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Background: Blood derivatives therapy is a conventional clinical treatment, while the treatment for Alzheimer's disease (AD) is relatively novel. To provide clinical references for treating AD, this meta-analysis was performed to evaluate the efficacy and safety of blood derivatives therapy on the patients with AD. Methods: A systematic articles search was performed for eligible studies published up to December 6, 2021 through the PubMed, Embase, Cochrane library, ClinicalTrials.gov, Chinese National Knowledge Infrastructure database, and Wanfang databases. The included articles were screened by using rigorous inclusion and exclusion criteria. Study selection and data-extraction were performed by two authors independently. Random effects model or fixed effects model was used. Quality of studies and risk of bias were evaluated according to the Cochrane risk of bias tool. All analyses were conducted using Review Manager 5.4. The study was designed and conducted according to the Preferring Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Results: A total of three plasma administrations (two plasma exchange and one young plasma infusion) and five intravenous immunoglobulin (IVIG) randomized controlled trials with a sample size of 1148 subjects diagnosed with AD were included. There was no significant difference in cognitive improvement and all-cause discontinuation between intervention and placebo groups (RR 1.10, 95% CI 0.79–1.54). And Intervention groups showed not a statistically significant improvement in cognition of included subjects measured by the ADAS-Cog (MD 0.36, 95% CI 0.87–1.59), ADCS-ADL (MD −1.34, 95% CI − 5.01–2.32) and NPI (MD 2.20, 95% CI 0.07–4.32) score compared to the control groups. IVIG is well tolerated for AD patients even under the maximum dose (0.4 g/kg), but it is inferior to placebo in Neuropsychiatric Inventory scale in AD patients (MD 2.19, 95% CI 0.02–4.37). Conclusions: The benefits of blood derivatives therapy for AD are limited. It is necessary to perform well-designed randomized controlled trials with large sample sizes focusing on the appropriate blood derivatives for the specific AD sub-populations in the future. Systematic review registration: PROSPERO CRD42021233886 [ABSTRACT FROM AUTHOR]