Alzheimer's disease

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Alzheimer's disease (AD) or senile dementia of Alzheimer's type is a disorder or loss of mental functions resulting from brain tissue changes; the causes are yet to be fully elucidated (mutations in at least four genes predisposing to AD have been identified).

The disease was thought to be uncommon, until the 1960s when it was realized that much of what had been regarded as the normal process of aging was actually the result of this disease.

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Clinical features

The typical visible symptom is progressive and chronic memory loss. Alzheimer's disease is also manifested in behavorial changes, which may include confusion, disorientation, sudden periods of defiance, abusive behavior, or violence, etc. in people who have no previous history of such behavior (rarely, an affected person experiences euphoria). Thus, Alzheimer's disease presents a problem in patient management, as well. Average duration is approximately 10 years.

Pathology

There are several changes found in the brain in AD.

  • The deposition of an abnormal protein outside nerve cells in the form of amyloid. These are called plaques or sometimes senile plaques.
  • The accumulation of abnormal filaments of protein inside nerve cells in the brain. The protein is called tau and is normally present to stabilise microtubules. In AD, an abnormally phosphorylated form of tau protein accumulates as paired helical filaments. Tau accumulates
    • As masses of filaments inside nerve cell body termed neurofibrillary tangles
    • Inside nerve cell processes in the brain termed neuropil threads
    • Inside nervce cell processes that surround amyloid plaques - termed plaque neurites.
  • Amyloid accumulation in the walls of small blood vessels in the brain. Termed amyloid angiopathy (also called congophilic angiopathy)
  • Diffuse neuropathology, nerve cells die and are lost from key brain regions. This results in atrophy of the affected areas and enlargement of the ventricles.
  • Loss of synaptic contacts between neurons. Seems to be related to the regulation of cell adhesion proteins by presenilin.

These features are seen down the microscope using histology and can only be determined post mortem.

Etiology

There is compelling evidence that genetic predispositions underlie the development of Alzheimer's disease.

However most cases seen are 'sporadic' with no clear family history. It is probable that environmental factors have to interact with a genetic susceptibility to cause development of disease. Head injury has been consistently shown to be linked to later development of AD in epidemiological studies.

Studies have not shown any link with toxins, vitamins, metals or diet. However other causes of dementia NOT AD have been linked with exposure to environmental agents or lack of specific vitamins.

Inheritance of the ApoE4 gene is regarded as a risk factor for development of disease.

Rare cases are caused by dominant genes that run in families. These cases often have an early age of onsent. Mutations in presenilin-1 or presenilin-2 genes have been documented in some families. Mutations in the APP gene on chromosome 21 can also cause disease.

The presence of the APP gene on chromosome 21 is believed to explain the high incidence of AD in patients with Down's syndrome (trisomy 21).

Prevalence

Alzheimer's disease is the most frequent reason for dementia in the elderly and affects almost half of all patients with dementia.

3-10% of persons aged 65 show signs of the disease, while 50% of persons aged 85 have symptoms of Alzheimer's. The proportion of persons with Alzheimer's begins to decrease after age 85 because of the increased mortality due to the disease, and relatively few people over the age of 100 have the disease.

Diagnosis

Unfortunately, a definitive diagnosis of Alzheimer's disease must await an autopsy, at present. Many increasingly sophisticated diagnostic tests have been proposed (including: brain scans, behavioral tests and testing for genetic predisposition) but these are at present used to identify or rule out possible alternative explanations of the symptoms.

Psychological testing generally focuses on memory, attention, abstract thinking, the ability to name objects, and other cognitive functions. However, results of psychological tests do not easily distinguish between Alzheimers Disease and other types of dementia. Psychological testing can be helpful in establishing the presence of and severity of dementia. It can also be useful in distinguishing true dementia from temporary (and more treatable) cognitive impairment due to depression or psychosis, which has sometimes been termed pseudodementia.

Treatment

There is no cure, although there are drugs which reduce neurotransmitter degradation and delay the symptoms of the disease. Non-steroidal anti-inflammatory drugs (including ibuprofen, acetaminophen, and aspirin) also seem to slow progress of the disease, according to clinical trials, but the mechanism is not understood.

There are ongoing tests of an Alzheimer's disease vaccine. This was based on the idea that if you could reverse deposition of amyloid you would stop the disease. Initial results in animals were promising. However when the first vaccines were used in humans, brain inflammation resulted and the trials were stopped. 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.

Anticholinesterase treatment is important because there is selective loss of forebrain cholinergic neurons as a result of Alzheimer's. Here are some examples of some drugs:

tetrahydroaminoacridine (THA or Tacrine) - Modest improvement in memory and cognition in 40% of cases. Must be taken four times a day. The treatments causes nausea cramps and is hepatotoxic
donepezil - Single daily dosage, slightly less side effects than tacrine but no efficacy increase.
rivastigmine - Has shown the most effective improvement in cognition, although does also induce nausea and vomiting.

Anticholinesterases treat symptoms but do not prevent cell death!

Nutrition and Alzheimer's

Some work is being done to investigate the role of raised levels of homocysteine, and possible nutritional prevention or treatment through taking of foods high in B vitamins and antioxidants to control the levels of homocysteine.

This view is supported by Teodoro Bottiglieri, a neuropharmacologist at the Baylor Institute of Metabolic Disease in Dallas, Texas, and Andrew Mc Caddon, a researcher at the University of Wales. (See the Times newspaper, January 31 2004 "Could vitamins help delay the onset of Alzheimer?s?" by Jerome Burne).

A study (Archives of Neurology 2004;61:82-88) has reported that vitamins E and C might reduce the risk of Alzheimer's disease.

See also: Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002 Feb 14;346(7):476-83.

Genetic and Population Effects

Various gene alleles have been associated with Alzheimer's disease, most notably the apolipoprotein E (ApoE) gene. ApoE normally functions to regulate cholesterol metabolism. In addition, it has recently been discovered that Chinese and North American populations differ significantly in development of full-fledged Alzheimer's from early warning symptoms. Whether the reason for this is genetic, dietary, or social has yet to be investigated.

Social issues

Alzheimer's is considered to be a major public health challenge since the average age of the industrialized world's population is increasing.

History

The symptoms of the disease as a distinct nosologic entity were first identified by Emil Kraepelin, and the characteristic neuropathology was first observed by Alois Alzheimer in 1906. In this sense, the disease was co-discovered by Kraepelin and Alzheimer, who worked in Kraepelin's laboratory. Because of the overwhelming importance Kraepelin attached to finding the neuropathological basis of psychiatric disorders, Kraepelin made the generous decision that the disease would bear Alzheimer's name (J. Psychiat. Res., 1997, Vol 31, No. 6, pp. 635-643).

Famous Alzheimer's sufferers

See also

Familial Alzheimer disease

External links


References

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