19 January 2018

Pharma giant Pfizer stops research on medication for Alzheimer’s and Parkinson’s:

‘The question is still: where do these diseases start?’

Pharma giant Pfizer stops research on medication for Alzheimer’s and Parkinson’s diseases. Years of major investments still have not resulted in significant breakthroughs. “The question is still: where do these diseases start?”, explains Alzheimer’s researcher Prof. Elly Hol from the UMC Utrecht Neurological Centre. “It’s time to look at neurodegenerative diseases from a new perspective”, adds Parkinson’s researcher and Utrecht University Professor Aletta Kraneveld.

    Prof. Elly Hol, University Medical Center Utrecht
    Prof. Elly Hol, University Medical Center Utrecht

    “Alzheimer’s is a disease that develops very slowly. That means you have to follow patients for years before you know whether a new drug works or not. That makes research very expensive. From a pure cost-benefit analysis perspective, I can understand Pfizer’s decision”, replied Elly Hol, Professor at Utrecht University and President of the Scientific Advisory Council of Alzheimer Nederland.

    Plaques, tangles and an inflammation reaction

    Alzheimer’s, Parkinson’s and other diseases that affect neurons in the brain appear more difficult to understand than had been assumed. Hol explains that when you look at the brains of Alzheimer’s patients under a microscope, you see three differences in comparison to normal brains. First, there are the amyloid plaques, an accumulation of proteins between the nerve cells. These seem to be the trigger for the disease process. After a time, an inflammation reaction to the plaques also occurs, and accumulations of proteins, called neurofibrillary tangles, begin to occur in the neurons themselves.

    Why do people develop dementia?

    For both diseases, pharmaceutical companies have mainly invested in drugs that deal with the proteins in the plaques (amyloids in Alzheimers), and the Lewy bodies (α-synuclein in Parkinson’s), explains Prof. Aletta Kraneveld, who is specialised in research into the relationship between the brain, the immune system and the intestines. However, scientists still wonder whether the accumulation of proteins is indeed the actual cause of the damage to neurons in the brain. It may also be a protective measure. “Alzheimer himself described the plaques 100 years ago. And yet we still ask which cellular process comes first in dementia?” Hol adds.

    150 hypotheses

    Fundamental research has contributed considerably more knowledge, however. Hol estimates that there are now around 150 different hypotheses for the development of Alzheimer’s, due to the complexity of the various symptoms and their interrelations. Plaques are the trigger for the disease process, for example, but some people with plaques never develop Alzheimer’s. And the inflammation reaction that Hol studies is probably a result of the plaques, and may therefore be the indirect cause of dementia.

    Promising route

    Hol considers this discovery to be a promising new route for the treatment of Alzheimer’s The inflammation reaction is in effect an ‘overload’ of the glial cells in the brain, which facilitate the communications between neurons and clear away accumulations of proteins. “But if the glial cells constantly have to clear away plaques, they don’t get to support communications between the neurons. This leads to cognitive deterioration, and eventually to dementia. Perhaps now we can discover a drug that can prevent this reaction, or even reverse it.”

    A second chance for vaccines?

    Scientists are also working on making amyloid vaccines, a breakthrough from the 1990s, more safe. These vaccines appeared to work well in clearing away the plaques in mice. However, a preliminary clinical trial was quickly terminated when some patients developed an immune reaction. Hol thinks that this may still be an interesting option, however, because amyloid proteins are the first trigger in the process of dementia. “But the best chance of developing a successful therapy is to know which cellular process causes Alzheimer’s.”

    Different perspective needed

    Aletta Kraneveld
    Aletta Kraneveld (central) with colleague-researchers

    The same applies to Parkinson’s, explains Prof. Kraneveld. She believes that it is also time to look at neurodegenerative diseases from a new perspective: “The results of research by my group and others around the world have shown that changes in gut flora can have an effect on damage to brain cells. It is increasingly clear that we will have to do much more systemic research into the entire human body.”

    Gap

    Prof. Hol explains that it is still unclear what consequences Pfizer’s decision will have on scientific research. The company is a co-financer of one of her research projects, but other major pharmaceutical firms will continue their research into drugs for Parkinson’s and Alzheimer’s. Hol also sees opportunities for collaboration with the start-ups that many university researchers have already set up. But there is a gap between these companies and larger firms, which prefer to continue research into a drug only once the pre-clinical research results have been a success. Unfortunately, individual scientists and start-ups cannot finance these trials.

    More funding

    Should the government therefore step in with funding for this field of research? Hol laughs: “Yes, that would help a lot! The government and charities have already made a big contribution over the past few years, like with the Dementia Delta Plan. But the impact of the disease on society is vastly larger than the amount of funding that’s been made available. More than half of everyone reaching the age of 80 will develop Alzheimer’s, so public funding for research is definitely justified.”