Cognitive Enhancers in Moderate to Severe Alzheimer's Disease

The treatment of moderate to severe Alzheimer’s disease is reviewed with regard to mechanisms of action, pharmacokinetics, metabolism, safety/tolerability, and efficacy in reducing cognitive, behavioral/psychiatric, functional and global symptoms. The cholinesterase inhibitors donepezil, rivastigmine and galantamine and the N-methyl-d-aspartate receptor channel blocker memantine are moderately beneficial. Small improvements over a few months are followed by slowed mental decline. Concerning cognitive, functional and global functions, these drugs are similarly effective. Cholinesterase inhibitors also reduce apathy, memantine counteracts agitation and aggression. Serious adverse effects are rare with all four drugs. Cholinesterase inhibitors bear a risk for patients with cardiac diseases. Adverse emetic events are typical for oral formulations of these drugs, but less for rivastigmine transdermal patches. Other routes of administration and use of a galantamine prodrug are currently investigated. The superiority of combination therapies over monotherapies requires further support. Promising investigational drugs include the copper/zinc ionophore PBT2 and multifunctional hybrid molecules.