What is the role of pre-symptomatic outcome prognosis in dementia in the absence of a disease modifying treatment? (Session chair: Prof Clare Mackay)

Dementia is the leading cause of death in the UK. Around 850,000 individuals are living with dementia, but only around 540,000 (66%) of these have received a diagnosis.

It often takes years to establish whether someone who is worried about their memory has dementia or not. Earlier and more accurate diagnosis would reduce distress and allow for earlier treatment. This will be particularly important to ensure access to emerging disease-modifying treatments (DMTs) that might reduce the burden of dementia on patients, carers and society. However, currently if someone is thought to be at a risk of developing dementia, there is very little that can be done; therefore, the majority of perceived advantages for having an earlier diagnosis (or prognosis) in dementia are focusing on the indirect benefits that it would bring.

What are the key challenges of recruiting homogenous cohorts of dementia patients, i.e., patients with the same disease subtype, at the same stage of disease progression? (Session chair: Prof Masud Husain)

Akrivia Health curates one of the largest psychiatric EHR databases in the world, providing curation and AI-structuring services to 16 NHS Mental Healthcare Organisations (HCOs) on 3 million+ patients’ records under a strict information governance model. As part of this service, Akrivia’s research team has developed a Natural Language Processing (NLP) pipeline based on deep learning Neural Networks to extract valuable structured information from the free text progress notes that contain ~80% of actionable clinical information (medication, symptoms, full diagnosis history etc) in psychiatric EHRs. A key application of the Akrivia dataset and data structuring pipeline is to identify cohorts for research studies and clinical trials for patients with dementias. Given the potential breadth of information available in psychiatric EHRs, our development work to support these activities is focused on identifying meaningful disease subtypes, and capturing levels of disease progression. Within the key question set out above, we are keen to explore the following: – What is the current state of the art in terms of understanding dementia subtypes? – To what extent are these subtypes utilised in clinical practice? (and if so, how would subtype features and progression states be recorded by clinicians?) – What is the current state and future direction of early detection methods for dementia (or for specific subtypes)

Where in the clinical management and treatment of dementia will objective broad-domain assessment (cognition, mood, language, sleep, neurophysiology) be of most value to patients and families?
(Session chair: Dr. Vanessa Raymont)

The Cumulus Neuroscience platform is used to assess multiple domains of patient state during trials of new therapies for dementia, using wearable EEG recording, synchronised tablet-based behavioural tasks and cloud-based analytics. Each task or domain is grounded in the relevant scientific literature, before “translating” it into a form that is suitable for patients to use unsupervised and repeatedly in the home. This lower burden on health systems enables more regular assessment of multiple relevant domains (cognition, mood, language, sleep, neurophysiology) in a more natural setting, and makes it possible to factor out day-to-day variation, or track longitudinal change in a more granular fashion. We would value expert clinical and scientific guidance on what part of the patient pathway would be most suited to the additional evidence that this approach provides – such as screening, differential diagnosis, response to treatment, etc.

What changes in clinical management of early or presymptomatic patients may result upon receipt of a polygenic risk score that stratifies risk for future onset of Alzheimer’s disease? (Session chair: Prof John Gallacher)

Cytox has validated a Polygenic Risk Score test for evaluating risk for lifetime onset of Alzheimer’s disease. Understanding risk for the purposes of both clinical trial recruitment and clinical practice is important so as to enable better decisions at the earliest opportunity.

What is the neuronal mechanism driving Alzheimer’s Disease, and how can it be intercepted? (Session chair: Prof Noel Buckley)

Neuro-Bio currently has 6 independent assets covered by 16 patent families, all inspired by a previously unknown biological process. This novel technology is inspired by a previously unknown neurochemical (T14), that we are showing underlies a very basic biological system promoting cell growth and renewal. Our proposition is that neurodegeneration occurs as an aberrant reactivation of development. We have designed a new type of drug, NBP14, that is actually a structurally changed, inactive variant of T14 itself that blocks the actions of its naturally occurring counterpart when operating inappropriately. For example, chronically administered NBP14 is effective in AD mouse models and displaces excessive T14 in post mortem AD brain. Our approach is very different from, and we believe potentially much more effective than, anti-amyloid drugs: unlike the competition, we are targeting the pivotal ‘upstream’ mechanism itself of neurodegeneration.

How can we link neuroinflammatory biomarkers to disease modification? (Session chair: Dr. Emma Mead)

We have an overall interest in the neuroinflammatory aspect of Alzheimer’s disease and diagnostic/prognostic biomarkers so our question all evolve around this.

How can biomarkers help us dissect the heterogeneity of dementia and navigate towards precision medicine. What role can multi-omic approaches play? (Session chair: Prof Cornelia van Duijn)

The pathophysiological diversity of dementia imposes challenges to the development of disease modifying treatments. Biomarker discovery studies are increasing our understanding of this multifaceted process and can provide valuable insights for the stratification of patients for clinical trials.

We propose to discuss how the recent fluid biomarker advancements are improving our disease knowledge and contributing to the accurate classification of dementia subtypes, progression through the Alzheimer’s disease (AD) continuum and associated comorbidities. What are the limitations of current biomarker strategies for clinical applicability? What have we learned from our efforts in AD that can be translated to other types of dementia?

Olink’s vision is to accelerate proteomics together with the drug development and research communities to achieve the goal of precision medicine based on a deep understanding of real-time human biology.

How can we determine whether elevation of oligomeric amyloid-ß in the blood of asymptomatic controls from the age of 55 onwards is part of aging or diagnosis of pre-symptomatic onset of Alzheimer’s or another neurological disease? (Session chair: Assoc. Prof Laura Parkkinen)

Our assays measure oligomeric proteins in blood. Our assays for oligomeric amyloid-ß and α-synuclein show that both proteins are elevated in Alzheimer’s disease, Parkinson’s disease, Dementia with Lewy Bodies and Multiple System Atrophy. Virtually all of the oligomeric proteins are associated with blood cells and non-detectable in plasma. Our assays use an immuno-affinity capture designed for whole blood to enrich the oligomers and a specialised assay configured to measure oligomers, not monomers or total protein.

The attached file presents the evidence for association of oligomeric amyloid-ß and α-synuclein in the erythrocyte fraction following ficol gradient centrifugation. It also shows elevation of oligomeric amyloid-ß in the blood of asymptomatic controls from the age of 55 onwards, but no elevation of α-synuclein

Where next for Alzheimer’s disease research in patient-derived iPSC in vitro models? (Session chair: Prof Richard Wade-Martins)

We have a cell bank of PBMCs and iPSCs from 102 sporadic Alzheimer’s disease patients with associated clinical and lifestyle histories. We wish to collaborate with other organisations to better understand the underlying mechanisms of the early stages of the disease, to design better diagnostics and to identify new therapeutic targets. In your opinion, what are the most important areas of focus for these three areas of interest?