Genetics, Modifiable Risk Factors, Brain Health & Cognitive Function

Donate to support dementia research

The global population is ageing rapidly, with major implications for population health. Cognitive decline across adulthood, which often precedes dementia, is a particular concern, as very limited or no options are currently available to slow or halt its progression. 

Both genetic and environmental factors contribute to dementia. However, despite decades of research, only a fraction of the genetic variability and environmental risk underlying cognitive decline has been identified, and the biological mechanisms through which these exposures influence brain ageing remain largely unclear.

Rare genetic variants (with frequencies below 1%) have emerged as promising contributors because they may exert strong individual effects on disease risk. In parallel, poor cardiometabolic and mental health are well established modifiable risk factors for accelerated cognitive decline and neurodegeneration. Therefore, part of the unexplained cognitive variability may reflect interactions between rare genetic variants and major risk exposures.

This project investigates whether genetic variability in biological mechanisms essential for maintaining optimal cellular, tissue, and organ function, heightens vulnerability to neurocognitive decline and dementia when interacting with modifiable risk factors such as high blood pressure, elevated glucose and cholesterol levels, low physical activity, and poor mental health.

Ultimately, by applying a comprehensive, mechanism level analytical framework across multiple interconnected biological ageing mechanisms, and drawing on large established cohort data, this project will: (a) enhance novel gene discovery by assessing the impact of rare variants in ageing related pathways, in combination with modifiable risk factors, on cognitive decline and dementia; and (b) develop ageing mechanism based polygenic risk scores with direct relevance to prevention and precision medicine.

Links to our research articles related to this project

• DNA repair genetic variability and cardiometabolic risk (Learn more) 
• Antioxidant genetic variability and cardiometabolic risk (Learn more)

Talk to us

If you would like to find out more, please contact our research team through the button below.

Email us

Learn more about our research supported by the Dementia Research and Prevention Fund at ANU.

DNA Repair Genetic Variability and Cardiometabolic Risk in Brain Health & Cognitive Function

Background and aim

DNA damage accumulation is increasingly recognized 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 hypothesize 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.

Link to published paper

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

Antioxidant Genetic Variability and Cardiometabolic Risk in Brain Health & Cognitive Function

Background and aim

Oxidative stress and dysregulation of antioxidant defence mechanisms are recognized as major contributors to biological ageing, neuronal dysfunction, and cognitive decline. The ageing brain is characterized 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 modify 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.

Link to published paper

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