Approximately 200,000 people in Catalonia and one million in Spain have a variant of the APOE gene that causes the characteristic brain damage of Alzheimer's in almost all of those affected, according to research led by the Sant Pau hospital in Barcelona presented yesterday at the journal Nature Medicine. This brain damage leads to the appearance of the first symptoms of Alzheimer's at the average age of 65 and dementia at 74.
"We have demonstrated the existence of a genetic form of Alzheimer's that was not recognized until now," says neurologist Juan Fortea, first author of the research. Between 2% and 3% of the population of European descent is affected by this hereditary form of the disease.
Although the discovery will not change the attention given to affected people in the short term, it will allow research to be carried out on this group with the perspective that an early diagnosis will allow them to access effective treatment.
Given that no treatment has yet been proven to be effective for this new form of Alzheimer's, "at the moment it is not indicated" to do genetic diagnostic tests unless it is in the context of research, Fortea declares.
The APOE4 variant of the APOE gene was until now considered a genetic risk factor for developing Alzheimer's. But no research had distinguished between people who inherit two copies of the APOE4 variant, one from the father and one from the mother, and those who inherit only one.
Other variants of the same gene are APOE3 (the most common, which is considered to neither increase nor reduce the risk of Alzheimer's) and APOE2 (which reduces it).
The St. Paul researchers used public data from 13,336 patients from the US, Canada, Spain, Australia and Japan, which allowed them to analyze the progression of the disease based on the variants of the APOE gene that each person has. The Spanish participants are part of a project of the BarcelonaBeta center, the research institute of the Pasqual Maragall Foundation.
The results confirm that having a copy of the APOE4 variant, as occurs in approximately 20% of the population of European descent, increases the risk of developing Alzheimer's. The important innovation is that having two copies fulfills the three requirements that define a hereditary genetic disease: that all those affected develop the disease (unless they die earlier from other causes); that the age of onset of symptoms is predictable (as for the three other hereditary forms of Alzheimer's), and that the disease process from the onset of symptoms is also predictable.
If two copies of the APOE4 variant are inherited, the entire Alzheimer's process is advanced by about nine years relative to non-hereditary sporadic cases. The onset of symptoms takes place at an average age of 65 years, instead of 74; dementia at 74 instead of 83, and death at 80 instead of 89.
Between 15% and 20% of all Alzheimer's cases are in people who have two copies of the APOE4 variant. Unlike other inherited diseases, in this case the disorder can be inherited without having a family history, since it is possible that both the father and the mother have only one copy of the APOE4 variant, but that some of their children in have two
"There can be different pathways that lead to the pathology of Alzheimer's, but once it starts, the evolution is similar", explains Víctor Montal, neuroscientist at Sant Pau Hospital and the Barcelona Supercomputing Center, who has led the investigation together with Juan Fortea.
In the case of the APOE gene, which produces a protein involved in fat metabolism and cholesterol transport in neurons, the precise mechanisms by which the APOE4 variant causes Alzheimer's are unknown. The hypotheses point to the fact that there may be two mechanisms involved. On the one hand, the APOE4 variant is associated with a higher cardiovascular risk, which in turn negatively affects the blood supply to the brain and increases the risk of Alzheimer's. On the other hand, APOE4 directly affects the development and maintenance of the brain from childhood.
The advance "has crucial implications for the field of Alzheimer's", says Yadong Huang, from the University of California in San Francisco, in an analysis article published in Nature Medicine. "It opens new avenues for research [...], for the development of therapies and for the design of clinical trials".
From now on, clinical trials will have to analyze patients separately based on the number of copies of the APOE4 variant they have. This will allow therapies to slow the disease to be evaluated in people at higher risk of progressing to dementia at an earlier age than the average population. In addition, it will allow studying prevention strategies based on lifestyles, such as the regular practice of physical activity or following a healthy diet, in this group.
"Now we have drugs that can modify the course of the disease", declares Fortea with reference to the new antibodies against the beta-amyloid protein. "Clinical trials can be carried out in this population before symptoms appear."
The research has been financed mainly with contributions from the Government through the Carlos III Health Institute, the Generalitat through the Department of Health and the La Caixa Foundation.
