According to a study, people with a duplicate version of the so-called APOE4 gene in their genome almost always develop signs of Alzheimer’s. In addition, the disease begins several years earlier in them than in non-hereditary Alzheimer’s, A research team led by Juan Fortea from the Sant Pau Institute in Barcelona reports in the journal Nature Medicine. The gene combination is therefore relatively common in the population.
The APOE4 gene has long been associated with a higher risk of developing Alzheimer’s, Fortea is quoted as saying in a press release from the institute. “But we now know that virtually all people who carry duplicates of this gene develop physical Alzheimer’s traits. This is important because these people make up between two and three percent of the population.” German experts speak of “convincing work” that brings about a “significant increase in knowledge”.
In Germany, more than a million people are currently suffering from Alzheimer’s disease, the most common form of dementia. The cause of the disease has not yet been precisely clarified. The main suspicion, however, is directed against the protein fragment beta-amyloid (Aß), which forms deposits between nerve cells in the brain, so-called plaques. They lead to a cascade of brain changes that ultimately damage nerve cells and lead to dementia.
APOE4 has long been considered a risk factor for Alzheimer’s
APOE is the abbreviation for apolipoprotein E. The job of this protein is to bring important nutrients to the nerve cells in the brain. There are three different variants of the protein in humans: APOE2, APOE3 and APOE4. Due to the double set of chromosomes, every person basically has two genetic predispositions for this protein. These can, but do not have to be, the same variant.
The APOE4 variant has long been considered a risk factor for Alzheimer’s. According to the German Center for Neurodegenerative Diseases (DZNE), studies suggest that APOE4 disrupts the supply of nutrients to the brain and therefore damages the nerve cells. In addition, APOE4 proteins massively accelerated the formation of amyloid plaques. It was already clear that people who carry duplicate APOE4 genes in their genome are particularly often affected by Alzheimer’s. In these cases, experts speak of APOE4 homozygosity.
According to the Alzheimer’s Research Initiative (AFI), Alzheimer’s disease is only hereditary in very rare cases. So far, three genes (APP, PSEN1 and PSEN2) are known that are responsible for a hereditary form. According to the AFI, those affected often become ill relatively early, namely between the ages of 30 and 65. With APOE4, a fourth gene could now be added. Unlike APP, PSEN1 and PSEN2, a person must carry not just one but two APOE4 genes, i.e. be homozygous, in order to have a very high probability of developing the hereditary form of Alzheimer’s.
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Juan Fortea’s team investigated how strong the connection is between APOE4 homozygosity and Alzheimer’s disease. To do this, the researchers looked at data from several large health studies. This included information on more than 3,000 brain donors, of which almost one in ten carried the APOE4 gene in duplicate. The team also analyzed data on biomarkers and disease progression in over 10,000 people, including people with two APOE4 genes.
“The results showed that almost all APOE4 homozygous carriers showed Alzheimer’s pathology and, from the age of 55, had significantly higher levels of Alzheimer’s biomarkers than APOE3 homozygous carriers,” writes Fortea’s team. By the age of 65, more than 95 percent of those affected had high levels of amyloid in their cerebrospinal fluid; amyloid deposits in the brain could be detected in three out of four patients. This suggests that homozygous carriers of the APOE4 gene almost always develop Alzheimer’s features, according to the study authors.
In one also in Nature Medicine published commentary on the study says: “Redefining APOE4 homozygosity as a genetic form of Alzheimer’s disease would change the way researchers think about Alzheimer’s and how they study the disease. This new definition establishes APOE4 as a causal factor of Alzheimer’s disease, and not just a risk factor .” There is an urgent need to develop a drug that specifically targets this.
Alfredo Ramírez, head of the Molecular Neuropsychiatry Section at the University Hospital of Cologne, is convinced by the results: “There is not much left to do to consider APOE4 as a monogenic form of Alzheimer’s disease.” However, it still needs to be correctly determined, among other things, how high the probability of homozygous carriers actually being of developing Alzheimer’s disease is.
Nicolai Franzmeier, who researches the development of Alzheimer’s disease at the Ludwig Maximilians University in Munich, says: “However, the study has practically no influence on diagnostics in clinical routine – at least not currently in Germany.” In clinical routine, APOE4 diagnostics are usually not recommended as there are currently no therapeutic consequences, although this could change in the future. According to Franzmeier, a new antibody therapy that could soon be approved in the EU has more significant side effects in APOE4 carriers than in carriers of other APOE variants.