Towards a memorable breakthrough

Alzheimer’s disease continues to present one of the most significant health challenges of the 21st century. A degenerative brain disease, it already affects more than 55 million people worldwide. And that number is set to rise fast as the global population ages, given that it predominantly affects older people. What’s more, while testing for a plethora of other conditions – from cancers to diabetes and HIV – can have a direct and immediate impact on treatment pathways, the same cannot be said about Alzheimer’s, where treatment pathways remain in their infancy.

Currently, cognitive tests, cerebrospinal fluid (CSF) testing and Positron Emission Tomography (PET) are used to diagnose Alzheimer’s disease and monitor its progression. As the disease can evolve slowly over many years, early detection can allow patients and their families to plan future care. While these tests are effective, they can take many months and eat up valuable healthcare resources – CSF testing and PET scans, for instance, are expensive to run, meaning accessing them can be difficult through some country’s healthcare systems.

A blood bond The spotlight has fallen on blood-based biomarker tests that could remove some of the complexity surrounding an Alzheimer’s diagnosis, improving accuracy, reducing cost and cutting timelines for detection. Hannah Churchill, research communications manager at UK charity the Alzheimer’s Society, says that simple blood-based tests could one day be used to confirm the presence of disease-related proteins in the brain. Unlike PET scans, a blood test could be used at the point of first contact with primary care or GPs, without the need for scans using radiography devices.

Dr Rosa Sancho, head of research at Alzheimer’s Research UK, agrees that biomarkers are reshaping the Alzheimer’s research landscape. “We might still be a long way from a single standard of dementia diagnosis, however, research on biomarkers to date has in turn given us a far greater understanding of the diseases that cause dementia and will help shape future drug development and more effective clinical trials,” she says.

In particular, there has been a focus on what are known as the hallmark Alzheimer’s proteins, amyloid beta and tau. Crucially, blood tests that home in on these and other markers appear to offer a significant advantage in their ability to detect a build-up of proteins linked to Alzheimer’s years – even decades – before symptoms emerge.

The research in this field is collaborative and global. Promising results have come from Washington University in St Louis, where researchers have developed a blood test that measures levels of amyloid beta proteins that misfold and clump together, forming aggregates called “oligomers”. These oligomers provide an early indication of Alzheimer's disease. Amyloid beta folding is also a focus for a network of researchers led by the German Cancer Research Centre.

Another study came out of the Karolinska Institutet in Stockholm and showed that a protein called GFAP (glial fibrillary acidic protein) – a presumed biomarker for activated immune cells in the brain – can provide an early indication of Alzheimer’s. GFAP is also an area of research for Dr Lisa Vermunt and her colleagues at the Clinical Chemistry and Alzheimer Center Amsterdam at Amsterdam University Medical Centers in the Netherlands, whose paper on GFAP in autosomal dominant Alzheimer's disease was recently published in the journal Alzheimer’s & Dementia.

Long time coming

Dr Vermunt says the fast-paced nature of bloodbased Alzheimer’s diagnostics right now is the result of a marriage of science, technology and many decades’ worth of accumulated data. “I think the main reason for this growth is technological advancement,” she says, adding that scientists now have access to long data sets that are accelerating research. “The Alzheimer’s field has also grown a lot in the last 20 years due to increased attention and increased funding, but also because it’s blood and blood is so accessible. It raises interest from people who are maybe not Alzheimer’s researchers, but epidemiologists or cardiologist researchers … maybe their Alzheimer’s patients have had blood taken before. Maybe they have a study that’s been running for 30 years and we can now test that blood as well.”

Just as significantly, the pivotal role of diagnostics in the Alzheimer’s ecosystem is now fully understood. “I think many people realise that to get to the end point of getting better treatments and better prevention, diagnostics are essential because they increase our understanding of the disease,” says Dr Vermunt. “For example, if you can predict what age people will get symptoms, you can get a very clear view of that timeline before people have symptoms.”

Crucially, Dr Vermunt says predicting who will – or won’t – get Alzheimer’s disease a decade or more down the line could also guide clinical trials. Identifying and recruiting patients for earlier inclusion in trials could ultimately accelerate the development of new drugs. “This is why I expect more progress [in treatments] in the coming years, because if we get more rationale or a better understanding of who to include and why, then your trials become better with better design, and you get more progress,” she explains.

In living memory

The significance of this point cannot be overstated, given the degree to which Alzheimer’s treatment research remains in the developmental phase. Identifying at-risk patients for inclusion in clinical studies could not only improve trial outcomes, but also save healthcare resources. This distinction has been made by a team at the Dementia Research Centre at the University College London’s Queen Square Institute of Neurology. In presenting the findings of their work on blood tests that measure the amyloid beta protein, Professor Jonathan Schott predicted that biomarker tests could “radically” reduce the cost of clinical trials due to a reduction in the number of potential trial patients who would need more expensive PET scans.

But Dr Vermunt sees a role for biomarker blood tests well after detection. Once disease-modifying treatments are available, Dr Vermunt says they could also be used to more efficiently track the patient journey. A blood test would be used to help make an initial diagnosis – either on its own or in combination with other diagnostic tools – and then it would be repeated at regular intervals to measure disease progression and to guide treatment. “In the future, we will want to start treatments not too early and not too late,” she says. “One of the powerful aspects of GFAP is that it might help predict when people are going to decline. When treatments are available, you would do a test to see how far away you are from developing dementia. Maybe five years before, you would then want to start preventive treatment and then you are going to want to also monitor the effects of that treatment.”

Ultimately, it’s possible that blood tests could be combined with other technology to help detect and monitor cognitive decline. Alzheimer’s Research UK’s ambitious Early Detection of Neurodegenerative Diseases programme, for example, is using data collected from mobile apps and wearable devices to identify digital, behavioural signatures of Alzheimer’s in an effort to facilitate early detection and intervention.

Ethical and practical challenges of integrating Alzheimer’s testing into wider clinical environment exist – not least concerns about providing emotional support for patients who are told they may – many years later – develop a condition for which there is no effective treatment. Currently, as blood testing remains confined to the research environment, responsibility for patients with these “ticking time bomb” diagnoses must comply with trial ethics. For the moment, Dr Vermunt sees no reason for this to change and no benefit in pushing for blood testing for Alzheimer’s to be commercialised and made available in a community setting. “I think in terms of testing on individual level to predict disease in ten years … I don’t see a reason yet for aiming for that. You would only do that, I think, once there were good treatments available,” she says.

As the mysteries of Alzheimer’s slowly unravel, it’s no coincidence that an increased understanding of the disease has evolved alongside diagnostic tools that are going back to the future in search of early signs of disease. But are effective treatments now finally on the horizon? “I always say that if I didn't think that it was possible, I wouldn't work on it,” Dr Vermunt says. “That’s the easiest answer.”