Cerebral amyloid angiopathy (CAA), an age-related form of cerebral small-vessel disorder, is characterized by progressive deposition of β-amyloid protein (Aβ) within the walls of small arteries and capillaries in the pia mater and cortex (1, 2). CAA is most commonly observed in older adults, and its prevalence in patients with Alzheimer’s disease (AD) is as high as 80–90% (3, 4). Although both CAA and AD share Aβ as a pathological factor, they show differences in terms of deposition sites and clinical manifestations, leading to a complex pathological relationship that can be summarized as “one peptide, two pathways” (5). The key clinical and imaging features of CAA are provided in Table 1 (6–8). The diagnosis of CAA is primarily based on the Boston criteria 2.0 (9, 10); however, no effective treatments are available for this disease.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases capable of degrading almost all components of the extracellular matrix (ECM), and they play central roles in various physiological and pathological processes, including tissue remodeling, angiogenesis, and inflammatory responses (11, 12). MMP activity is strictly regulated by tissue inhibitors of metalloproteinases (TIMPs) (13, 14). Physiological conditions are characterized by a delicate equilibrium between MMPs and TIMPs. However, under pathological conditions, including cerebral ischemia, carotid atherosclerotic plaques, arteriovenous malformations, and aneurysms, this equilibrium is disrupted, causing increased MMP expression and proteolytic activity and ultimately resulting in excessive ECM degradation, tissue structural damage, and functional impairment (15, 16).

In cerebrovascular diseases, excessive MMP activation has been linked to blood–brain barrier (BBB) disruption, neuroinflammation, and secondary injury following intracerebral hemorrhage (ICH) (17, 18). Since the core pathology of CAA involves compromised structural integrity of the vascular wall, an imbalance in the MMP/TIMP system may play a crucial role in its pathogenesis (19). For example, excessive MMP activity may degrade collagen and laminin in the vascular basement membrane, causing thinning of the blood vessel wall, decreased elasticity, and rupture and bleeding during blood-pressure fluctuations (20, 21). These findings were first demonstrated in a preclinical study that identified MMP activation as a downstream executor of the vascular damage caused by CAA-associated pathological factors (such as activated platelets), and showed that vascular integrity can be effectively preserved by inhibiting MMP activity (22). Several recent studies have also focused on the changes in MMP and TIMP expression in CAA and their relationship with clinical manifestations. In particular, since Aβ serves as a shared pathological factor for CAA and AD, studies are required to determine whether the observed dysregulation of MMPs/TIMPs can be precisely attributed to cerebrovascular Aβ deposition (i.e., CAA pathology), parenchymal Aβ plaques (as in AD), or both. Unraveling this relationship is key to understanding the specificity of MMP/TIMP alterations in CAA and developing targeted therapeutic strategies.

The ongoing development of matrix metalloproteinase inhibitors (MMPIs) initially focused on antitumor therapy (23, 24). However, with a deeper understanding of the complexity and specificity of the function of MMPs, highly selective MMPIs targeting CAA may also be developed (25, 26). Tetracycline antibiotics, including doxycycline and minocycline, have also been found to act as nonantibiotic-dependent MMPIs (27, 28).

Against this research background, we aimed to systematically review and integrate the findings of existing studies on MMPs in CAA to gain a deeper understanding of the pathogenesis and assess the potential value of MMPs as biomarkers or therapeutic targets.

This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (20, 29) and was prospectively registered on the PROSPERO platform on November 19, 2025 (CRD420251230405). Since this study analyzes previously published data, ethical review is not required.

This systematic review synthesized evidence supporting the conclusion that MMP/TIMP system imbalances are the mechanism underlying CAA vascular lesions, and that targeting this system may provide new directions for effective diagnosis and treatment of CAA. Multiple studies have provided evidence that the MMP/TIMP balance is disrupted in the cerebral blood vessels of patients with CAA. Although upregulation of TIMP-3 and TIMP-4 may represent a compensatory response to increased MMP activity, it cannot completely inhibit the destructive effects of MMPs (31, 34). In CAA-ICH, upregulation of MMP-9 expression and relative downregulation of TIMP-3 expression may cause the degradation rate of the vascular basement membrane to exceed its repair capacity, thereby accelerating the risk of hemorrhage (33). This imbalance is not limited to brain tissue and manifests in alterations of humoral biomarkers. Moreover, in comparison with changes in the levels of individual molecules, reductions in the MMP/TIMP ratios (e.g., the MMP-2/TIMP-2 and MMP-14/TIMP-2 ratios) in CSF may more reliably reflect the pathological status of CAA. Therefore, reduced MMP/TIMP ratios (such as the MMP-2/TIMP-2 and MMP-14/TIMP-2 ratios) could serve as more dependable diagnostic biomarkers (19). Notably, TIMP-4 expression is upregulated in the brain tissue of patients with CAA but is downregulated in CSF and elevated in serum, indicating a complex regulatory mechanism. The decline in TIMP-4 expression in CSF may have diagnostic value; however, its exact significance and the underlying reasons for the difference in expression between brain tissue and CSF warrant further elucidation in future studies (31). By showing that MMP inhibition confers cerebrovascular protection against CAA-associated damage (22), the preclinical evidence provided a theoretical basis for exploring MMPIs as potential therapeutic agents for CAA. Future efforts should focus on developing highly selective inhibitors of key MMPs, such as MMP-9, and on evaluating the efficacy of existing drugs, including tetracyclines, in CAA models (27).

This systematic review had several limitations. First, an important consideration arising from this review was whether the observed MMP/TIMP dysregulation is a direct consequence of cerebrovascular Aβ deposition (CAA pathology) or if it is also influenced by concurrent parenchymal Aβ pathology, as commonly observed in AD. Most of the included studies focused on cohorts defined by the CAA criteria; however, given the high co-occurrence of CAA and AD, complete dissociation of vascular and parenchymal Aβ effects remains challenging. Second, a major limitation of this review was the small sample size of the included original studies, which diminished the statistical power of individual findings and weakened the robustness of the existing qualitative evidence base. Third, the large variations in the clinical manifestations and pathological backgrounds of the patients included in the study resulted in substantial heterogeneity, limiting the scope to perform quantitative pooled analysis. Finally, inconsistencies in CSF sample-collection methods and times may have influenced the results for measurement of protease expression levels.

On the basis of these findings, the following directions are recommended for future research. First, investigations using designs that explicitly compare pure CAA, pure AD, and mixed-pathology cases, together with spatially resolved molecular analyses, are required to elucidate the specific contribution of vascular Aβ to MMP/TIMP imbalances. This distinction is crucial for assigning biomarker changes and therapeutic targets specifically to CAA. Second, to develop highly selective inhibitors, future studies should aim to identify the MMP types that play key roles in CAA (36). Third, the optimal timing of early intervention requires exploration, and biomarkers should be used to guide treatment (16). Reliable biomarkers, including CSF and imaging techniques, may play an important role in this process (19, 31). Fourth, studies should focus on improving the permeability of drugs to the BBB by, for example, using delivery systems that target transferrin receptors (37). Finally, randomized double-blind placebo-controlled trials with long-term follow-up data are essential for assessing the effects of MMPIs on disease recurrence and long-term prognosis.

The studies reviewed in this paper indicate dysregulation of MMPs/TIMPs in CAA. Although MMP/TIMP levels in brain tissue and CSF show potential as biomarkers, the existing evidence is inadequate to support the clinical use of these parameters. Future studies with more refined designs, larger sample sizes, and clearer pathological stratification are required to clarify the underlying mechanisms and determine whether MMPs/TIMPs can serve as reliable diagnostic tools or therapeutic targets for CAA.