Abstract-- Background: As a potential disease-modifying treatment for Alzheimer disease (AD), 3-amino-1-propanesulfonic acid (3APS) is a compound that binds to amyloid (A), a toxic protein known to aggregate, leading to amyloid plaque deposition in the brain. Methods: We assessed the safety, tolerability, and pharmacokinetic/pharmacodynamic effect of 3APS in a randomized, double-blind, placebo-controlled Phase II study in which 58 subjects with mild-to-moderate AD were randomly assigned to receive placebo or 3APS 50, 100, or 150 mg BID for 3 months. At the end of the double-blind phase, 42 of these subjects entered an open-label phase in which they received 3APS 150 mg BID for 17 months. Assessments included plasma and CSF 3APS concentrations, CSF levels of A (A₄₀ and A₄₂), and total tau, as well as cognitive (Alzheimer’s Disease Assessment Scale-cognitive subscale, Mini-Mental State Examination) and clinical (Clinical Dementia Rating scale-Sum of Boxes) measures. Results: 3APS had no significant impact on vital signs or laboratory test values. The most frequent side effects were nausea, vomiting, and diarrhea, which were intermittent and mild to moderate in severity. Seven 3APS-treated subjects discontinued because of side effects (all causalities) over the course of the study, and there were no 3APS-related serious adverse events. 3APS crossed the blood-brain barrier, and dose-dependently reduced CSF A₄₂ levels after 3 months of treatment. There were no psychometric score differences between groups over the 3-month double-blind period. Conclusion: Long-term administration of 3-amino-1-propanesulfonic acid is safe, tolerated and reduces CSF A₄₂ levels in patients with mild-to-moderate Alzheimer disease.