DPUK aims to deliver breakthroughs in dementia research through experimental medicine studies. These are funded or supported through DPUK, and in many cases, they will recruit through the clinical studies register, to enable studies with a better chance of success.
Deep & Frequent Phenotyping
A study within DPUK, led by Simon Lovestone, University of Oxford
One of the principal challenges for the dementia research community worldwide is how we can study the brain in the very early stages of the disease. Damage in the brain can start to occur up to 15 years before we see symptoms of Alzheimer’s disease and researchers need to be able to investigate and test interventions at this critical early stage. At present, proving that a new early-stage treatment works is difficult because any symptoms will be a long way off.
The Deep and Frequent Phenotyping (DFP) Study aims to address this by creating a database of different measures – regular brain scans, cognitive and memory testing, retinal imaging, blood tests and the use of wearable technology to measure movement and gait – which will be tracked as the disease develops. In the future we will be able to use the data obtained through DFP to understand if early interventions are working.
DFP is the most detailed study into preclinical Alzheimer’s disease for its size in the world. Currently work is underway to recruit 250 suitable participants for the study from a number of DPUK cohorts. To date the research team are recruiting from UK Biobank, EPIC and the Generation Scotland cohorts. The extensive programme of testing will be coordinated across eight different study centres and four imaging centres.
Not all of the study sites have the capacity to do every type of testing required in this study so some participants will travel to nearby centres for certain tests. Enabling research teams to make use of facilities in other centres is a key reason underlying DPUK’s work in setting up standardised protocols for use with the new research infrastructure in the UK.
How do peripheral and central vascular markers relate to cognitive decline?
A DPUK-funded study, led by Ian Deary, University of Edinburgh
Testing potential biological signs, the 'biomarkers' of cognitive ability in late life is of interest for both theory and practice in dementia research. Not only might such biomarkers be informative about the causes of age-related cognitive decline, they may also be predictive of developing dementia. They may thus be used in the 'prodromal' phase of the disorder to distinguish those who will experience pathological cognitive ageing from those who will age more healthily. In this project, the team examines one set of possible cognitive ability level and change biomarkers: lipidomics and lipoproteins.
The goal is to investigate the potential links between plasma lipidomics and lipoproteins and cognitive and neurovascular imaging parameters that index variation in age-related decline. The project will test whether these lipidomic parameters could be used to stratify subjects relevant to diverse populations with varied risk of decline in cognitive performance, vascular health and lifestyle measures. The results would provide data that could support potential therapeutic strategies for vascular causes of cognitive impairment and dementia.
Integration of clinical and cellular phenotypes in the DFP cohort
A DPUK-funded study, led by Richard Wade-Martins, University of Oxford
The Deep and Frequent Phenotyping (DFP) Study will be almost certainly the most extensively assessed cohort of people with very early Alzheimer’s and mild cognitive impairment. All participants will have at baseline very extensive clinical and biological assessments, including detailed cognitive measures and biological measures of pathology: both amyloid and tau PET, and molecular assays of both of these in the cerebrospinal fluid. All participants are approached for consent to donate cells for iPSC stem cell generation, and all give consent for follow up from electronic health records and other linked data.
The hypothesis to be tested is that the cellular phenotype (what the cells looks like) of iPSC-derived neurons from patients will reflect the clinical phenotyping using an extensively ‘deep phenotyped’ Alzheimer’s cohort.
Multi-modal imaging correlates of Astroglial activation, β-amyloid deposition and neuronal activity as markers of cognitive impairment in Alzheimer's disease
A DPUK-funded study, led by Paul Matthews, Imperial College London
This is a proof-of-concept study to characterise the brain uptake of a new astroglial imaging marker, [11C]BU99008, in a mixed population of mild to moderately severely affected patients with Alzheimer’s. The relationships between [11C]BU99008 brain uptake, Aβ deposition and brain glucose metabolism will be defined. The potential clinical significance of astroglial activation measured in this way will be explored by testing for relationships with cognitive performance activities of daily living and functional MRI measures of brain activity. This pilot study will help accelerate the potential utility and application of [11C]BU99008 in dementia research and provide a means to assess multi-modal imaging correlates that may predict patient outcomes.
Crosstalk: the impact of cardiac anatomy and function on brain structure and health
A DPUK-funded study, led by Steve Williams, King’s College London
The brain and the heart are the two organs which have been studied more than any other, providing a profound, though still incomplete, understanding of development, ageing and pathology. Imaging studies have allowed detailed investigation of the structure and function of the brain and heart, but imaging these organs in isolation will not provide a comprehensive understanding of systemic vascular risk.
This project applies automated image analysis to heart and brain images acquired by UK Biobank. The group are looking for early evidence of structural and functional correlates between heart and brain in a cross-section of the mature UK adult population, with particular interest in early indicators of adverse brain changes which might be coupled across organs. Identifying early indicators would potentially provide insight into early systemic pathological ageing affects and give additional motivation for protecting cognitive function by maintaining cardiac health.
PET imaging: changes in cerebral protein synthesis rates in Alzheimer's disease
A DPUK-funded study, led by Giovanna Mallucci, University of Cambridge
This study looks at how the shape of protein in the brain affects disease.
In Alzheimer’s disease and related neurodegenerative disorders, activation of the unfolded protein response (UPR) parallels the progression of clinical and pathological disease. However, the role of this in neurodegeneration in Alzheimer's disease is unknown. This is a key gap in our understanding, which is potentially essential for developing new treatments for dementia. In mouse models, UPR over-activation causes reduced cerebral protein synthesis (CPS) rates, leading to synaptic failure and neurodegeneration. Critically, both genetic and pharmacological UPR manipulations that restore CPS rates prevent both neurodegeneration and clinical disease in AD-like mouse models. A key question, therefore, is whether UPR over activation in Alzheimer's disease leads to reduced CPS rates. If so, then drugs targeting the UPR may be disease modifying in Alzheimer's disease. This study will provide essential ‘go-no go’ information to inform clinical trials with drugs targeting the UPR to prevent dementia.
New Therapeutics in Alzheimer’s Disease
A multi-funder study led by DPUK, by James Rowe, University of Cambridge
There is evidence for a direct relationship between amyloid and tau pathology and synaptic dysfunction, which in turn impairs the network dynamics which underpin cognition. Moreover, physiological changes precede cell death. This group is exploring the proposal that changes in plasticity, local circuit physiology and large-scale neural dynamics occur early in Alzheimer’s disease. The long-term goal is to arrest pre-symptomatic disease, but this study will also identify sensitive and tractable neurophysiological biomarkers for next-generation experimental medicine studies.
It is funded by DPUK, Janssen, Alzheimer’s Research UK and MedImmune.
Rates, Risks and Routes to Reduce Vascular Dementia
A multi-funder study led by DPUK, by Joanna Wardlaw, University of Edinburgh
Stroke commonly affects cognition and, by definition, vascular dementia is driven by stroke disease in some way. However, fundamental knowledge about risk factors is widely acknowledged to be missing, restricting mechanistic understanding, prevention, treatment, and patient services.
This study will recruit a wide range of patients with stroke to determine rates of, and risk factors for, cognitive and related impairments after stroke, to assess mechanisms and improve prediction models. Outputs will include reliable data on cognition long-term after stroke. Participants will be in follow-up and consented for re-contact, facilitating future clinical trials.
It is funded by Stroke Association, British Heart Foundation, Alzheimer's Society and Dementias Platform UK.
European Prevention of Alzheimer’s Dementia
An adaptive trial recruiting participants through DPUK.
The overall aim of the European Prevention of Alzheimer’s Dementia (EPAD) project is to develop an infrastructure that efficiently enables proof of concept studies for the development of new drugs for the prevention of Alzheimer’s dementia.
The EPAD project is creating a virtual Europe-wide register (EPAD Register) of around 24,000 people who already participate in national and regional research studies, long-term cohorts or clinical registers.
From this register, people across the probability-spectrum of developing Alzheimer’s dementia will be invited to join a research cohort (EPAD Cohort). These people will participate in standardised tests and will be followed over time. Researchers hope that studying these people will help them to identify factors that contribute to the onset of clinical symptoms of dementia. This stage of the project is currently in progress across several European countries.
Around 1,500 people from the cohort will be invited to take part in early stage adaptive clinical trials (EPAD trials) of new medicines that are designed to prevent Alzheimer’s dementia.
DPUK provides cohort data for testing disease and health economic models.
The ‘Real world outcomes across the Alzheimer’s disease spectrum for better care: multi-modal data access platform’ (ROADMAP) project provides the foundation for an integrated data environment and framework for real-world evidence (RWE) in Alzheimer’s disease.
Real-world evidence concerns the realistic use of drugs or other treatments once they are approved for prescription – this can often be different to how effective the treatment is in clinical trials. Understanding how treatments work in everyday life for patients is critical for the development of effective treatment.
This includes the development of key outcome measures and data integration tools for dataset characterisation and outcome classification, as well as guidelines on the handling and interpretation of RWE data.