Scientists say they have identified a new genetic form of Alzheimer’s disease

Researchers in the US said almost all of the people who carry two copies of the APOE4 gene variant, known as APOE4 homozygotes, are likely to develop signs of the neurological condition.

They said this gene is already associated with a higher risk of developing Alzheimer’s.

But scientists now believe 95% people who are over 65 and carry two copies of APOE4 show early signs of the disease, making it a distinct genetic form of Alzheimer’s.

These people also develop the condition earlier than those with other variants of the APOE gene, they added.

The 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.

Dr Juan Fortea, director of the research area on neurological diseases, neuroscience, and mental health at the Sant Pau Research Institute in Barceclona, Spain, said: “These data represent a reconceptualisation of the disease or what it means to be homozygous for the APOE4 gene.

“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% and 3% 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, added: “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.”

Mutations in three genes, APP, PSEN1 and PSEN2, are known to cause a rare form of Alzheimer’s known as ADAD (early-onset autosomal dominant Alzheimer’s disease).

This form of the disease runs in families.

APOE is one of many other genes associated with Alzheimer’s and comes in three different variations: APOE2, APOE3, and APOE4.

Everyone carries two copies of APOE, one inherited from each parent.

Previous studies have shown that having at least one APOE4 gene variant, which about 25% 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 current research, the team found a majority of people with two copies of APOE4 showed signs of the disease by the age of 55, compared with those with another gene variant, such as APOE3.

And by the age of 65, almost all (95%) 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% 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.

Commenting on the study, Professor Jonathan Schott, chief medical officer at Alzheimer’s Research UK, added: “In this large well-conducted study, researchers showed that people who inherited two copies of APOE4 almost all developed Alzheimer’s changes in the brain by their mid 60s.

“These individuals were more likely to develop dementia and tended to do so at a younger age than those with different APOE combinations.

“At the present time we do not advise that people have genetic testing for APOE except when taking part in research, but this may change in the future.”

He said that Alzheimer’s UK is funding research projects to try to understand why having the APOE4 gene increases the risk of disease.

Dr Richard Oakley, Alzheimer’s Society’s associate director of research and innovation, added: “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.”