Around a million people in Spain have a variant of the APOE gene that causes the brain damage typical of Alzheimer's in practically all of those affected, according to research led by the Sant Pau hospital in Barcelona that is presented today in the journal Nature. Medicine. These brain damages lead to the appearance of the first symptoms of Alzheimer's at age 65 on average and dementia at age 74.
“We have demonstrated the existence of a genetic form of Alzheimer's that until now was not recognized,” declares neurologist Juan Fortea, first author of the research. Between 2% and 3% of the population of European ancestry is affected by this hereditary form of the disease.
Although the discovery will not change the care provided 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 access to effective treatment.
Given that the effectiveness of any treatment for this new form of Alzheimer's has not yet been demonstrated, "at the moment it is not indicated" to perform genetic diagnostic tests except 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 their father and one from their mother, and those who inherit just 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 Sant Pau researchers have used public data from 13,336 patients from the US, Canada, Spain, Australia and Japan, which has 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 from 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 around 20% of the population of European ancestry, increases the risk of developing Alzheimer's. The important novelty is that having two copies meets the three requirements that define an inherited genetic disease: that all those affected develop the disease (unless they die first from other causes); that the age of onset of symptoms is predictable (as well 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 compared to non-hereditary sporadic cases. The onset of symptoms occurs 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 occur in people who have two copies of the APOE4 variant. Unlike what happens in other hereditary 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 have two.
“There may be different pathways that lead to Alzheimer's pathology but, once it starts, the evolution is similar,” explains Víctor Montal, a neuroscientist at the Sant Pau hospital and the Barcelona Supercomputing Center (BSC), who has led the research together to Juan Fortea.
In the case of the APOE gene, which produces a protein involved in fat metabolism and the transport of cholesterol to neurons, the precise mechanisms by which the APOE4 variant causes Alzheimer's are unknown. The hypotheses suggest 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 blood flow 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,” assesses Yadong Huang, from the University of California, 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 the evaluation of therapies to slow the disease in people with a higher risk of progressing to dementia at an earlier age than the population average. Likewise, it will allow us to study prevention strategies based on lifestyles, such as the habitual 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 in reference to the new antibodies against the beta-amyloid protein. “Clinical trials can be done in this population before symptoms appear.”
The research has been financed mainly with contributions from the Government through the Carlos III Health Institute, from the Generalitat through the Health Department and from the 'la Caixa' Foundation.
