Antioxidant Genetic Variability and Cardiometabolic Risk in Brain Health & Cognitive Function
Genetic variation in antioxidant defence mechanisms may modify the association between cardiometabolic health and cognitive outcomes.

Background and aim

Oxidative stress and dysregulation of antioxidant defence mechanisms are recognised as major contributors to biological ageing, neuronal dysfunction, and cognitive decline. The ageing brain is characterised by increased production of reactive oxygen species (ROS) and decline in antioxidant enzyme activity, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), particularly in metabolically demanding regions such as the hippocampus and frontal cortex. This progressive imbalance between ROS production and antioxidant capacity is thought to drive genetic instability, neurovascular dysfunction, neuroinflammation, and ultimately cognitive impairment.

Cardiometabolic health has emerged as a critical lifelong determinant of cognitive reserve and brain structural integrity, with cardiometabolic multimorbidity associated with accelerated cognitive decline and reduced brain volumes across grey matter, white matter, and hippocampal structures beginning as early as middle adulthood.

Despite recognition that both oxidative stress and cardiometabolic dysfunction contribute substantially to cognitive ageing, there is a paucity of evidence examining whether genetic variation in antioxidant defence mechanisms modifies the association between cardiometabolic health and cognitive outcomes.

Methodology

  • Participants (n=376,533) of white-British ancestry from the UK Biobank with cognitive, neuroimaging, and whole-exome sequencing data were included.
  • Six cognitive outcomes were assessed: fluid intelligence (FIQ), symbol-digit matching task (SDMT), visual matching (MATCH), trail making (TRAIL1/TRAIL2), and prospective memory (PMEM).
  • Seven brain regions were assessed: total brain (TBV), grey matter (GM), white matter (LWM/RWM), hippocampi (LHC/RHC), and white matter hyperintensities (WMH).
  • A total of 4,659 genetic variants across 75 antioxidant genes were tested.
  • SNP and gene-level associations were tested using regression models adjusted for age, sex, APOE ε4, ancestry, and outcome-specific covariates. Genetic interactions with a multidimensional cardiometabolic risk index (CMRI), encompassing eight lifestyle and health factors, were evaluated.

Main findings

  • We identified 121 genetic variants (94.2% extremely rare) across 47 antioxidant genes associated at Bonferroni-significance (p≤1.1×10-5) with neurocognitive and brain outcomes.
  • The highest number of associations were observed for WMH and SDMT (36 variants each), with most associations in the NOS1, SOD2, and NQO2 genes.
  • Crucially, 60 variants were identified only in interaction models with CMRI.
  • Variants across 45 of the 47 identified genes were also nominally associated (p<0.05) with dementia.

Publication

Cognitive variability is partly explained by interactions between antioxidant genetic variants and cardiometabolic risk. Under review.