The field of Alzheimer's disease (AD) research is in transition. Advances in our knowledge of AD pathology are translating into improved understanding of pharmacological agents that may have benefits across the spectrum of the illness. A major focus of current research is the potential ability of cholinergic therapy to enhance function and quality of life in all patients affected by AD, from the mildest to the most advanced stages.

The pathological processes that lead to Alzheimer's disease (AD) begin decades before the onset of dementia. Brain abnormalities in genetically susceptible individuals have been observed even in young adults. Patients with AD differ from normal elderly patients in brain morphology and neurochemistry. Important observations include increasing appearance of amyloid plaques and neurofibrillary tangles, progressive loss of hippocampal volume, reduced cerebral glucose utilization, inflammatory processes, glial activation, and impairment of cholinergic function with losses of nicotinic acetylcholine receptors. These changes appear to begin in the asymptomatic stages and continue as cognition and then function and behavior are disrupted. Mild cognitive impairment (MCI) may be the first cognitive manifestation of this pathogenic process moderated by ongoing compensatory neurochemical mechanisms in the cholinergic system. Recent advances in positron emission tomography imaging techniques, including the development of the Pittsburgh B compound (PIB), allow in vivo visualization of amyloid plaques. These techniques have the potential to enable brain amyloid load to be monitored over time and to be related to brain function. Emerging evidence suggests that β-amyloid may interact with nicotinic receptors. This interaction may have clinically significant downstream effects and may mediate amyloid neurotoxicity. The cholinesterase inhibitors may have multiple actions, depending on the stage of the disease, from very mild to severe.

Early initiation of Alzheimer's disease (AD) treatment is advantageous because it can potentially keep patients in milder stages of the disease longer than delayed treatment. Early initiation of cholinesterase inhibitor therapy is an effective intervention for mild AD. Therefore, it is critical to identify and monitor patients who are at risk for AD and to initiate treatment once AD is diagnosed. A new diagnostic category, mild cognitive impairment (MCI), has been evolving to identify patients who demonstrate objective memory impairment but have essentially intact function or only limited functional impairment and do not meet diagnostic criteria for dementia. The amnestic subtype of this condition is associated with a high risk of AD – 16% of amnestic MCI patients convert to AD each year compared with 1% to 3% of normal elders. A recent three-year study found that patients with amnestic MCI who were treated with donepezil had a significantly reduced likelihood of progression to dementia in the first 12 months of treatment. The effect of donepezil in delaying onset of dementia was supported by significant differences favoring donepezil in the Mini-mental State Examination, the Clinical Dementia Rating-Sum of the Boxes, the Global Deterioration Scale, and the modified Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-Cog) over the first 18 months of treatment. A previous study evaluated the effects of donepezil on memory and cognition in patients with MCI. Although donepezil had no significant effect on memory as measured by the New York University Paragraph Recall Test, it significantly improved scores on the modified ADAS-Cog. Donepezil therefore shows promise in this patient population and warrants further investigation using extended study durations and refined outcome measures.

Acetylcholinesterase inhibitors have demonstrated safety and efficacy in patients with mild to moderate Alzheimer's disease (AD). Although studies of biomarkers in AD suggest a neurobiological rationale for continuing cholinomimetic therapy in patients with severe AD, there have been few studies on the effects of these drugs in such patients. While the interpretation of earlier studies on therapy for severe AD has been complicated by the inclusion of patients with moderate AD, a recent study in Swedish nursing home residents demonstrates the clinical utility of donepezil in a population of exclusively severe patients – i.e. those with Mini-Mental State Examination scores of 1 to 10 inclusive. Significant differences favoring donepezil treatment were observed at the end of this six-month, double-blind placebo-controlled study on the two primary outcome measures: the Severe Impairment Battery (SIB) and Modified Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory for Severe AD (ADCS-ADL-severe). Donepezil-treated patients showed a mean improvement on the SIB after six months compared with baseline, and less decline on the ADCS-ADL-severe than would be expected for untreated patients. These results extend and confirm earlier data suggesting that donepezil is effective in patients with moderate and severe AD.