Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia (accounting for 50 – 80 percent of all cases). AD is the leading neurodegenerative disease and is estimated to affect as many as 5.3 million Americans; and a disease that has no known cure. AD is not a normal part of the aging process – however, the greatest known risk factor is increasing age. With an aging population, AD is expected to create a significant toll on the populous and as such, creating an effective treatment or cure is a huge goal in the biomedical community.


A hallmark of AD is extracellular amyloid plaques, composed mainly of 40-42 residue amyloid peptides. In this, now widely accepted hypothesis, an imbalance between the production and removal of A peptides is believed to exist leading to an increased level of A; and it is the high levels of A that triggers a series of events that lead to neuronal dysfunction and dementia. This hypothesis has spurred the research into finding drugs that prevent the A formation. Unfortunately, AD has no known cure and the available therapies only treat symptoms. These treatments can help slow the progression of the disease and provide for an improved quality of life for the patients and caregivers. Currently there are 5 FDA approved medications for AD. These treatments are classified into two groups: NMDA (N-methyl-D-aspartate) receptor antagonist (memantine) or cholinesterase inhibitors (donepazil, galantamine, rivastigmine, and tacrine). Memantine works by regulating the activity of glutamate, which helps protect cells from damage. The cholinesterase inhibitors work by slowing down the disease activity that breaks down a key neurotransmitter. Unfortunately, these drugs only work in ~50% of the patients that take them, and for those patients they are only effective for 6 to 12 months.


It is generally accepted that the loss of cholinergic function is key to the cognitive impairment in AD. Early studies revealed that disease progression is accompanied by the loss of cholinergic neurons. In addition, A has been shown to cause a number of harmful effects on cholinergic neurons and the levels of A and cholinergic deficit correlate well in the disease state. Pre-clinical studies have shown that antagonists of mAChR cause cognitive deficits. These studies have been further validated using mouse knock-out models. These early studies have since been clinically validated by the current FDA-approved cholinesterase inhibitors which increase endogenous levels of acetylcholine. However, in addition to the loss of efficacy after a short time period (1 – 2 years), these drugs have significant undesirable side effects, often termed SLUDGE (salivation, lacrimation, urination, diaphoresis, gastrointestinal motility, and emesis). These adverse events (AE) are thought to result from the non-selective activation of all mAChR subtypes (i.e., these drugs are not selective for specific mAChR subtypes).