Efficacy of Bacopa monnieri (Linn.) on Cognitive Function and Alterations in Blood Metabolites in Patients With Amnestic Mild Cognitive Impairment and Early Alzheimer Disease: Protocol for an Exploratory Double-Blind, Randomized, Placebo-Controlled Trial.

BACKGROUND: Amnestic mild cognitive impairment (aMCI) represents a transitional stage between normal aging and Alzheimer disease (AD), where early intervention is critical for preserving cognition and delaying or preventing progression to dementia. Due to the limited availability of curative pharmacological treatments, there is growing interest in traditional and indigenous medicinal interventions, such as Bacopa monnieri (Linn.) or Brahmi, a widely used Ayurvedic nootropic herb. Bacopa consumption is known to enhance cognitive performance in healthy individuals and is associated with alterations in pathways related to branched-chain and aromatic amino acid biosynthesis. These pathways have been implicated in MCI due to AD pathophysiology. Hence, the efficacy of Bacopa in aMCI and the mediating metabolic changes need to be systematically evaluated through clinical trials. OBJECTIVE: The aim of this study is to assess the effects of B. monnieri on cognitive function and plasma metabolites in individuals with aMCI (early or prodromal AD). METHODS: This study will employ a double-blind, randomized, placebo-controlled trial design, with 76 participants (38 per group) of aMCI diagnosed using the clinical National Institute on Aging-Alzheimer's Association 2011 criteria in a tertiary care setting in India. Participants will receive either B. monnieri (Linn.) (300 mg standardized plant extract) or a matched placebo daily for 12 weeks. Comprehensive cognitive assessments (0, 12, and 24 wk) and untargeted plasma metabolomic profiling (0 and 12 wk) will be conducted to evaluate both cognitive changes and alterations in plasma metabolites. MetaboAnalyst 6.0 (with integrated features like Kyoto Encyclopedia of Genes and Genomes and the Human Metabolome Database) will be used for a comprehensive statistical and functional analysis pertaining to the metabolomics. The primary outcome will be a change in the composite z score of memory between the 2 groups at 12 weeks. The secondary outcomes will include alterations in metabolites and pathways, and adverse events at 12 weeks, and cognitive performance at 12 and 24 weeks. RESULTS: The study was funded in October 2023, and the first participant was enrolled in April 2024. As of November 2025, a total of 60 participants have been recruited, with a mean (SD) age of 62.2 (8.1) years. The cohort predominantly comprises men (53/60, 88.3%), individuals with at least a high school education (47/60, 78.3%), and participants at elevated risk for cognitive decline. Specifically, 39 of 60 participants (65%) have diabetes, 29 (48.3%) have hypertension, and 13 (21%) report a positive family history of dementia. Data collection will conclude in June 2026, after which data analysis will begin and be completed by September 2026, with primary findings targeted for publication in spring 2027. CONCLUSIONS: This protocol investigates the efficacy of B. monnieri (Linn.) in improving cognitive function and altering the blood metabolites in patients with aMCI. If effective, this intervention could provide an accessible and cost-effective approach to manage early AD in resource-limited settings.