Major characteristics of Alzheimer's disease (AD) are synaptic loss, cholinergic dysfunction, and abnormal protein depositions in the brain. The amyloid -peptide (A), a proteolytic fragment of amyloid  precursor protein (APP), aggregates to form neuritic plaques and has a causative role in AD. A present focus of AD research is to develop safe A-lowering drugs. A selective acetylcholinesterase inhibitor, phenserine, in current human trials lowers both APP and A. Phenserine is dose-limited in animals by its cholinergic actions; its cholinergically inactive enantiomer, posiphen (ϩ)-[phenserine], was assessed. In cultured human neuroblastoma cells, posiphen, like phenserine, dose-and time-dependently lowered APP and A levels by reducing the APP synthesis rate. This action translated to an in vivo system. Posiphen administration to mice (7.5-75 mg/kg daily, 21 consecutive days) significantly decreased levels of total APP (tissue mass-adjusted) in a dose-dependent manner. A 40 and A 42 levels were significantly lowered by posiphen (Ն15 mg/kg) compared with controls. The activities of ␣-, -, and ␥-secretases were assessed in the same brain samples, and -secretase activity was significantly reduced. Posiphen, like phenserine, can lower A via multiple mechanisms and represents an interesting drug candidate for AD treatment.Alzheimer's disease (AD) is typified by progressive impairment in short-term memory and emotional disturbances that result from dysfunction and death of neurons in the hippocampus and associated regions of the limbic system and cerebral cortex. These aberrations are considered to result, in part, from microtubule-associated protein () tangles and abnormal aggregates of cytoskeletal proteins (Cairns et al., 2004), oxidative stress, and the overproduction and accumulation of amyloid- peptide (A) in and surrounding neurons (Selkoe, 2005).This 39-to 43-amino acid peptide (molecular mass ϳ4.1 kDa) is a core constituent of amyloid plaques and results from two catalytic cleavages of the larger integral membrane protein, amyloid- precursor protein (APP; ϳ110 -130 kDa), at the N terminus (-secretase) and C terminus (␥-secretase) of A (Sambamurti et al., 2002;Lahiri et al., 2003b;Selkoe, 2005). Significant evidence indicates that A changes conformation from a physiological to a pathological, fibrillar peptide form, which not only induces local structural disruption of synapses and neurite breakage but also results in cell death due to perturbed calcium homeostasis and oxidative stress. In addition, soluble aggregates of A or A-derived diffusible ligands found in the brains of AD patients have been recently shown to target synapses (Gong et al., 2003) and play a role in inhibiting LTP (Walsh et al., 2002;LaFerla and Oddo, 2005). Conjointly, these studies point to the importance of A in learning and memory, suggest a causative role of A in AD pathophysiology, and thereby support its