Scientists are urging a major shift in the fight against Alzheimer's disease, calling for future therapies to target a specific gene they say is responsible for the vast majority of cases in the United Kingdom.
A New Target for Alzheimer's Therapies
Researchers from University College London (UCL) argue that drug developers should concentrate their efforts on two risk-raising variants of a gene known as Apoe. They claim that interventions designed to block the harmful effects of these variants hold "vast potential" for preventing the devastating neurodegenerative condition.
This call to action comes in the wake of the first wave of Alzheimer's drugs, which work by clearing toxic proteins from the brain. While these treatments can slow disease progression, their benefits are modest. Consequently, the UK's National Institute for Health and Care Excellence (Nice) has rejected them for widespread use within the NHS, highlighting the urgent need for more effective alternatives.
Dr Dylan Williams, a genetic epidemiologist at UCL, stated: "Most Alzheimer's disease cases would not arise without the contribution of just this single gene: Apoe. We need to think about it as a direct target. Almost all potential Alzheimer's cases could benefit from Apoe-related interventions."
The Overwhelming Influence of the Apoe Gene
More than half a million people in the UK, and over 40 million globally, live with Alzheimer's, the most common form of dementia. While lifestyle factors like smoking, obesity, and high blood pressure contribute to risk, genetics play a crucial role.
The UCL team analysed medical records from more than 450,000 individuals of European ancestry to quantify the Apoe gene's impact. Everyone inherits two copies of the gene, with three main variants: Apoe2, Apoe3, and Apoe4.
Traditionally, Apoe4 is known to significantly raise Alzheimer's risk, Apoe3 is considered neutral, and the rare Apoe2 variant is seen as protective. However, Dr Williams and his colleagues propose a different perspective. Publishing in the journal npj Dementia, they calculate that compared to carrying two copies of the protective Apoe2, both the Apoe3 and Apoe4 variants increase disease risk.
Their striking conclusion is that without the detrimental effects of Apoe3 and Apoe4, between 72% and 93% of Alzheimer's cases, and roughly 45% of all dementia, would not have occurred.
Challenges and Expert Reaction
The path to such gene-targeted therapies is fraught with difficulty. The Apoe gene is essential for transporting cholesterol and fats around the body and brain, so completely disabling it could cause severe problems. Future treatments might involve editing the gene variants or reducing their activity, but such technologies are not yet imminent or risk-free.
Another significant hurdle is scale: the study found that over 99% of people carry either the Apoe3 or Apoe4 variants. Preventing Alzheimer's on a population level could therefore mean treating nearly everyone, potentially through complex and invasive procedures.
The research has received a mixed reception from the scientific community. Professor Tim Frayling, a human genetics expert, cautioned that the high attribution rate was analogous to saying most road deaths wouldn't occur without cars, noting that "people should not worry if they have the risk versions of the gene, because 99.4% of us do."
Others welcomed the focus. Professor Tara Spires-Jones from the University of Edinburgh said understanding risk factors like Apoe was "essential for developing effective treatments and prevention strategies."
Dr Sheona Scales from Alzheimer's Research UK highlighted the significance of Apoe3 being implicated, as it was previously thought neutral. She added: "This research raises lots of interesting questions... about whether targeting these variants could be a promising avenue for treatment and prevention." She also reminded the public that Apoe testing is not available on the NHS, and anyone concerned about their dementia risk should consult their GP.
