A recent study led by UCL researchers indicates that brain volume loss observed in Alzheimer's disease patients undergoing new immunotherapies is likely due to the removal of amyloid plaques rather than the destruction of brain tissue. This finding offers a new perspective on the effects of these treatments, suggesting that brain shrinkage could be a sign of successful therapy. The research, published in Lancet Neurology, analyzed data from a dozen clinical trials focusing on amyloid-targeting immunotherapies, including lecanemab.
The team, led by Professor Nick Fox from the UCL Dementia Research Centre, introduced the term "amyloid-removal-related pseudo-atrophy" (ARPA) to describe this phenomenon. They found that the observed brain volume loss was consistent across different studies and correlated with the effectiveness of the therapies in removing amyloid plaques. This correlation suggests that the volume loss is a direct consequence of plaque removal and not necessarily indicative of harm to the brain.
Understanding ARPA and its Implications
"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 unrecognized toxicity to the brains of treated patients," explained Professor Fox. "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."
The researchers emphasize that the volume occupied by beta-amyloid plaques in the brains of Alzheimer's patients is significant, accounting for approximately 6% of the cortex in post-mortem studies. The extent of volume change observed in treated patients is considerably lower than the total volume occupied by these plaques, further supporting the theory that the shrinkage is related to plaque removal.
Call for Further Evaluation
Dr. Christopher Belder, the first author of the study, stressed the importance of better reporting these changes in clinical trials. "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," said Dr. Belder.
The MHRA in the UK recently licensed lecanemab for use in the early stages of Alzheimer's disease. This drug targets beta-amyloid, a protein that accumulates in the brains of individuals with Alzheimer's and is believed to initiate neuronal dysfunction and cell death. While the National Institute for Health and Care Excellence (NICE) has expressed concerns about the cost-effectiveness of lecanemab, the decision is under review, highlighting the ongoing debate surrounding the drug's accessibility and value.
Considerations for Clinical Practice
Despite the reassuring findings, the researchers caution that long-term data on these new medications are limited, and specialists should proceed cautiously as the drugs become more widely available. Further research is needed to fully understand the long-term trajectory of volume changes and whether excess volume change after beta-amyloid removal adversely influences long-term outcomes.
