Alzheimer's disease

Alzheimer's disease

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ICD-10	G30
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ICD-9	331.0
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DiseasesDB	{{{DiseasesDB}}}

Dementia in Alzheimer's disease

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ICD-10	F00
ICD-O:	{{{ICDO}}}
ICD-9	290.1
OMIM	{{{OMIM}}}
MedlinePlus	{{{MedlinePlus}}}
eMedicine	{{{eMedicineSubj}}}/{{{eMedicineTopic}}}
DiseasesDB	{{{DiseasesDB}}}

"Alzheimer" redirects here.

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 most striking early symptom is memory loss (amnesia), which usually manifests as minor forgetfulness that becomes steadily more pronounced with illness progression, with relative preservation of older memories. As the disorder progresses, cognitive (intellectual) impairment extends to the domains of language (aphasia), skilled movements (apraxia), recognition (agnosia), and those functions (such as decision-making and planning) closely related to the frontal and temporal lobes of the brain as they become disconnected from the limbic system, reflecting extension of the underlying pathological process.

History

The symptoms of the disease as a distinct entity were first identified by Emil Kraepelin, and the characteristic neuropathology was first observed by Alois Alzheimer, a German psychiatrist, 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.

For most of the twentieth century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45-65 who developed symptoms of presenile dementia, which was considered to be a more or less normal outcome of the aging process. In the 1970s and early 1980s, because the symptoms and brain pathology were identical, the name "Alzheimer's disease" began to be used, within and outside the medical profession, equally for individuals age 65 and older with senile dementia, and was eventually adopted formally for all individuals with the common symptom pattern and disease course in the psychiatric and neurological nomenclature.

Clinical features

The usual first symptom noticed is short term memory loss which progresses from seemingly simple and often fluctuating forgetfulness (with which the disease should not be confused) to a more pervasive loss of short-term memory, then of familiar and well-known skills or objects or persons. Aphasia, disorientation and disinhibition often accompany the loss of memory. Alzheimer's disease may also include behavioral changes, such as outbursts of violence or excessive passivity in people who have no previous history of such behavior. In the later stages, deterioration of musculature and mobility, leading to bedfastness, inability to feed oneself, and incontinence, will be seen if death from some external cause (e.g. heart attack or pneumonia) does not intervene. Average duration of the disease is approximately 7-10 years, although cases are known where reaching the final stage occurs within 4-5 years, or up to 15 years.

Diagnosis

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. No medical tests other than brain biopsy are available to diagnose Alzheimer's disease conclusively pre-mortem. Thus, Alzheimer's disease is primarily a clinical diagnosis based on the presence of characteristic neurological features and the absence of alternative diagnoses. While expert clinicians who specialize in memory disorders can now diagnose AD with an accuracy of 85-90%, a definitive diagnosis of Alzheimer's disease must await microscopic examination of brain tissue, generally at autopsy.

Interviews with family members and/or caregivers are extremely important in the initial assessment, as the sufferer him/herself may tend to minimize his symptomatology or may undergo evaluation at a time when his/her symptoms are less apparent, as quotidian fluctuations ("good days and bad days") are a fairly common feature. Such interviews also provide important information on the affected individual's functional abilities, which are a key indicator of the significance of the symptoms and the stage of dementia.

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 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, which has sometimes been termed "pseudodementia".

Pathology

Microscopy

There are several characteristic neuropathological changes found in the brain in AD:

• 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. Recently evidence has begun to accumulate implicating simpler, soluble forms of amyloid (oligomers) in the pathological process, and the presence of plaque amyloid does not correlate well with the degree of dementia. Amyloid also accumulates in the walls of small blood vessels in the brain. This is termed amyloid angiopathy (also called congophilic angiopathy).
• Accumulation of abnormal protein filaments inside nerve cells in the brain, formed from aggregation of tau protein, which normally stabilizes 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 dystrophic neurites or plaque neurites.
• Diffuse atrophy and loss of neurons, neuronal processes and synapses in the cerebral cortex and certain subcortical regions. This results in gross atrophy of the affected regions and enlargement of the lateral ventricles.

Disease mechanism

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 function of the cholinergic neurons. All of the first-generation anti-Alzheimer's drugs are based on this hypothesis and work to preserve acetylcholine by inhibiting acetylcholinesterases (enzymes that break down acetylcholine). These medications, though sometimes beneficial, have not led to a cure. In all cases, they have served to only treat symptoms of the disease and have neither halted nor reversed it.

Genetics of AD

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 AD in epidemiological studies. In addition, small cranial diameter has been shown to correlate well with early onset of recognizable symptoms. Inheritance of the epsilon 4 allele of the ApoE 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. There is speculation among genetic experts that there are other risk and protective factor genes that may influence the development of late onset Alzheimer's disease (LOAD). 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 [2], the beta secretase enzymes [3], insulin-degrading enzyme [4], endothelin-converting enzymes [5], and inflammatory 5-lipoxygenase gene [6].

Genetic linkage

Alzheimer's disease is linked to the 1st, 14th, and 21st chromosomes, but other linkages are controversial and not, as yet, confirmed. While some genes predisposing to AD have been identified , such as ApoE4 on chromosome 19, sporadic AD also involves other risk and protective genes still awaiting confirmation.

Epidemiology and Prevention

Alzheimer's disease is the most frequent type of dementia in the elderly and affects almost half of all patients with dementia. Correspondingly, advancing age is the primary risk factor for Alzheimer's. Among people aged 65, 2-3% show signs of the disease, while 25 - 50% of people 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. Every five years after the age of 65, the probability of having the disease doubles. 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. It is important to understand that 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 are often at risk from confounding variables. Several recent large, randomized controlled trials—in particular the Women's Health Initiative—have called into question preventative mesasures based on cross-sectional studies. Some proposed prevenative measures are even based on studies conducted solely in animals.

Risk reducers

• Intellectual stimulation (i.e., playing chess or doing the crossword)
• Regular physical exercise
• A generally healthy diet low in saturated fat supplemented in particular with:
  • Choline the acteylcholine precursor
  • B vitamins
  • Omega-3 fatty acids, especially DHA
  • 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 PMID 14732624
• Cholesterol-lowering drugs (statins) reduce Alzheimer's risk in observational studies but so far not in randomized controlled trials
• Hormone replacement therapy is no longer thought to prevent dementia based on data from the Women's Health Initiative
• Regular use of non-steroidal anti-inflammatory drugs like ibuprofen and aspirin reduces the chance of dementia but the risks appear to outweigh the drugs' benefit as a method of primary prevention

Risk factors

• Advancing age
• ApoE epsilon 4 genotype
• Head injury
• Poor cardiovascular health (including smoking, diabetes, hypertension, high cholesterol)
• Exposure to heavy metals, particularly aluminum, is a proposed but not widely-accepted risk factor [7]

Treatment

There is currently no cure for Alzheimer's disease, although there are drugs which offer symptomatic benefit, specifically with respect to short-term memory impairment.

Acetylcholinesterase inhibitors

Acetylcholinesterase (AChE) inhibition was thought to be important because there is a reduction in activity of the cholinergic neurons. 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 - (marketed as Aricept)
• galantamine - (marketed as Razadyne, formerly Reminyl)
• rivastigmine - (marketed as Exelon)

Recently, a controversy has erupted about cholinesterase inhibitors because a study in the respected medical journal The Lancet has suggested they are ineffective. The pharmaceutical companies, but also many independent clinicians, dispute the findings of the study, based on methodologic grounds.

NMDA antagonists

Recent 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, and has been shown to be moderately clinically efficacious.

Potential Treatments

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, 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 possible benefit in the form of slower progression of the disease.

In 2006, a new vaccine by researchers in Japan has promising results, reducing amyloid deposits between 15.5 and 38.5 percent, with no adverse side effects. [8] Tests are underway in monkeys and if successful human trials would be about three years away.

Ginkgo biloba

Some studies, summarised in a 2004 conference paper,[9] have suggested that ginkgo biloba shows promise for alleviating the effects of Alzheimer's; however, the paper concedes that 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. Currently a major controlled clinical trial is underway to determine if Gingko has any effect. 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).

See also

• Familial Alzheimer disease
• Dementia with Lewy bodies
• Frontotemporal lobar degeneration
• Corticobasal degeneration
• Memory and aging
• Memory loss
• Memory

External links

• Alzheimer's Association - The major Alzheimer's support and advocacy group in the United States provides excellent information on topics ranging from basics of diagnosis and caregiving to the disease's legal implications and ways to talk to children about the disease
• Alzheimer's Research Forum - A website intended to provide information to and foster collaboration among scientists and physicians conducting research on Alzheimer's. Features debates between and article annotations by many top Alzheimer's researchers
• National Institute on Aging - Substantial website by a division of the U.S. National Institutes of Health with links to information about ongoing clinical studies
• Journal of Alzheimer's Disease - Subscription required for full text
• eMedicine - Well-organized article on Alzheimer's

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