Our experience with studies investigating central nervous system active compounds in Alzheimer disease (AD) patients suggest that conducting a "bridging study," in which patients from the target population are included in Phase I, could expedite the drug development process in AD. With one acetylcholinesterase (AChE) inhibitor compound (velnacrine), we found that AD patients tolerated considerably lower dosages than young normals and healthy elderly subjects, whereas our findings were exactly the opposite with another AChE inhibitor (eptastigmine). In studies of a muscarinic agonist (CI-979), AD patients were able to tolerate dosages higher than those that were well tolerated in young normals. A possible explanation for differences in drug effect and tolerance in the target population may be the pathologic changes in both the brain and the peripheral nervous system that are associated with AD.