Efficacy and tolerability of therapeutic plasma exchange for Alzheimer’s disease: a systematic review and meta-analysis

Abstract

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder marked by progressive short-term memory impairment, along with deficits in language, visuospatial processing, and executive function, with histopathological features including intracellular neurofibrillary tangles composed of tau protein and extracellular amyloid-β (Aβ) plaques. Based on the concept of dynamic equilibrium between central and peripheral Aβ pools, TPE has been proposed as a potential disease-modifying strategy in AD. TPE has been associated with reductions in circulating Aβ levels in experimental and early clinical studies, however, its clinical relevance remains uncertain. Objective: This systematic review and meta-analysis aimed to evaluate the effectiveness of therapeutic plasma exchange (TPE) in the management of patients with AD. The primary objective was to assess its efficacy, and the secondary objective was to examine the occurrence of adverse effects. Methods: We searched MEDLINE, Cochrane, and Web of Science for randomized controlled trials (RCTs) and observational studies comparing TPE to placebo in the treatment of mild-to-moderate AD. Statistical analyses were performed using R, with odds ratios (ORs) and standardized mean differences (SMDs) reported with 95% confidence intervals (CIs). A random-effects model was applied to all outcomes. Results: Three studies were included: one real-world observational cohort and two RCT, with a total of 615 patients, 22% of whom received TPE. TPE demonstrated statistically significant improvements in global cognition, with a reduction in Alzheimer’s Disease Assessment Scale – Cognitive (ADAS-Cog) scores (MD −2.19; 95% CI [−2.43, −1.95]; I² = 0%; p < 0.01)) and increased Mini-Mental State Examination scores (MMSE) (MD 1.72 95% CI [0.43, 3.01]; I² = 0%; p < 0.01). Significant improvement was also observed in language performance as measured by the Boston Naming Test (BNT) (MD 1.30; 95% CI [0.22, 2.38]; p=0.02; I²=0%), however, verbal fluency showed non-significant trends (Semantic Verbal Fluency: MD 1.41; 95% CI [−0.11; 2.92]; I² = 85%; p = 0.06); Phonemic Verbal Fluency: MD 1.44; 95% CI [−0.25; 3.12]; I² = 71%; p = 0.09). Adverse events occurred in 15% of procedures, predominantly minor and puncture-related. Conclusion: This meta-analysis suggests that TPE may be effective and safe in treating AD, with a significant improvement in global cognition and language performance. Despite favorable signals, the overall evidence remains limited by small study samples, heterogeneity across secondary outcomes, and the influence of individual trials