AbstractBackgroundThe potential benefit of anti‐Aβ drugs to cognition in Alzheimer’s disease (AD) remains under active debate. Anti‐Aβ drugs also frequently cause accelerated changes to brain volume. This is concerning because loss of brain tissue is the proximate cause of cognitive dysfunction in AD and volume changes are supportive and objective evidence of disease progression.MethodPubMed, Embase and Clinicaltrial.gov databases were searched to evaluate brain volume changes caused by different sub‐classes of anti‐amyloid beta (Aβ) drugs trialed in patients with Alzheimer’s disease. The inclusion criteria for this systematic review and meta‐analysis were: (1) randomized controlled trials of patients treated with anti‐Aβ drugs that have demonstrated to favorably 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. Amyloid‐Related Imaging Abnormalities (ARIA) were investigated when reported in clinical trials. Of the 145 trials reviewed, 31 were included in the final analyses (n = 8062 to 10279).ResultA 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 = 6.22×10⁻⁷).ConclusionThese 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.