SDAT accounts for over half of all cases of dementia in old age. It is present in 5 per cent of people over age 65 and 20 per cent of people over 80. Women are affected nearly twice as often as men, probably mainly reflecting women's longer lifespan.
AD is also the commonest of the primary 'presenile' dementias, with onset earlier in life, say, between the ages of 40 and 60.
Genetic predisposition exists and a link with allele e4 of apolipoprotein E is established. About 20-30 per cent of the population has at least one copy of e4; about 50 per cent of AD patients have at least one copy of e4. However, most cases are probably polygenic and multifactorial.
Most cases of early-onset AD arise sporadically, but others are inherited, usually in polygenic fashion, although in a few families there is a dominant gene. Mutations in the amyloid precursor protein (APP) gene on chromosome 21 have been found in a few affected families. APP is implicated in the formation of senile plaques, one of the key neuropathological findings in AD. The role of APP ties in with the well-known increased rate of AD in trisomy 21 (Down's syndrome) patients.
Genetic testing is seldom done in clinical practice unless the AD is strongly familial.
Shrinkage of the brain causes enlargement of the ventricles and sulci, as revealed by CT or MRI brain scanning Microscopically, there are three characteristic changes: neuronal loss, senile plaques, and neurofibrillary tangles. Neurons are decreased both in number and size, and astrocytes proliferate. Senile plaques, which have argyrophilic cores containing an amyloid-like substance, develop in the grey matter. Nerve fibres form tangles called Alzheimer's neurofibrillary degeneration. Lewy bodies (see below) may also be present.
Post-mortem brain studies show a deficiency of the enzyme choline acetyltrans-ferase, which is concerned in the synthesis of acetylcholine, and defective cholinergic transmission is considered the likely basis of the symptoms. Cerebral blood flow and oxygen consumption are reduced. The EEG usually shows theta or delta waves, with alpha rhythm slow or absent. Brain scans show cerebral atrophy, selectively affecting the medial temporal lobe in early cases.
Onset is gradual over a year or more. Loss of recent memory is usually the first symptom, and is followed by deterioration in other mental functions, emotional lability or sustained depression, and personality change. Delusions and hallucinations, fits, and neurological signs may occur in advanced cases. Insight is usually absent, and the patient comes to medical attention because relatives or neighbours notice failing memory, confusion, poor hygiene, and self-neglect. Diagnosis is made on clinical grounds, as there is no laboratory test for AD, although tests may be required to exclude other causes of dementia.
In early-onset dementia, rapid progression was said to be usual, but there is doubt as to whether deterioration is really quicker, on average, than in later-onset cases. Marked neurological abnormalities are common.
The acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine are now licensed for use in AD. Their use was sanctioned by NICE in 2001 (http:// www.nice.org.uk/page.aspx?o=14487), but with the following conditions:
• prescription to be initiated in specialist clinics, most services now running a 'memory clinic' for this purpose
• treatment normally to continue only if MMSE > 12, and judged to be of overall clinical benefit.
It is unusual for such conditions to be attached to drug licences; this reflects the high cost of the drugs, and the continuing doubts about their effectiveness. Trial data indicate improvements, or at least slower declines, in measures of cognitive function, which are claimed to delay the requirement for the patient to enter institutional care. However, clinical experience is that dramatic responses are unusual. The overall impact of the drugs in clinical practice has been modest.
Memantine is an NMDA-receptor antagonist that affects glutamate transmission; it is licensed for treating moderate to severe AD; however, its cost-effectiveness has been doubted (http://www.nice.org.uk/page.aspx?o=322952).
NICE recently reviewed the effectiveness of all these drugs in relation to their cost; the manufacturers - not surprisingly, considering the potential size of the market - have entered appeals, as have other groups; this debate can be followed at the NICE website. At the time of writing, NICE has just - controversially -withdrawn approval for the NHS use of these drugs in early dementia in England, although they remain available in Scotland.
Dementia shortens life. Pneumonia is a frequent terminal event. Death 5 years after the onset of dementia would be a typical course, but much depends on overall health and the quality of care.
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