Amyloid-beta-targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer's disease.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of randomized controlled trials
PubMed 41985900 · doi:10.1002/14651858.CD016297
What was done
A Cochrane systematic review searched CENTRAL, MEDLINE, Embase, and clinical trial registries up to August 7, 2025, for randomized controlled trials (RCTs) lasting at least 12 months that compared amyloid-beta-targeting monoclonal antibodies with placebo or no treatment in people with mild cognitive impairment or mild Alzheimer's disease dementia. Risk of bias was evaluated using RoB 2, and certainty was assessed with GRADE. Outcomes of critical importance included cognitive function (ADAS-Cog), dementia severity (CDR-SB), functional ability (ADCS-ADL scales), amyloid-related imaging abnormalities (ARIA-E and ARIA-H), serious adverse events, and all-cause mortality, primarily pooled at 18 months using random-effects meta-analysis.
What was found
The review included 17 RCTs (20,342 participants; mean age 70–74 years) evaluating seven monoclonal antibodies (aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, and solanezumab) against placebo. At 18 months: - Cognitive function (ADAS-Cog): Standardised mean difference (SMD) -0.11 (95% CI -0.16 to -0.06; 13 studies, 9,895 participants; moderate certainty). - Dementia severity (CDR-SB): SMD -0.12 (95% CI -0.24 to -0.00; 9 studies, 8,053 participants; low certainty). - Functional ability: ADCS-ADL SMD 0.09 (95% CI 0.03 to 0.16; 3 studies, 3,478 participants; moderate certainty); ADCS-iADL SMD 0.21 (95% CI 0.10 to 0.32; 1 study, 1,252 participants; low certainty); ADCS-ADL-MCI SMD 0.23 (95% CI 0.12 to 0.33; 4 studies, 2,802 participants; low certainty). - Harms: ARIA-E had an absolute risk difference (ARD) of 107 more per 1,000 (95% CI 77 to 148 more; 11 studies, 13,595 participants; moderate certainty). Symptomatic ARIA-E ARD was 29 more per 1,000 (95% CI 22 to 38 more; 2 studies, 3,522 participants; moderate certainty). Symptomatic ARIA-H ARD was 4 more per 1,000 (95% CI 1 fewer to 31 more; 1 study, 1,795 participants; moderate certainty). Any ARIA-H was heterogeneous (I² = 81%, 3 studies) and could not be pooled. - Serious adverse events (ARD 6 more per 1,000, 95% CI 10 fewer to 26 more; 9 studies, 11,904 participants; high certainty) and all-cause mortality (ARD 2 more per 1,000, 95% CI 3 fewer to 11 more; 7 studies, 9,733 participants; high certainty) showed no significant differences.
Why it matters
This systematic review demonstrates that across the class, amyloid-beta-targeting antibodies produce only trivial-to-small differences in cognitive decline and dementia severity at 18 months, alongside an increased risk of amyloid-related imaging abnormalities (ARIA).
Limits
All 17 included trials were funded by the pharmaceutical industry. Efficacy outcomes had risk of bias concerns due to potential functional unblinding from detectable side effects such as ARIA. High statistical heterogeneity prevented pooled analysis for any ARIA-H. Most trials evaluated outcomes at 18 months, with only six trials reporting follow-up at 24 months or beyond.
Cited by
- supports A Cochrane analysis of 17 studies encompassing 20,342 individuals on beta-amyloid-lowering drugs for Alzheimer's found the clinical benefit was trivial while 20% to 25% of patients developed brain hemorrhages, brain swelling, or death.