Discovery of a new genetic form of Alzheimer's disease that appears at an early age

A team of scientists said it has identified a new genetic form of Alzheimer's disease, underscoring the urgent need to develop specialized treatment and prevention strategies.

The team from the US found that almost all individuals who carry two copies of the APOE4 gene variant, known as APOE4 homozygotes, are likely to show signs of the neurological condition earlier than those with other variants of the APOE gene.

The term homozygosity, or heterozygosity, refers to the degree to which two copies of a gene share the same genetic sequence, in other words, the degree to which alleles (one copy or alternative form of the gene) are similar in an organism.

Scientists now believe that 95% of those over the age of 65 who carry two copies of APOE4 show early signs of the disease, making it a distinct genetic form of Alzheimer's.

The findings suggest that for people who carry two copies of the gene, APOE4 is not just a risk factor, but an underlying cause of the mind-stealing disease.

Symptoms can begin seven to ten years before they appear in other older people who develop Alzheimer's disease. This calls for the development of specialized research strategies, treatment methods and clinical trials for these people, according to scientists.

The results, published in the journal Nature Medicine, are based on clinical data from more than 10,000 people, in addition to pathological data from more than 3,000 brain donors.

“These data represent a reimagining of the disease or what it means to be homozygous for the APOE4 gene,” said Dr. Juan Fortea, director of the Neurology, Neuroscience and Mental Health Research Area at the Sant Pau Research Institute in Barcelona, ​​Spain.

"This gene has been known for more than 30 years to be associated with an increased risk of Alzheimer's disease, but we now know that all individuals with this duplicate gene develop Alzheimer's disease, which is important because they represent between 2 and 3% of the population."

Mutations in three genes, APP, PSEN1 and PSEN2, are known to cause a rare form of Alzheimer's disease known as ADAD (autosomal dominant early onset Alzheimer's disease). This type of disease is genetically spread.

The APOE gene is one of many other genes associated with Alzheimer's and comes in three different forms: APOE2, APOE3, and APOE4. Each person carries two copies of APOE, one inherited from each parent.

Previous studies have shown that having at least one variant of the APOE4 gene nearly triples the risk of developing the disease, while having two copies of it increases the risk up to twelve-fold.

In the recent study, the team found that the majority of those with two copies of APOE4 showed signs of the disease by age 55, compared to those with another genetic variant, such as APOE3.

By age 65, almost all of them (95%) had abnormal levels of a protein known as amyloid in the fluid that surrounds the brain and spinal cord, a major sign of Alzheimer's disease. 75% of them had positive amyloid brain scans.

Based on these findings, scientists suggest that the genetic variant of the APOE4 gene is not only a risk factor for Alzheimer's disease, as previously thought, but could also represent a distinct genetic form of Alzheimer's disease.