Alzheimer's disease

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Alzheimer's disease Classification and external resources
Histopathologic image of senile plaques seen in the cerebral cortex in a patient with Alzheimer disease of presenile onset. Silver impregnation.
ICD-10	G30., F00.
ICD-9	331.0, 290.1
OMIM	104300
DiseasesDB	490
MedlinePlus	000760
eMedicine	neuro/13
MeSH	D000544

Alzheimer's disease (AD), also called Alzheimer disease or simply Alzheimer's, is the the most common cause of dementia. A Delphi study formed an expert consensus estimate that 24 million people worldwide had dementia in 2006, and projected a doubling every twenty years.^[1] Alzheimer's is a degenerative and terminal disease for which there is no known cure. In its most common form, it afflicts individuals over 65 years old, although a less prevalent early-onset form also exists. The disease can develop many years before it is eventually diagnosed. In its early stages, memory loss, shown as a difficulty to remember recently learned facts, is the most common symptom, although it is often thought to be caused by aging or stress by the sufferer at first.^[2] Later symptoms include confusion, anger, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as his or her senses decline.^[2][3] The sufferer gradually loses minor and major bodily functions leading to death.^[4] Each individual experiences the symptoms of AD in unique ways.^[5] The duration of the disease is between 5 and 20 years.^[6][7]

The symptoms of Alzheimer's disease are generally reported to a physician when memory loss becomes apparent. If AD is suspected as the cause, the physician or healthcare specialist will confirm the diagnosis with behavioral assessments and cognitive tests, often followed by a brain scan, if it is available.^[8]

The cause and progression of Alzheimer's disease is not well understood. Current research indicates that the disease is associated with plaques and tangles in the brain.^[9] No treatment has been found to stop or reverse the disease, and it is not known whether current treatments slow the progression, or simply manage the symptoms. Many preventive measures have been suggested for Alzheimer's disease, but their value is unproven in reducing the course and severity of the disease. Mental stimulation, exercise and a balanced diet are often recommended, both as a possible prevention and as a sensible way of managing the disease.^[10]

Due to the incurable and degenerative nature of the disease, management of Alzheimer's patient is essential. The role of the main caregiver is often taken by the spouse or a close relative.^[11] Caregivers may themselves suffer from stress, over-work, depression, and being physically hit or struck.^[12]

Contents 1 Characteristics 1.1 Predementia 1.2 Early dementia 1.3 Moderate dementia 1.4 Advanced 2 Causes 3 Pathophysiology 3.1 Neuropathology 3.2 Biochemical characteristics 3.3 Disease mechanism 3.4 Genetic 4 Diagnosis 4.1 Diagnostic criteria 4.2 Diagnostic tools 5 Prevention 6 Management 6.1 Pharmaceutical 6.2 Psychosocial intervention 6.3 Caregiving 6.4 Clinical research 7 Prognosis 8 Epidemiology 9 History 10 Society and culture 10.1 Social costs 10.2 Caregiving burden 10.3 Notable cases 11 References 12 Further reading

[edit] Characteristics

The disease course is divided into four stages, with a different pattern of cognitive and functional impairment expressed during each stage.

[edit] Predementia

Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria of diagnosis.^[13] These early symptoms can have an effect on daily living activities of patients . Recent studies show impairments in the most complex activities of AD patients.^[14] The most noticeable deficit is memory loss , shown as a difficulty to remember recently learned facts and an inability to acquire new information.^[15][16] In addition, subtle executive function problems or semantic memory impairments can also occur.^[17][18] Apathy can be observed at this stage, and is the most common and persistent neuropsychiatric symptom throughout the course of the disease.^[19][20][21] This stage of the disease has also been termed mild cognitive impairment,^[22] but there is still a debate on whether this term corresponds to a different diagnostic entity by itself or just a first step of the disease.^[23]

[edit] Early dementia

In most people with the disease the increasing impairments in learning and memory will lead to diagnosis, while in a small proportion of them language, executive or visuoconstructional difficulties will be more salient.^[24] Nevertheless, memory problems do not affect all memory subcapacities equally. Older memories of the patient's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat) are affected to a much lesser degree than the capacities needed to learn new facts or make new memories.^[25][26] Language problems are mainly characterised by a shrinking vocabulary and a decreased word fluency which leads to a general impoverishment of oral and written language. The Alzheimer's patient is usually capable of adequately communicating basic ideas.^[27][28][29] While performing fine motor tasks such as writing, drawing or dressing, certain visoconstructional difficulties, or apraxia, may be present, which may appear as clumsiness.^[30] As the disease progresses to the middle stage, patients might still be able to live and perform tasks independently for most of the time, but may need assistance or supervision with the most complicated activities.^[24]

[edit] Moderate dementia

In the early stage, people with Alzheimer's can usually care for themselves. At the moderate stage, progressive deterioration seriously hinders the possibility of independence.^[24]

Speech difficulties become clearly noticeable: the person makes frequent paraphasias due to difficulties in finding words, and content is poor. Reading and writing are also progressively forgotten.^[27][31] As time passes, complex motor sequences become less coordinated, costing the patient most of their daily-living abilities.^[32] Memory problems worsen, and the person may not recognize close relatives.^[33] Long-term memory, which was previously left intact, is now also impaired.^[34] At this stage, behavior changes are the norm. Common neuropsychiatric manifestations in this stage are irritability and labile affect, leading to crying or outbursts of unpremeditated aggression and physical violence, even in patients whose life-long behavior has been peaceful. Approximately 30% of the patients also develop illusionary misidentifications and other delusional symptoms.^[19][35] Often urinary incontinence develops.^[36] Because of the communication deficit along with delusions, patients often resist when caregivers attempt to provide care.^[37] It is important to prevent escalation of resistiveness to care into combativeness when patient might strike out. All these symptoms create stress for relatives and caretakers, increasing the likelihood of moving the patient from home care to other long-term care facilities.^[24][38]

[edit] Advanced

In the last stage of Alzheimer's disease the subject with the disease is fully dependent. Language is reduced to simple phrases or even single words before being lost altogether.^[27] Nevertheless many patients can receive and return emotional signals long after the loss of verbal language.^[39] Although aggressiveness can still be present, extreme apathy and exhaustion are much more common.^[24] Patients will ultimately not be able to perform even the most simple tasks independently. Finally, deterioration of muscle and mobility will develop, leading the patient to become bedridden,^[40] and to lose the ability to feed oneself,^[41] if death from some external cause, such as infection due to pressure ulcers or pneumonia, does not occur first.^[42][43]

[edit] Causes

Three major competing hypotheses exist to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is known as the cholinergic hypothesis and suggests that AD is due to reduced biosynthesis of the neurotransmitter acetylcholine. However, the medications that treat acetylcholine deficiency only affect symptoms of the disease and neither halt nor reverse it.^[44] The cholinergic hypothesis has not maintained widespread support in the face of this evidence, although cholinergic effects have been proposed to initiate large-scale aggregation,^[45] leading to generalised neuroinflammation.^[46]

In 1991 the amyloid hypothesis was proposed,^[47] while research after 2000 is also centered on tau proteins. The two positions differ with one stating that the tau protein abnormalities initiate the disease cascade, while the other states that amyloid beta (Aβ) deposits are the causative factor in the disease.^[48]

The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques does not correlate well with neuron loss.^[49] In this model, hyperphosphorylated tau begins to pair with other threads of tau and they become tangled up together inside nerve cell bodies in masses known as neurofibrillary tangles.^[50] When this happens, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in communication between neurons and later in the death of the cells.^[51]

A majority of researchers support the alternative hypothesis that Aβ is the primary causative agent.^[48] The amyloid hypothesis is compelling because the gene for the amyloid beta precursor (APP) is located on chromosome 21, and patients with trisomy 21 (Down Syndrome) who thus have an extra gene copy almost universally exhibit AD-like disorders by 40 years of age.^[52][53] It should be noted further that ApoE4, the major genetic risk factor for AD, leads to excess amyloid build-up in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD.^[54] It is known that some types of inherited AD involve only mutations in the APP gene (although this is not the most common type—others involve genes for "pre-senilin" proteins which process APP and may also have still-unknown functions).^[55] However, another strong support for the amyloid hypothesis, which looks at Aβ as the common initiating factor for Alzheimer's disease, is that transgenic mice solely expressing a mutant human APP gene develop fibrillar amyloid plaques.^[56]

[edit] Pathophysiology

Main article: Biochemistry of Alzheimer's disease

[edit] Neuropathology

At a macroscopic level, AD is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.^[46]

Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains.^[9] Plaques are dense, mostly insoluble deposits of amyloid-beta protein and cellular material outside and around neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. Though many older people develop some plaques and tangles, the brains of AD patients have them to a much greater extent and in different brain locations.^[57]

[edit] Biochemical characteristics

Alzheimer's disease has been identified as a protein misfolding disease, or proteopathy, due to the accumulation of abnormally folded A-beta and tau proteins in the brains of AD patients.^[58] Plaques are made of a small peptide (39 to 43 amino acid residues) called beta-amyloid (also A-beta or Aβ), a protein fragment snipped from a larger protein called amyloid precursor protein (APP). APP is a transmembrane protein; which means that it sticks through the neuron's membrane; and is believed to help neurons grow, survive and repair themselves after injury.^[59][60] In AD, something causes APP to be divided by enzymes through a mechanism called proteolysis.^[61] One of these fragments is beta-amyloid. Beta-amyloid fragments (amyloid fibrils) outside the cell form clumps that deposit outside neurons in dense formations known as senile plaques.^[62][9]

AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Healthy neurons have an internal support structure, or cytoskeleton, partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell down to the ends of the axon and back. A special kind of protein, tau, makes the microtubules stable through a process named phosphorylation and is therefore called a microtubule-associated protein.^[63] In AD, tau is changed chemically, becoming hyperphosphorylated.

[edit] Disease mechanism

If damage from Aβ is the primary initiating cause of AD, the exact mechanism has not been elucidated. The traditional formulation of the amyloid hypothesis points to the cytotoxicity of mature aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis and thus inducing apoptosis.^[64] It is also known that Aβ selectively builds up in the mitochondria of samples from the brains of humans with AD, and in mitochondria from transgenic mice with APP genes, and in both cases inhibits certain mitochondrial enzyme functions, and a similar decrease in glucose utilization in neurons to the one which is a known characteristic of AD. This process may also lead to the formation of damaging reactive oxygen species, calcium influx, and apoptosis. Mechanisms which involve direct damage from Aβ before it forms fibrils and plaques also address the issue that neuronal damage is not correlated as well with plaques, since in this model it is not the plaques themselves which cause the major damage, but rather the precursor Aβ protein directly, via another mechanism.^[65]

Various inflammatory processes and inflammatory cytokines may also have a role in the pathology of Alzheimer's disease. However, these are general markers of tissue damage in any disease, and may also be either secondary causes of tissue damage in AD, or else bystander "marker" effects.^[66]

[edit] Genetic

While earlier disease familial onset is mainly explained by three genes, later age of disease onset representing most cases of AD has yet to be explained by a purely genetic model. In the second case the APOE gene is the strongest genetic risk factor discovered but it is far from explaining all occurrences of the disease.^[67]

Only 10% of AD cases occurring before 60 years of age are due to autosomal dominant (familial) mutations, which represents less than 0,01 of all patients.^[67][68] These mutations have been discovered in three different genes: amyloid precursor protein or APP,^[69] and presenilins 1,^[70] and 2^[71]. Most mutations in the APP and presenilin genes increase the production of a small protein called Abeta42, which is the main component of senile plaques in brains of AD patients.^[72]

Most cases of Alzheimer's disease do not exhibit familial inheritance. In this case genes may act as risk factors. The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (ApoE). This gene is regarded as a risk factor for development of up to 50% of late-onset sporadic Alzheimer's.^[73] Genetic experts agree that there are other risk and protective factor genes that influence the development of late onset Alzheimer's disease.^[67] Over 400 genes have been tested for association with late-onset sporadic AD.^[74]

[edit] Diagnosis

Dementia is by definition a clinical condition but not an exact diagnosis. Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions.^[75][76] Advanced medical imaging with CT or MRI, and with SPECT or PET are generally used to help to diagnose the subtype of dementia and exclude other cerebral pathology.^[77] Neuropsychological evaluation including memory testing and assessment of intellectual functioning can further characterize the dementia.^[78] Medical organizations have created diagnostic criteria to ease and standardize the process for practicing physicians. Sometimes the diagnosis can be confirmed or made at postmortem when brain material is available and can be examined histologically and histochemically.^[79]

[edit] Diagnostic criteria

The diagnostic criteria for Alzheimer of the NINCDS-ADRDA (NINCDS and the ADRDA) are among the most used.^[80] These criteria require that the presence of cognitive impairment and a suspected dementia syndrome be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD while they need histopathologic confirmation (microscopic examination of brain tissue) for the definitive diagnosis. They have shown good reliability and validity.^[81] They specify as well eight cognitive domains that may be impaired in AD (i.e., memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional abilities). Similar to the NINCDS-ADRDA Alzheimer's Criteria are the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria published by the American Psychiatric Association.^[82][83]

[edit] Diagnostic tools

Neuropsychological screening tests as the Mini mental state examination (MMSE) are widely used to evaluate the cognitive impairments needed for diagnosis, but more comprehensive batteries are necessary for high reliability by this method, especially in the earliest stages of the disease.^[84][85] Neurological examination in early AD will usually be normal, independent of cognitive impairment; but for many of the other dementing disorders is key for diagnosis. Therefore, neurological examination is crucial in the differential diagnosis of Alzheimer and other diseases.^[78] In addition, interviews with family members are also utilised in the assessment of the disease. Caregivers can supply important information on the daily living abilities, as well as on the decrease over time of the patient's mental function.^[86] This is especially important since a patient with AD is commonly unaware of his or her own deficits (anosognosia).^[87] Many times families also have difficulties in the detection of initial dementia symptoms and in adequately communicating them to a physician.^[88] Finally, supplemental testing provides extra information on some features of the disease or are used to rule out other diagnoses. Examples are blood tests, which can identify other causes for dementia different than AD,^[78] which rarely may even be reversible;^[89] or psychological tests for depression, as depression can both co-occur with AD or, on the contrary, be at the origin of the patient's cognitive impairment.^[90][91]

Increasingly, the functional neuroimaging modalities of single photon emission computed tomography (SPECT) and positron emission tomography (PET) are being used to diagnose Alzheimer's, as they have shown similar ability to diagnose Alzheimer's disease as methods involving mental status examination.^[92] Furthermore, the ability of SPECT to differentiate Alzheimer's disease from other possible causes, in a patient already known to be suffering from dementia, appears to be superior to attempts to differentiate the cause of dementia cause by mental testing and history.^[93] A new technique known as "PiB PET" has been developed for directly and clearly imaging beta-amyloid deposits in vivo using a contrasting tracer that binds selectively to the Abeta deposits.^[94][95][96] Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau proteins.^[97] Both advances (neuroimaging and cerebrospinal fluid analysis) have led to the proposal of new diagnostic criteria.^[80][78]

[edit] Prevention

At present contradictory results in global studies, incapacity to prove causal relationships between risk factors and the disease, and possible secondary effects indicate a lack of specific measures to prevent or delay the onset of AD.^[98] Different epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing AD. Only further research, including clinical trials, will reveal whether, in fact, these factors can help to prevent AD.^[99]

The components of a Mediterranean diet, which include fruit and vegetables, bread, wheat and other cereals, olive oil, fish, and red wine, may all individually or together reduce the risk and course of Alzheimer's disease. There is evidence that frequent and moderate consumption of alcohol (beer, wine or distilled spirits) reduces the risk of the disease,^{[100] [101]} but it is still considered premature to make dietary recommendations on this basis.^[102][103] Vitamins B and C, or folic acid have appeared to be related to a reduced risk of AD,^[104] but other studies indicate that they do not have any significant effect on the onset or course of the disease, but may have important secondary effects in conjunction with other therapies.^[105] Curcumin in curry has shown some effectiveness in preventing brain damage in mouse models.^[106]

Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD,^[107][108] statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease.^[109][110] However long-term usage of non-steroidal anti-inflammatory drug (NSAIDs), is associated with a reduced likelihood of developing AD in some individuals.^[111]

Other pharmaceutical therapies such as female hormone replacement therapy are no longer thought to prevent dementia,^[112][113] and a 2007 systematic review concluded that there was inconsistent and unconvincing evidence that ginkgo has any positive effect on dementia or cognitive impairment.^[114]

Intellectual activities such as playing chess, completing crossword puzzles or regular social interaction, may also delay the onset or reduce the severity of Alzheimer's disease.^[115][116] Bilingualism is also related to a later onset of Alzheimer.^[117]

[edit] Management

There is no known cure for Alzheimer's disease. Available treatments offer relatively small symptomatic benefit but remain palliative in nature. Current treatments can be divided into pharmaceutical, psychosocial and caregiving.

[edit] Pharmaceutical

Four medications, to treat the cognitive manifestations of AD, are currently approved by regulatory agencies, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). Three are acetylcholinesterase inhibitors and the other is memantine, an NMDA receptor antagonist. No drug has an indication for delaying or halting the progression of the disease.

Because reduction in the activity of the cholinergic neurons in the disease is well known,^[118] acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (ACh) is broken down and so to increase the concentration of ACh in the brain, thereby combatting the loss of ACh caused by the death of the cholinergin neurons.^[119] Cholinesterase inhibitors currently approved include donepezil (brand name Aricept),^[120] galantamine (Razadyne),^[121] and rivastigmine (branded as Exelon,^[122] and Exelon Patch^[123]). There is also evidence for the efficacy of these medications in mild to moderate Alzheimer’s disease,^[124] and some evidence for their use in the advanced stage. Only donepezil is approved for treatment of advanced AD dementia.^[125] The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of AD.^[126] Most common side effects include nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately ten to twenty percent of users and are mild to moderate in severity. Less common secondary effects include muscle cramps; decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid.^{[127][128][129][130]}

Glutamate is a useful excitatory neurotransmitter of the nervous system, although excessive amounts in the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of glutamate receptors. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as Parkinson's disease and multiple sclerosis.^[131] Memantine (brand names Akatinol, Axura, Ebixa/Abixa, Memox and Namenda),^[132] is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA glutamate receptors and inhibits their overstimulation by glutamate.^[131] Memantine has been shown to be moderately efficacious in the treatment of moderate to severe Alzheimer’s disease. Its effects in the initial stages are unknown.^[133] Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue.^[134] Memantine used in combination with donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".^[135]

Neuroleptic anti-psychotic drugs commonly given to Alzheimer's patients with behavioural problems are modestly useful in reducing aggression and psychosis, but are associated with serious adverse effects, such as cerebrovascular events, movement difficulties or cognitive decline, that do not permit their routine use.^{[136][137][138]}

[edit] Psychosocial intervention

Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behavior, emotion, cognition or stimulation oriented approaches. Research on efficacy is unavailable and rarely specific to the disease, focusing instead on dementia.^[139]

Behavioral interventions attempt to identify and reduce the antecedents and consequences of problem behaviors. This approach has not shown success in the overall functioning of patients,^[140] but can help to reduce some specific problem behaviors, such as incontinence.^[141] There is still a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering.^[142][143]

Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration or snoezelen, and simulated presence therapy. Supportive psychotherapy has received little or no formal scientific study, but some clinicians find it useful in helping mildly impaired patients adjust to their illness.^[139] Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, many times with the aid of photographs, household items, music and sound recordings, or other familiar items from the past. Although there are few quality studies on the effectiveness of RT it may be beneficial for cognition and mood.^[144] Simulated presence therapy (SPT) is based on attachment theories and is normally carried out playing a recording with voices of the closest relatives of the patient. There is preliminary evidence indicating that SPT may reduce anxiety and challenging behaviors.^[145][146] Finally, validation therapy is based on acceptance of the reality and personal truth of another's experience, while sensory integration is based on exercises aimed to stimulate senses. There is little evidence to support the usefulness of these therapies.^[147][148]

The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining is the restoration of cognitive deficits. Reality orientation consists in the presentation of information about time, place or person in order to ease the understanding of the person about its surroundings and his place in them. On the other hand cognitive retraining tries to improve impaired capacities by exercitation of mental abilities. Both have shown some efficacy improving cognitive capacities,^[149][150] although in some works these effects were transient and negative effects, such as frustration, have also been reported.^[139]

Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind of recreational activities for patients. Stimulation has modest support for improving behavior, mood, and, to a lesser extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation therapies is the improvement in the patient daily life routine they suppose.^[139]

[edit] Caregiving

Further information: Caregiving and dementia

Since there is no cure for Alzheimer's, caregiving is an essential part of the treatment. Due to the eventual inability for the sufferer to self-care, Alzheimer's has to be carefully care-managed. Home care in the familiar surroundings of home may delay onset of some symptoms and delay or eliminate the need for more professional and costly levels of care.^[151] Many family members choose to look after their relative,^[12] but two-thirds of nursing home residents have dementias.^[152]

Modifications to the living environment and lifestyle of the Alzheimer's patient can improve functional performance and ease caretaker burden. Assessment by an occupational therapist is often indicated. Adherence to simplified routines and labeling of household items to cue the patient can aid with activities of daily living, while placing safety locks on cabinets, doors, and gates and securing hazardous chemicals can prevent accidents and wandering. Changes in routine or environment can trigger or exacerbate agitation, whereas well-lit rooms, adequate rest, and avoidance of excess stimulation all help prevent such episodes.^[153][154] Appropriate social and visual stimulation can improve function by increasing awareness and orientation. For instance, boldly colored tableware aids those with severe AD, helping people overcome a diminished sensitivity to visual contrast to increase food and beverage intake.^[155]

[edit] Clinical research

Main article: Alzheimer's disease clinical research

As of 2008, the safety and efficacy of more than 400 pharmaceutical treatments are being investigated in clinical trials worldwide, and approximately one-fourth of these compounds are in Phase III trials, which is the last step prior to review by regulatory agencies.^[156] It is unknown as to whether any of these trials will ultimately prove successful in treating the disease.

A critical area of clinical research is focused on treating the underlying disease pathology. Reduction of amyloid beta levels is a common target of compounds under investigation. Immunotherapy or vaccination for the amyloid protein is one treatment modality under study. Unlike vaccines which seek to prevent disease, this therapy would be used to treat diagnosed patients, and is based upon the concept of training the immune system to recognize, attack, and reverse deposition of amyloid, thereby altering the course of the disease.^[157] An example of such a vaccine under investigation is ACC-001.^[158][159] Similar agents are bapineuzumab, an antibody designed as identical to the naturally-induced anti-amyloid antibody,^[160] and MPC-7869, a selective amyloid beta-42 lowering agent.^[161] Other approaches are neuroprotective agents, such as AL-108,^[162] metal-protein interaction attenuation agents, such as PBT2,^[163] or tumor necrosis factor-alpha receptor fusion proteins, such as etanercept.^[164] There are also many basic investigations attempting to increase the knowledge on the origin and mechanisms of the disease that may lead to new treatments.

[edit] Prognosis

As the disease progresses, the patient will advance from mild cognitive impairment, when the suspected underlying pathology may or may not yet have been diagnosed, to mild and advanced stages of dementia, finally reaching a severe stage of dementia.^[24] Individual variations in the presentation and development of the symptoms can make a patient's disease difficult to classify into one specific stage. Once Alzheimer's has been diagnosed, the average life expectancy is approximately seven years, while less than three percent of the patients live more than fourteen years.^{[165][166][167][6]}

[edit] Epidemiology

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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 the disease. Among people aged 65, two to three percent show signs of the disease, while twenty-five to fifty percent of people aged 85 have symptoms of Alzheimer's and an even greater proportion 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.^[168] People over the age of 85 form the fastest growing segment of the Alzheimer's disease population in the US, although current estimates suggest the 75–84 population has about the same number of patients as the over 85 population.^[169]

The World Health Organization estimates that globally the total disability adjusted life years (DALY) for AD and other dementias exceeded eleven million in 2005, with a projected 3.4% annual increase.^[170] A study in Denmark found that women aged 65 are at significantly higher risk (22 percent) of developing AD by age 95 than their male counterparts (nine percent), while vascular dementias were nearly equal.^[171]

Some studies have shown a relationship between risk of developing AD and lifetime magnetic field exposure, although the mechanism is unknown.^[172][173] Other research does not confirm this link.^[174] The role of metals in the disease is also controversial.^[175]

[edit] History

Although the concept of dementia goes as far back as the ancient Greek and Roman philosophers and physicians,^[176] it was in 1901 when Alöis Alzheimer, a German psychiatrist, identified the first case of what became known as Alzheimer's disease in a fifty-year-old woman he called Auguste D. Alöis Alzheimer followed her until she died in 1906, when he first reported the case publicly.^[177] In the following five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease.^[176] The official consideration of the disease as a distinctive entity is attributed to Emil Kraepelin, who included Alzheimer’s disease or presenile dementia as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published in 1910.^[178]

For most of the twentieth century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a conference concluded that the clinical and pathological manifestations of presenile and senile dementia were almost identical, although the authors also added that this did not rule out the possibility of different etiologies. This eventually led to the use of Alzheimer's disease independently of onset age of the disease.^[179][180] The term senile dementia of the Alzheimer type (SDAT) was used for a time to describe the condition in those over 65, with classical Alzheimer's disease being used for those younger. Eventually, the term Alzheimer's disease was formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology.^[181]

[edit] Society and culture

[edit] Social costs

Because the median age of the industrialised world's population is gradually increasing, AD is a public health challenge. The solvency of governmental social safety nets will be impacted by the increased aged population which may develop Alzheimer's in the same proportions as earlier generations.^[182]

[edit] Caregiving burden

Further information: Caregiving and dementia

The role of family caregivers has become more prominent in both reducing the social cost of care and improving the quality of life of the patient. Home-based care also can have economic, emotional, and psychological costs to the patient's family. Although family members in particular often express the desire to care for the sufferer to the end,^[11] Alzheimer's disease is known for effecting a high burden on caregivers.^[12]

Alzheimer's disease can incur a variety of stresses on the caregivers: typical complaints are stress, depression, and an inability to cope. Reasons for these complaints can include: high-demands on the caregiver's concentration, as Alzheimer's sufferers have an ever-decreasing regard for their own safety (and can wander when unattended, for example); the lack of gratitude received when the sufferer is unaware of the help being given; and the lack of satisfaction when the sufferer's condition does not abate. Alzheimer's sufferers can be verbally and physically aggressive, and can stubbornly refuse to be helped. Aggression in particular can lead to a temptation to retaliate, which can put both the sufferer and carer at risk. It is additionally stressful for caregivers who are friends and family to witness a sufferer lose his or her identity, and eventually be unable to recognise them.^[12]

Family caregivers often give up time from work and forego pay to spend 47 hours per week on average with the person with AD. From a 2006 survey of US patients with long term care insurance, direct and indirect costs of caring for an Alzheimer's patient average $77,500 per year.^[183]

[edit] Notable cases

Further information: Alzheimer's in the media

As a result of the prevalence of the disease, many notable people have contracted it. Well-known examples are former United States President Ronald Reagan and Irish writer Iris Murdoch, both of whom have scientific articles on how their cognitive capacities deteriorated with the disease.^[184][185] Other cases include the retired footballer Ferenc Puskas,^[186] the former British Prime Minister Harold Wilson,^[187] the actress Rita Hayworth,^[188] the actor Charlton Heston,^[189] and the novelist Terry Pratchett.^[190]

Alzheimers has also been portrayed in films such as Iris (2001),^[191] (based on John Bayley's memoir of his wife Iris Murdoch),^[192] The Notebook (2004),^[193] (based on Nicholas Sparks' 1996 novel of the same name)^[194] Thanmathra (2005),^[195] Memories of tomorrow (Ashita no Kioku) (2006),^[196] (based on Hiroshi Ogiwara's novel of the same name),^[197] and Away From Her (2006), (based on Alice Munro's short story The Bear Came Over the Mountain),^[198] in documentaries, such as Malcolm and Barbara: A Love Story (1999) and Malcolm and Barbara: Love’s Farewell (2007) both featuring Malcolm Pointon,^[199] and in television series. In The Cider House Rules the affliction of a character with Alzheimer's is mistaken as Alcoholism.

[edit] References

[edit] Further reading

• Cummings JL, Frank JC, Cherry D, Kohatsu ND, Kemp B, Hewett L, Mittman B (2002). "Guidelines for managing Alzheimer's disease: Part I. Assessment". American Family Physician 65 (11): 2263–2272. PMID 12074525. 
• Cummings JL, Frank JC, Cherry D, Kohatsu ND, Kemp B, Hewett L, Mittman B (2002). "Guidelines for managing Alzheimer's disease: Part II. Treatment". American Family Physician 65 (12): 2525–2534. PMID 12086242. 
• Genes, lifestyles, and crossword puzzles: Can Alzheimer's disease be prevented (PDF). US Department of Health and Human Services, National Institute of Aging. Retrieved on 2008-02-29.
• Russell D, Barston S, White M (2007-12-19). Alzheimer’s Behavior Management: Learn to manage common behavior problems. helpguide.org. Retrieved on 2008-02-29.

v • d • e WHO ICD-10 mental and behavioral disorders (F · 290–319) Neurological/symptomatic Dementia (Alzheimer's disease, multi-infarct dementia, Pick's disease, Creutzfeldt-Jakob disease, Huntington's disease, Parkinson's disease, AIDS dementia complex, Frontotemporal dementia) · Delirium · Post-concussion syndrome · Organic brain syndrome Psychoactive substance alcohol (drunkenness, alcohol dependence, delirium tremens, Korsakoff's syndrome, alcohol abuse) · opioids (opioid dependency) · sedative/hypnotic (benzodiazepine withdrawal) · cocaine (cocaine dependence) · general (Intoxication, Drug abuse, Physical dependence, Withdrawal) Psychotic disorder Schizophrenia (disorganized schizophrenia)  · Schizophreniform disorder  · Schizotypal personality disorder · Delusional disorder · Folie à deux · Schizoaffective disorder Mood (affective) Mania · Bipolar disorder · Clinical depression · Cyclothymia · Dysthymia Neurotic, stress-related and somatoform Anxiety disorder (Agoraphobia, Panic disorder, Panic attack, Generalized anxiety disorder, Social anxiety, Social phobia) · OCD · Acute stress reaction · PTSD · Adjustment disorder · Conversion disorder (Ganser syndrome) · Somatoform disorder (Somatization disorder, Body dysmorphic disorder, Hypochondriasis, Nosophobia, Da Costa's syndrome, Psychalgia)  · Neurasthenia Physiological/physical behavioral Eating disorder: Anorexia nervosa · Bulimia nervosa Sleep disorder: Dyssomnia (Hypersomnia, Insomnia) · Parasomnia (REM behavior disorder, Night terror) · Nightmare Sexual dysfunction: Erectile dysfunction · Premature ejaculation · Vaginismus · Dyspareunia · Hypersexuality · Female sexual arousal disorder Postnatal depression Adult personality and behavior Personality disorder · Passive-aggressive behavior · Kleptomania · Trichotillomania · Voyeurism · Factitious disorder · Munchausen syndrome · Ego-dystonic sexual orientation · Fetishism Mental retardation Mental retardation Psychological development (developmental disorder) Specific: speech and language (expressive language disorder, aphasia, expressive aphasia, receptive aphasia, Landau-Kleffner syndrome, lisp) · Scholastic skills (dyslexia, dysgraphia, Gerstmann syndrome) · Motor function (developmental dyspraxia) Pervasive: Autism · Rett syndrome · Asperger syndrome Behavioral and emotional, childhood and adolescence onset ADHD · Conduct disorder · Oppositional defiant disorder · Separation anxiety disorder · Selective mutism · Reactive attachment disorder · Tic disorder · Tourette syndrome · Speech (stuttering · cluttering)

v • d • e Pathology of the nervous system, primarily CNS (G00-G47, 320-349) Inflammatory diseases of the CNS Meningitis (Arachnoiditis) - Encephalitis - Myelitis - Encephalomyelitis (Acute disseminated) - Tropical spastic paraparesis - Cavernous sinus thrombosis Systemic atrophies primarily affecting the CNS Huntington's Spinocerebellar ataxia (Friedreich's ataxia, Ataxia telangiectasia, Hereditary spastic paraplegia) Spinal muscular atrophy: Werdnig-Hoffman - Kugelberg-Welander - Fazio Londe - MND (ALS, PMA, PBP, PP, PLS) Extrapyramidal and movement disorders Parkinson's disease - Neuroleptic malignant syndrome - Postencephalitic parkinsonism - Pantothenate kinase-associated neurodegeneration - Progressive supranuclear palsy - Striatonigral degeneration Dystonia/Dyskinesia (Spasmodic torticollis, Meige's, Blepharospasm) Essential tremor - Myoclonus - Lafora Chorea (Choreoathetosis) - Restless legs - Stiff person Other degenerative/ demyelinating diseases dementia: Alzheimer's - Pick's - Dementia with Lewy bodies - Frontotemporal lobar degeneration mitochondrial disease: Leigh's demyelinating: Multiple sclerosis - Devic's - Central pontine myelinolysis - Transverse myelitis - Marchiafava-Bignami disease - CAMFAK syndrome - Alpers' Seizure/epilepsy Focal (Simple partial, Complex partial) - Generalised (Tonic-clonic, Absence, Atonic, Benign familial neonatal) Lennox-Gastaut - West - Epilepsia partialis continua - Status epilepticus (Complex partial status epilepticus) Headache Migraine (Familial hemiplegic) - Cluster - Vascular - Tension Vascular Transient ischemic attack (Amaurosis fugax, Transient global amnesia) Cerebrovascular disease (MCA, ACA, PCA, Foville's, Millard-Gubler, Lateral medullary, Weber's, Lacunar stroke) Sleep disorders Insomnia - Hypersomnia - Sleep apnea (Ondine's curse) - Narcolepsy - Cataplexy - Kleine-Levin - Circadian rhythm sleep - Delayed sleep phase - Advanced sleep phase Intracranial hypertension Hydrocephalus (Normal pressure) - Idiopathic intracranial hypertension Other encephalopathy Brain herniation - Cerebral edema - Reye's Other spinal cord disease Syringomyelia - Syringobulbia - Morvan's syndrome - Spinal cord compression