Luteolin for Alzheimer's disease and related cognitive impairment: a systematic review and meta-analysis of efficacy and molecular mechanisms
Abstract
The multifactorial pathogenesis of Alzheimer's disease (AD) renders conventional single-target therapies largely ineffective. Luteolin, a natural flavonoid, has demonstrated promising pleiotropic neuroprotective potential. This study aims to systematically evaluate the preclinical efficacy and multi-target mechanisms of luteolin in rodent models of AD and associated cognitive impairment. Eight major electronic databases were systematically searched from January 1, 2000 to June 1, 2026. In vivo preclinical studies evaluating luteolin monotherapy in AD-specific and general cognitive impairment rodent models were included. Methodological quality was assessed using the SYRCLE risk of bias tool. Standardized mean differences and 95% confidence intervals were calculated using a random-effects model. Fifteen eligible studies were included. Meta-analysis revealed that luteolin significantly ameliorated cognitive and memory impairments in both AD-specific and non-AD cognitive impairment models. Mechanistically, luteolin significantly restored redox homeostasis and suppressed neuroinflammatory cascades at both transcriptional and translational levels. Subgroup analyses indicated that oral administration and prolonged interventions were associated with significant efficacy; however, these observations are heavily influenced by study-level confounding and cannot conclusively establish pharmacokinetic superiority. Furthermore, the certainty of evidence is limited by predominantly unclear risks of bias, substantial statistical heterogeneity, and potential publication bias. Current preclinical evidence suggests that luteolin is a promising multi-target neuroprotective candidate for AD and related cognitive impairments, highlighted by its anti-inflammatory and antioxidant properties. However, given the substantial methodological limitations and extremely large pooled effect sizes, these findings must be interpreted with caution. Future research must prioritize rigorous preclinical designs, advanced brain-targeted delivery systems, and GLP-compliant toxicological profiling before clinical translation.