Genetics, Modifiable Risk Factors, Brain Health & Cognitive Function

DNA Repair Genetic Variability and Cardiometabolic Risk in Brain Health & Cognitive Function
Interactions between rare genetic variants involved in DNA repair mechanisms and cardiometabolic risk may explain some of the observed cognitive variability.

Background and aim

DNA damage accumulation is increasingly recognised as a central driver of genomic instability, biological ageing, and neurodegeneration. The brain is particularly vulnerable to DNA damage due to its high metabolic demands, which produce more reactive oxygen species (ROS), and relatively lower antioxidant defences compared to other tissues. Neurons, being post-mitotic, cannot “reset” DNA damage through cell division, making DNA repair mechanisms essential for maintaining genomic stability in the brain. However, DNA repair efficiency declines with age, contributing to genomic instability, cellular senescence, and cognitive impairment.

Cardiometabolic health has emerged as one of the most important modifiable risk factors for cognitive ageing and brain structural integrity. Elevated cardiometabolic risk is associated with accelerated cognitive decline, reduced global and regional brain volumes, and increased white matter hyperintensity burden. A recent meta-analysis demonstrated that diabetes, hypertension, and obesity each independently contribute to accelerated brain ageing, with diabetes exerting more than twice the effect of hypertension or obesity. The pathophysiological mechanisms linking cardiometabolic dysfunction to cognitive and brain outcomes likely involve chronic systemic inflammation, cerebral hypoperfusion and microvascular injury, blood-brain barrier disruption, amyloid-beta accumulation, energy deprivation, and oxidative stress.

Given these independent associations between DNA repair capacity and cardiometabolic risk with cognitive and brain outcomes, we hypothesise that part of the unexplained cognitive variability reflects interactions between rare genetic variants in DNA repair genes and major cardiometabolic risk exposures.

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 and TRAIL2), and prospective memory (PMEM). 
  • Seven brain regions of interest were assessed: total brain (TBV), grey matter (GMV), left and right white matter (LWM/RWM), left and right hippocampi (LHC/RHC), and white matter hyperintensities (WMH) volumes. 
  • A total of 3487 genetic variants across 39 DNA repair genes were tested. 
  • SNP and gene/gene-set 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 established risk factors, were assessed.

Main findings

  • We detected 107 genetic variants (mostly extremely rare) across 36 DNA repair genes associated at Bonferroni-significance (p≤1.4×10−5) with neurocognitive and brain outcomes. 
  • Most associations were observed for WMH (43 variants across 27 genes) and SDMT (26 variants across 17 genes). Most associations (60.8% of variants) were identified only in interaction models with CMRI. 
  • Associations across 35 of the 36 previously identified genes were also observed (p<0.05) for dementia. 
  • Interactions between rare genetic variants involved in DNA repair mechanisms and cardiometabolic risk may explain some of the observed cognitive variability.

Published paper

Interactions between rare variants in DNA repair genes and cardiometabolic risk explain more variability in cognitive function. GeroScience (2026).