People with genetic variants that naturally lower cholesterol were found to have up to 80 per cent lower dementia risk in a study of more than one million participants.
The research analysed data from Denmark, England and Finland to assess how genes that mimic the effects of cholesterol-lowering drugs such as statins and ezetimibe influence dementia risk.
Scientists found that reducing blood cholesterol by one millimole per litre was linked to as much as an 80 per cent reduction in dementia risk for certain drug targets, suggesting possible benefits from cholesterol-lowering treatment.
The researchers used a method known as Mendelian randomisation, which allows scientists to study the effects of lowering cholesterol while avoiding confounding factors such as diet, weight and other lifestyle habits.
Dr Liv Tybjærg Nordestgaard led the research while at Bristol and now works at Copenhagen University Hospital–Bispebjerg and Frederiksberg hospital.
Dr Nordestgaard said: “What our study indicates is that if you have these variants that lower your cholesterol, it looks like you have a significantly lower risk of developing dementia.”
Some people are born with genetic variants that naturally affect the same proteins targeted by cholesterol-lowering drugs such as statins and ezetimibe.
By comparing these individuals with those without such variants, the researchers were able to measure differences in dementia risk.
Mendelian randomisation uses genetic variation as a natural experiment.
Because genes are inherited randomly at conception, this method can mimic randomised clinical trials and offer stronger evidence for cause-and-effect relationships than traditional observational research.
The findings suggest that having low cholesterol, whether due to genetics or medical treatment, could help reduce the risk of developing dementia. However, the study does not provide definitive evidence about the effects of the medicines themselves.
One of the main challenges in dementia research is that symptoms typically appear later in life, requiring decades of follow-up to detect meaningful changes. This makes long-term clinical trials difficult to conduct.
The biological link between high cholesterol and dementia is not yet fully understood. Dr Nordestgaard suggested that atherosclerosis — the build-up of cholesterol in blood vessels — may play a key role.
Dr Nordestgaard said: “Atherosclerosis is a result of the accumulation of cholesterol in your blood vessels.
“It can be in both the body and the brain and increases the risk of forming small blood clots—one of the causes of dementia.”
Blood clots can block small vessels in the brain, leading to vascular dementia — the second most common form of the condition after Alzheimer’s disease.
Even small clots can damage brain tissue over time and contribute to cognitive decline.
The study used data from large genetic research projects including the UK Biobank, the Copenhagen General Population Study, the Copenhagen City Heart Study, the FinnGen study and the Global Lipids Genetics Consortium.
These resources provide genetic and health information from diverse populations, improving the reliability of the findings across different ethnic and geographical groups.
The UK Biobank includes data from around 500,000 participants aged 40–69, while the Copenhagen studies have tracked Danish populations for several decades, providing detailed health records for long-term analysis.
“It would be a really good next step to carry out randomised clinical trials over 10 or 30 years, for example, where you give the participants cholesterol-lowering medication and then look at the risk of developing dementia,” Dr Nordestgaard added.
Such trials would provide direct evidence about whether cholesterol-lowering drugs can prevent dementia, rather than relying on genetic data.
However, their length and cost make them difficult to conduct.