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

BackgroundEmerging evidence suggests that microbiota play a role in Alzheimers 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. MethodsParticipants from the Gwangju Alzheimers 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. ResultsOf 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. ConclusionThe 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.