Taxifolin for prevention of COGnitive impairment (T-COG trial): a study protocol for a randomized, double-blind, placebo-controlled trial.

Background: In 2023 and 2024, the novel anti-β-amyloid antibodies lecanemab and donanemab have been approved for treatment of mild cognitive impairment and mild dementia in several countries, including Japan and the United States. Although they successfully eliminate accumulated β-amyloid, they merely delay cognitive deterioration and do not improve cognitive function. This suggests that β-amyloid elimination is insufficient for cognitive improvement. Therefore, novel treatments with pleiotropic neuroprotective effects are warranted. Taxifolin, a bioactive flavonoid, shows pleiotropic effects, such as inhibition of amyloid-β aggregation and oligomerization and hippocampal neuroinflammation, as well as stimulation of brain lymphatic vessel formation in our previous experimental studies. Furthermore, our preliminary observational study showed that oral administration of taxifolin was associated with cognitive improvement in patients with mild cognitive impairment or mild dementia. Methods: This is a randomized, double-blind, placebo-controlled, crossover trial involving 60 patients with mild cognitive impairment or mild dementia. All participants will take 100-mg taxifolin or placebo capsules orally once daily for 12 weeks. The washout period will be 6 weeks. The primary objective is to determine the effect of taxifolin on cognitive impairment using the Montreal Cognitive Assessment. The main secondary objectives are to evaluate the impact of taxifolin on (i) prevention further cognitive decline, as evaluated by changes in the scores for total Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 and trail making test and (ii) changes in white matter hyperintensity volume and number of cerebral microbleeds on brain magnetic resonance imaging. Discussion: This T-COG trial may provide valuable insights into new therapeutic approaches, considering that taxifolin has multitarget neuroprotection, which could prevent further cognitive decline, along with its highly safe profile and inexpensive cost. Clinical trial registration: https://jrct.mhlw.go.jp, jRCTs051250004.