1.8, 95%CI 1.4–2.6), high SVD burden (presence of ≥3 SVD compared to none: OR = 2.1, 95%CI 1.1‐4.3), and greater microstructural white‐matter changes. In the CSF sample, MetS was associated with higher CSF/serum albumin ratio. In analyses stratified by sex, men with MetS (reference: no‐MetS) had increased odds of higher SVD burden, particularly of enlarged perivascular spaces (ePVS; OR = 2.9, 95%CI 1.7–5.0). Such differences were not observed between women with and without MetS. No associations were observed between MetS and amyloid and tau biomarkers.ConclusionMetS in late‐life increased the likelihood of neurodegenerative and cerebrovascular pathologies. SVD, especially ePVS, appears more prominent in men with MetS than women.