Why do you think there has been so little progress, if any, in developing a drug that can slow the progression of neurodegenerative disorders?

A major problem remains the preclinical to clinical translation. For some of the drugs that have failed in phase 3 clinical testing, it is clear that from the preclinical data it would have been very surprising if they had worked. Another big issue is that we now have far better insight into how the pathology of Alzheimer’s disease progresses some 10-15 years in advance of the clinical symptoms – or at least those symptoms that can be detected using clinical measurement instruments such as the ADAS-cog. The drugs that have failed were all tested in mild-to-moderate AD, at a stage in the disease when the pathology is already well-advanced. So, it is likely that we shall need to test drugs much earlier in the disease process. Another issue is that many of the therapeutics that have been tested did not have an appropriate separation of safety and efficacy for the medicines to be tested at doses that might have shown efficacy. Finally, patient ascertainment – ensuring that the patients that you recruit really have Alzheimer’s disease – needs to be markedly improved to remove ‘noise’ in the clinical efficacy signals.

Are you discouraged by the progress that has been made, particularly after the failure of recent drugs?

Disappointed? Yes. Discouraged? No. As I have explained above, many of the clinical failures can be explained. With each avenue tested, the field moves forward to new avenues and one of these will be successful. Compared to other diseases of the brain, such as schizophrenia for example, I think we understand neurodegenerative diseases comparatively well. Now is the time to redouble our efforts and keep going. Many new approaches are being tested and innovative trial designs, including prevention studies, are underway.

What needs to happen before we can successfully treat the individual causes of neurodegenerative disorders?

We need much more research into fundamental disease mechanisms. For example, the field still does not have a good description of how a neuron dies in neurodegenerative diseases. The field needs to start to translate the genetic findings into cell biological experiments and ultimately into preclinical in vivo studies so that we can draw a more complete picture of the disease. Some of the systems biology approaches looking at patterns of gene expression are starting to do this as well. I think that, for Alzheimer’s disease for example, it is not far-fetched to believe that we will be able to intervene so as to delay the onset of the disease by decades so as to effectively prevent the disease.

If we lived an ideal scientific environment and your organisation had unlimited resources to do a single experiment, something you could not afford right now, what would you do?

I would enrol thousands of people into a longitudinal study that would follow their cognitive performance, lifestyle, medical events, and so on in a frequent and detailed manner. I would have blood samples taken for genome analysis. I would measure their brain function in a multimodal manner – MRI, amyloid PET, FDG-PET etc – and take CSF for biomarker measurement and discovery. This cohort could be used as appropriate for clinical trials, and because of the detailed pre-analysis, very well defined cohorts could be used for specific clinical experiments.

In your opinion, what would the benefits be for ARUK by partnering with JPND?

ARUK wants to be able to fund the best research into neurodegenerative diseases, and to ensure that there is collaboration between different research groups. Finding treatments for these diseases is a massive challenge, and it seems like we need to co-ordinate our scarce resources effectively to make optimal progress.