Alzheimer's disease

Comparison of a normal aged brain (left) and the brain of a person with Alzheimer's (right). Characteristics that separate the two are pointed out.
ICD-10	G30
ICD-O:	{{{ICDO}}}
ICD-9	331.0
OMIM	{{{OMIM}}}
MedlinePlus	{{{MedlinePlus}}}
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DiseasesDB	{{{DiseasesDB}}}

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive deterioration together with declining activities of daily living and neuropsychiatric symptoms or behavioral changes. It is the most common cause of dementia, the progressive decline in cognitive function beyond what might be expected from normal aging.

The most striking early symptom of Alzheimer's disease is memory loss, which usually manifests as minor forgetfulness that becomes steadily more pronounced as the illness progresses. Older memories are relatively preserved in comparison to newer memories. As the disorder progresses, language and reasoning are also impaired.

There is no cure for Alzheimer's disease, but some individuals with the disease receive modest symptomatic benefit from current treatments, which do some to slow progression.

Although Alzheimer's disease may progress to the point that the sufferer cannot even remember his or her own spouse, child, or close friends, this does not mean the individual loses the human need for love or the ability to experience joy. The person can still appreciate beauty in nature or art, give and receive love, laugh, cry, and participate in his or her religious traditions, including rituals, prayer, worship, and meditation. In a way, the caregivers are provided with a difficult, but yet special opportunity to express love unconditionally, for they are providing a rich experience of love to a person who may no longer recognize their longtime history together.

History

German psychiatrist Emil Kraepelin first identified the symptoms of Alzheimer's disease, and German psychiatrist Alois Alzheimer is credited with providing the first thorough, unified description of the clinical symptoms and pathological features of the disease in 1906. Kraepelin, Alzheimer's mentor, named the disease after his protege in 1910 because Alzheimer had identified its neuropathological basis (Maurer 2000).

For most of the twentieth century, the diagnosis of Alzheimer's disease was reserved for younger individuals between the ages of 45 and 65 who developed symptoms of pre-senile dementia. Until the late 1970s, senile dementia was considered to be a normal part of the aging process. In the late 1970s and early 1980s, the name "Alzheimer's disease" began to be used both within and outside the medical profession for individuals age 65 and older with senile dementia, because the symptoms and brain pathology were identical. Eventually, the term was adopted formally for all individuals with the common symptom pattern and disease course in the psychiatric and neurological nomenclature (Ballenger 2006).

Clinical features and diagnosis

The first obvious symptom is usually short-term memory loss, which progresses from minor forgetfulness to a more pervasive loss of short-term memory. Eventually, sufferers lose decision-making and planning skills and do not recognize familiar people or objects. Disorientation, disinhibition, and Aphasia, or impaired speech, often accompany the loss of memory.

Alzheimer's disease may also include behavioral changes, such as violent outbursts or excessive passivity in people who have no previous history of such behavior. In the later stages, deterioration of musculature and mobility may render sufferers bedridden, unable to feed themselves, and incontinent. These symptoms will be seen unless a person with Alzheimer's disease dies from some external cause, such as heart attack or pneumonia, before they appear. Researchers have found that people with Alzheimer's disease live 4 to 15 years (on average 7 to 10 years) after reaching the final stages of the disease.

Although Alzheimer's disease is frequently diagnosed clinically, a definitive diagnosis is only possible by examining brain tissue for the characteristic plaques and tangles, generally done after death by autopsy. However, clinicians who specialize in memory disorders can diagnose Alzheimer's disease with an accuracy of up to 90 percent, according to the United States National Institutes of Health. The diagnosis is made primarily on the basis of history, clinical observation, and tests of short-term memory and intellectual functioning over a series of weeks or months, with various physical tests (blood tests and neuroimaging) being performed to rule out alternative diagnoses. Functional neuroimaging studies such as PET or SPECT scans can provide additional supportive evidence for the diagnosis.

Interviews with family members and/or caregivers are extremely important in the initial assessment, as people who suffer from the disease often minimize their symptoms and sometimes undergo evaluation at a time when their symptoms are less apparent. Quotidian fluctuations ("good days and bad days") are a fairly common characteristic. The interviews also provide important information on the affected individual's functional abilities, which are a key indicator of how far the disease has progressed.

Initial suspicion of dementia may be strengthened by performing the mini mental state examination, after excluding clinical depression. Psychological testing generally focuses on memory, attention, abstract thinking, the ability to name objects, visuospatial abilities, and other cognitive functions. Results of psychological tests may not readily distinguish Alzheimer's disease from other types of dementia, but they can be helpful in establishing the presence of and severity of dementia. They can also be useful in distinguishing true dementia from temporary (and more treatable) cognitive impairment due to depression or psychosis, sometimes called "pseudodementia."

Pathology

Microscopy

The two hallmarks of Alzheimer's disease are abnormal clumps called "amyloid plaques" and tangled bundles of fibers called "neurofibrillary tangles," found in the brain. Both plaques and tangles are composed of misplaced proteins. Scientists are not sure if plaques or tangles cause Alzheimer's disease, or are symptoms. There are also other changes found in the brains of people who suffer from the disease.

• Plaques are aggregates of amyloid beta, a protein fragment snipped from a larger protein called amyloid precursor protein, that are deposited outside nerve cells. Amyloid plaques are toxic to nerve cells.
• Tangles are twisted strands of protein filaments inside nerve cells in the brain, formed from aggregation of tau protein, which normally stabilizes microtubules. In Alzheimer's disease, an abnormally phosphorylated form of tau protein accumulates as tangles of paired helical filaments that eventually accumulate in such amounts that they burst the nerve cell, killing it. Tau accumulates in various forms:
  • As masses of filaments called neurofibrillary tangles inside nerve cell bodies
  • Inside nerve cell processes in the brain termed neuropil threads
  • Inside dystrophic neurites or plaque neurites, which are nerve cell processes that surround amyloid plaques.
• Diffuse atrophy and loss of neurons, neuronal processes, and synapses in the cerebral cortex and certain subcortical regions. This wasting away results in gross atrophy of the affected regions and enlargement of the lateral ventricles.

Disease mechanism

Scientists still do not fully understand the mechanism for Alzheimer's disease. One theory is that Alzheimer's begins as a deficiency in the production of acetylcholine, a vital neurotransmitter. Much therapeutic research during the twentieth century was based on this hypothesis, including restoration of the function of the cholinergic neurons. As a result, all of the first-generation anti-Alzheimer's drugs work to preserve acetylcholine by inhibiting acetylcholinesterases (enzymes that break down acetylcholine). These medications, though sometimes beneficial, have not led to a cure. They only treat symptoms and have neither halted nor reversed the disease.

Genetics of Alzheimer's disease

Unfortunately, the most obviously genetic cases are also the rarest. Most cases identified are "sporadic" with no clear family history. Head injury has been consistently shown to be linked to later development of Alzheimer's disease in epidemiological studies. In addition, small cranial diameter has been shown to correlate well with early onset of recognizable symptoms.

Genetic inheritence, or familial Alzheimer's disease, accounted for about three percent of the estimated 4 million Alzheimer's disease cases in the United States in 2006. Inheritance of the epsilon 4 allele of the ApoE gene is regarded as a risk factor for development of disease. Even so, large-scale genetic association studies raise the possibility that even inheriting the allele does not indicate susceptibility so much as how early one is likely to develop Alzheimer's. Some genetic experts speculate that there are other risk and protective factor genes that may influence the development of late onset Alzheimer's disease. 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. These hypotheses include the amyloid beta precursor protein [1], the beta secretase enzymes [2], insulin-degrading enzyme [3], endothelin-converting enzymes [4], and inflammatory 5-lipoxygenase gene [5].

Genetic linkage

Mutations in three genes are known to cause Alzheimer's disease: APP, PSEN1, and PSEN2, which are located on chromosomes 21, 14, and 1, repsectively. Other linkages have been proposed but not yet confirmed. Scientists have also identified some genes that predispose people to Alzheimer's disease, such as ApoE4 on chromosome 19.

Epidemiology and prevention

Alzheimer's disease is the most common type of dementia in the elderly and affects almost half of all patients with dementia. Advancing age is the primary risk factor for Alzheimer's. Every five years after the age of 65, the probability of having the disease doubles. Among people age 65, two percent to three percent show signs of the disease. By age 85, 25 to 50 percent of people have symptoms of Alzheimer's and an even greater number have some of the pathological hallmarks without the characteristic symptoms. The proportion of people 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. Famous Alzheimer's disease sufferers have included President Ronald Reagan, Ralph Waldo Emerson, and Rita Hayworth.

The evidence relating certain behaviors, dietary intakes, environmental exposures, and diseases to the likelihood of developing Alzhemier's varies in quality and its acceptance by the medical community. Interventions that reduce the risk of developing disease in the first place may not alter disease progression after symptoms become apparent. Due to their observational design, studies examining disease risk factors could potentially confound variables. Several large, randomized controlled trials have called into question preventative mesasures based on cross-sectional studies; in particular, the Women's Health Initiative—a 15-year research program launched in 1991 to address the most common causes of death, disability, and poor quality of life in postmenopausal women. Some proposed preventative measures are even based on studies conducted solely in animals.

Risk

Scientists have proven that a variety of risk factors increase susceptibility to Alzheimer's disease, but there are ways to reduce risk.

Whether there is a connection between hormone therapy and Alzheimer's disease is controversial. Data from the Women's Health Initiative showed that hormone therapy increased risk of dementia in postmenopausal women, but other studies have found the opposite (Shumaker 2003, Henderson 2006, Casadesus 2006).

Risk factors

• Advancing age
• ApoE epsilon 4 genotype
• Head injury
• Poor cardiovascular health (including tobacco smoking), diabetes, hypertension, high cholesterol)
• Exposure to heavy metals, particularly aluminum, is a proposed but not widely accepted risk factor, according to the U. S. National Institutes of Health.

Risk reducers

• Intellectual stimulation (i.e., playing chess or doing crossword puzzles)(Verghese 2003)
• Regular physical exercise (Larson 2006)
• A generally healthy diet low in saturated fat supplemented in particular with:
  • Choline the acetylcholine precursor
  • B vitamins
  • Omega-3 fatty acids, especially DHA (Lim 2006; Morris 2005)
  • High doses of the antioxidant Vitamin E (in combination with vitamin C) seem to reduce Alzheimer's risk but are not currently a recommended preventive measure because of observed increases in overall mortality (Boothby 2005)
• Cholesterol-lowering drugs (statins) reduce Alzheimer's risk in observational studies but so far not in randomized controlled trials
• Regular use of non-steroidal anti-inflammatory drugs like ibuprofen and aspirin reduces the chance of dementia (Szekely 2004)

Treatment

There is presently no cure for Alzheimer's disease. None of the currently approved drugs is known to stop the underlying degeneration of brain cells, but some drugs may temporarily delay memory decline for some people with the disease. The emotional and behavioral symptoms of the disease can also be treated with some drugs approved to treat other illnesses.

Acetylcholinesterase inhibitors

Acetylcholine (ACh) is a neurotransmitter, a chemical that conducts electrical signals between a neuron and another cell. ACh is naturally broken down in the brain by the enzyme Acetylcholinesterase (AChE). Cholinergic neurons, which use ACh, are important for modulating learning and memory formation. Alzheimer's disease is associated with a loss of cholinergic neurons. Therefore, researchers developed drugs, called AChE-inhibitors, that reduce the rate at which ACh is broken down, increasing the levels of ACh in the brain and thereby enhancing cholinergic activity in the affected brain regions. Acetylcholinesterase inhibitors seem to moderate symptoms modestly, but they do not prevent disease progression.

Examples include:

• tacrine - no longer used clinically
• donepezil - (marketed as Aricept)
• galantamine - (marketed as Razadyne, formerly Reminyl)
• rivastigmine - (marketed as Exelon)

A controversy erupted in 2004 over the effectiveness of cholinesterase inhibitors after a study in the respected medical journal The Lancet suggested they are ineffective (Courtney 2004). Pharmaceutical companies and several independent clinicians disputed the findings, saying the study was poorly designed.

N-methyl D-aspartate excitotoxic amino acid (NMDA) antagonists

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 (it blocks toxic effects associated with excess gluatmate and regulates glutamate activation), and has been shown to have modest benefits (Areosa 2004).

Potential Treatments

Vaccine

There are ongoing tests of an Alzheimer's disease vaccine. The vaccine is based on the idea that if the immune system could be trained to recognize and attack beta-amyloid, the immune system might reverse deposition of amyloid and thus stop the disease. Initial results in animals were promising, but researchers had to stop a human trial in 2002 after 18 participants developed potentially fatal brain inflammation called meningoencephalitis. Follow-up with some participants in the halted trials showed that the vaccine had cleared plaques from the brains of people with the disease (Janus 2003).

In 2006, a new vaccine developed by Japanese researchers showed promising results. Amyloid deposits were reduced between 15.5 percent and 38.5 percent in mice, with no adverse side effects (Okura 2006). In 2006, researchers began tests in monkeys, expecting to follow with human trials about three years later if successful.

Ginkgo biloba

Some studies have suggested that ginkgo biloba shows promise for alleviating the effects of Alzheimer's (Ahlemeyer 2003, Le Bars 1997, Schulz 2003, Sierpina 2003); however, further research is required, as consumption of ginkgo biloba can have undesirable side-effects, especially for those with blood circulation disorders and those taking certain medications (Witkam 2004). Ginkgo should not be used by anyone taking anti-coagulants, pregnant women, or anyone using the anti-depressant drugs known as monoamine oxidase inhibitors (MAOI).

References

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• Ahlemeyer, B., and J. Krieglstein. 2003. Neuroprotective effects of Ginkgo biloba extract. Cellular and Molecular Life Sciences 60(9):1779-92.
• Areosa, S. A., F. Sherriff, and R. McShane. 2005. Memantine for dementia. Cochrane database of systematic reviews (3):CD003154.
• Ballenger, J. F. 2006. Progress in the history of Alzheimer's disease: The importance of context. Journal of Alzheimer's Disease 9:5-13.
• Boothby, L. A., and P. L. Doering. 2005. Vitamin C and vitamin E for Alzheimer's disease. Annals of pharmacotherapy 39(12):2073-80.
• Casadesus, G., et al. 2006. The estrogen myth: potential use of gonadotropin-releasing hormone agonists for the treatment of Alzheimer's disease. Drugs in R&D 7(3):187-93.
• Courtney, C., et al. 2004. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): Randomised double-blind trial. Lancet 363(9427):2105-15.
• Henderson, V. W. 2006. Estrogen-containing hormone therapy and Alzheimer's disease risk: understanding discrepant inferences from observational and experimental research. Neuroscience 138(3):1031-9.
• Janus, C. 2003. Vaccines for Alzheimer's disease: how close are we? CNS Drugs 17(7):457-74.
• Larson, E. B., et al. 2006. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Annals of internal medicine 144(2):73-81.
• Le Bars, P. L., et al. 1997. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. Journal of the American Medical Association 278:1327-1332.
• Lim W. S., J. K. Gammack, J. Van Niekerk, and A. D. Dangour. 2006. Omega 3 fatty acid for the prevention of dementia. Cochrane database of systematic reviews (1):CD005379.
• Maurer, K., et al. 2000. Augusta D.: The History of Alois Alzheimer's First Case, Concepts of Alzheimer Disease: Biological, Clinical and Cultural Perspectives P. J. Whitehouse, K. Maurer, and J. F. Ballenger. Baltimore: Johns Hopkins University Press.
• Morris, M. C., D. A. Evans , C. C. Tangney, J. L. Bienias, and R. S. Wilson. 2005. Fish consumption and cognitive decline with age in a large community study. Archives of neurology 62(12):1849-53.
• Okura, Y. 2006. Nonviral AB DNA vaccine therapy against Alzheimer’s disease: Long-term effects and safety. Proceedings of the National Academy of Sciences 103(25):9619-24.
• Schulz, V. 2003. Ginkgo extract or cholinesterase inhibitors in patients with dementia: what clinical trials and guidelines fail to consider. Phytomedicine 4:74-9.
• Shumaker S., et al. 2003. Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women: The Women's Health Initiative Memory Study: A Randomized Controlled Trial. Journal of the American Medical Association 289:2651-2662.
• Sierpina, V. S., B. Wollschlaeger, and M. Blumenthal. 2003. Ginkgo biloba. American Family Physician 68(5):923-6.
• Szekely, C. A., et al. 2004. Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer's disease: a systematic review. Neuroepidemiology 23(4):159-69.
• Verghese, J., et al. 2003. Leisure activities and the risk of dementia in the elderly. New England Journal of Medicine 348(25):2508-16.
• Weber, M. M. 1997. Aloys Alzheimer, a coworker of Emil Kraepelin. Journal of psychiatric research 31(6):635-43.
• Witkam, L., and I. Ramzan. 2004. Ginkgo biloba in the treatment of Alzheimer's disease: A miracle cure? [6].