Intended for healthcare professionals


Science commentary: Rational drug design for Alzheimer's disease

BMJ 1999; 318 doi: (Published 06 March 1999) Cite this as: BMJ 1999;318:633
  1. Abi Berger, Science editor
  1. BMJ

    The loss of cholinergic neurotransmitter activity was first identified in the 1970s at necropsy in brains removed from people with Alzheimer's disease, and it has since been confirmed in living patients by positron emission tomography (figure). These observations have led to the development of a number of acetylcholinesterase inhibitor drugs, which have been rationally designed to boost the apparent chemical deficiency in Alzheimer's disease (MR Farlow et al, Neurology 1998;51(suppl 1):36-44S).

    Acetylcholinesterase inhibitors have been designed to stop the breakdown of acetylcholine in the brain. Unfortunately, these drugs are non-selective and thus the action of the enzyme is blocked in other parts of the body, causing an undesirable build up of the neurotransmitter at other sites. The gut is one of the more common sites where this happens, and this can lead to side effects such as increased motility and nausea. Most of the drugs in this family are reversible—that is, the action of the enzyme is only blocked while the drug is being taken.

    The chief pathways of acetylcholine that are affected in Alzheimer's disease seem to be in the series of nuclei that project from the forebrain nucleus up to the cerebral cortex and, more specifically, into the hippocampus, which is known to be involved with the function of memory. The aim is, therefore, to boost acetylcholine concentrations in the hippocampus.

    Embedded Image

    Coloured positron emission tomography scans (horizontal sections) of the brain of a normal patient (left) and a patient with Alzheimer's disease (right). Red and yellow areas show high brain activity; blue and black areas show low activity. The scan from the patient with Alzheimer's disease shows that both function and blood flow in both sides of the brain are reduced. Acetylcholinesterase inhibitor drugs may boost the apparent chemical deficiency in Alzheimer's disease. The aim is to increase concentrations in the hippocampus, which is involved in memory

    To date, most trials of the effectiveness of acetylcholinesterase inhibitors in dementia have followed patients for a minimum of six months. But no one yet knows how quickly an alteration in acetylcholine concentrations might result in a measurable restoration of memory. And, to achieve optimal benefits, it may also prove necessary to offer a period of “retraining” to reorient the brain, in addition to improving the neurotransmitter concentrations.

    It remains to be seen how well these drugs actually work in Alzheimer's disease. In future it may be shown that other types of dementia with less complex pathological processes may be more responsive. One example is the dementia associated with Lewy bodies in which the pathological process does not also include the presence of amyloid or tangles to the same extent as in Alzheimer's disease.