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Alzheimer's disease

Alzheimer's disease (AD) or senile dementia of Alzheimer's type is a neurodegenerative disease which results in a loss of mental functions due to the deterioration of brain tissue. Its exact etiology (cause) is still unknown, but environmental as well as genetic factors are thought to contribute (mutations in at least four genes predisposing to AD have been identified).

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


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.


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 diffuse plaques and amyloid also forms the core of more organized plaques called senile or neuritic 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 nerve 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 and their processes including synapses 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. May be related to the regulation of cell adhesion proteins by presenilins. The presenilins have been identified as part of the processing apparatus that produces the amyloid beta protein.

There is also regional involvement of gross atrophy, and enlarged ventricles in the brain. Massive synaptic and dendritic loss is expected. The neurotransmitters serotonin, acetylcholine, norepinephrine, and somatostatin are at decreased levels. Glutamate levels are usually elevated.

Many of these features can be seen with the microscope using special histological techniques and are only seen when the brain is examined after death.


Three competing hypotheses exist to explain the cause of the disease.

The oldest hypothesis is the "cholinergic hypothesis". It states that Alzheimer's begins as a deficiency in the production of acetylcholine, a vital neurotransmitter. Much early therapeutic research was based on this hypothesis, including restoration of the "cholinergic nuclei". The possibility of cell-replacement therapy was investigated on the basis of this hypothesis. All of the first-generation anti-Alzheimer's medications are based on this hypothesis and work to preserve acetylcholine by interfering with acetylcholinesterases (enzymes that break down acetylcholine). Results had from these medicines have not been promising. In all cases, they have served to only treat symptoms of the disease and have neither halted nor reversed it. These results and other research have led to the conclusion that acetylcholine deficiencies may not be causal but are a result of widespread brain tissue damage, damage so widespread that cell-replacement therapies are likely to be impractical.

The other two hypotheses are of generally equal acceptance. "Tau-ists" believe that the tau protein abnormalities come first and lead to a full disease cascade. "bA-ptists" believe that beta amyloid deposits are the causative factor in the disease. For example, the presence of the APP gene on chromosome 21 is believed to explain the high incidence of AD in patients with Down syndrome (trisomy 21). The terms "tau-ist" and "ba-ptist" are used (lightheartedly) in scientific publications by Alzheimer's disease researchers. A third protein, alpha synuclein, which has already been shown to be important in Parkinson's disease, has recently been proposed as the etiological candidate, giving rise to the "syn-ners". By 2004, several researchers have come to the conclusion that Alzheimer's disease may be a "triple-protein pathology", wherein interactions among all three lesions are what give rise to Alzheimer's disease, rather than any one of the three.

There is compelling evidence that genetic predispositions underlie the development of Alzheimer's disease. However, the most obviously genetic cases are also the rarest. Most cases identified 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. In addition, small cranial diameter has been shown to correlate well with early onset of recognizable symptoms. The most commonly accepted explanation for this last feature is that larger brains simply may have more cells that can afford to be lost. Inheritance of a specific variation of the ApoE gene (epsilon 4) is regarded as a risk factor for development of disease, but large-scale genetic association studies raise the possibility that even this does not indicate susceptability so much as how early one is likely to develop Alzheimer's. Intriguing work is currently going on investigating the possibility that the regulatory regions of various Alzheimer's associated genes could be important in sporadic Alzheimer's, especially inflammatory activation of these genes.

Studies have not shown strong link with toxins, vitamins, metals or diet, although rabbits fed a high-cholesterol diet in the presence of copper ions in their water did develop amyloid brain lesions and cognitive deficiencies [1]
, [2]
. Likewise, linkage has been found between zinc or copper and reactive oxidative stress contributing to Alzheimer's pathology [3]
, and the amyloid precursor protein has been shown to alter expression in response to metal supplementation and chelation [4]
, [5]
, [6]
. Therefore, it is hasty and premature to dismiss any and all environmental effects out of hand. There have been studies that link aluminium to the progression of Alzheimer's, but the results from these studies have not been confirmed and are not widely accepted by Alzheimer's experts.

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 of presenilin 1 (PS1) lead to the most aggressive form of familial AD (FAD). Evidence from rodent studies suggests that the FAD mutation of PS1 results in impared hippocampal-dependent learning which is correlated with reduced adult neurogenesis in the dentate gyrus (Wang et al, 2004
). Mutations in the APP gene on chromosome 21 can also cause disease.


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

2-3% of persons aged 65 show signs of the disease, while 25% 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.


While expert clinicians who specialize in memory disorders can diagnose AD with an accuracy of 85-90%, a definitive diagnosis of Alzheimer's disease must await an autopsy. Many increasingly sophisticated diagnostic tests are also used(including: brain scans, behavioral tests and testing for genetic predisposition ) but these are, at present, used mainly to identify or rule out possible alternative explanations for 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 such as normal pressure hydrocephalus. 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.


There is no cure, although there are drugs which reduce neurotransmitter degradation and alleviate some of the symptoms of the disease. Non-steroidal anti-inflammatory drugs such as ibuprofen (Advil, Motrin) and aspirin seem to slow progress of the disease, according to population studies, but they seem to be more effective at preventing or delaying the onset of the disease. It should be noted that some similar drugs such as acetominophen, naproxen, and the 'COX2 inhibitors' have no demonstrated effect.

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 seem to treat symptoms but do not prevent disease progression including cell death.

Examples include:

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 dispute the findings of the study.

NMDA antagonists

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


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 occurred in a small fraction of participants, 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.

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.

Many studies have indicated that non-steroidal anti-inflammatory drugs (NSAIDS) like aspirin and ibuprofen delay the onset of Alzheimer´s disease. Presently there are also studies going on testing cholesterol-lowering drugs, so-called statins, like simvastatin etc. as a means of preventing or delaying Alzheimer´s. There seems to be a connection between the cholesterol level inside the brain cells and the deposition of toxic amyliod plaques which make the brain cells die.

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.


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


  • Areosa SA, McShane R, Sherriff F. Memantine for dementia. Cochrane Database Syst Rev 2004(4);CD003154.pub2. PMID 15495043
  • Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, Edwards S, Hardyman W, Raftery J, Crome P, Lendon C, Shaw H, Bentham P; AD2000 Collaborative Group. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105-15. PMID 15220031

External links

  • Alzheimer's Disease: Molecular Mechanisms
  • Journal of Alzheimer's Disease
  • Mental Health Matters: Alzheimer's Disease
  • Psych Forums: Alzheimer's Forum
  • Molecule that could stop protein clumping preceding Alzheimer
  • Alzheimer's Association

Last updated: 02-05-2005 00:12:17
Last updated: 05-02-2005 20:08:19