Increase in brain atrophy due to Alzheimer’s disease drugs

New Alzheimer’s drugs: Progress and challenges in combating brain atrophy

Drug development for Alzheimer’s disease remains a difficult endeavour, despite occasional glimmers of hope. One example is the monoclonal antibody lecanemab, which is seen as a potential “beacon of hope”.

However, there are downsides: Anti-amyloid agents like this antibody seem to cause further shrinkage of already atrophied brains.

This phenomenon is not new: Already in 2016, researchers reported an increase in ventricular volume under the antibody bapineuzumab. In November last year, the US neurologist and dementia expert Professor Madhav Thambisetty from Johns Hopkins University also mentioned this phenomenon in an article.

A recent systematic study analysis now shows that pharmacological therapies against beta-amyloid and amyloid plaques are associated with further brain shrinkage in Alzheimer’s patients. The results of this study evaluation were published in the journal Neurology on 27 March 2023.

Systematic review of 31 studies

The systematic review and meta-analysis included adult participants from randomised controlled trials of anti-Aβ drugs (n = 8062 to 10279). MRI brain volume measurements were used as the primary endpoint of the studies. Amyloid-related imaging abnormalities (ARIA) were included if documented in the clinical trials. Finally, of 145 studies reviewed, 31 were included in the final analysis.

Anti-Aß drug therapy is associated with cerebral volume reduction

The analysis showed that treatment was associated with a decrease in cerebral volume. Secretase inhibitors led to accelerated atrophy of the hippocampus and whole brain. Similarly, the ARIA-inducing antibodies lecanemab and donanemab accelerated whole brain volume loss, with a notable correlation between ventricular volume and the incidence of ARIA.

In two large lecanemab trials, participants receiving the highest dose of the drug showed an average brain volume loss of 28% compared to placebo after about 18 months. This corresponded to an additional loss of 5.2 millilitres (ml) of brain mass. The authors of the current study analysis also reported that anti-amyloid antibodies – unlike secretase inhibitors – led to an increase in brain ventricle size.

“We don’t know exactly what these changes might mean”, says Dr Jonathan Jackson, a neuroscientist at Massachusetts General Hospital. But, “These data are extremely concerning, and it is likely that these changes are harmful.”An Eisai spokesperson, on the other hand, again pointed out that the shrinkage could also be a “good”sign. For example, participants in the lecanemab pivotal trial had shown a “greater loss of cortical volume with lecanemab compared to placebo”but this volume reduction could be due to the monoclonal antibody removing beta-amyloid from the brain and reducing inflammatory processes.

But this is pure speculation, some scientists feared, according to the science journal SCIENCE. “We don’t know what it means”that the brain shrinks more in treated participants than in people receiving a placebo, Professor Lon Schneider (California Alzheimer’s Disease Center, University of Southern California) is quoted as saying. But “when we see a loss of volume on MRI, we think that’s not good”, Schneider continues.