New form of Alzheimer’s identified that 95% of gene carriers develop

Scientists say they have identified a new form of Alzheimer’s disease and called for people who carry a duplicate gene to begin treatment at a much younger age.

Almost everyone over the age of 65 who carries two copies of the APOE4 gene variant showed early signs of the disease, making it a distinct genetic form of Alzheimer’s, an international group of researchers said. These people also develop the condition earlier than those with other variants of the APOE gene, according to the scientists.

Their findings, published in the journal Nature Medicine, are based on clinical data from more than 10,000 people, as well as pathological data from more than 3,000 brain donors.

Previous studies have shown that having at least one APOE4 gene variant, known as APOE4 homozygotes, which about 25 per cent of people in the UK are thought to carry, almost triples the risk of getting the disease, while having two copies increases the risk by up to twelve-fold.

In the latest research, the team found a majority of people with two copies of APOE4 showed signs of the disease by the age of 55.

And by the age of 65, almost all (95 per cent) of them had abnormal levels of a protein known as amyloid in the fluid that surrounds the brain and spinal cord – a key sign of Alzheimer’s disease.

Scans showed that 75 per cent of over-65 APOE4 homozygotes had abnormal build-up of amyloid protein in the brain, which is seven to 10 years earlier than symptom development for other APOE variants.

Lead author Dr Juan Fortea, director of the research area on neurological diseases, neuroscience, and mental health at the Sant Pau Research Institute in Barcelona, Spain, said: “This gene has been known for over 30 years and it was known to be associated with a higher risk of developing Alzheimer’s disease. But now we know that virtually all individuals with this duplicated gene develop Alzheimer’s biology.”

He said the findings are important because APOE4 homozygotes represent between 2 per cent and 3 per cent of the general population. This warrants the development of specialised research strategies, treatment approaches and clinical trials for these people, according to the researchers.

Dr Reisa Sperling, professor in neurology at Harvard Medical School, and director of the Centre for Alzheimer Research and Treatment at Brigham and Women’s Hospital in Boston, Massachusetts, in the US, said: “This research really suggests that we should be treating them quite early, at a younger age and at an early stage of pathology because we know they are very likely to progress to impairment quickly.

“So we have to think about how we can treat APOE4 carriers. These individuals are desperate – they have seen it (the disease) in both of their parents.”

Dr Richard Oakley, Alzheimer’s Society’s associate director of research and innovation, said: “This study has shown us that this particular gene might play an important role in Alzheimer’s disease development, suggesting its presence is not only a risk factor, but could also indicate a new form of Alzheimer’s disease.

“The insights from the study suggest that in the future it could be important to take into account a person’s genetics when planning how to reduce their risk of developing Alzheimer’s disease, or when considering their treatment if they already have the disease.”

Compelling data triggers calls for earlier testing

We have known for 30 years that inheriting certain genes can increase an individual’s risk of developing Alzheimer’s. The best known of these is a gene called APOE. There are three different versions of this gene, APOE2, APOE3, and APOE4.

Each of us carries two copies of APOE, one inherited from each parent – and this means there are different combinations people can carry. APOE2 decreases and APOE4 increases risk for Alzheimer’s disease. Between 15 and 25 per cent of us carry one copy of APOE4 and about 1 in 50 people carry two copies.

Despite the study showing that people who inherited two copies of APOE4 almost all developed Alzheimer’s changes in the brain by their mid-sixties, dementia experts do not advise people to have genetic testing for APOE except when taking part in research, as the test results cannot fully predict who will or won’t develop Alzheimer’s.

This may change in the future. Charities such as Alzheimer’s Research UK are funding research projects to try to understand why having the APOE4 gene increases the risk of disease.

Professor Paul Matthews, from the UK Dementia Research Institute Centre at Imperial College, London, said: “Because APOE4 homozygotes is common in the population, have predictable ages of onset and rates of progression of disease and, as demonstrated in the paper, show easy to measure biomarker changes as their disease evolves, they also constitute an attractive population for clinical trials of new treatments for Alzheimer’s disease.”

Several dementia experts not involved in the research agreed that the study, while not a surprise in reaching its conclusions, adds “compelling” data to suggest that people with two copies of APOE4 are almost guaranteed to develop Alzheimer’s if they live long enough and that they will develop Alzheimer’s earlier than people without this gene.

By Paul Gallagher