A well-known risk gene can trigger the disease independently

#wellknown #risk #gene #trigger #disease #independently

It has long been known that a certain genetic variant increases the risk of Alzheimer’s. A new study now suggests that the gene even triggers the disease.

When only simple things are possible: everyday situation in a residential group for people with dementia.

Annick Ramp / NZZ

When it comes to Alzheimer’s disease, things have been relatively clear so far. There were the very rare cases of inherited Alzheimer’s and the very common sporadic Alzheimer’s cases. In the inherited, familial forms of the dreaded dementia, mutations in three genes practically always lead to mental deterioration – and this occurs very early in the affected person’s life. In sporadic Alzheimer’s, however, there are “only” risk genes. These promote dementia to a greater or lesser extent, which occurs much later in life – but they cannot trigger the disease themselves.

This is how people have thought about Alzheimer’s to this day. Spanish researchers now have this understanding in a study on Monday work published in the journal “Nature Medicine”. thrown overboard. In their study, they examined the most important Alzheimer’s risk gene called APOE. This gene – like the dependent gene product apolipoprotein E – occurs in different variants. Variant four (APOE4) increases the risk of dementia the most – by up to 15 times.

It plays a role whether someone inherited the risk gene only from their mother or father – or from both parents. If there are two risk genes in the genome, one speaks of homozygous APOE4 carriers. Practically all of these people develop Alzheimer’s disease, as Juan Fortea and his colleagues have now shown. In addition, dementia develops seven to ten years earlier in them than in Alzheimer’s patients without this genetic constellation.

Double genetic load is relatively common

According to the research group, the results of the study show that the presence of two APOE4 gene variants in the genome leads to an independently inherited form of Alzheimer’s. This means that two APOE4 genes not only increase the risk of the disease, but can also trigger Alzheimer’s dementia.

This has important implications. About 2 percent of the population carries two APOE4 variants in their genome. This makes the genetic constellation relatively common. According to estimates, it is found in 15 percent of Alzheimer’s patients – at least in our latitudes. Ethnic and geographical differences in the frequency of this gene variant are known.

To provide their evidence, the Spanish researchers from various Alzheimer’s cohorts in Europe and the USA analyzed the clinical, laboratory and pathological data of more than 10,000 people, including 519 people with double APOE4 burden. As it turned out, suspicious laboratory values ​​(Alzheimer biomarkers) could be detected in them from the age of 55. From the age of 65, almost all of them had abnormal levels of the Alzheimer’s-typical protein amyloid in the brain-nerve fluid, and in 75 percent, amyloid deposits could be detected in the brain.

The occurrence of the biomarkers increased with increasing age. According to the Spanish scientists, this means that people with two APOE4 genes will almost always develop Alzheimer’s disease later in life. In this case, one speaks of complete penetrance of the problematic gene variant. The situation is therefore comparable to that of the known, very rare inherited forms of Alzheimer’s, according to the researchers.

No relevance for early detection yet

But what do the new findings mean for the diagnosis and early detection of Alzheimer’s disease? Independent experts asked by the German Science Media Center provide differentiated opinions. In general, they consider the results and conclusions of the Spanish research group to be easy to understand. You also speak of a “significant increase in knowledge”.

According to the experts, the fact that APOE4 has not yet been identified as a causal Alzheimer’s gene is probably due to the fact that this hypothesis has never been investigated as rigorously as in the study from Spain. In addition, the single and double carriers of the gene variant have always been analyzed in a common group in previous studies. This may have diluted the effect of the double gene variant.

According to the experts, what is still open on the subject is how: through which molecular and cellular mechanisms does the double gene variant trigger the brain disease that ultimately leads to manifest dementia? The new study does not provide an answer to this question.

To date, determining the APOE genotype is not recommended in routine diagnostics. That is likely to remain the case for the time being. Alzheimer’s researcher Nicolai Franzmeier from the Ludwig Maximilian University of Munich puts it this way to the Science Media Center: “I would not currently recommend being tested for APOE4, as there are no therapeutic consequences. In the future, APOE4 genotyping can certainly become relevant for early detection and therapy, provided we manage to develop sensible treatment approaches.”