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Major progress has been made in the past decade to develop drugs to treat the symptoms of AD. Some of the principal drugs that are available for clinical use are listed in Table 14.3. To date, important advances have been made regarding the reversal of the disease process. In particular with respect to preventing the accumulation of Ab and in defining strategies for preventing the central inflammatory response which appears to initiate the neurotoxic changes. Undoubtedly the following decade will see the development of vaccines, and other strategies, that will alter the course of the disease. Thus we can expect the therapeutic pessimism of the past to be replaced by therapeutic optimism in the future.

Table 14.3. Anti-dementia drugs currently available

Type Possible efficacy

Nootropic agents, antihypoxic agents No evidence for efficacy in AD

E.g. piracetam, amiracetam, pramiracetam, oxiracetam


E.g. arecoline, levocarnitine, milameline, xanomeline


E.g. physostigmine, tacrine, donepezil, metrifonate, huperzine A, eptastigmine, velnacrine, galantamine, rivastigmine

Anti-inflammatory drugs

E.g. prednisone, indomethacin, celecoxib, rofecoxib, propentofyline


E.g. vitamin E+seligiline

Chelating agents

E.g. desferroxamine, clioquinol


Ginkgo biloba alkaloids Others

E.g. memantine

Limited efficacy in AD

Efficacy in early stages of AD

May be preventative as evidenced by epidemiological studies; no evidence of efficacy in patients with AD

Limited efficacy

?Some improvements in cognitive function

May have a preventative role but no efficacy in AD

Slight effect on cognitive function but not sufficient for therapeutic use

Glutamate antagonist (AMPA receptors). Clinical trials show modest improvement in cognitive function

Other approaches

Benzodiazepine receptor agonists are known to cause amnesia, whereas those drugs which act as inverse agonists on the benzodiazepine receptor exert promnestic properties, at least under experimental conditions. Attempts are therefore being made to develop inverse agonists with cognitive-enhancing properties. ZK 93426 is a benzodiazepine inverse agonist which has similar cognitive-enhancing effects in human volunteers to drugs that facilitate central cholinergic transmission, and experimental evidence suggests that ZK 93426 facilitates acetylcholine release. In this respect this inverse agonist resembles some of the centrally acting angiotensin-converting enzyme inhibitors, such as captopril, which have been shown to exhibit cognitive-enhancing properties in experimental studies, possibly by stimulating acetylcholine release.

Despite the numerous animal studies in which neuropeptides (analogues of adrenocorticotrophic hormone, vasopressin, cholecystokinin, beta-endorphin) have been shown to have potent and reproducible effects in facilitating learning and memory, there is to date no convincing evidence to suggest that these drugs are of any therapeutic benefit to patients with Alzheimer's disease.

The ampakines are a group of compounds that facilitate transmission by stimulating the AMPA glutamate receptors (see p. 58). The AMPA receptor is believed to play a major role in long-term potentiation, a physiological process that is important in memory formation. Experimental studies in aged rats have already shown that the ampakines can reverse age-associated memory loss but their activity in Alzheimer's patients has yet to be determined.

Another approach has been based on the epidemiological finding that oestrogens, antioxidants and anti-inflammatory drugs might delay the onset of Alzheimer's disease. Of the drugs undergoing studies under the auspices of the Alzheimer's Disease Co-operative Study in the USA, particular attention is being given to the antioxidant vitamin E and the monoamine oxidase-B (MAO-B) inhibitor deprenyl (selegeline) which has been widely used as an adjunct to L-dopa therapy in the treatment of Parkinson's disease. In addition to its MAO-B inhibitory effects, deprenyl has also been shown to act as an antioxidant. The rationale for studying such drugs is based on the belief that reactive oxygen-free radicals are produced in excessive amounts in the ageing brain and that this process is particularly prominent in the brain of the Alzheimer's patient. Furthermore, there is evidence that excessive production of free radicals is linked to the neurotoxic effects of beta-amyloid which is predominantly found in degenerative nerve terminals in the brain of the Alzheimer's patient.

In cell culture, it has been found that beta-amyloid can increase the synthesis of hydrogen peroxide and free hydroxyl radicals which can act directly on neuronal membranes and thereby damage the integrity of the cell. The neurotoxicity of beta-amyloid can be prevented, at least in vitro, by the addition of antioxidants including vitamin E. Whether the prophylactic administration of such antioxidants will delay the degenerative changes that precede Alzheimer's disease in those patients who are predisposed to the disease is unknown but initial clinical findings are disappointing.

Finally, it may be possible to reduce the excessive influx of calcium into neurons which may be a contributing factor to cell death in Alzheimer's disease. It is known that the density of calcium channels is increased threefold in the neurons of aged rats in comparison to younger animals. Such changes are correlated with memory and learning deficits in the animals. Thus the use of centrally acting calcium channel inhibitory drugs might have a neuroprotective role to play. Which, if any, of these approaches will lead to drugs that are both effective and safe in slowing the decline in neurodegeneration remains to be proven.

Table 14.4. Treatment decisions for Alzheimer's disease

• Treatment of choice - a centrally acting cholinesterase inhibitor (e.g. donepezil, galantamine, rivastigmine)

• Switching - an alternative cholinesterase inhibitor

• Augmentation - a cholinesterase inhibitor plus vitamin E

• Other options - memantine, selegiline, Ginkgo biloba alkaloids

Note: There is no evidence that nootropics (e.g. piracetam, nimodepine) are beneficial but some (e.g. co-dergocrine) may cause a minor improvement in neuropsychological and behavioural parameters.

Treatment decisions for Alzheimer's disease are shown in Table 14.4.

In CONCLUSION, despite the very limited advances that have been made in developing drugs that are of real benefit to the patient with Alzheimer's disease, there have been some developments which may ultimately lead to this goal. The discovery of the defect in the forebrain cholinergic system has led to a treatment strategy which, although limited in its clinical value, raises the prospect of rational drug development.

Another important research strategy concerns the reasons why brain cells die prematurely in patients with Alzheimer's disease. Is this due to a genetically programmed change in the chemistry of the neurofibrillary tangles? One possible approach to this question would involve studying the nature of the cross-linking of the proteins that compose these filaments. It is not without interest that a dominant mutation has recently been described in a nematode worm (C. elegans) that results in a toxic gene product causing degeneration of specific neurons in the adult. Could such a toxic gene product also be responsible for selective neuronal degeneration in patients prone to Alzheimer's disease?

A third approach involves studies on the way neurotrophic factors affect the functioning and viability of brain cells. The finding that the synthesis of the neuropeptide somatostatin is defective in Alzheimer's disease lends added impetus to the assessment of the role of brain peptides which may have neuromodulatory and/or trophic functions.

Other strategies include detailed studies of the changes in brain carbohydrate metabolism in ageing and how this may differ in patients with Alzheimer's disease. Changes in the composition and biophysical properties of neuronal membranes may also be of crucial importance in regulating the cytosolic free calcium, which could affect cellular homeostasis.

Finally, there is an increasing need to evaluate the importance of environmental toxins in the pathology of Alzheimer's disease. There has been much interest lately in the role of aluminium as a causative factor, while the studies of dementia associated with the acquired immunodeficiency syndrome have focused attention on the effects of slow viruses in causing brain cell death.

The systematic study of Alzheimer's disease commenced only relatively recently, despite the fact that Alois Alzheimer described the disease over 90 years ago. In the last decade our knowledge of the disease and of its possible aetiology has advanced from almost total ignorance to the stage where it is possible to develop therapeutic strategies. Perhaps we should be optimistic that the next decade will enable early diagnosis of this devastating disease to be followed by effective symptomatic treatment and attenuation of the inevitable destruction of the brain.

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