Computerized cognitive training enhances cognitive function in Alzheimer's disease by downregulating Ruminococcus-TMAO pathway.

BACKGROUND

The microbiota-gut-brain (MGB) axis is implicated in Alzheimer's disease (AD), but evidence for interventional strategies targeting this axis remains limited.

METHODS

In a 24-week, single-blind, randomized controlled trial, 84 individuals with mild cognitive impairment (MCI) or mild AD received either computerized cognitive training (CCT) or treatment as usual (TAU). Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) was the primary outcome. We also assessed functional connectivity (fNIRS), plasma trimethylamine N-oxide (TMAO) levels, and gut microbiota at baseline and 24 weeks.

RESULTS

Seventy-four participants completed the study. The CCT group showed significant improvement in ADAS-cog scores compared to controls (Cohen's d = 1.57 by week 24). Notably, CCT also induced a distinct reorganization of prefrontal functional connectivity and significantly reduced plasma TMAO levels. Microbiome analysis revealed that CCT mitigated the expansion of Ruminococcus torques group (R.torques), which was observed in the control group. Crucially, R.torques was the only genus significantly correlated with improvements in cognition (ADAS-cog, r = 0.407), neuropsychiatric symptoms (NPI, r = 0.395), TMAO reduction (r = 0.443), and functional connectivity changes (r = 0.449).

CONCLUSION

A 24-week CCT program improves cognitive function in MCI and mild AD, potentially through downregulating the R.torques-TMAO pathway within the MGB axis. This pathway represents a promising novel target for multi-domain intervention in AD.