Do cholinesterase inhibitors have disease-modifying effects in Alzheimer's disease?

During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer disease (AD) has resulted in drugs being registered for the first time in the US and Europe for this specific indication. The 3 agents registered are cholinesterase inhibitors (ChEIs). The major therapeutic effect of ChEIs in patients with AD is the maintenance of cognitive function, as compared with placebo, during a B-month to 1-year period of treatment. Additional drug effects that may occur are the slowing of cognitive deterioration and improvement of behaviour and daily living activities. Comparison of clinical effects of 6 ChEIs demonstrates a rather similar magnitude of improvement in cognitive outcome measures. For some drugs, this level may represent an upper limit, while for others it may be possible to increase the benefit further. In order to maximise and prolong positive drug effects it is important to start treatment early and adjust the dosage during treatment. Recent studies that used this administration strategy have shown that in many patients, the stabilisation effect produced by ChEIs can be prolonged for as long as 36 months. This long-lasting effect suggests mechanisms of action other than symptomatic ones. In this article, the effects of ChEIs on P-amyloid metabolism are postulated to explain the stabilising (i.e. disease-modifying) effects of the drugs. Evidence for such a mechanism is available at the experimental but not yet at the clinical level.