Cholinesterase-inhibitor therapy for dementia: novel clinical substrates and mechanisms for treatment response

Historically, drugs that increase central cholinergic transmission have primarily been investigated for relieving cognitive symptoms in mild-to-moderate Alzheimer's disease. These efforts have led to the somewhat unexpected findings that cholinergic therapy has a beneficial effect on selected neuropsychiatric symptoms in AD across disease stages. In Parkinson's disease with dementia and dementia with Lewy bodies, cholinergic deficits are more severe than in AD, and there is emerging evidence that cholinesterase inhibitors are efficacious in treating core symptoms of attentional disturbance and psychosis. Recent data also suggest a rational basis for cholinergic therapy in vascular dementia. The cognitive and neuropsychiatric effects of cholinergic therapy observed in AD and other dementias form the crux of an integrative model of cholinergic therapeutic efficacy that encompasses the diverse central nervous system actions of acetylcholine and its complementary interactions with central monoamine transmitters. This heuristic framework highlights the broader therapeutic potential of cholinergic therapy for symptom-based indications in other neuropsychiatric disorders.