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

To evaluate brain volume changes caused by different subclasses of anti-β-amyloid (Aβ) drugs trailed in patients with Alzheimer disease.

PubMed, Embase, and ClinicalTrials.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 = 8,062-10,279). The inclusion criteria were as follows: (1) randomized controlled trials of patients treated with anti-Aβ drugs that have demonstrated to favorably change at least one biomarker of pathologic 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 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.

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 (Δ placebo - Δ drug: -37.1 µL [19.6% more than placebo]; 95% CI -47.0 to -27.1) and whole brain (Δ placebo - Δ drug: -3.3 mL [21.8% more than placebo]; 95% CI -4.1 to 2.5). Conversely, ARIA-inducing monoclonal antibodies accelerated ventricular enlargement (Δ placebo - Δ 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 × 10^-7). Mild cognitively impaired participants treated with anti-Aβ drugs were projected to have a material regression toward brain volumes typical of Alzheimer dementia ∼8 months earlier than if they were untreated.

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.