Association between transthyretin levels and Alzheimer's disease: A meta-analysis

BACKGROUND: Transthyretin (TTR) has been implicated in amyloid-β (Aβ) binding, cerebrospinal fluid homeostasis, and neurodegenerative processes in Alzheimer's disease (AD), but clinical evidence regarding its levels in AD and mild cognitive impairment (MCI) remains inconsistent. OBJECTIVE: This meta-analysis aimed to clarify the association between blood/cerebrospinal fluid (CSF) TTR levels and AD/MCI. METHODS: Following the PRISMA guidelines, this meta-analysis systematically identified and included 18 eligible studies from databases including PubMed, Web of Science, Embase, and Cochrane Library. RESULTS: Random-effects meta-analysis showed lower TTR levels in AD versus healthy controls (HC) (Hedges' g = -0.77, 95% CI: -1.50, -0.04; p = 0.04), with no significant differences in MCI versus HC. Subgroup analyses confirmed a significant reduction in TTR levels across multiple dimensions: 1) sample types (serum); 2) population characteristics (age difference < 5 years and sex difference ≥ 10%); and 3) detection methods (immunoassay). Multivariate meta-regression with region, sample source, detection technology, and female ratio difference as covariates, accounted for 36.81% of the between-study heterogeneity. Sensitivity analysis verified result robustness, and publication bias was resolved after excluding an outlier study. CONCLUSIONS: Lower TTR levels are significantly associated with AD. This finding suggests that TTR warrants further investigation as a candidate biomarker for AD, although prospective studies are needed to validate its clinical utility.