Dr Ashvini Keshavan and her trial identifying accurate and quick blood tests to diagnose dementia

What first attracted you to the area of dementia research?

Encountering patients was the key. While I was in early medical training as a “senior house officer” at Queen Square I once went on a ward round with Jonathan Schott, and that is when I first really learnt that there were symptoms and signs that could indicate not just that a patient had dementia but give clues as to what type of dementia, and that this could link to the type of protein pathology in their brain!

When I returned to Queen Square a couple of years later, as the registrar to the cognitive neurology firm, I encountered more people with younger onset, rarer forms and atypical presentations of dementia, and around that time I began to think of how I might contribute to research. Ultimately I applied for and was awarded a Wolfson clinical PhD studentship in neurodegeneration at UCL, which was my route into dementia fluid biomarker research.

You are involved in the Blood Biomarker Challenge which aims to revolutionise dementia diagnosis. Can you explain what biomarkers are, why are they important, and how they might help us develop treatments?

A biomarker is anything that can be measured in or from a living organism, that indicates something about either a normal or a pathological process. Biomarkers are particularly important in dementia because different underlying pathologies may cause similar symptoms, and in order to be successful in targeting treatments to the underlying causes, we need to know what those underlying pathologies are.

Currently most patients with suspected dementia in the UK who are seen in memory services do not have access to disease-specific biomarkers, as the only ones licensed for use are those for aiding diagnosis of Alzheimer’s disease, and they are either expensive (amyloid PET scans) or relatively invasive (cerebrospinal fluid biomarkers obtained by lumbar puncture). Ideally we need to have biomarkers that are accurate, easily scalable and cheap, in order to improve dementia diagnosis. Blood biomarkers aim to meet this need, at several levels of the pathway to treatment.

Firstly, we want to be able to diagnose people with dementia accurately; next, we want to be able to stage their disease (which could include those with prodromal or mild symptoms) and this might be the point at which screening to clinical trials might be benefited by applying blood tests before moving on to the “gold standard” biomarkers for confirmation. Thirdly, biomarkers measuring response to treatment might be helpful in the clinical trial setting, to discern individuals/sub-groups who benefit from a particular treatment, and eventually might even help to decide on the duration of treatment.

What are some of the next steps with this project?

Two projects were granted funding by the Blood Biomarker Challenge; I shall focus on the ADAPT study which I am co-leading with Prof Jonathan Schott at UCL, in conjunction with colleagues at University College London Hospitals NHS Trust, Imperial College London, the University of Kent and the London School of Economics.

There will be three stages to ADAPT. In stage 1, we will compare two types of plasma p-tau217 tests in terms of how well they predict a patient’s result on the current gold standard CSF and PET tests for Alzheimer’s disease, and we will also examine how robust the p-tau217 test will be to different sampling and handling conditions. We will then derive cut-points and develop guidance about how to interpret the blood test result. 

In stage 2, we will test plasma p-tau217 over a 3 year period in patients who are having amyloid PET scans through a study at Imperial College/Charing Cross Hospital, and determine whether our cut-points remain stable over time.

Stage 3 will be a large study involving up to 20 NHS memory clinics. We want to see what difference the p-tau217 result will make when added to a standard memory clinic assessment. Out of 1100 people taking part, half will find out their p-tau217 results after 3 months, and the remainder after 12 months. We will find out whether the p- tau217 result makes a difference to how many people are diagnosed with AD, the care they receive, the cost of care, and their experience of this. 

Are there particular future challenges in this area?

The main challenge we foresee in integrating blood tests into the existing pathways for dementia diagnosis is that we need to support clinicians and patients in knowing what a result means, and that we resist any implication that a test result means anything on its own outside of an appropriate clinical context. Plasma p-tau217 in particular, for example, is known to increase even in individuals who have no symptoms but who are developing brain amyloid pathology, and only about a third of these individuals eventually develop symptomatic Alzheimer’s disease.

We are therefore advocating that the test should not be offered to people who do not have symptoms suggesting Alzheimer’s disease. However if tests become available to patients on a direct-to-consumer basis, in the future, we might see that people who are worried about their dementia risk for other reasons, but currently have no symptoms, end up with positive results and get referred for assessments to already stretched NHS memory clinics.

This challenge will need to be met by ensuring that such individuals are still assessed only by the appropriate pathways (in primary care and then referred onward only if concerns for Alzheimer’s disease are identified) and also signposted to research studies which are looking to recruit individuals who have no symptoms.

The discovery of drugs such as lecanemab has been heralded as the beginning of the end for Alzheimer’s. To what extent do you think we are entering a new era when it comes to tackling neurodegenerative diseases?

Certainly, the licensing of lecanemab and donanemab on the FDA’s accelerated approval scheme in the USA for treating mild Alzheimer’s disease has raised the hopes for the prospect of it becoming a condition in which the course of disease might be slowed by treatment.

There is still much debate, among clinicians as well as the general public, over whether the extent of benefits demonstrated by these drugs in the clinical trials is enough to outweigh the potential side effects, and whether this therefore is cost-effective for public-funded health care systems such as the NHS in the UK. NICE is assessing them currently, and if these treatments were approved by NICE to be used in the NHS, there is some concern that they might magnify existing ethnoracial and socioeconomic inequalities in access to dementia diagnosis and care, as they currently require the gold standard biomarkers (PET or CSF tests) in order to to be appropriately used, and require monitoring with MRI scans to look out for potential side effects (the main one being amyloid related imaging abnormalities or ARIA - which manifests as either swelling or bleeding on the brain).

The blood tests do have the potential to reduce these inequalities somewhat, by making molecular diagnostics more accessible, but would not be the answer to solving these issues of unequal access to treatment on their own. However even if they are not approved for use in the NHS, they have demonstrated in the broader sense that the level of engagement with and awareness of dementia in the general public is only likely to rise and it is an important priority for healthcare systems to fund research into finding effective treatments that tackle different parts of the pathway to symptomatic Alzheimer’s disease, in parallel with increasing the funding to diagnosing and caring for patients who already have the condition now. 

About Dr Ashvini Keshavan

Dr Ashvini Keshavan is a senior clinical research fellow and honorary consultant neurologist at the Dementia Research Centre UCL Queen Square Institute of Neurology. A graduate of Trinity College, Cambridge, she completed postgraduate medical training in London, and obtained her PhD in 2019 on Cerebrospinal fluid and blood biomarkers of Alzheimer’s disease. Her ongoing work examines these biomarkers in clinical and pre-clinical cohorts, aiming toward future application in more real-world settings, serving diverse populations. She is the joint primary investigator for the UK-wide ADAPT (Alzheimer’s disease Diagnosis and Plasma p-Tau217) study.

Related

• Dr Ashvini Keshavan's academic profile
• UCL Queen Square Institute of Neurology