The efficacy and safety of anti-Aβ agents for delaying cognitive decline in Alzheimer’s disease: a meta-analysis

BACKGROUND: This meta-analysis evaluates the efficacy and safety of amyloid-β (Aβ) targeted therapies for delaying cognitive deterioration in Alzheimer’s disease (AD). METHODS: PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov were systematically searched to identify relevant studies published before January 18, 2023. RESULTS: We pooled 33,689 participants from 42 studies. The meta-analysis showed no difference between anti-Aβ drugs and placebo in the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), and anti-Aβ drugs were associated with a high risk of adverse events [ADAS-Cog: MDs = −0.08 (−0.32 to 0.15), p = 0.4785; AEs: RR = 1.07 (1.02 to 1.11), p = 0.0014]. Monoclonal antibodies outperformed the placebo in delaying cognitive deterioration as measured by ADAS-Cog, Clinical Dementia Rating–Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL), without increasing the risk of adverse events [ADAS-Cog: MDs = −0.55 (−0.89 to 0.21), p = 0.001; CDR-SB: MDs = −0.19 (−0.29 to −0.10), p < 0.0001; MMSE: MDs = 0.19 (0.00 to 0.39), p = 0.05; ADCS-ADL: MDs = 1.26 (0.84 to 1.68), p < 0.00001]. Intravenous immunoglobulin and γ-secretase modulators (GSM) increased cognitive decline in CDR-SB [MDs = 0.45 (0.17 to 0.74), p = 0.002], but had acceptable safety profiles in AD patients. γ-secretase inhibitors (GSI) increased cognitive decline in ADAS-Cog, and also in MMSE and ADCS-ADL. BACE-1 inhibitors aggravated cognitive deterioration in the outcome of the Neuropsychiatric Inventory (NPI). GSI and BACE-1 inhibitors caused safety concerns. No evidence indicates active Aβ immunotherapy, MPAC, or tramiprosate have effects on cognitive function and tramiprosate is associated with serious adverse events. CONCLUSION: Current evidence does not show that anti-Aβ drugs have an effect on cognitive performance in AD patients. However, monoclonal antibodies can delay cognitive decline in AD. Development of other types of anti-Aβ drugs should be cautious. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (https://www.crd.york.ac.uk/prospero/), identifier CRD42023391596.