Beyond symptomatic effects: potential of donepezil as a neuroprotective agent and disease modifier in Alzheimer's disease

Alzheimer's disease (AD) is associated with neurodegenerative changes resulting clinically in progressive cognitive and functional deficits. The only therapies are the cholinesterase inhibitors donepezil, galantamine and rivastigmine and the N‐methyl‐D‐aspartate‐receptor antagonist memantine. Donepezil acts primarily on the cholinergic system as a symptomatic treatment, but it also has potential for disease modification and may reduce the rate of progression of AD. This review explores the potential for disease modifying effects of donepezil. Several neuroprotective mechanisms that are independent of cholinesterase inhibition, are suggested. Donepezil has demonstrated a range of effects, including protecting against amyloid β, ischaemia and glutamate toxicity; slowing of progression of hippocampal atrophy; and up‐regulation of nicotinic acetylcholine receptors. Clinically, early and continuous treatment with donepezil is considered to preserve cognitive function more effectively than delayed treatment. The possible neuroprotective effects of donepezil and the potential for disease pathway modification highlight the importance of early diagnosis and treatment initiation in AD.