Accelerated Brain Volume Loss Caused by Anti-β-Amyloid Drugs: A Systematic Review and Meta-analysis.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of randomized controlled trials
PubMed 36973044 · doi:10.1212/WNL.0000000000207156
What was done
The authors searched PubMed, Embase, and ClinicalTrials.gov for randomized controlled trials of anti-beta-amyloid drugs in adults with Alzheimer disease. Included trials were required to demonstrate favorable changes in at least one amyloid biomarker and report detailed MRI volumetric data for at least one brain region (such as hippocampus, lateral ventricle, or whole brain). Amyloid-related imaging abnormalities (ARIAs) were examined when reported. Out of 145 trials reviewed, 31 randomized controlled trials encompassing 8,062 to 10,279 participants met inclusion criteria and were evaluated using the highest dose tested in each trial.
What was found
Anti-beta-amyloid drugs accelerated brain volume loss, with effects differing by drug class. Secretase inhibitors accelerated atrophy in the hippocampus (difference in change between placebo and drug: -37.1 microliters, representing 19.6% more loss than placebo; 95% CI -47.0 to -27.1) and whole brain (-3.3 mL, 21.8% more loss than placebo; 95% CI -4.1 to 2.5). ARIA-inducing monoclonal antibodies accelerated ventricular enlargement (+2.1 mL, 38.7% more enlargement than placebo; 95% CI 1.5 to 2.8). Ventricular volume change correlated strongly with ARIA frequency (r = 0.86, p = 6.22 x 10^-7). Participants with mild cognitive impairment treated with anti-beta-amyloid drugs were projected to regress toward brain volumes typical of Alzheimer dementia approximately 8 months earlier than untreated individuals.
Why it matters
This review shows that anti-amyloid therapies consistently accelerate structural brain volume loss and ventricular enlargement compared to placebo, with ventricular expansion tightly linked to ARIA frequency.
Limits
Only 31 of 145 reviewed trials provided adequate MRI volumetrics and biomarker data for inclusion. Total participant numbers varied across regional analyses (8,062 to 10,279). The abstract reports projected rather than directly observed long-term clinical progression timelines, and whether volume loss stabilizes or reverses after drug cessation was not reported.
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