Alzheimer therapeutics—what after the cholinesterase inhibitors?

In the 1970s and early 1980s, biochemical and neuropathological evidence emerged, implicating the degeneration of basal forebrain acetylcholinergic neurons in Alzheimer’s disease (AD) [1]. The ‘cholinergic hypothesis’ of AD held that cholinergic dysfunction causes cognitive decline and that dementia therefore might be mitigated by the augmentation of acetylcholine activity in brain. The logical therapeutic objective was to boost the levels of the transmitter by inhibiting its catabolic enzyme, acetylcholinesterase. Today, several cholinesterase inhibitors are marketed for the treatment of mild-to-moderate dementia. They have been demonstrated to improve, relative to placebo, various cognitive and functional capacities [2], and there is evidence that they may slow the pathogenesis of AD [3]. Additionally, an inhibitor of ionotropic neurotransmitter receptors (memantine) recently was approved for use in moderate-to-severe dementia [4]. However, because multiple neuronal systems are severely damaged in AD, the benefits of agents that selectively target the activity of certain transmitters are small. The limitations of the current generation of AD therapies led, in 2005, to a tentative proposal by the National Institute of Clinical Excellence (NICE) not to recommend donepezil, rivastigmine, galantamine or memantine for the treatment of dementia (provisional recommendation of the cholinesterase inhibitors for moderate dementia has since been reinstated; the final recommendations are due in July 2006 [5]). Although these drugs offer hope, and probably some benefit, to many patients, the improvements are modest and mainly symptomatic, and the patients and their families must eventually face the reality that the drugs cannot halt the relentless deterioration of mental capacities. Fortunately, recent research on the fundamental pathogenesis of AD reveals promising new strategies for arresting or preventing the disease.