Abstract INTRODUCTION S‐adenosyl methionine (SAMe) is a pivotal metabolite in multiple neuronal pathways, including tau dephosphorylation. Reduced SAMe availability has been reported in the Alzheimer's disease (AD) brain, prompting interest in supplementation as a potential therapeutic strategy. METHODS This multicenter, randomized, double‐blind, placebo‐controlled phase 2 study recruited people ( n = 63) with a clinical AD diagnosis. Participants received 180 days of SAMe (400 mg daily) or placebo. Primary outcome was change in plasma phosphorylated tau (p‐tau)217 concentration. Secondary endpoints included safety, tolerability, and cognitive outcomes. RESULTS Mean percentage change in plasma p‐tau217 in the SAMe group was an increase of 53.22 (standard deviation SD 159.19) compared to 25.34 (SD 94.83) in the placebo group (standardized mean difference 37.58, 95% confidence interval −32.61, 107.76; p = 0.288). No significant differences were observed in safety or other secondary endpoints. DISCUSSION SAMe did not demonstrate disease‐modifying efficacy at the dose and duration studied; however it was safe and well tolerated. TRIAL REGISTRATION ACTRN12620000506998. Registered on the Australian New Zealand Clinical Trials Registry ( http://www.anzctr.org.au )
Holper et al. (Wed,) studied this question.