Tackling dementia: Key milestones for progress

A new paper published in the journal Alzheimer’s & Dementia: Translational Research & Clinical Interventions outlines six key issues in dementia research, along with practical recommendations for how the field should tackle them in order to increase success in therapeutic translation. 

Despite dementia being made a global priority following the 2013 G8 summit, a number of gaps still persist in dementia research, which may be hindering the successful development of treatments for the millions of people living with dementia. To identify, discuss and address these issues, Alzheimer’s Research UK convened a collaborative meeting in May 2018 with leading experts from the field, including a number of UK DRI researchers. This article is the result of that meeting; an insightful overview of the current dementia landscape, it also outlines the somewhat complex roles of different bodies and initiatives in the UK and beyond. Here we give a flavour of the group’s discussions and suggestions, but highly recommend reading the full article for yourself here. 

The six themes discussed are:

1. Utilising knowledge gained of genetic risk factors

Current research aims to identify disease risk genes and understand their role in disease development, ultimately leading to treatment and prevention of Alzheimer’s disease (AD). While there has been much progress in gene identification, the bridge to a treatment has yet to be crossed. The group suggest that this requires different tools and expertise, from cell biology to in silico techniques, and use of emerging technologies, such as induced pluripotent stem cells. Collaboration is key.

2. Understanding vulnerability and resilience in neurons

The neurodegenerative process is complex, with some neurons and brain regions showing vulnerability, and others resilience. Understanding why they are affected differently may lead to novel drug targets. It is recommended that integration of different datasets would be beneficial to the field - this would require a great deal of cooperation and support between research institutions.

3. Achieving robust and reproducible research

There is currently no disease-modifying treatment for AD, and so there is a real need to identify robust and reproducible drug targets. Unfortunately validation studies are limited in the current ‘publish or perish’ model and the authors suggest a paradigm shift is required. Suggestions included supporting publication of negative results, possibly through open research platforms.

4. Better selection of clinical trial cohorts

There is remarkably high attrition of AD drugs between Phase 1 clinical trials and regulatory approval. One reason for this is that in early phase clinical trials, participants are selected to take part that have very similar symptoms and few other health problems, which maximises the chance of the drug being effective. This can lead to failures later on, when the drug is tested on a wider population with more complex health and different symptoms. The group makes a number of suggestions to tackle this, including merging longitudinal phenotyped cohorts with clinical trials.

5. Improving methods to assess drug-target engagement

This theme focuses on the importance of being able to make decisions on whether to continue developing a drug early on in the pipeline, to minimise risk and maximise potential for success later in the clinical trial phase. For example, cerebrospinal fluid (CSF) to test pharmacological endpoints is not readily used across the UK, and could be increased through raising awareness of general tolerability of lumbar puncture.

6. Revolutionising clinical trial design if earlier detection becomes available

The disease process of AD begins decades before current methods are able to detect symptoms, contributing to the high rate of failure in clinical trials, as it may be too late for the drug to make a difference. It is necessary to find tools and approaches to detect who has the disease much earlier, but, this will create new challenges for clinical trials. Enrolled participants will have to be followed for a long period of time to track any change. Innovative and scalable approaches are required to detect very early, subtle neurodegenerative; the group suggest that digital technologies may play an important role.

Dr Giovanna Lalli, Director of Scientific Affairs at the UK DRI HQ, attended the meeting:

"Defeating dementia requires a collective effort. This ARUK meeting was a great opportunity to hear different perspectives and engage in open discussions with UK and international experts coming from a variety of disciplines and sectors.

That's also our philosophy at UK DRI - our strength comes from establishing multidisciplinary approaches, fostering links between the lab and the clinic, developing partnerships with industry to accelerate finding new ways to prevent and treat dementia."

You can read the full paper here.