Association of inflammatory fluid biomarkers with the progression of Alzheimer’s disease: a protocol for a systematic review and meta-analysis

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that typically begins with mild cognitive impairment (MCI) and gradually worsens to mild, moderate, and severe dementia. There is increasing evidence that inflammatory responses in both peripheral and central compartments contribute to the pathophysiology of AD. However, meta-analyses that compare the changes in inflammatory biomarkers according to AD stages remain limited. This study aims to systematically evaluate the differences in inflammatory marker levels according to AD progression stages and to assess their potential utility as stage-specific biological indicators. METHODS: This meta-analysis will be conducted according to the PRISMA-P guidelines. PubMed, Embase, Cochrane Library, and MEDLINE will be searched for studies involving elderly people aged 60 years or older with MCI or AD diagnosed through June 30, 2025. According to the PECO framework, the primary comparison will be each AD-related clinical stage, including MCI, mild AD, moderate AD, and severe AD, versus cognitively normal older adults. Secondary analyses will examine between-stage comparisons when sufficient data are available. The primary outcomes will be inflammatory biomarker levels measured in blood-derived samples, including serum and plasma. Cerebrospinal fluid inflammatory biomarkers will be included as predefined secondary outcomes and analyzed separately. Biomarkers of interest include IL-6, CRP, TNF-α, IL-1β, YKL-40, complement C3, C5a, IL-2, IFN-γ, GFAP, sTREM2, ferritin, and related inflammatory markers. Literature selection and data extraction will be performed independently by two reviewers. Statistical analysis will be performed using JASP to calculate the standardized mean differences (SMD) and 95% CI. A heterogeneity test, meta-regression, subgroup analysis, sensitivity analysis, and publication bias test will also be performed. DISCUSSION: This study will systematically evaluate stage-specific changes in inflammatory biomarkers and identify potential response patterns and biological relevance of each marker in relation to AD progression. This review will examine whether some biomarkers follow nonlinear trajectories rather than linear changes, which may help explore their association with pathological mechanisms such as microglial activation and peripheral-central immune axis changes. This meta-analysis may provide foundational data for the development of inflammatory fluid biomarkers for early diagnosis and stage-specific prognosis in AD. SYSTEMATIC REVIEW REGISTRATION: As this protocol is not eligible for registration in PROSPERO, a preliminary search has been performed to confirm that there are no duplicate systematic reviews.