Neurodegeneration and glial activation related blood biomarkers in Alzheimer's disease: A systematic review and an updated meta- analysis.

BACKGROUND AND

OBJECTIVES

This systematic review and meta-analysis aims to evaluate blood biomarkers associated with neurodegeneration and glial activation, specifically GFAP, NfL, YKL-40, MCP-1, neurogranin, GAP-43, S100B, and NSE, in individuals diagnosed with Alzheimer's Disease (AD).

METHODS

PubMed and Web of Science were searched until February 20, 2025, without restrictions on language, time, or study design, to identify studies reporting blood levels of the biomarkers in individuals along the AD continuum (including those with MCI and AD dementia) and cognitively unimpaired (CU) controls. Pooled effect sizes were calculated using the Hedges' g method with a random-effects model.

RESULTS

A total of 3684 studies were identified, with 144 meeting inclusion criteria (AD continuum n = 42,587, CU n = 30,000). Compared with CU individuals, patients on the AD continuum showed higher levels of NfL (SMD = 0.82, 95 % CI 0.67-0.96, p < 0.05), GFAP (SMD = 1.57, 95 % CI 1.26-1.88, p < 0.05), and YKL-40 (SMD = 1.39, 95 % CI 0.56-2.21, p < 0.05). Both biomarkers were significantly elevated in more advanced stages of the disease, particularly in AD dementia compared with mild cognitive impairment (MCI) (GFAP SMD = 0.79, 95 % CI 0.55-1.03, p < 0.05; YKL-40 SMD = 0.98, 95 % CI 0.17-1.79, p = 0.02). No significant differences were found for MCP-1, neurogranin, S100B, or NSE.

DISCUSSION: Our findings suggest that these biomarkers reflect AD-related pathology. Limitations include the lack of cultural and linguistic diversity in the study populations. Future research should focus on biomarker-defined AD populations for further validation.