Last year, a new medication, lecanemab, hit the headlines when Phase III trial results confirmed that it had become the first of its kind to slow cognitive decline in people with Alzheimer’s disease. The findings not only appear to validate the long-standing amyloid-cascade hypothesis in the disease, but also seemingly support the theory of ‘right drug, right patient, right time’, in which targeted selection of participants at the early stages of the disease - those with mild cognitive impairment due to Alzheimer’s in this trial - is thought to offer the drug the best chance of disrupting disease progression before extensive neuronal loss occurs. Intervening before the onset of even the most subtle of symptoms has the potential for even greater benefit.
But if an individual is at the earliest stages of Alzheimer’s, and does not present with any symptoms of the disease, how can they be accurately diagnosed and identified as prime candidates for clinical trials? This is where the field looks to ‘biomarkers’ - biological measures or ‘signposts’ that aid in the identification and monitoring of a person’s disease.
Amyloid beta is the protein implicated in the amyloid-cascade hypothesis, and its accumulation in Alzheimer’s is used as an early biomarker either through positive cerebrospinal fluid (CSF) samples or a Positron emission tomography (PET) brain imaging scan. However, the build-up of amyloid beta plaques in the brain occurs many years to decades before people have symptoms. If a substantial number of amyloid-positive trial participants do not go on to develop symptoms of Alzheimer’s, this can have a major impact when verifying the effectiveness of a new drug.
The Grand Challenge
With most cognitive measures declining too late in disease to be useful, and the presence of amyloid beta alone proving an unreliable predictor of symptom onset, there is an unmet need for a new type of biomarker that can accurately diagnose the earliest stages of Alzheimer’s. This grand challenge is the subject of a new £1.7 million investment from UK DRI led by UKRI Future Leader Fellow and UK DRI Group Leader at UCL, Dr Marc Aurel Busche.
In this highly collaborative project, involving multiple experts from outside the dementia field, the team aims to develop a functional biomarker that measures subtle changes to the brain’s circuitry at an early stage of Alzheimer’s, and before the tipping point into irreversible cognitive decline.
"I think a good analogy would be cardiology – if you were concerned for the cardiovascular health of a patient, you would not only take a blood test to measure something like cholesterol, you would also perform electro- and echocardiograms to gain a more accurate picture of the state of the heart at work. As a clinician, I may receive the results of abnormal fluid biomarkers suggesting the presence of Alzheimer’s pathology in a patient, but I can never be sure if they are one of the 30% of people who will not go on to develop cognitive symptoms. What we need is a reliable readout that confirms there are early pathophysiological changes to the brain, one which more accurately predicts and tracks the development of disease and symptoms.”
Dr Busche’s pioneering research investigates the impact of abnormal proteins like amyloid beta on the brain’s cells and circuitry, using innovative mouse models and cutting-edge techniques that are custom-built in his laboratory. Notably, he has shown that amyloid-beta causes hyperexcitability in the brain’s neuronal networks early in Alzheimer’s, leading to impaired learning and memory.