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.
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