Preclinical evidence for icariin in Alzheimer's disease: Methodological quality, efficacy, and mechanisms

Alzheimer's disease (AD) currently lacks effective curative treatments. Icariin (ICA), a flavonoid from Epimedium, has been widely investigated in AD animal models with emerging neuroprotective potential. However, the methodological quality, reporting rigor, and translational reliability of this preclinical evidence have not yet been systematically evaluated. Studies investigating ICA in AD were retrieved from eight databases up to May 12, 2026. The reporting quality, risk of bias, and study quality were assessed using the ARRIVE 2.0 guidelines, the SYRCLE risk-of-bias tool, and the CAMARADES checklist, respectively. Meta-analyses were conducted to assess the therapeutic efficacy of ICA, and potential mechanisms were summarized. A total of 59 studies were included. The average reporting rate for ARRIVE 2.0 items was 56.12%, with major deficiencies in sample size calculation (0%), inclusion/exclusion criteria (0%), protocol registration (0%), randomization (5.08%), and blinding (11.86%). The SYRCLE assessment revealed that only a few domains were rated as low risk of bias. CAMARADES scores ranged from 2 to 5 (out of 10). Meta-analyses showed that ICA significantly improved cognitive performance in behavioral tests. In the Morris water maze, escape latency was reduced (SMD = -2.51, 95% CI -3.02 to -2.01), with similar improvements observed in the novel object recognition and Y-maze tests. ICA also significantly attenuated amyloid pathology, reducing hippocampal amyloid plaque number (SMD = -2.43, 95% CI -3.80 to -1.05), plaque area, and soluble Aβ₁-₄₂ levels. Preclinical evidence from AD animal models suggests that ICA improves cognitive performance and reduces amyloid burden through mechanisms involving neuroinflammation, amyloid and tau regulation, synaptic plasticity, mitochondrial and redox homeostasis. However, substantial methodological shortcomings-particularly in sample size calculation, randomization, blinding, and outcome pre-specification-limit confidence in the robustness and translational reliability of these findings. Strengthening methodological rigor and reporting transparency will be essential to support future clinical development.