According to a recent study, people are very likely to develop Alzheimer’s symptoms if the so-called APOE gene is present twice in a particular variant. In addition, the disease begins several years earlier in them than in non-hereditary Alzheimer’s, a Spanish research team now reports in the journal “Nature Medicine”.
APOE is the abbreviation for apolipoprotein E, which has the task of bringing important nutrients to the nerve cells in the brain. In humans it occurs in three forms: APOE2, APOE3 or APOE4. And due to the double set of chromosomes, everyone carries the corresponding APOE gene twice in their genome. This may or may not be the same variant; It is then either homozygous or heterozygous, as it is called in technical jargon. According to the study, APOE4 homozygous people have a significantly increased risk of developing Alzheimer’s disease over the course of their lives compared to heterozygotes or non-carriers.
The APOE4 gene variant has long been associated with a higher risk of developing Alzheimer’s, explains first author Juan Fortea from the Hospital de la Santa Creu i Sant Pau in Barcelona. “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, depending on the region.
also read
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, so-called plaques, between nerve cells in the brain that are typical of the condition. These trigger a cascade of brain changes that ultimately damage the nerve cells – and lead to dementia.
also read
According to the Alzheimer Research Initiative (AFI), this dementia is only rarely hereditary. So far, three genes – for the amyloid precursor protein, APP, presenilin 1 and 2, PSEN1, PSEN2 – were known that can be responsible for a hereditary form if mutations are present. According to the AFI, those affected become ill relatively early: between the ages of 30 and 65. APOE has also been suspected for a long time, but as a “risk factor” rather than a “risk gene”. And as has now been shown, among other things, there is a so-called dose effect with regard to the two APOE gene variants 3 and 4.
From risk factor to risk gene
According to the German Center for Neurodegenerative Diseases (DZNE), studies suggest that APOE4, for example, 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. According to the conclusions of the current study, APOE4 is likely to be considered a fourth, important risk gene in the future if it is homozygous. Because unlike APP, PSEN1 and PSEN2, a person has to have the APOE4 variant not just once, but twice in order to have a very high probability of developing a hereditary form of Alzheimer’s.
For the current study, the team led by Juan Fortea and Víctor Montal 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 almost 3,300 brain donors, almost one in ten of whom had the APOE4 gene variant in duplicate. The team also analyzed data on characteristic biomarkers and disease progression from more than 10,000 people, including APOE4 homozygotes.
also read
“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,” reports Fortea’s team. By the age of 65, more than 95 percent of those affected would have had high amyloid levels in their cerebrospinal fluid; Amyloid deposits in the brain were 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.
A commentary published simultaneously in Nature Medicine by researchers at the University of California, San Francisco, said of the study: “Redefining APOE4 homozygosity as a genetic form of Alzheimer’s disease would change the way researchers think about Alzheimer’s disease and how they research the disease. This new definition establishes APOE4 as a causal factor of Alzheimer’s, and not just a risk factor. There is an urgent need to develop a drug that specifically targets it. Around 15 percent of all Alzheimer’s cases can be traced back to this. If you look at the proportion of APOE4 homozygotes in the population of around two percent, this genetic form of Alzheimer’s is probably one of the most common inherited diseases worldwide.
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.” But, among other things, it still needs to be correctly determined , how high the probability of developing Alzheimer’s actually is for homozygous carriers.
Here you will find content from third parties
In order to display embedded content, your revocable consent to the transmission and processing of personal data is necessary, as the providers of the embedded content require this consent as third party providers [In diesem Zusammenhang können auch Nutzungsprofile (u.a. auf Basis von Cookie-IDs) gebildet und angereichert werden, auch außerhalb des EWR]. By setting the switch to “on”, you agree to this (revocable at any time). This also includes your consent to the transfer of certain personal data to third countries, including the USA, in accordance with Art. 49 (1) (a) GDPR. You can find more information about this. You can revoke your consent at any time using the switch and privacy at the bottom of the page.
“However, the study has practically no impact on diagnostics in clinical routine – at least not currently in Germany,” says Nicolai Franzmeier, who researches the development of Alzheimer’s disease at the Ludwig Maximilians University in Munich. 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.
In any case, the Spanish researchers are convinced that their results will have an impact on advice and recommendations for APOE screening in the population. This may also need to be taken into account when examining patients with cognitive complaints.