Anti-Amyloid Drugs Accelerate Brain Atrophy Loss, Meta-Analysis Suggests

Scott Ayton, PhD

Recently published findings from a meta-analysis of trials that assessed anti-amyloid therapies at their highest dose revealed that drug-induced acceleration of volume changes in hippocampus, ventricle, and whole brain atrophy. In addition, investigators identified an arresting correlation between the frequency of amyloid-related imaging abnormalities (ARIA) with the degree of ventricular enlargement.

The meta-analysis included 31 trials of anti-amyloid drugs that demonstrated favorable change on at least 1 biomarker of pathological amyloid-ß and had detailed MRI data sufficient to access the volumetric changes in at least 1 brain region. Brain regions commonly reported included the hippocampus (n = 8974), lateral ventricle (n = 8062), and whole brain (n = 10,279). The analysis included aducanumab (Aduhelm; Biogen), bapinezumab (Janssen), donanemab (Eli Lilly), lecanemab (Leqembi; Eisai), solanezumab (Eli Lilly), semagacestat (Eli Lilly), gantenerumab (Roche), tramiprosate (Neurochem), AAC-001 (Pfizer), IV Immunoglobulin (Takeda), and verubecestat (Merk Sharp).

Senior investigator Scott Ayton, PhD, head of the Translational Neurodegeneration laboratory, and Deputy Director of the Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, and colleagues pulled data on the highest dose of each trial. Pooled random effects showed that these therapies significantly accelerated volumetric changes to the ventricles (mean difference, +0.9 ml; 95% CI, 0.3-1.5), whole brain (mean difference, –1.4 ml; 95% CI, –2.4 to –0.4), and hippocampus (- 14.5 μL; 95% CI, –24.9 to –4.1).

At the conclusion of the analysis, investigators provided a number of recommendations, including that "data safety monitoring boards (DSMB) serving current clinical trials of anti-Aβ drugs should review volumetric data to determine if patient safety is at risk, particularly in patients that develop ARIA." They added that, "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 if brain atrophy is progressive, particularly in patients who develop ARIA."

Secretase inhibitors were found to accelerate atrophy of the hippocampus (mean difference, –37.1; 95% CI, –47.0 to –27.1) and whole brain (–3.3 ml; 95% CI, –4.1 to –2.5) but not ventricles. Monoclonal antibodies caused accelerated ventricular enlargement (mean difference, +1.3 ml; 95% CI, 0.6-2.1), which was driven by the subset of monoclonal antibodies that cause increased ARIA (+2.1 ml; 95% CI, 1.5-2.8). Both donanemab (mean difference, –4.6 ml; 95% CI, –7.6 to –1.6) and lecanemab (–5.2 ml; 95% CI, –8.1 to –2.4) had an effect on whole brain volume, whereas aducanumab and bapinezumab did not.

Just as increased frequency of ARIA induced by anti-amyloid therapies was dependent on the drug type and dose, the enlargement of ventricles was strongly correlated with percentage of ARIA (r = 0.86; P = 6.22 x 10-7). Furthermore, the frequency of ARIA was associated with hippocampus volume change (r = 0.51; P = .002), but not the whole brain when explored in a similar analysis.

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When assessing whether change in brain volume was associated with the reduction in amyloid-ß plaque measured by PET, investigators found that the standardized uptake ratio (SUVR) was negatively correlated with ventricular enlargement (r = 0.76; P = 7.5 x 10-5) but not volume changes to hippocampus or whole brain. Notably, the frequency of ARIA was also correlated with the extent of SUVR reduction by anti-amyloid drugs (r = ­–0.682; P = 1.70 x 10-5), which may have confounded associations between SUVR reduction and volume changes.

Ayton and colleagues modeled the projected influence of anti-amyloid drugs on the volume changes of lateral ventricles, hippocampus, and whole brain atrophy that occurs between mild cognitive impairment (MCI) and Alzheimer dementia. The analysis predicted that patients with MCI taking secretase inhibitors will develop whole brain volume (treated: 3.0 years; non-treated: 3.6 years; difference: 7.7 months) and hippocampal volume (treated: 3.7 years; non-treated: 4.4 years; difference: 8.7 months) typical of someone with Alzheimer dementia in a materially earlier time point. Furthermore, monoclonal antibodies that induced ARIA accelerated the timeframe for patients with MCI to develop enlargement of the lateral ventricle typical of Alzheimer dementia (treated: 1.5 years; non-treated: 2.1 years; difference: 7.0 months), which was not observed with monoclonal antibodies that did not induce ARIA (2.1 years) or secretase inhibitors (2.3 years).

"Pharmaceutical companies that have conduced trials of anti-Aβ drugs should interrogate prior data on brain volume (e.g. stratifications by ARIA, analysis of additional brain structures), report the findings, and release the data for researchers to investigate,” the study investigators recommended. "Clinicians should monitor brain volume changes of individual patients that receive ARIA- inducing anti-Aβ monoclonal antibodies to determine whether continued treatment is appropriate."

REFERENCE
1. Alves F, Kallinowski P, Ayton S. Accelerated brain volume loss caused by anti-ß-amyloid drugs: a systematic review and meta-analysis. Neurology. Published online March 27, 2023.