The global incidence of cognitive decline due to cerebral small vessel disease is expected to rise significantly with ageing populations [1], underscoring the critical need to understand and address modifiable risk factors for cognitive decline. Among these, midlife cardiovascular risk factors have long been recognised as significant contributors to cognitive impairment and dementia [2,3]. A subset of cardiovascular risk factors, collectively known as the metabolic syndrome (METS), include obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C) levels, hypertension, hyperglycaemia, and waist circumference [3,4]. Over the past decades, a wealth of evidence has demonstrated the detrimental effects of METS components on brain health [5]. The modifiability of these risk factors underscores the potential for early prevention strategies to mitigate cognitive decline.

The relationship between METS and brain health is complex and multifaceted. Recent studies suggest that METS and brain structural alterations may share common underlying mechanisms, including atherosclerosis, endothelial dysfunction, oxidative stress, and small vessel injuries [[5], [6], [7], [8]]. These shared pathways may exacerbate both metabolic and cognitive decline over time [9]. While extensive research has examined the effect of METS on brain structure, fewer studies have investigated its effects on cerebral haemodynamics, an equally crucial aspect of brain function. Traditionally, METS is diagnosed when an individual has three or more of the following traits: excessive abdominal fat, elevated blood pressure, high triglycerides, elevated blood glucose, or reduced HDL-C [4]. However, this approach fails to account for the severity of each risk factor and its overall impact on metabolic health. Recent research has shown that higher severity of each risk factor is associated with accelerated neurodegeneration [[10], [11], [12]]. Recognising these limitations, a recently developed continuous score known as the metabolic syndrome severity score (cMETS), might offer a more nuanced and accurate assessment of metabolic health [13].

Large-scale studies, such as the UK Biobank, have found strong associations between METS components and various brain health markers, including lower brain volume, increased white matter hyperintensities, and poorer cognitive performance [5,14]. Additionally, research has demonstrated that older adults with multiple METS-associated risk factors exhibit reduced cerebral blood flow (CBF) in brain regions vulnerable to ageing and vascular damage [[15], [16], [17]]. These findings highlight the importance of considering the cumulative impact of metabolic risk factors on brain function and cerebral haemodynamics.

Previous research has demonstrated important relationships between individual components of METS and CBF, as measured through MRI arterial spin labelling (ASL) techniques [[16], [17], [18], [19], [20], [21]]. Building upon these findings, examining the spatial coefficient of variation (sCoV) alongside CBF provides additional insights into macrovascular efficiency, offering a more comprehensive understanding of cerebral haemodynamics. This combined approach of analysing cerebral haemodynamics could reveal crucial mechanisms linking metabolic syndrome to cerebrovascular health, potentially identifying early markers of dysfunction before the clinical manifestation of cognitive decline. To our knowledge, this is the first study to examine the relationship between overall cMETS and cerebral haemodynamics using both CBF and sCoV measurements. While extensive research has examined the impact of METS on brain structure, fewer studies have investigated its effects on cerebral haemodynamics, an equally crucial aspect of brain function.

Therefore, we aim to investigate the relationship between cMETS and cerebral haemodynamics and their effects on cognition. We further aim to examine whether reduced haemodynamics mediates the relationship between cMETS and cognition. We hypothesise that cMETS is associated with altered cerebral haemodynamics and cognitive performance and that these relationships reflect underlying mechanisms linking metabolic health to brain function. Understanding these cerebral haemodynamic patterns could provide unique insights into the early vascular mechanisms linking metabolic dysfunction to cognitive decline. As cerebral blood flow alterations often precede structural brain changes, this knowledge could enable earlier intervention opportunities and help develop targeted treatments that specifically address vascular dysfunction before permanent cognitive impairment develops.