It has been described as a historical “turning point” in Alzheimer’s treatment - the first time a chemical has been found that can halt the death of brain tissue in a neurodegenerative disease, and could potentially lead to a single pill treatment. But some warn a degree of caution is needed, and we really shouldn’t jump to conclusions just yet.
For a start, the study, carried out by scientists at a Medical Research lab at Leicester University, relates to another disorder: prion disease, a rare neurodegenerative disorder that counts Creutzfeldt-Jakob Disease (CJD) or “mad cow disease” among its family. But scientists have also said that a resulting medicine could treat other neurodegenerative diseases including Parkinson’s - and Alzheimer’s.
While some are keen to emphasise the similarities between these neurodegenerative brain conditions, others emphasise the difference.
“The results of the preclinical study in a mouse model of prion disease are indeed very impressive. However, the drug used may be very specific for this kind of disease, as the authors have indicated,” Christian Holscher, Professor of Neuroscience at Lancaster University, said.
“Alzheimer’s and Parkinson’s diseases are very different conditions all together. I cannot see a lot of overlap, so any claim this treatment will be successful in diseases other than prion-induced diseases will have to be substantiated by testing the drug in animal models of those diseases first.”
Why Alzheimer’s?
Alzheimer’s is the most common cause of dementia (which is estimated to affect about 35.6m people worldwide). It affects how we think, remember things, act and go about our daily lives. And it’s progressive so gets worse over time.
The sheer scale of the disease dwarfs that of prion but it may not automatically follow that the prion findings will work in the same way.
Alzheimer’s happens when protein molecules in brain cells fail to fold properly, which then tangle and form clumps and insoluble protein deposits called “plaques”. Researchers at Cambridge recently mapped this pathway to show how smaller molecular fragments called oligomers in people with Alzheimer’s are also able to spread around the brain, triggering creating many more.
In many neurodegenerative diseases this process activates a defence system that shuts down new protein production. But without new proteins, brain cells start to die. It was this process that the tested compound was able to halt. And because this system is also triggered in Parkinson’s and Huntington’s diseases, the excitement is palpable: any resulting medicine could also be used to treat them too.
Lost in translation
Another big but with any discovery like this is translating findings from animal models to human, although this is the routine start to any drug. And then there’s the long, hard process of clinical trials and development.
“We have seen a series of very promising drugs fail in clinical trials,” Holscher said. “We therefore will have to wait for such experiments to show positive results [in Alzheimer’s and Parkinson’s]. I am sure the authors had no intention to overstate the importance of their findings, but it is not helpful to claim a new cure for Alzheimer’s and Parkinson’s disease is just around the corner when there is very little evidence. One should be very conservative about these issues, too many promises have turned to dust in the past.”
Therein lies the rub: when can we get excited about discoveries that may lead to solving or at least keeping pace with some of our biggest health challenges?
Roger Morris, Professor of Molecular Neurobiology at King’s College London, said while it took decades for new medicines to come to fruition this was the first convincing study of its kind.
“This finding will be judged by history as a turning point in the search for medicines to control and prevent Alzheimer’s Disease for two reasons: it is the first experimental demonstration that a small molecule drug can arrest neurodegeneration in living brain … And, at least equally as important, is the manner of its demonstration.”
Two unique features in prion disease allowed the earliest stages of functional impairment and death of neurons in the brain to be identified and studied, Morris said.
“It is infectious, and once infection in the brain is initiated it proceeds like clockwork, so the earliest steps of neuronal damage can be followed on a day-by-day basis. This experimental precision allowed Professor Mallucci’s group [at Leicester] to identify the drug target, select an inhibitor, and show the inhibitor arrests neuronal degeneration. Scientifically, it shifts the focus from the role of misfolding of individual proteins in causing these diseases, to the common response of neurons to the stress caused by accumulation of misfolded protein.”
While “a cure for Alzheimer’s is not just around the corner,” Morris said, there was considerable evidence that the way neurons die in both diseases is similar. “Lessons learned in mice from prion disease have proved accurate guides to attenuate the progress of Alzheimer’s disease in patients.”
Target the brain
A potentially bigger problem lies in the defence mechanism itself, because it isn’t just triggered in the brain but is part of the body’s defence against physical and pathological stress in other tissues.
“The mechanism is found from yeast to man,” Morris said. “It is the persistent, long-term stress of neurodegenerative diseases that causes the neurons to die. To produce an effective medicine, drugs will have to be designed so their action is restricted to the brain, and allow this essential mechanism to function in the rest of the body.”
So if the compound was to work in both humans and in Alzheimer’s, it would also need to target the specific cells in the brain. The finding is a breakthrough and as Morris said, “science progresses by landmark experiments.” But it may take those decades for any mainstream drug to come to fruition.