"Many fewer resources are invested in Alzheimer's research than in heart disease and cancer research, even though the number of patients is similar"

This is what two of the winners of the Dan David Prize, Prof. John Hardy from University College London, and Prof. Peter St. George-Hyslop from the Universities of Cambridge and Toronto, say in an interview with the Hadaan website. According to them there is room for optimism regarding finding solutions to prevent Alzheimer's and to a certain extent also for treatment. They also emphasize the need to increase basic research, due to the high risk in these studies, so that there are alternative routes to drugs that fail

On Sunday this week, a ceremony was held at Tel Aviv University to award the Dan David Prize to seven researchers in three dimensions of time, past, present and future (See news).
Following the ceremony, the scientist website interviewed two of the prize winners in the present time dimension, both geneticists engaged in Alzheimer's disease research. The three winners in the field of the war on memory loss jointly won a prize worth one million dollars for their contribution to society and humanity."

Prof. John A. Hardy from University College London is a molecular geneticist specializing in the study of the genetics of Alzheimer's disease and other dementias. He was the first to discover a mutation in the gene encoding the amyloid protein, which plays a central role in the brain degeneration processes associated with Alzheimer's disease.

Prof. Peter St. George-Hyslop, from the Department of Clinical Neuroscience at the University of Cambridge and the Tenez Center for Research in Neurodegenerative Diseases at the University of Toronto was the first to discover key mutations in proteins involved in the early onset of Alzheimer's disease. These proteins also play a role in the late onset of this disease.

We asked them why it is so difficult to cure Alzheimer's and why the disease is so common, to which Prof. Hardy replied: "Alzheimer's disease is common because of the aging of the population. With increasing life expectancy and improved cures for deadly diseases such as cancer and heart disease, Alzheimer's has become a significant disease because more people are reaching the age when it breaks out."

Is Alzheimer's one disease or a group of diseases?

Prof. Hardy: "There are clearly many causes of Alzheimer's, but we estimate that there are factors they have in common. Another reason for the difficulty in curing Alzheimer's is the difficulty in penetrating the blood-brain barrier. It is true that Alzheimer's research also began late, perhaps only at the end of the eighties of the 20th century, while research in the fields of cancer and heart disease preceded these efforts by a full decade. In addition, it is very difficult to reach the tissue affected by the disease, but only with the help of imaging methods that have developed greatly in the last five years and allow us to observe the progress of the disease. I am optimistic and confident that we will be able to move forward, but we still have a long way to go."

Prof. Peter St. George-Hyslop: "Unlike other organs such as the liver, the heart or the kidneys are composed of few types of cells, but the brain is composed of many types of nerve cells and many types of supporting cells. Due to this complexity, it is very difficult to do something that will improve the condition of one cell without causing damage to other cell types. It is the complexity of the brain that makes it difficult to prepare specific compounds for a large group of cells. We want to improve the condition of certain cells without interfering with the functioning of neighboring cells, because if you do that, you make the problem worse."

Prof. Hardy: "There is another problem and that is funding. Large sums of money were not invested in brain research. The funding for research in the fields of cancer and heart disease was by an order of magnitude greater than in Alzheimer's, the situation is starting to change, but the investment in these fields is still 10 times greater than the investment in Alzheimer's research."
Prof. Saint-George-Hislop: "The investment in research in the fields of cancer and heart disease is of course important and justified, but given the fact that the number of patients with Alzheimer's and other neurological diseases is similar to the number of cancer patients and heart disease, we would expect similar amounts of money to be invested in research and this is not the case. Of course, we do not demand a reduction in financial investments in the field of cancer and the heart, but we propose to increase the investment in research into neurological diseases."

What are the areas in Alzheimer's research in which it is especially necessary to promote the research?
Prof. Hardy: In my opinion, there are two areas: the first area is curing amyloid (ways to stop its accumulation or even break it down AB) and translate this into drugs. Good clinical studies are needed to test the compounds currently in development. The second area is the urgent need to expand the targets for drugs. In most diseases, patients do not receive one drug that works against one target, but multiple drugs against several targets. In Alzheimer's we have not sufficiently developed the understanding of the biology of other molecular targets.

Prof. St. George-Hyslop: "The question is what to do next. We are always testing ideas and there is a risk that they will not succeed in their purpose. For example, everyone is looking for drugs, people are pushed to speed up the clinical trials, without taking the time to ask is this the best compound, is this the best approach? When to give the medicine and when not to give it. As a result, many of the clinical trials carried out in the last four to five years did not reach the hoped-for results. They did not inquire whether the antibody was correct, whether the medicine was given at the correct time, whether the dosage was correct. The question is even if it is just the amyloid or amyloid plus tau, have enough simulations been performed? We need a more rational approach. We must have a backup plan of basic research that will enable the discovery of new potential targets, that if the current research is not successful, that will open up additional options to us, that will allow us to develop drugs that in five years will be ready for clinical trials. I'm afraid that too many research institutions in the world today are pushing to get to the drug now, no matter how poor it is, and maybe it might not work, and of course we're losing time."

You both deal with different aspects of the genetics of Alzheimer's disease. What are the innovations in this field and how will it lead to new treatments?

Prof. Hardy: One of the genes we discovered last year is involved in the process of creating inflammation. In fact, Peter studied mice used as a model of Alzheimer's disease and discovered that the same gene involved in causing inflammation was increased in these mice. We have two different approaches that led to the same result - that the inflammatory response to amyloid plays an important role and this is something that all pharmaceutical companies will be able to use as a therapeutic goal, that from different studies we reached the same conclusion and explain how the microglial cells react to amyloid.

Prof. Saint-Georges-Hyslop: Genetics gives us small hints about the role of different systems in the body on the accumulation of amyloid, cholesterol (which we already knew about its effect) and now also inflammation. The next step is to connect all these details in a good way, to see how they are related to each other and to find the points where they can be used, but this takes time.

Prof. Hardy. I would look at it as a puzzle, one piece of which deals with inflammation, and another piece of which deals with cholesterol metabolism, and another piece deals with beta amyloid metabolism. We actually have three areas of the image but we have no idea how the amyloid piece and the inflammation piece fit together. These are still separate pieces and we have to put them together before we can get an understanding of the whole picture.

If so, is there a connection between apparently separate diseases such as cholesterol, Alzheimer's and perhaps diabetes?
Prof. Hardy: "There are so-called soft data linking diabetes, high blood pressure and Alzheimer's, but it is difficult to say exactly what the connection is and whether this connection is biologically useful."

Prof. Saint-George-Hyslop: "The connection between Alzheimer's and diabetes is a soft connection (referring to my circumstances. AB), but from the genetic work we can point to common aspects of these diseases, for example improper folding of proteins, inflammatory reaction to them It happens quite often, when we look at genetics, that two diseases that we thought were separate diseases become different types of one disease. This could significantly change the way we treat these diseases. We can take insights we learned about Alzheimer's and apply them to diseases such as Parkinson's and ALS."

From your research it appears that there is a genetic difference between people who suffer from Alzheimer's at a relatively young age and those who suffer from the disease in old age. Is this true, and what is its effect?

Prof. Hardy: "That's right. Peter's and mine's works, for which we received the Dan David Prize, dealt with Alzheimer's disease at a young age, but today we are both researching the aspects of Alzheimer's in old age. These are separate diseases, by and large different genes are involved in them, not completely different, but many of the genes involved in different diseases between Alzheimer's at a young age and Alzheimer's at an older age."

Prof. St. George-Hyslop: "There are also differences in the impact of these diseases on the patients. In Alzheimer's disease at a young age, the disease develops rapidly and puts the patients in a difficult situation. On the other hand, the effect on those with it in old age is much weaker."

If someone discovers that he has a gene that will cause him to get Alzheimer's at a relatively young age, what can he do to prevent the disease?

Prof. Hardy: "Today there are networks of clinical trials that treat young Alzheimer's patients, for example the DIAN Network, an international partnership organized by researchers at Washington University in St. Louis, which works to collect the people who carry these mutations and conduct clinical trials on them. I don't know if there is such a center in Israel, for sure there is a center in London."

Prof. Saint-George-Hislop: "It is desirable that that person avoid other causes of brain damage such as stroke or injury that may increase the effect of the disease and worsen his condition. In general, good advice for those people is to check their blood pressure regularly. If he is diabetic, he must balance his diabetes, if he suffers from high blood pressure - he must reduce his blood pressure, and so of course also in the case of cholesterol. He must also be active and involved, activity is a protective factor. Take care of your brain, treat the other diseases, and be active. This is the best advice that can be given to these people."

Is gene therapy for Alzheimer's on the horizon?

Prof. Hardy: "Not in my horizon".
Prof. St. George-Hyslop: "The disease breaks out in late stages of life and there is no point in changing the genes. You live 60-70 years reasonably well and you only want to improve your condition for 5-10 years, you won't be able to do that by changing genes, especially not changing genes in the brain, which would probably be quite tricky to do. There are certainly easier ways to postpone the disease. Therefore, I do not see a gene therapy for Alzheimer's on the horizon. Genetics will have a role in identifying the people who are at risk so that they can start preventive treatments in the early stages."

If and when we succeed in eradicating these diseases associated with old age, will we be able to increase human life expectancy?

Prof. St. George-Hyslop: "I think there is a limit to the ability to extend life, even if we can prevent these diseases (and prevention is a better strategy than treating the disease when it breaks out), the improvement in the quality of life of the adults will be great. I believe that there will be other diseases around the corner, I am sure that another series of diseases that affect people at these ages - for example, disruptions in the musculoskeletal system: they will suffer from osteoporosis, their muscles will be lost and they will suffer from weakness, they will suffer from vision disorders. These will be the next diseases that medical science will have to deal with. Eliminating Alzheimer's will not make us immortal. In any case - eradicating Alzheimer's will improve the quality of life because it is an unpleasant disease for the patients and also for the members of their families who have to treat patients with these diseases, but getting rid of the diseases that harm the nervous system is, as mentioned, a huge task."

Winning the Dan David prize - recognition of the importance of the field

The two greatly appreciate winning the Dan David Prize for 2014, and both see it as recognition in the field, which, as we mentioned at the beginning, despite its importance, suffers from a budget deficit.

Prof. Hardy, we must point out, both myself and Peter and on behalf of the third partner for the award, Prof. Brenda Milner (a trailblazer in the field of memory and learning), that we all enjoyed the visit to Israel and the meeting with the Israeli researchers, it was a positive thing, there are particularly good young scientists here . Yesterday we were at a ceremony where they handed out scholarships to young Israeli scientists and scientists from around the world, this is one of the important things for us. The Dan David Award is a salute to our work and the work of our colleagues.

Prof. St. George-Hyslop: "The award also draws attention to the field and brings it out of the dark. If the Dan David Prize Committee has chosen a field, it sees it as an important field and the politicians see it and say, 'If a private philanthropic organization sees this as an important field, and in particular a prize of this magnitude, it is a sign that more needs to be done.'"