Brain Volume Loss Linked to Lecanemab May Be a Sign of Effectiveness

A loss of brain volume associated with new immunotherapies for Alzheimer’s disease may be caused by the removal of amyloid plaques, rather than the loss of neurons or brain tissue, finds a study led by UCL researchers.

The research published in Lancet Neurology, analysed data from a dozen different trials of amyloid-targeting immunotherapy - including lecanemab which has recently been approved by the UK’s regulator MHRA.

While brain shrinkage is usually an undesirable outcome, the team found that the excess volume loss was consistent across studies and correlated with how effective the therapy was in removing amyloid and was not associated with harm.

As a result, the researchers believe that the removal of amyloid plaques, which are abundant in Alzheimer’s patients, could account for the observed brain volume changes. And, as such, the volume loss should not be a cause for concern.

To describe this phenomenon, the research team coined a new phrase: “amyloid-removal-related pseudo-atrophy” or ARPA.

Senior author and Director of the UCL Dementia Research Centre, Professor Nick Fox said: “Amyloid-targeting monoclonal antibodies represent a significant therapeutic breakthrough in the treatment of Alzheimer’s disease. These agents work by binding to and triggering the removal of amyloid plaques from the brain.

“One area of controversy has been the effect of these agents on brain volumes. Brain volume loss is a characteristic feature of Alzheimer’s disease, caused by progressive loss of neurons.

“Amyloid immunotherapy has consistently shown an increase in brain volume loss – leading to concerns in the media and medical literature that these drugs could be causing unrecognised toxicity to the brains of treated patients.

“However, based on the available data, we believe that this excess volume change is an anticipated consequence of the removal of pathologic amyloid plaques from the brain of patients with Alzheimer’s disease.”

First author, Dr Christopher Belder (UCL Dementia Research Centre, and The University of Adelaide), said: “We are calling for better reporting of these changes in clinical trials, and for further evaluation to better understand these brain volume changes as these therapies enter more widespread use.”

In August, the Medicines and Healthcare Products Regulatory Agency (MHRA) licensed lecanemab, for use in the early stages of Alzheimer’s disease in the UK *.

The drug works by targeting beta amyloid – a protein that builds up in the brains of people with Alzheimer’s disease and is thought to be the triggering event leading to neuronal dysfunction and cell death.

The National Institute for Health and Care Excellence (NICE) that decide whether drugs should be made available on the NHS have published draft guidance advising that the benefits of lecanemab are too small to justify the cost to the NHS. However, the decision will be reviewed following a public consultation and a second independent committee meeting later this year.

Reference: Belder CRS, Boche D, Nicoll JAR, et al. Brain volume change following anti-amyloid β immunotherapy for Alzheimer’s disease: amyloid-removal-related pseudo-atrophy. The Lancet Neurol. 2024;23(10):1025-1034. doi: 10.1016/S1474-4422(24)00335-1

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