Pharmacotherapy for Alzheimer's disease: progress and prospects

doi:10.1016/S0165-6147(02)02056-4

Trends in Pharmacological Sciences

Volume 23, Issue 9, 1 September 2002, Pages 426-433

https://doi.org/10.1016/S0165-6147(02)02056-4 Get rights and content

Abstract

The number of people with Alzheimer's disease has never been greater and is set to increase substantially in the decades ahead as the proportion of the population aged 65 years or more rises sharply. There is, therefore, a substantial and increasing need for effective pharmacotherapy. Increased understanding of disease pathophysiology has led to palliative treatments for both cognitive and non-cognitive changes in behaviour. This, together with the prospect of drugs that slow or perhaps even halt the course of the disease, raises hope that this devastating disorder will soon be more amenable to pharmacotherapy with new drugs that either ameliorate specific symptoms or alter the course of the disease.

Section snippets

ACh dysfunction

Efforts to improve the cognitive impairments associated with AD have been dominated by the cholinergic hypothesis 6., 7.; Table 2]. In addition to its established role in learning and memory [6], ACh plays a crucial role in attentional processing [8]. Thus, ACh-mimetic drugs ameliorate the impairments in attentional function observed in AD patients [9]. Because impaired attention probably contributes to cognitive dysfunction, ACh-mimetics can affect memory mechanisms either directly, as

Non-cognitive behavioural abnormalities

Non-cognitive behavioural abnormalities, including psychosis, apathy, depression, anxiety, verbal and physical aggression, agitation, overactivity, sexual disinhibition, sleep disturbances and hyperphagia [17], are common in AD patients. Many of these behaviours increase the risk of injury to patients, and all make patient management more difficult and increase the need for institutional care [18]. Several hypotheses that provide a neuronal basis for non-cognitive behavioural changes are

Prospects for slowing or halting disease progress

Although the cause of the characteristic, selective loss of neurones in AD is not fully understood, several aetiological factors have been proposed. Understanding the aetiology and pathogenesis of the disease provides a foundation from which to develop therapies to slow or halt disease progress (Box 2).

Concluding remarks

It is likely that pyramidal cells, which use EAAs as neurotransmitters, are the neurones that are central to the pathophysiology of AD and the emergence of cognitive dysfunction. Developing drugs that target this system has proved difficult because of side-effects [55] and the possibility of excitotoxicity [46], although the low affinity NMDA receptor antagonist memantine appears to be well-tolerated and have both symptomatic and neuroprotective effects [56]. Although several AChE inhibitors

Acknowledgements

I thank Prof. Steve DeKosky and Dr Paul Francis for their helpful comments on an earlier version of this manuscript.

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Trends in Pharmacological Sciences

ReviewPharmacotherapy for Alzheimer's disease: progress and prospects

Abstract

Section snippets

ACh dysfunction

Non-cognitive behavioural abnormalities

Prospects for slowing or halting disease progress

Concluding remarks

Acknowledgements

FASEB J.

Behav. Brain Res.

Eur. J. Pharmacol.

J. Neurochem.

Cell. Mol. Life Sci.

J. Neural Transm.

Br. J. Psychiatry

Curr. Opin. Neurobiol.

Biol. Psychiatry

CNS Drugs

Drug Discov. Today

Trends Neurosci.

Ann. New York Acad. Sci.

Brain Res. Rev.

New Engl. J. Med.

J. Am. Med. Assoc.

Front. Neurobiol.

Ann. New York Acad. Sci.

Mol. Mech. Neurodegen. Dis.

J. Neurosci.

Trends Neurosci.

Brain Res.

Neurotoxic. Res.

J. Am. Med. Assoc.

Neurology

J. Neurochem.

Arch. Neurol.

Treatment of AD

New Engl. J. Med.

Imaging of onset and progression of AD with voxel-compression mapping of serial magnetic resonance images

Lancet

Cortical connections and the pathology of Alzheimer's disease

Neurodegeneration

The autonomic higher order processing nuclei of the lower brain stem are among the early targets of the Alzheimer's disease-related cytoskeletal pathology

Acta Neuropathol.

Age-specific incidence of Alzheimer's disease in a community population

J. Am. Med. Assoc.

The cholinergic hypothesis of Alzheimer's disease: a review of progress

J. Neurol. Neurosurg. Psychiatry

Acetylcholine affects the spatial scale of attention: evidence from Alzheimer's disease

Neuropsychology

Use of acetylcholinesterase inhibitors in Alzheimer's disease

Expert Rev. Neurotherapeutics

Neurochemical studies of Alzheimer's disease

Neurodegeneration

Facilitative effects of the ampakine CX516 on short-term memory in rats: enhancement of delayed-nonmatch-to-sample performance

J. Neurosci.

Cognitive and behavioral heterogeneity in Alzheimer's disease: seeking the neurobiological basis

Neurobiol. Aging

Review
Pharmacotherapy for Alzheimer's disease: progress and prospects