Some Anti-Amyloid are linked to Accelerated Brain Atrophy

[Julie G]

You can see the Medscape coverage of this meta-analysis here. I hesitated to share it with the community for fear of frightening our members, who are participating in the lecanamab trials, but please note that volume loss was not found with that specific drug, but other effects were found. On balance, I think this is a well-researched, unbiased examination of long term effects.

Accelerated Brain Volume Loss Caused by Anti–β-Amyloid Drugs: A Systematic Review and Meta-analysis
https://n.neurology.org/content/early/2 ... 0000207156

Abstract
Objectives: To evaluate brain volume changes caused by different sub-classes of anti-amyloid beta (Aβ) drugs trialled in patients with Alzheimer’s disease.

Methods: PubMed, Embase and Clinicaltrial.gov databases were searched for clinical trials of anti-Aβ drugs. This systematic review and meta-analysis included adults enrolled in randomized controlled trials of anti-Aβ drugs (n=8062 to 10279). The inclusion criteria were as follows: (1) randomized controlled trials of patients treated with anti-Aβ drugs that have demonstrated to favourably change at least one biomarker of pathological Aβ; and (2) detailed MRI data sufficient to assess the volumetric changes in at least one brain region. MRI brain volumes were used as the primary outcome measure; brain regions commonly reported include the hippocampus, lateral ventricle and whole brain. Amyloid-Related Imaging Abnormalities (ARIA) were investigated when reported in clinical trials. Of the 145 trials reviewed, 31 were included in the final analyses.

Results: A meta-analysis on the highest dose of each trial on hippocampus, ventricle, and whole brain revealed drug-induced acceleration of volume changes that varied by anti-Aβ drug class. Secretase inhibitors accelerated atrophy to the hippocampus (mean difference: -37.1 µL [-19.6% relative to change in placebo]; 95% confidence interval: -47.0 to -27.1) and whole brain (-3.3mL [-21.8% relative to change in placebo]; 95% confidence interval: -4.1 to 2.5). Conversely, ARIA-inducing monoclonal antibodies accelerated ventricular enlargement (mean difference: +2.1mL [+38.7% relative to change in placebo]; 95% confidence interval: 1.5 to 2.8) where a striking correlation between ventricular volume and ARIA frequency was observed (r=0.86, p=6.22x10-7). Mild Cognitively Impaired participants treated with anti-Aβ drugs were projected to have a material regression toward brain volumes typical of Alzheimer’s dementia ∼8 months earlier than if they were untreated.

Conclusions: These findings reveal the potential for anti-Aβ therapies to compromise long-term brain health by accelerating brain atrophy, and provide new insight into the adverse impact of ARIA. Six recommendations emerge from these findings.

[NF52]

You can see the Medscape coverage of this meta-analysis here. I hesitated to share it with the community for fear of frightening our members, who are participating in the lecanamab trials, but please note that volume loss was not found with that specific drug, but other effects were found. On balance, I think this is a well-researched, unbiased examination of long term effects.

Accelerated Brain Volume Loss Caused by Anti–β-Amyloid Drugs: A Systematic Review and Meta-analysis
https://n.neurology.org/content/early/2 ... 0000207156

Abstract
Objectives: To evaluate brain volume changes caused by different sub-classes of anti-amyloid beta (Aβ) drugs trialled in patients with Alzheimer’s disease....
Results: A meta-analysis on the highest dose of each trial on hippocampus, ventricle, and whole brain revealed drug-induced acceleration of volume changes that varied by anti-Aβ drug class....
...a striking correlation between ventricular volume and ARIA frequency was observed...
Conclusions: These findings reveal the potential for anti-Aβ therapies to compromise long-term brain health by accelerating brain atrophy, and provide new insight into the adverse impact of ARIA....

Julie,

I appreciate your honest concern for those of us in trials or treatment with lecanemab, donanemab or Aduhelm. The issue of the potential for some people treated with anti-amyloid monoclonal antibodies to show volume changes in one or more areas of the brain is not welcome. But it is not news to me, although it may be to others, having been discussed at the Alzheimer's Association meeting last summer and, I believe, at the November CTAD conference.

In quoting your excerpt, I deleted the section on changes in secretase (BACE- inhibitor) trials, because all of those trials, including Generations I and II in people with normal cognition, were stopped by July 2019 due to these changes and have not been resumed.

Both the article you linked and an accompanying editorial comment are behind a paywall, but available for 24-hour access for $39. each. I have 24 hour access to both articles and appreciate the care with which the authors (a biostatistician and two post-docs in neurology in Melbourne Australia) addressed several possible explanations for observed changes, based on aggregated, not individual data and a model that assume the rate of change will continue over time.

This is part of their Discussion section:

These meta-analyses permit robust conclusions regarding the effect of anti-Aβ drug classes on different brain structures, but the lack of individual patient data (which has yet to be released) limits the interpretations of our findings. We do not have data from individual cases to determine whether people who develop ARIA exhibit accelerated changes to the ventricles....donanemab and lecanemab which caused the greatest reduction in [amyloid plaque] SUVR compared to all other drugs did not cause the greatest acceleration to ventricular enlargement. These findings imply that the extent of SUVR change is related to the frequency of ARIA, with the latter being the more likely driver of ventricular volume enlargement.

It is possible that the symptoms that result from drug-induced brain volume loss to different structures are not related to cognition – especially for monoclonal antibodies that tend not to affect the hippocampus.[/b] Therefore, the clinical impact of drug-induced brain damage may not have been measured using the clinical instruments employed in the trials of these drugs. It is possible that volume changes do not reflect neurodegeneration, for example these drugs may cause CSF malabsorption (e.g. by blocking glymphatics) leading to a temporary and/or non-deleterious outcome,.

And I wholeheartedly support this recommendation:

....when dealing with the possibility of brain damage we should be cautious in our interpretation and gather more data before dismissing this finding and its usual interpretation. Our analysis calls for urgent revaluation of prior trials and renewed procedures to monitor patients in current trials and in the community, which we enumerate in six recommendations

Without quoting more of the article, the recommendations are all reasonable and doable:

• Clinicians should inform themselves about data on specific drugs and should also inform prospective patients of the observed changes (ex. ventricular enlargement)

• Monitoring MRIs for brain changes,

[Note: I will have my 8th MRI in 2 weeks since the trial began to do just that; 6 were scheduled; two were "unscheduled" to check for ARIA-E (none) and ARIA-H, one "probably <5mm micro-hemorrhage at about the 6 month mark; months since then. Regarding brain volume changes, all have come back "No change"]

• Data safety monitoring boards (DSMB) should review volumetric data, particularly in patients with ARIA-Edema,

• Ethics boards that approve trials for anti-Aβ drugs should request that volume changes be actively monitored.

• Long term follow-up should be designed into new trials to determine if brain atrophy is progressive especially in those with ARIA-E.

AHEAD and trials of donanemab (TRAILBLAZER) have been in place for a similar amount of time in those with amyloid and normal cognition and the outside data-safety monitoring boards have not stopped them due to observed negative or safety issues. It this is likely to happen in people in pre-clinical stages without synaptic damage of neurons seen in MCI, it may happen only very gradually.

AlzForum posted What About the Brain Shrinkage Seen with Aβ Removal?
presenting multiple viewpoints on this issue and possible reasons for the observed changes here, with this graph from the Alves, et al meta-analysis that suggests that those without ARIA-Edema did not experience the atrophy. The vertical line on the graph is the midpoint between changes on MRI favoring placebo (i.e. less atrophy on placebo) vs. favoring the drug (less atrophy on the drug). Lecanemab shows a wide divergence with overall median showing no clear advantage for placebo.

An accompanying editorial Brain Shrinkage in Anti–β-Amyloid Alzheimer Trials: Neurodegeneration or Pseudo-atrophy? by Frederick Barkhof, MD, PhD, who serves on the external mandatory "Data Safety Monitoring Board" for the A45-AHEAD studies and Dr. David Knopman, a neurologist clinician and researcher at Mayo Clinic's Alzheimer's Research Center and a Deputy Editor of Neurology (the journal that published the meta-analysis) is complimentary of the meta-analysis and focuses on what may be important to follow over the long term.

The reality in 2023 is that the relevance of brain volume reductions in this therapeutic context remains uncertain. Longer periods of observation will be needed to know whether the brain volume losses continue at an accelerated rate, or if they attenuate or disappear. Ultimately, it's the clinical outcomes that matter, regardless of the MRI changes.

FWIW, I certainly support upcoming trials of drugs that appear not to result in ARIA, including the APOLLO E4 study of ALZ-801 in people with MCI/mild AD. https://clinicaltrials.gov/ct2/show/NCT04770220 which should show result in late 2024 or early 2025. In the meantime, I hope the NIA and FDA require more in-depth analysis by ARIA, APOE4 and other possible contributors (inflammatory markers, vascular disease) by the drug companies.