Do cholinergic therapies have disease-modifying effects in Alzheimer's disease?

The most widely studied and used therapies for Alzheimer's disease (AD) are based on improving cholinergic function in the central nervous system. The acetylcholine-esterase inhibitors (ChEIs) tacrine, donepezil, rivastigmine, and galantamine are all approved, and the latter three are widely used for the symptomatic treatment of mild to moderate AD. Recent research has found that these drugs may act by a variety of other mechanisms including inhibition of butylcholinesterase, regulation of nicotinic receptors, decreasing amyloid precursor protein (APP) and Aβ production, and regulation of tau phosphorylation that may influence disease progression. There is also emerging evidence from clinical trials that the ChEIs may delay cognitive and functional progression. Other cholinergic drugs such as muscarinic agonists have been explored, and although they are not approved, there is robust preclinical evidence for a beneficial, perhaps disease-modifying effect. This review summarizes evidence suggesting that these drugs may do more than improve symptoms; they may delay biological progression of the disease.