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 (dementia) 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.

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 usual first symptom is progressive memory loss. Alzheimer's disease can include behavorial changes, such as mental, disorientation, sudden periods of defiance, abusive behavior and violence, in people who have no previous history of such behavior. Thus, Alzheimer's disease presents a considerable problem in patient management. Average duration is approximately 7-10 years.

Diagnosis

The diagnosis is made clinically, but various tests (blood tests and medical imaging) are usually performed to rule out alternative diagnoses. No medical tests are available to conclusively diagnose Alzheimer's disease.

Initial suspicion of dementia may be strengthened by performing the mini mental state examination, excluding clinical depression, and various other tests. Reports from family members and/or carers are often important in assessing how severely the dementia is affecting the patient's life.

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.

Psychological testing generally focuses on memory, attention, abstract thinking, the ability to name objects, and other cognitive functions. Results of psychological tests do not easily distinguish between Alzheimer's 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".

Pathology

Microscopy

There are several changes found in the brain in AD (in order of appearance):

The deposition of an abnormal protein (amyloid beta) 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 degree of amyloid correllates with the severity of the disease, while the diffuse plaques may not cause any disease.
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 in various forms:
- 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)

General non-specific findings include:

Diffuse neuropathology, nerve cells, their processes, and synapses 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 pathways that produce the amyloid beta protein.

Neurochemistry

The neurotransmitters serotonin, acetylcholine, norepinephrine, and somatostatin are at decreased levels. Glutamate levels are usually elevated.

Disease mechanism

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 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 each have their advocates. "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 pathology 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. The "ba-ptist" theory is finding new supporters due to recent discoveries of impaired vascular and cerebrospinal fliud transport of beta amyloid out of the brain tissues, resulting in a greater risk for plaque formation. A third protein, alpha synuclein, which has already been shown to be important in Parkinson's disease, has also been demonstrated to be associated with the plaques in AD.

The presence of the plaques and tangles, however, does not always correlate with Alzheimer's; in other words, not all people who have the plaques and tangles manifest the disease. Recent research is focusing on the possibility that the plaques and tangles grow as a defense against another, as yet undiscovered, substance that causes the disease. Researchers are intrigued by the idea that the plaques and tangles might not be the problem, but rather a symptom of the problem. The plaques and neurofibrillary tangles might be doing an adequate job of "containing" the disease until they simply are overwhelmed.

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 epsilon 4 gene 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 susceptibility 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] (http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12920183), [2] (http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=14506299). Likewise, linkage has been found between zinc or copper and reactive oxidative stress contributing to Alzheimer's pathology [3] (http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T0V-483ST4V-1&_coverDate=04%2F30%2F2003&_alid=187240288&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4872&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=c4bdc9c6cb9a59aa2a676e79124856d3), and the amyloid precursor protein has been shown to alter expression in response to metal supplementation and chelation [4] (http://iospress.metapress.com/app/home/contribution.asp?wasp=nntr48wqwp5xnjarpv5m&referrer=parent&backto=issue,10,17;journal,1,29;linkingpublicationresults,1:105656,1), [5] (http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TCR-4B37JCB-2&_coverDate=01%2F15%2F2004&_alid=187240616&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=5177&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=f8157cd24891e6a93e263dae23299e96), [6] (http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0002-8614&date=2003&volume=51&issue=8&spage=1143). 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 onset. 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 (http://www.sciencedirect.com/science/article/B6T0F-4CB0G5C-B/1/f88958872d2aed83eebc6cbd76f9341f)). Mutations in the APP gene on chromosome 21 can also cause early onset disease.

Epidemiology

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 - 50% of persons aged 85 have symptoms of Alzheimer's and an even greater number have some of the pathological hallmarks of the disease without the characteristic symptoms. 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.

Prevention

Efforts to find a cure Alzheimer's after-the-fact have so far been disappointing. Age is the primary risk factor for Alzheimer's. The baby boom is approaching its golden years. Indeed, much of the concern about the solvency of the governmental social safety net is founded on estimates of the costs of caring for baby boomers, assuming that they develop Alzheimer's in the same proportions as earlier generations.

Some studies have indicated that non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and aspirin may delay the onset, and lower the ultimate risk, of Alzheimer´s disease. According to population studies, low but consistent daily NSAID used over a period of years such as ibuprofen (Advil, Motrin) seems to slow the progress of Alzheimer's. It seems that NSAIDs may affect the onset of the disease but is of little use for treating it once it has progressed to early or full-blown Alzheimer's.

It should be noted that some drugs such as acetaminophen, naproxen, and the 'COX-2 inhibitors' were found to have no demonstrated benefit (and some evidence of cardiac harm). This ineffectiveness and the increase in adverse cardiac events associated with these agents was reported in various studies in 2004 and highlights the key role of ibuprofen in the original studies showing moderated risk associated with NSAID use.

A study (Archives of Neurology 2004; 61:82-88) has reported that the combination of vitamins E and C might, over time, sharply reduce the risk of Alzheimer's disease. Marked reduction (up to 80% risk reduction) was achieved after a period of more than five years, but only if dosage was 400 i.u. per day of vitamin E plus 500 mg or more per day of vitamin C. Lesser amounts, such as those found in multivitamin pills, appeared markedly less effective. Large doses of vitamin E without vitamin C had only a mild effect, while large doses of vitamin C without vitamin E had no benefit. However in one small study, 2000 i.u. per day of vitamin E did appear to delay the progression of early Alzheimer’s by several months. Other evidence suggests that vitamin E becomes a damaging pro-oxidant if given in isolation (without other antioxidants). In isolation vitamin E is not recharged after absorbing a free radical by another antioxidant such as vitamin C or Alpha-Lipoic Acid. Some studies suggest that a ratio of at least 1000 mg of vitamin C to 400 i.u. of vitamin E is ideal. Recent studies suggest that the most common forms of E sold in supplements, the dl-alpha or d-alpha tocopherol form, are of little value, and that the gamma form of vitamin E, or a mixture of all the tocopherols and tocotrienols that collectively make up vitamin E from food, provide the most benefit. Vitamin E is markedly less effective unless taken with oil.

In a number of retrospective studies, regular physical exercise has appeared to be inversely related to the development of Alzheimer’s. The Alzheimer's risk of those exercising regularly was half that of the least active. This research is consistent with the observation that virtually all measures designed to promote cardiac fitness and reduce stroke risk also seem to reduce Alzheimer's risk. However in one study, dance appeared to be the only exercise effective in reducing risk. The presence of cardiovascular risk factors -- diabetes, hypertension, high cholesterol and smoking -- in middle age (ages 40 to 44) was found very strongly associated with late-life dementia, as reported in Neurology 2005;64:277-281.

Improved nutritional status of the B vitamin folic acid was found to reduce Alzheimer's incidence in a study of an order of nuns, many of whom volunteered to have their mental status assessed and donated their brains for study after death. The "Nun's study" also revealed nuns who, in life, showed little or no dementia, but upon autopsy were found to have extensive Alzheimer’s plaques. The unimpaired nuns’ brains were free of evidence of stroke, including micro-strokes. Nuns whose brains revealed both plaques and stroke damage, however, were severely impaired in functioning while alive. Thus avoidance of risk factors for stroke may be a key element in preventing final progression to being disabled by Alzheimer's dementia. The discovery of the co-founding role of stroke supports other research showing that quitting smoking, weight reduction, and avoidance of diabetes all reduce Alzheimer's risk. Diabetes greatly increases Alzheimer's risk, and one factor at work may be that the enzyme charged with removing excess insulin from the blood, the Insulin Degrading Enzyme (IDE), also has the responsibility for removing Beta-amyloid plaques from the brain. Perhaps the excess insulin involved in the pre-diabetic metabolic syndrome, as well as insulin used to treat existing diabetes, may demand more IDE than the body is able to produce, leaving none to remove accumulating beta amyloid plaques from the brain.

Some evidence suggests that Alzheimer's risk may also be reduced by inclusion of fish in the weekly diet.

The spice turmeric reduces Alzheimer's incidence in a mouse model and actually dissolves human senile plaques in the test tube. These factors suggest that inclusion of a bit of turmeric or curry spice in the diet may provide preventive value. Turmeric is a powerful antioxidant and a powerful anti-inflammatory.

Presently there are also studies going on testing cholesterol-lowering drugs, so-called statins, like lovastatin, 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 amyloid plaques which make the brain cells die. In addition to lowering cholesterol, the statins may have a beneficial role in reducing inflammation.

The recent observation that nicotine exposure leads to delayed onset of Alzheimer's has stimulated plenty of research into the relationship of nicotine intake and the disease. This is the focus of ongoing debate, and no consensus has been reached.

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).

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.

Treatment

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

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.

Examples include:

tacrine - no longer clinically-used
donepezil
galantamine
rivastigmine

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 moderately clinically efficacious. (Areosa et al., 2004)

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 placque, 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.

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 median age of the industrialized world's population is increasing gradually. For this reason, money spent informing the public of available effective prevention methods may yield disproportionate benefits.

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

Reference

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 (http://www.benbest.com/lifeext/Alzheimer.html)
Journal of Alzheimer's Disease (http://www.j-alz.com)
Mental Health Matters: Alzheimer's Disease (http://www.mental-health-matters.com/disorders/dis_details.php?disID=5)
Psych Forums: Alzheimer's Forum (http://www.psychforums.com/forums/viewforum.php?f=155)
Molecule that could stop protein clumping preceding Alzheimer (http://news.bbc.co.uk/2/hi/health/3959381.stm)
Alzheimer's Association (http://alz.org)ca:Malaltia d'Alzheimer

da:Alzheimers sygdom de:Morbus Alzheimer es:Enfermedad de Alzheimer eo:Alchajmero he:מחלת אלצהיימר ms:Alzheimer nl:Ziekte van Alzheimer ja:アルツハイマー型痴呆 pl:Choroba Alzheimera pt:Alzheimer tr:Alzheimer

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Categories: Eponymous diseases | Memory disorders | Neurology