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We recently wrote about the challenge for dementia clinical services if immunotherapy for Alzheimer’s disease proves to be successful.
It is important to plan for the future but there is some thinking and planning to be done before we arrive there.
The focus of research has shifted significantly away from established and moderately severe Alzheimer’s disease to the much earlier stages of the illness and in some cases when symptoms are very mild or even absent. People have called this “Prodromal” Alzheimer’s disease or “Asymptomatic” Alzheimer’s disease.
For technocrats like us, of course, dementia is defined as a clinical syndrome and by definition has to have symptoms. So one would not talk about pre symptomatic dementia (that would include everybody who did not have dementia, a bit like the club of which we are members ie people who have not yet won the Nobel Prize for medicine). As Alzheimer’s disease is largely defined in terms of the brain deposition of amyloid plaques and abnormal tangles of nerve fibres (due to the deposition of tau protein), you can certainly have these in the absence of symptoms.
In some situations, probably less than 1% of the total number, Alzheimer’s disease is passed on by a familial gene (APP and presenilin) for which testing is available. Since these rare gene mutations lead to disease with consistent ages at onset within families, there is a unique opportunity to study the earliest development of the changes in the brain such as amyloid deposition. In addition there is an opportunity to intervene before symptoms develop.
There are two major examples of this approach. The Alzheimer’s Prevention Initiative study, taking place in Medellin, Colombia involves about 300 participants from local families that can be traced to a common descendant who had a rare genetic mutation. The second is the DIAN TU study which is looking to determine the safety, tolerability, and effectiveness of two potentially disease modifying therapies in individuals who carry one of the gene mutation that causes dominantly inherited Alzheimer’s disease. Individuals in the UK are participating in the DIAN TU study at the UCL centre.
It is likely that disease modifying treatments will be based on their ability to tackle amyloid deposition in the brain. Amyloid is detected using a positron emission tomography scan, which currently costs about £1,400. There are three tracers available which use fluorine 18 to bind the tracer approved by the USA Food and Drug Administration in 2012, 2013 and 2014 respectively – they are: florbetapir, trade name Amyvid from Eli Lilly flutemetamol, trade name Vizamyl from GE Healthcare and florbetaben, trade name Neuraceq from Piramal Imaging). Amyloid can be detected before there are any symptoms and there are studies being developed of people who have positive amyloid scans but no symptoms.
The A4 study is the first trial designed to prevent memory loss by identifying individuals who have the earliest changes of Alzheimer’s disease but are asymptomatic. Tau can be detected using similar techniques but the technology is less well advanced.
At the same time as all this excitement in dementia, the 100,000 genome project has been established in the NHS. Facilitated by 13 genomic medical centres across England, the aims include increasing discovery of pathogenic variants leading to new treatments, devices and diagnostics and to advance genomic practice into the NHS.
The opportunities for Alzheimer’s disease are significant in terms of potentially identifying people at risk, elucidating pathological mechanisms, perhaps helping predict who may respond to treatment allowing us to target interventions.
What are the implications for us? First, what we need is a collective and agreed view on the different ways of investigating people in the early stages of Alzheimer’s disease. Who should get an amyloid scan and when? More and closer working between clinical disciplines involved in memory assessments is crucial here.
Second, If and when one of the monoclonal antibodies is shown to have an effect in slowing the progression of Alzheimer’s disease then it will be one of the most significant events in the unfolding of the dementia story, we must be ready for it and in the sense of there being no surprises we must prepare the ground, working with colleagues across the system and reflecting work done by organisations such as Alzheimer’s Research UK and the Alzheimer’s Society is key. We are aware that there are similar protocols that have been developed for monoclonal antibody work in conditions such as rheumatoid arthritis.
Third, we need to harness the power of genomics and specifically the 100,000 genomes project to mainstream dementia in general and Alzheimer’s disease in particular.
The field of dementia is on the threshold of change which will benefit people with the condition, their families and carers. We all have a responsibility to make the most of the opportunities.
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