Could anti-amyloid drugs actually promote neurodegeneration?

After years of failed trials, two and possibly three anti-amyloid monoclonal antibodies have shown efficacy at removing beta-amyloid from the brain of subjects with mild Alzheimer’s disease. Two of them, lecanemab and donanemab, have also shown significant slowing of cognitive impairment. Aducanumab is less effective in amyloid removal than the other two, and only one of two studies showed a benefit on slowing cognitive deterioration. One of the puzzles concerning these anti-amyloid drugs is that there has been no slowing of brain volume loss, a surrogate measure of neurodegeneration. A paper published this week in Neurology provides results of a meta-analysis of brain volume changes in 31 trials of anti-amyloid drugs including secretase inhibitors and monoclonal antibodies. None of the secretase inhibitors were effective in slowing cognitive impairment, and none of them caused brain volume loss.  Significant loss of brain volume was seen in most of the anti-amyloid drug trials, and this association was most pronounced in trials of drugs complicated by amyloid-related imaging abnormalities (ARIA).  Recall that ARIA represent areas of brain swelling and/or microhemorrhages. Most of the time, ARIA are mild and resolve with pausing of the drug, but in 1 – 2% of participants in the aducanumab, donanemab and lecanemab trials, ARIA were severe, requiring hospitalization. Three deaths associated with ARIA were reported in the lecanemab trial, and three deaths were also reported in the donanemab trial, although the relationship to ARIA has been disputed.

Why should brain volume be decreased in patients given these drugs?  Several possibilities have been suggested.  One is that the brain volume loss is simply due to the removal of beta-amyloid plaques, but this has been disputed by the fact that the total volume of amyloid plaques is estimated to be less than 1/1000 of the total brain volume. Another explanation is that the brain volume loss is due to pseudoatrophy, a phenomenon seen in treatment of multiple sclerosis as the inflammatory MS lesions are brought under control. This is a possibility for Alzheimer’s, but the role of inflammation appears to be much less in Alzheimer’s than it is in MS, and inflammation would be expected to increase, not decrease, with ARIA. Another opinion is that the cause of brain volume loss seen with ARIA-associated medications is irrelevant as long as the patients receiving the medication have significant, cognitive benefit.  

The authors of the new Neurology paper argue that we can’t neglect the possibility that the adverse consequences of brain volume loss may not show up until later and that we must be vigilant for late adverse consequences in patients receiving these drugs. They make the following recommendations: 

1. Clinicians who prescribe ARIA-inducing anti-Aβ monoclonal antibodies should inform current and new patients that these drugs have been shown to accelerate markers of neurodegeneration (for example, ventricular enlargement). 

2. Clinicians should review the volumetric data from the clinical trials of ARIA-inducing anti-Aβ monoclonal antibodies when assessing the risk/benefit profile of these therapies.

3. Clinicians should monitor brain volume changes of individual patients who receive ARIA-inducing anti-Aβ monoclonal antibodies to determine whether continued treatment is appropriate.

4. The data safety monitoring boards serving current clinical trials of anti-Aβ drugs should review volumetric data to determine whether patient safety is at risk, particularly in patients who develop ARIA. 

5. Ethics boards that approve trials for anti-Aβ drugs should request that volume changes be actively monitored. Long-term follow-up of brain volumes should be factored into the trial designs to determine whether brain atrophy is progressive, particularly in patients who develop ARIA. 

6. Pharmaceutical companies that have conducted trials of anti-Aβ drugs should interrogate prior data on brain volume (e.g., stratifications by ARIA and analysis of additional brain structures), report the findings, and release the data for researchers to investigate.