It is a complex neurodegenerative disease, but research is bringing us to the discovery of new risk factors and possible treatments. The leader of the Neuropathology group at IDIBELL, Isidre Ferrer, has explained his latest developments.
What is Alzheimer's disease?
This is one of the current problems with Alzheimer's. There is still no clear definition of what is Alzheimer's disease compared to changes in the brain that might be considered normal in the aging process. If we remember history we see that the concept of Alzheimer's disease has been changing over time.
Forward ...
Alois Alzheimer first described the disease in the early twentieth century in a woman younger than 65 who suffered a dementia. He observed two types of alterations in the brain: senile plaques and tangles that stained with silver salt in the neurons that showed neurofibrillary degeneration. It took more than seventy years to scientific community to accept that these changes linked to Alzheimer's were also in people over 65 years. The concept changed: it is now clear that the disease does not necessarily affect people under 65 years. Alzheimer disease may affect people above and under this age.
From my point of view, Alzheimer is a biological process associated with age, above 65 it is very frequent to find brain alterations restricted in very specific areas of the brain but only a small proportion of these changes increases, in an aggressive or a discrete way, to develop Alzheimer's dementia.
What do we know now about Alzheimer?
It presents alterations in two major proteins: TAU and amyloid protein which explain the neurofibrillary tangles and the plaques described by Alzheimer's but in the last hundred years we have discovered that there are more alterations: in energy production, in the transport of substances through the membrane, damage by oxidative stress, disruption of cell membranes and alterations in the mechanisms of destruction and removal of substances that are no longer useful. By analogy with the human body: there is a respiratory system failure (energetic failure), a renal system failure (degradation and removal of harmful substances), a liver failure (protein production) and a skin failure (cell membranes). Neurons suffer multiple organ failure.
This is coupled with alterations in the glial cells, in the blood vessels ... and now it is known that alterations not only occur in brain cortex but they also are distributed throughout different brain regions.
How research is approached from a process so complex?
In fact there are two schools. On the one hand, some believe that the process has a single cause; in this case altering the protein amyloid triggers a cascade of events that cause other changes. From their point of view, if we cut the first change we would stop the cascade and therefore the disease. Other researchers, including my group, believe that there is not a single cause but there are a number of factors that enhance each other. In any case, the research objectives should be, first, clearly defines the disease, preclinical study ways to discover biomarkers that allow early detection of disease and to investigate new treatments.
What is the status of his group in Alzheimer's research?
Our aim is, through a multidisciplinary approach to disease, to understand why there is Alzheimer's disease, how it could be diagnosed and how it could be treated. It sounds very ambitious but we are moving forward with the cooperation of other groups around the world and through participation in international projects.
Through the Brain bank of the Institute of Neuropathology of IDIBELL’s biobank we get data from people without dementia but with brain disorders, with these data it intends to make a computational and bioinformatics register to study on the one hand, potential biomarkers in the early stages of the disease and, on the other, the pathways that may be involved in its development. We also work with animal models of Alzheimer's disease (transgenic mice) to test possible therapies aimed at pre-symptomatic stages.
In what new treatments are you working on?
We are currently conducting several experiments with different substances and hope to be able to carry out two pilot tests with people over the next year with two different treatments.
Treatment of erythropoietin (EPO) to treat neuronal hipooxygenation has worked well in mice in early stages of Alzheimer; it improves learning and memory and reduces the number of senile plaques. The problem is that the mice present an excess of red blood cells and, therefore, it cannot be administered directly to humans. We are working with a lab to get an EPO-like molecule. But we have to keep in mind that this molecule could increase the tumors and that EPO is socially stigmatized by their use in doping of athletes.
We are also working with cannabinoid treatments in early stages of the disease. It has worked very well in cell cultures because they have an important role in oxidative stress, inflammatory processes and reduces cell damage. We are working with the labs that manufacture the drug Sativex, a product that is already on the market to treat different illness and it has no psychotropic effects, to conduct clinical trials in a highly selective population of people with early stages of Alzheimer's.
Other treatments are in confirmation phase of possible substances that affect the metabolism of amyloid proteins and molecules involved in the formation of senile plaques, and products involved in lipid metabolism.
In any case, when we finally find effective treatments, we should work on combined therapies, because Alzheimer's is a very complex disease that must be attacked on several fronts.
In Spain there are over 700 000 people with Alzheimer's and is expected to double this figure in 2050 ...
Alzheimer's disease is a social emergency. Before, we were dying at age 60 and now with 80 or 90 years, and Alzheimer's disease is related to age, there will be ever more people sick, find solutions is becoming an urgency. The emergency is not cure the disease but to delay its start, turn it into a chronic disease, on the assumption that it appears dementia, instead of appearing at age of 60 or 70 years, it would appear at age of 110 or 120 years. And in the future, as pretended in other diseases, if we get to know widely the disease, we will seek treatments for each patient.
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