Alzheimer's disease

Alzheimer's disease (AD), a neurodegenerative disorder, is the most common cause of dementia and characterised clinically by progressive intellectual deterioration together with declining activities of daily living and neuropsychiatric symptoms or behavioral changes. The most striking early symptom is memory loss (amnesia), usually manifest as minor forgetfulness that becomes steadily more dense with illness progression, with relative preservation of older memories. As the disorder progresses, cognitive (intellectual) impairment extends to the domains of language (aphasia), coordinated movement (apraxia), recognition (agnosia) and those functions (such as decision-making and planning) closely related to the frontal lobe of the brain, reflecting extension of the underlying pathological process. This consists principally of neuronal (cell) loss (or atrophy), together with deposition of amyloid plaques and neurofibrillary tangles. Genetic factors are known to be important, and polymorphisms (variations) in three different autosomal dominant genes - Presenilin 1, Presenilin 2, and A-Beta - have been identified that account for a small number of cases of familial, early-onset AD. For late onset AD (LOAD), only one susceptibility gene has so far been identitified - the epsilon 4 allele of the APOE gene. Age of onset itself has a heritability of around 40%.

Treatment

There is no cure, although there are drugs which temporarily reduce neurotransmitter degradation and alleviate some of the symptoms of the disease.

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Acetylcholinesterase inhibitors

Acetylcholinesterase (AChE) inhibition was thought to be important because there is selective loss of forebrain cholinergic neurons as a result of Alzheimer's. AChE-inhibitors reduce the rate at which acetylcholine (ACh) is broken down and hence increase the concentration of ACh in the brain (combatting the loss of ACh caused by the death of the cholinergin neurons). Acetylcholinesterase-inhibitors seemed to modestly moderate symptoms but do not prevent disease progression including cell death.

Related Topics:
Acetylcholinesterase - Cholinergic

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Examples include:

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• tacrine - no longer clinically used
• donepezil
• galantamine
• rivastigmine (marketed as Exelon)

Recently, a controversy has erupted about cholinesterase inhibitors because a study by Courtney (2004) in the respected medical journal The Lancet has suggested they are ineffective. The pharmaceutical companies, but also many unbiassed clinicians, dispute the findings of the study, based on methodologic grounds.

Related Topics:
Recently - The Lancet

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NMDA antagonists

Recent evidence of the involvement of glutamatergic neuronal excitotoxicity in the aetiology of Alzheimer's disease led to the development and introduction of memantine. Memantine is a novel NMDA receptor antagonist, and has been shown to be moderately clinically efficacious. (Areosa et al., 2004)

Related Topics:
Glutamatergic - Excitotoxicity - Aetiology - Memantine - NMDA receptor - Antagonist

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Vaccine

There are ongoing tests of an Alzheimer's disease vaccine. This was based on the idea that if you could train the immune system to recognize and attack beta-amyloid plaque, the immune system might reverse deposition of amyloid and thus stop the disease. Initial results in animals were promising. However, when the first vaccines were used in humans, brain inflammation occurred in a small fraction of participants, and the trials were stopped. Participants in the halted trials continued to be followed, and some showed lingering benefits in the form of slower progression of the disease. Recent studies in mice continue to show promise that an approach may be found to avoid the inflammation issue. It is hoped that research will provide a better formulation and that in the future it can be of use in families with history of Alzheimer's disease.

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Pure Medical Nicotine

One study indicated that intake of pure medical nicotine might help delay progression of Alzheimer's disease in carriers, but not non-carriers, of the ApoE4 gene. The issue of whether medical nicotine intake may delay Alzheimer's progression among some sub-populations of patients remains a focus of debate. But no one is advocating smoking, as distinct from prescription nicotine, for the treatment or prevention of Alzheimer's. In prospective studies and well-analyzed retrospective studies, smoking is shown to increase the risk of developing Alzheimer's. Biomed Pharmacother. 2004 Mar;58(2):95-9.

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