Accelerated Brain Volume Loss Caused by Anti-beta-Amyloid Drugs A Systematic Review and Meta-analysis

Background and Objectives To evaluate brain volume changes caused by different subclasses of anti-beta-amyloid (A beta) drugs trailed in patients with Alzheimer disease. Methods PubMed, Embase, and ClinicalTrials.gov databases were searched for clinical trials of anti-A beta drugs. This systematic review and meta-analysis included adults enrolled in randomized controlled trials of anti-A beta drugs (n = 8,062-10,279). The inclusion criteria were as follows: (1) randomized controlled trials of patients treated with anti-A beta drugs that have demonstrated to favorably change at least one biomarker of pathologic A beta 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 hippocampus, lateral ventricle, and whole brain. Amyloid-related imaging abnormalities (ARIAs) 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-A beta drug class. Secretase inhibitors accelerated atrophy to the hippocampus (Delta placebo - Delta drug: -37.1 mu L [19.6% more than placebo]; 95% CI -47.0 to -27.1) and whole brain (Delta placebo - Delta drug: -3.3 mL [21.8% more than placebo]; 95% CI -4.1 to 2.5). Conversely, ARIA-inducing monoclonal antibodies accelerated ventricular enlargement (Delta placebo - Delta drug: +2.1 mL [38.7% more than placebo]; 95% CI 1.5-2.8) where a striking correlation between ventricular volume and ARIA frequency was observed (r = 0.86, p = 6.22 x 10-7). Mild cognitively impaired participants treated with anti-A beta drugs were projected to have a material regression toward brain volumes typical of Alzheimer dementia;8 months earlier than if they were untreated. Discussion These findings reveal the potential for anti-A beta 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.

Automated summary

This study evaluates the brain volume changes caused by different subclasses of anti-beta-amyloid drugs in Alzheimer patients. The findings suggest that these drugs may accelerate brain atrophy and have varying effects on different brain regions.