Cumulative cognitive benefits and brain volume change with anti-amyloid therapies for Alzheimer’s disease

OBJECTIVE: This study aimed to evaluate the cumulative benefits of Food and Drug Administration (FDA)-approved monoclonal antibodies (mABs), administered at FDA-approved dosing regimens in slowing cognitive decline compared with placebo and acetylcholinesterase inhibitor (AChEI), and the dynamic relationships between cognitive decline, amyloid reduction and whole brain volume (WBV) changes in mAB treatment. METHODS: Five major databases were systematically searched for double-blinded randomised controlled trials of patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild AD treated with mAB or AChEI for at least 6 months. The primary outcomes were the change in cognitive function measured by Alzheimer's Disease Assessment Scale-cognitive subscale 14-Item (ADAS-Cog) and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SOB). The secondary outcomes included amyloid burden and WBV changes. RESULTS: There were 6479 participants across seven mAB trials, and 4993 participants in nine AChEI trials. Compared with placebo, the pooled percentage of cognitive slowing was 27.6% (95% CI 24.6% to 30.9%), and the pooled progression delay was 5.52 months over 19.5 months (1.40 to 9.65) on CDR-SOB in patients treated with mABs. For cognitive trajectories on ADAS-Cog, mAB progressively attenuated cognitive decline, whereas AChEI exhibited a smaller effect with large uncertainty and eventually provided no benefits. Additionally, the rates of cognitive decline and amyloid reduction stabilised over time, while WBV initially showed a rapid decline but progressively slowed. Finally, WBV decline was not associated with worsening cognitive function. Instead, a 1 cm³ reduction in WBV was linked to a 0.0975-point reduction in CDR-SOB (0.0614 to 0.1336). CONCLUSIONS: In prodromal to mild AD, mAB therapy provided greater cumulative cognitive benefits than placebo and AChEI, and WBV reduction may reflect a treatment-related process rather than a detrimental sequela. PROSPERO REGISTRATION NUMBER: CRD42024628107.