Treatment with the Selective Muscarinic Agonist Talsaclidine Decreases Cerebrospinal Fluid Levels of Total Amyloid β‐Peptide in Patients with Alzheimer's Disease

: Brain amyloid load in Alzheimer's disease (AD) is, at least in genetic forms, associated with overproduction of amyloid β-peptides (Aβ). Thus, lowering Aβ production is a central therapeutic target in AD and may be achieved by modulating such key enzymes of amyloid precursor protein (APP) processing as β-, γ-, and α-secretase activities. Talsaclidine is a selective muscarinic M1 agonist that stimulates the nonamyloidogenic α-secretase pathway in model systems. Talsaclidine was administered double-blind, placebo-controlled, and randomized to 24 AD patients and cerebrospinal fluid (CSF) levels of total Aβ were quantitated before and after 4 weeks of drug treatment. We observed that talsaclidine decreases CSF levels of Aβ significantly over time within the treatment group (n=20) by a median of 16% as well as compared to placebo (n=4) by a median of 27%. We conclude that treatment with selective M1 agonists may reduce Aβ production and may thus be further evaluated as a potential amyloid-lowering therapy of AD.