A systematic review and meta-analysis of metalloproteinases in patients with Alzheimer's disease and mild cognitive impairment

Background Various studies have reported altered expression of metalloproteinases in Alzheimer's disease (AD); however, expression profiles of each metalloproteinase during cognitive decline have not yet been fully characterized. Objective The purpose of this systematic review was to generate a comprehensive overview of metalloproteinases and their cognate inhibitors expression in AD and mild cognitive impairment (MCI), across sample matrices, to determine whether metalloproteinases are dysregulated in AD and may have predictive power in individuals with cognitive decline. Methods An electronic literature search was conducted in PubMed, EMBASE, Scopus and MEDLINE from inception to December 2024. Sixty-one publications reporting metalloproteinase and inhibitor levels in 8576 patients with AD or MCI, and 7333 controls were included in the systematic review, twenty-one of which were extracted for meta-analysis. Standardized mean difference (SMD) was used to illustrate comparisons, and the Newcastle-Ottawa scale to assess bias. Results Higher levels of cerebrospinal fluid (CSF) tissue inhibitor of metalloproteinase-2 (TIMP-2; p = 0.0003) were observed in the AD group and in patients with MCI ( p = 0.0009) compared to cognitively healthy controls. Following sensitivity analysis, significantly higher levels of CSF MMP-10 ( p = 0.0005) and lower plasma TIMP-2 ( p = 0.004) were also noted in patients with AD. TIMP-3, across all sample matrices, was decreased in patients with MCI versus controls ( p = 0.01). Conclusions Significantly altered levels of metalloproteinases and their inhibitors were verified between patients with AD and MCI, representing potential biomarkers and prospective therapeutic targets for cognitive decline. This study was registered with PROSPERO, CRD42024628202.