Breakthrough reveals single gene driving most dementia – elevating hopes of radical new therapies

A single gene could be responsible for more than 90 per cent of Alzheimer’s disease cases, new research suggests – a finding that could open the door to a new generation of treatments targeting the condition at its genetic roots.

Scientists behind the study say that if the harmful influence of the gene could be neutralised, up to three-quarters – and possibly more – of Alzheimer’s cases might never develop.

The gene, known as APOE, has long been linked to Alzheimer’s, but researchers now say its contribution to the overall burden of the disease has been significantly underestimated.

Dr Dylan Williams, a senior Alzheimer’s research fellow at University College London and the study’s lead author, said: ‘We have long underestimated how much the APOE gene contributes to the burden of Alzheimer’s disease.’

While the E4 variant of the gene is already well recognised as a major genetic risk factor, Dr Williams said the role of another allele – E3, the most common form – has been widely misunderstood.

He said: ‘When we consider the contributions of E3 and E4 together, we can see that APOE potentially has a role in almost all Alzheimer’s disease.

‘Consequently, if we knew how to reduce the risk that these variants confer, we may be able to prevent most cases of the disease from occurring.’

In the most comprehensive review of its kind, involving more than 450,000 participants, researchers analysed existing studies examining how different APOE variants influence the risk of Alzheimer’s, dementia, and early brain changes that precede memory loss.

A single gene could be responsible for more than 90 per cent of Alzheimer’sdisease cases, new research suggests – a finding that could open the door to a new generation of treatments targeting the condition at its genetic roots

People with two copies of the E2 variant were considered low risk, while those carrying two copies of the E4 variant were found to be at the highest risk of developing the condition.

These patients also tended to develop the disease earlier than those with other genetic profiles, with almost all eventually showing signs of the condition.

However, the researchers stressed that carrying high-risk genes does not guarantee someone will develop dementia.

Lifestyle and environmental factors can significantly influence risk, with smoking, poor cardiovascular health and social isolation all known to increase the likelihood of developing the condition.

Dr Williams said: ‘Other research has suggested that perhaps half of dementia incidence could be prevented or delayed by improving modifiable risk factors such as smoking, high cholesterol or social isolation across populations.

‘With complex diseases like Alzheimer’s and other causes of dementia, there will be more than one way to reduce disease occurrence.’

He added: ‘Nonetheless, we should not overlook the fact that without the contributions of APOE E3 and E4, most Alzheimer’s disease cases would not occur, irrespective of what other factors are inherited or experienced throughout life.’

The findings, published in the journal npj Dementia, suggest that between 72 and 93 per cent of Alzheimer’s cases would not have occurred without the E3 and E4 variants of the gene.

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Overall, around 45 per cent of all dementia cases were linked back to APOE.

The researchers say this improves on previous estimates of genetic risk and could help identify the most appropriate people to include in future clinical trials.

They concluded that evidence from across multiple studies suggests the gene is likely to be responsible for at least three in four Alzheimer’s cases, and possibly more.

Dr Williams said: ‘The extent to which APOE has been researched in relation to Alzheimer’s, or as a drug target, has clearly not been proportionate to its importance.

‘There has been major progress in recent years in gene editing and other forms of gene therapy to target genetic risk factors directly.

‘Moreover, genetic risk also points us towards parts of our physiology that we could target with more conventional drugs.’

He added that intervening directly on APOE – or the molecular pathways linking the gene to the disease – could have ‘great, and probably under-appreciated, potential’ for preventing or treating a large majority of Alzheimer’s cases.

Independent experts welcomed the research but urged caution in interpreting the findings.

Professor Masud Husain, a neurologist at the University of Oxford who was not involved in the study, said it was a ‘really important study’, but warned: ‘It raises the question of whether knowing your genotype would be useful.

‘Currently, this is not available routinely in the NHS, largely because it is unclear what someone could do if they discovered they were at high risk of developing dementia.’

He added: ‘We need clinical trials that specifically focus on higher-risk individuals to establish whether new treatments can make a meaningful difference.’

Professor Anneke Lucassen, an expert in genomic medicine, also urged caution.

She said: ‘In reality, unless you carry two copies of the E4 variant – which is rare – your risk is heavily influenced by lifestyle factors.’

She added: ‘The study also confuses susceptibility with causality. Just because a gene increases risk does not mean the disease would not occur without it – it may simply require different environmental triggers.’

Dementia is estimated to claim around 76,000 lives a year, making it the UK’s biggest killer – often due to complications such as pneumonia or difficulty swallowing.

Alzheimer’s is the most common form of dementia, affecting around 982,000 people in the UK.

Early symptoms typically include memory problems, difficulties with thinking and reasoning, and language issues, which worsen over time.

However, experts believe that around 45 per cent of dementia cases may be preventable – or at least delayed – through improvements in lifestyle and cardiovascular health, potentially allowing people to live longer, healthier lives.

Dr Sheona Scales, director of research at Alzheimer’s Research UK, said: ‘This study highlights that more Alzheimer’s cases are linked to the APOE gene than previously thought.

‘However, not everyone with these variants will develop Alzheimer’s, demonstrating the complex relationship between genetics and other risk factors for dementia.’

She added: ‘These findings underline the importance of further research into APOE as we work towards more effective prevention and treatment strategies for Alzheimer’s disease.’

Dr Richard Oakley, associate director of research and innovation at Alzheimer’s Society, added: ‘This large-scale study offers a clearer picture of how the APOE gene influences the risk of developing Alzheimer’s, suggesting its impact may be even greater than we previously understood.

‘While these findings offer a better understanding of the role of genetics, it is important to remember that having a high-risk form of the gene is not a certain diagnosis.

‘As we continue to further our understanding of risks and causes, we must not lose sight of the risk factors that remain within our control.

He continued: ‘There are steps people can take today to reduce their risk of dementia, such as exercising, not smoking and managing long-term health conditions like blood pressure and diabetes. We know a holistic approach to good health is the best way to lower your risk of dementia.

“There is no single approach to treating dementia. We must continue to fund diverse research to help us find effective preventative measures and treatments that work for everyone, regardless of their genetics.’