Approved Research

The moderating effect of APOE e4 on lifestyle factors which affect metabolic risk, brain health, neural connectivity, and cognitive ability in later life.

Lay summary

The apolipoprotein E gene comes in three different forms, known as alleles. These alleles are called e2, e3 and e4. We inherit one allele from each parent. If you possess one or two copies of the e4 allele, the risk for stroke and dementia is increased. It is estimated that around 25% of people in the UK have one copy of the e4 allele, which increases the risk of dementia by 3 times, and a further 2% possess two copies, which increases risk by 12 times. Cognitive decline, changes in our thinking, memory and reasoning skills, is evident before any clinical symptoms. Despite the strong evidence that the e4 allele contributes to changes in thinking skills, the precise outcomes are not well understood. Given the significant risk associated with this gene, it is important to gain a greater understanding of how the gene works.

There are lifestyle factors, such as exercise and sleep, which might slow the age-related decline in our thinking skills. Engaging in social activities and challenging cognitive tasks are also associated with preserving our cognitive abilities as we get older. This study aims to understand how possessing the e4 allele alters the benefit of certain lifestyle factors. Interestingly, some studies have suggested that people who have one or more copies of the e4 allele (the one that increases risk of decline) might actually get more benefit from different lifestyles associated with better brain health. It will also investigate the biological changes associated with cognitive decline. The gene is involved in the transport of cholesterol, and high levels of cholesterol could affect the health of the brain. We will look at connections between brain cells to see how well the brain is connected, and how healthy the blood supply to the brain is.

The study will analyse data from UK Biobank, which is a research resource with data on half a million participants, including genetic data and measures of general health, brain health and cognitive ability. Keeping sharp as we get older is a concern for many people. An understanding of lifestyle factors which could reduce the negative effects of the APOE gene would help to prevent or slow down cognitive decline in those with increased genetic risk for dementia. Identifying changes in the brain through which APOE e4 possession has negative consequences could also guide further research to treat cognitive changes associated with ageing or disease.