Disease-modifying dementia drugs will require early diagnosis to be truly effective – but that's not as easy as it might seem
Often, the patient is the last person to know he or she has dementia, a fact that makes diagnosis frustratingly difficult. Yet early diagnosis is a key factor in ensuring the condition's impact is minimised, especially as the two most promising drug candidates to treat Alzheimer's both focus on the early stages of the disease.
Eli Lilly's solanezumab slowed cognitive decline by 34 percent in patients with mild Alzheimer's in clinical trials, plus those patients who started treatment in the earlier phases of the disease were mentally ahead of those given the drug after two years on placebo. The drug targets beta-amyloid plaques in the brain, which many researchers believe cause the disease. Biogen's aducanumab reduces beta-amyloid plaques but its results in cognitive function have been uneven, with data showing slowed mental decline at 3mg/kg and 10mg/kg doses but not at 6mg/kg.
"As well as the phase III solanezumab study in mild Alzheimer's dementia, we have two studies in pre-symptomatic patients," says Dr Mike Hutton, Lilly's chief scientific officer for neurodegenerative diseases. "We have a study in patients who carry mutations that mean they will get early-onset Alzheimer's disease in their fifties and sixties, and a study in patients who are amyloid-positive in PET scans but have not yet shown any symptoms."
But around 30 percent of those diagnosed with mild Alzheimer's don't have any amyloid plaques in their brain, highlighting the importance of early diagnosis. "Clearly, we want to give solanezumab to amyloid-positive, pre-symptomatic individuals," says Hutton, "and the only way to identify those patients is currently through an amyloid PET scan or a CSF assay which requires a lumber puncture."
Barriers to early diagnosis
While early diagnosis is widely seen as crucial for success with Alzheimer's, there is resistance to the idea from healthcare professionals who confuse it with screening, says Dame Gill Morgan, chair of NHS Providers and previous chair of the Alzheimer's Society.
"Early diagnosis is someone coming in with signs of forgetfulness and a healthcare professional doing what's needed to give a diagnosis," she says. "Screening means taking a population that has never complained of anything and testing them for dementia. There are all sorts of ethical questions around screening tests that have to be answered before the UK National Screening Committee can approve one – for example, you need to understand exactly what causes the disease and how you can treat it – which wouldn't make dementia suitable for screening."
As such, GPs are put off diagnosing patients with dementia or Alzheimer's early for fear of being unable to do anything about it. However, Morgan argues that this is not the case at all, and that there are many things that can be done at an early stage that don't involve a treatment.
"People are thinking about early diagnosis in a very medical way and not about the social side, about the patient's family and their ability to plan for the future," she says, adding that early diagnosis allows patients to adapt their lifestyle. "There are all sorts of things patients can do to cope more effectively and get more out of daily life. For example, living well by making sure you don't drink and you keep exercising. Anything that is good for heart health is good for reducing the severity of vascular dementia, and quite a few vascular dementias are also associated with Alzheimer's. There are also ways to make homes easier to live in as it gets more complicated, and you can help families prepare for a patient's changes in perception."
The search for biomarkers
Testing for dementia also presents a range of issues. "A key element in the future is increasing access to PET scans for amyloid," says Lilly's Hutton. "I'm sure access to the amyloid PET tracer will improve once we have a disease-modifying therapy but it's going to take some time for one to be widely available, so it is going to be a challenge to change the environment for early diagnosis. It's something that we're working on both through trying to demonstrate the benefits of the amyloid PET tracer but also trying to raise awareness and educate people," he says.
The charity Alzheimer's Research UK (ARUK) is currently funding research into a variety of biomarkers that could help detect dementia and Alzheimer's specifically more easily, such as imaging biomarkers – including tools to measure hippocampus size more accurately on MRI scans or new PET tracers – and blood biomarkers.
"If it exists, a blood biomarker would be quite easy because it's not invasive," says Dr Rosa Sancho, ARUK's head of research. "Because MRI scans are relatively commonplace and easy to perform, they would probably reach the clinic sooner than PET tracers, which are quite expensive and mainly used in a research setting."
Fear of the disease is another possible roadblock to early diagnosis, says Morgan. "People often don't realise they have the symptoms and, if they do, they can often be afraid. We know that people are now more frightened of Alzheimer's than cancer and, for years, we couldn't get people to go to their doctors if they suspected they had cancer because they'd rather avoid the diagnosis."
Science and technology company Cambridge Cognition, however, is looking at a new approach to identifying Alzheimer's that may help encourage people to self-present. One of their tests, CANTAB Mobile, which works on tablet computers and involves memorising the locations of hidden symbols, is currently used extensively by the NHS to diagnose Alzheimer's.
The ultimate goal is to allow people to monitor their mental health through tests on their own mobile devices, says Noah Konig, the company's marketing and communications manager. "You go to the dentist once a year, you get your eyes tested once a year, but there's no similar mental health check," he says. "Now we have the opportunity to allow people to measure their own mental health continuously without even knowing necessarily that they're doing it."
He points to the huge uptake in brain-training applications over the last ten years even though there's very little science behind them. "There's a real appetite for people to measure their own physical health, for example with Fitbit, and we think there's also going to be an appetite for that in mental health. We want to offer precise cognitive assessment backed by scientific validity on smart watches, smartphones, etc. They will test cognition in everyday life – things like how quickly you unlock your passcode, how many errors you make while typing, and your sleeping patterns – so people don't feel they are being formally assessed."
The company is working with leading universities and researchers to identify the best signs to measure. "We're just collecting data; when a person starts to deviate from the mean, it can be flagged up."
However, NHS Provider's Morgan is cautious. "There's a danger of over-medicalising the condition and of creating fear. The vast majority of people using these apps will not have Alzheimer's, and they might worry too much and over-interpret the results," she says.
The tests can have the opposite effect, counters Konig. "CANTAB Mobile has helped to reassure people who might previously have been concerned about their memory when it is in fact at the expected level for their age," he says. "The purpose of the assessments, because of their level of accuracy, is to identify those who are clinically impaired and reassure those who are not."
While such tests may help to make early diagnoses of future patients, Morgan emphasises the value of early diagnosis to those living with the disease today. "It's easy for people to get very excited about the glamour of a cure, but we have so many patients today for whom no drug is going to be a cure or a delay. What I'd like to see – and it's one of the things pharma has never been into – is a balanced investment programme, so that while we invest in a cure for the future we don't do it at the expense of care today. Often the care today is the bit that gets forgotten but in terms of individual people's lives today, tomorrow, next week, next year, that is the thing that makes the difference," she says.