medRxiv · Feb 6, 2026

Multistrain probiotics ameliorate tau pathology and preserve visuospatial cognition in early cognitive impairment: A double-blind, randomized controlled trial

By Seo EH, Kang S, Kim SG et al.

Abstract Background Emerging evidence suggests that microbiota play a role in Alzheimer’s disease (AD) pathology and cognitive performance. Interventions targeting the oral–brain axis may offer neuroprotective benefits, particularly during the early stages of cognitive impairment. This randomized controlled trial (RCT) investigated whether a multistrain probiotic supplement could modulate AD-related plasma biomarkers and cognitive function in older adults with early cognitive impairment. Methods Participants from the Gwangju Alzheimer’s Disease and Related Dementia (GARD) Cohort in Korea were enrolled in a double-blind, randomized, placebo-controlled trial. Older adults with early cognitive impairment were randomized to receive either a multistrain probiotic supplement (KL-P301) or a placebo for 24 weeks. Plasma pTau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were quantified at baseline and follow-up. Cognitive and clinical assessments included the Clinical Dementia Rating (CDR), Mini-Mental State Examination (MMSE), CERAD neuropsychological battery, Stroop test, and Rey–Osterrieth Complex Figure (ROCF). Treatment effects were analyzed using paired t-tests, linear mixed models, and ANCOVA adjusted for baseline and demographic covariates. Results Of the 87 participants analyzed (probiotic, n=40; placebo, n=47), the probiotic group exhibited a significant reduction in plasma pTau181 levels compared with the placebo group ( p < 0.001). While GFAP and NfL levels remained stable in the probiotic group, the placebo group showed significant longitudinal increases ( p = 0.014 and p = 0.041, respectively). Clinically, the probiotic group demonstrated improved CDR ( p = 0.010), primarily driven by the memory domain. Domain-specific cognitive analyses revealed that the probiotic group significantly improved in visuospatial construction (Constructional Praxis, p = 0.036; ROCF copy, p = 0.027) and maintained stable constructional recall, whereas the placebo group showed a significant decline ( p = 0.025). No significant between-group differences were observed in MMSE, verbal memory, or executive/attentional functions. Conclusion The multistrain probiotic supplement reduced tau-related pathology and neuroinflammation-associated biomarkers and selectively preserved visuospatial construction and visual memory in older adults with early cognitive impairment. These findings suggest that modulating the oral-immune–brain axis with multistrain probiotics represents a viable, non-pharmacological strategy to slow AD-related pathological progression and cognitive decline in early-stage patients.

doi.org/10.64898/2026.02.01.26345102Open accessInterventions