Alzheimer’s

Introduction

Alzheimer’s disease is a brain disorder named for German physician Alois Alzheimer, who first described it in 1906. Scientists have learned a great deal about Alzheimer’s disease in the century since Dr. Alzheimer first drew attention to it. Today we know that Alzheimer’s:

• Is a progressive and fatal brain disease. More than 5 million Americans now have Alzheimer’s disease. Alzheimer’s destroys brain cells, causing problems with memory, thinking and behavior severe enough to affect work, lifelong hobbies or social life. Alzheimer’s gets worse over time, and it is fatal. Today it is the seventh-leading cause of death in the United States. For more information, see Symptoms or Stages of Alzheimer’s Disease.

Inside the Brain: An Interactive Tour Learn how the brain works and how Alzheimer’s affects it.

• Is the most common form of dementia, a general term for the loss of memory and other intellectual abilities serious enough to interfere with daily life. Vascular dementia, another common type of dementia, is caused by reduced blood flow to parts of the brain. In mixed dementia, Alzheimer’s and vascular dementia occur together. For more information about other causes of dementia, please see Related Dementias.
• Has no current cure. But treatments for symptoms, combined with the right services and support, can make life better for the millions of Americans living with Alzheimer’s. We’ve learned most of what we know about Alzheimer’s in the last 15 years. There is an accelerating worldwide effort under way to find better ways to treat the disease, delay its onset, or prevent it from developing. Learn more about recent progress in Alzheimer science and research funded by the Alzheimer’s Association in the Research section.

Alzheimer’s and the brain

Just like the rest of our bodies, our brains change as we age. Most of us notice some slowed thinking and occasional problems remembering certain things. However, serious memory loss, confusion and other major changes in the way our minds work are not a normal part of aging. They may be a sign that brain cells are failing.

The brain has 100 billion nerve cells (neurons). Each nerve cell communicates with many others to form networks.
Nerve cell networks have special jobs. Some are involved in thinking, learning and remembering. Others help us see, hear and smell. Still others tell our muscles when to move.

To do their work, brain cells operate like tiny factories. They take in supplies, generate energy, construct equipment and get rid of waste. Cells also process and store information. Keeping everything running requires coordination as well as large amounts of fuel and oxygen.

In Alzheimer’s disease, parts of the cell’s factory stop running well. Scientists are not sure exactly where the trouble starts. But just like a real factory, backups and breakdowns in one system cause problems in other areas. As damage spreads, cells lose their ability to do their jobs well. Eventually, they die.

Learn more about Alzheimer’s: Take the Brain Tour

 

The role of plaques and tangles

Two abnormal structures called plaques and tangles are prime suspects in damaging and killing nerve cells. Plaques and tangles were among the abnormalities that Dr. Alois Alzheimer saw in the brain of Auguste D., although he called them different names.

• Plaques build up between nerve cells. They contain deposits of a protein fragment called beta-amyloid (BAY-tuh AM-uh-loyd). Tangles are twisted fibers of another protein called tau (rhymes with “wow”).
• Tangles form inside dying cells. Though most people develop some plaques and tangles as they age, those with Alzheimer’s tend to develop far more. The plaques and tangles tend to form in a predictable pattern, beginning in areas important in learning and memory and then spreading to other regions.

Scientists are not absolutely sure what role plaques and tangles play in Alzheimer’s disease. Most experts believe they somehow block communication among nerve cells and disrupt activities that cells need to survive.

Early stage and early onset

Early-stage is the early part of Alzheimer’s disease when problems with memory, thinking and concentration may begin to appear in a doctor’s interview or medical tests. Individuals in the early-stage typically need minimal assistance with simple daily routines. At the time of a diagnosis, an individual is not necessarily in the early stage of the disease; he or she may have progressed beyond the early stage. 

The term early-onset refers to Alzheimer’s that occurs in a person under age 65. Early-onset individuals may be employed or have children still living at home. Issues facing families include ensuring financial security, obtaining benefits and helping children cope with the disease. People who have early-onset dementia may be in any stage of dementia – early, middle or late. Experts estimate that some 500,000 people in their 30s, 40s and 50s have Alzheimer’s disease or a related dementia.

History

At a scientific meeting in November 1906, German physician Alois Alzheimer presented the case of “Frau Auguste D.,” a 51-year-old woman brought to see him in 1901 by her family. Auguste had developed problems with memory, unfounded suspicions that her husband was unfaithful, and difficulty speaking and understanding what was said to her. Her symptoms rapidly grew worse, and within a few years she was bedridden. She died in Spring 1906, of overwhelming infections from bedsores and pneumonia.

Dr. Alzheimer had never before seen anyone like Auguste D., and he gained the family’s permission to perform an autopsy. In Auguste’s brain, he saw dramatic shrinkage, especially of the cortex, the outer layer involved in memory, thinking, judgment and speech. Under the microscope, he also saw widespread fatty deposits in small blood vessels, dead and dying brain cells, and abnormal deposits in and around cells.

The condition entered the medical literature in 1907, when Alzheimer published his observations about Auguste D. In 1910, Emil Kraepelin, a psychiatrist noted for his work in naming and classifying brain disorders, proposed that the disease be named after Alzheimer.

Auguste D.

Dr. Alois Alzheimer

More….

from Wiki

Alzheimer’s disease

Alzheimer’s disease (AD), also called Alzheimer disease or simply Alzheimer’s, is the most common cause of dementia, afflicting 24 million people worldwide. Alzhiemer’s in a progressive and terminal disease for which there is currently no cure. In its most common form, it occurs in people over 65 years old (although a less-prevalent early onset form also exists).^[1] It usually begins many years before it is eventually diagnosed. In its early stages, short-term memory loss is the clearest symptom:^[2] this leads to confusion, anger, mood swings, language breakdown, long-term memory loss, and the general ‘withdrawal’ of the sufferer as his or her senses decline. Gradually the sufferer loses minor, and then major bodily functions, until death occurs.^[3] Although the symptoms are common, people commonly experience them in a unique way.^[4] The duration of the disease is commonly cited as being between 5 and 20 years.^[5][6]

Classification

Alzheimer’s is a neurodegenerative disease. Clinical signs of Alzheimer’s disease include progressive cognitive deterioration, declining ability to perform activities of daily living, and neuropsychiatric symptoms or behavioral changes. Plaques which contain misfolded peptides called amyloid beta (Aβ) are formed in the brain many years before the clinical signs of Alzheimer’s are observed. Together, these plaques and neurofibrillary tangles form the pathological hallmarks of the disease. These features can only be discovered at autopsy to confirm the clinical diagnosis. At this time medications can help reduce the symptoms of the disease, but they cannot change the course of the underlying pathology.

The ultimate cause of Alzheimer’s is unknown. Genetic factors are clearly indicated as dominant mutations in three different genes that account for the small number of cases of familial, early-onset AD that have been identified. For the more common form of late onset AD, ApoE is the only clearly established susceptibility gene. All four genes can contain mutations or variants that confer increased risk for AD, but they account for only 30% of the genetic picture of AD. Mutations in any of these four genes lead to the excessive accumulation in the brain of Aβ, the main component of the senile plaques that are prevalent in the brains of AD patients.^[7][8]

[edit] Characteristics

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

[edit] Predementia

Careful neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fullfils clinical criteria of diagnosis.^[9][10][11] It is not yet clear if these difficulties affect daily living activities. Recent studies show impairments in the most complex activities.^[12] The most noticeable deficit for most people is short-term memory loss and the consequent problems to acquire new information, but subtle executive problems or semantic memory impairments can also occur.^[13][14] Apathy can be seen at this stage, which is the most common and most persistent neuropsychiatric symptom through the disease.^[15][16][17] This stage of the disease has also been termed mild cognitive impairment,^[18] 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.^[19]

[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.^[20] Nevertheless memory problems do not affect all memory subcapacities equally. Older memories of the patient’s life (episodic memory) and facts he learned (declarative memory); or implicit memory (the memory of the body on how to do things, such as using a knife to eat) are affected to a much lesser degree than the capacities needed to learn new facts or make new memories.^[21][22] On the other hand, language problems are mainly characterized by a shrinking vocabulary and a decreased word fluency which leads to a general impoverishment of oral and written language but the person with the disease is usually capable of communicating ideas adequately.^[23][24][25] While performing fine motor tasks such as writing, drawing or dressing, certain visoconstructional difficulties, or apraxia, may present, which may appear as clumsiness.^[26] 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.^[20]

[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.^[20] Language 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.^[23][27] As time passes, complex motor sequences become less coordinated, costing the patient most of his daily-living abilities.^[28] Memory problems worsen, and the person may not recognize close relatives.^[29] Long-term memory, which was previously left intact, is now also impaired.^[30] Patients are usually almost completely unaware of their own deficits, and 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.^[15][31] Often urinary incontinence develops.^[32] 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.^[20][33]

[edit] Advanced

In the last stage of Alzheimer’s disease all human behavior is likely to become entirely automatic. Language is reduced to simple phrases or even single words before being lost altogether.^[23] Nevertheless many patients can receive and return emotional signals long after the loss of verbal language.^[34] Although aggressiveness can still present, extreme apathy and exhaustion are much more common.^[20] 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^[35] and to lose the ability to feed oneself^[36] if death from some external cause (such as infection due to pressure ulcers or pneumonia) does not occur first.^[37][38]

[edit] Etiology

Most cases of Alzheimer’s disease are sporadic, i.e., do not exhibit familial inheritance. Nonetheless, at least 80% of sporadic AD cases most likely involve genetic risk factors. Inheritance of the ε4 allele of the apolipoprotein E (ApoE) gene is regarded as a risk factor for development of up to 50% of late-onset sporadic Alzheimer’s. Genetic experts agree that there are other risk and protective factor genes that influence the development of late onset Alzheimer’s disease. Over 400 genes have been tested for association with late-onset sporadic AD.^[39]

On the other hand, 5 to 10% of AD cases involve a clear familial pattern of inheritance in which the patient has at least two first-degree relatives with a history of AD. These cases often have an early age of onset (usually <60 years). Nearly 200 different mutations in the presenilin-1 or presenilin-2 genes have been documented in over 500 families. Mutations of presenilin 1 (PS1) lead to the most aggressive form of familial Alzheimer’s disease. Over 20 different mutations in the amyloid precursor protein (APP) gene on chromosome 21 can also cause early onset of the disease. The presenilins have been identified as essential components of the proteolytic processing machinery that produces beta amyloid peptides through cleavage of APP. Most mutations in the APP and presenilin genes increase the production of a small protein (peptide) called Abeta42, the main component of senile plaques in brains of AD patients.

[edit] Pathophysiology

Main article: Biochemistry of Alzheimer’s disease

[edit] Neuropathology

MRI images of a normal aged brain (right) and an Alzheimer’s patient’s brain (left). In the Alzheimer brain, atrophy is clearly seen.

At a macroscopic level, AD is characterized 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.^[40]

Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains.^[41] Plaques are dense, mostly insoluble deposits of 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.^[42]

[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.^[43] Plaques are made of a peptide 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.^[44][45] In AD, something causes APP to be divided by enzymes through a mechanism called proteolysis.^[46] One of these fragments is beta-amyloid. Beta-amyloid fragments (amyloid fibrils) outside the cell come together into clumps that deposit outside neurons in dense formations known as senile plaques.^[47][41] 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.^[48] In AD, tau is changed chemically, becoming hyperphosphorylated. 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.^[49] 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.^[50]

[edit] Disease mechanism

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.^[51] 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,^[52] leading to generalized neuroinflammation.^[40]

Research after 2000 includes hypotheses centered on the effects of the misfolded and aggregated proteins, amyloid beta and tau. 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.^[53] The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques does not correlate well with neuron loss,^[54] but a majority of researchers support the alternative hypothesis that Aβ is the primary causative agent.^[53] 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.^[55][56] 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.^[57] 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.^[58] 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.^[59][60][61]

[edit] Diagnosis

Dementia is by definition a clinical condition, and thus can be confidently diagnosed with careful testing. A definitive diagnosis of Alzheimer’s disease as a particular cause of dementia must await microscopic examination of brain tissue; which generally occurs at autopsy and less often with a pre-mortem brain biopsy.^[62] Alzheimer’s disease is usually a clinically diagnosed condition based on the presence of characteristic neurological and neuropsychological features and the absence of alternative diagnoses. In this process, determination of neurological characteristics is made utilizing patient history and clinical observation,^[63] while neuropsychological evaluation includes memory testing and assessment of intellectual functioning.^[64] Medical organizations have created diagnostic criteria to ease and standardize the process for practicing physicians.

[edit] Diagnostic criteria

The diagnostic criteria for Alzheimer of the NINCDS-ADRDA (NINCDS and the ADRDA) are among the most used.^[62] 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.^[65] 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 DSM-IV-TR criteria published by the American Psychiatric Association.^[66][67]

[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.^[68][69] On the other hand neurological examination in early AD will usually be normal, independently 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.^[64] In addition, interviews with family members are also utilized 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.^[70] This is especially important since a patient with AD is commonly unaware of his or her own deficits (anosognosia).^[71] Many times families also have difficulties in the detection of initial dementia symptoms and in adequately communicating them to a physician.^[72] Finally supplemental testing provide extra information on some features of the disease or are utilized to rule out other diagnoses. Examples are blood tests, which can identify other causes for dementia different than AD;^[64] some of which may even be reversible;^[73] 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.^[74][75]

Increasingly, the functional neuroimaging modalities of SPECT and 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.^[76] Furthermore, the ability of SPECT to differentiate Alzheimer’s disease from other possible causes, in a given 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.^[77] Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau proteins.^[78] Both advances (neuroimaging and cerebrospinal fluid analysis) have led to the proposal of new diagnostic criteria.^[79][64]

[edit] Prevention

Although aging itself cannot be prevented, the senescence of it can be mitigated. The evidence relating certain behaviors, dietary intakes, environmental exposures, and diseases to the likelihood of developing Alzheimer’s varies in quality and its acceptance by the medical community.^[80]

Reducing cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, smoking, lack of physical activity, and high dietary saturated fats are implicated in concomitant reduction in risk for the onset and course of Alzheimer’s disease.^[81]

There are several intellectual or physical activities that may delay the onset or reduce the severity of Alzheimer’s disease. Intellectual stimulation, such as playing chess or completing crossword puzzles,^[82] regular physical exercise,^[83] and regular social interaction^[84] all have a positive effect on the disease.

[edit] Diet

A Mediterranean diet, which includes high consumption of fruit and vegetables, bread, wheat and other cereals, olive oil, olive leaf, fish, and red wine, may affect the risk and course of the disease. The diet is considered to be high in dietary fiber and monounsaturated fat and low in saturated fat.^[85][86] There is some evidence that B-vitamins and folic acid have a positive effect on the prevention and course of the disease.^[87] Recent data from research actually indicates that neither dietary folate nor vitamins B-12 and B-6 have any significant effect on the development of the disease.^[88][89] Another study has ruled out vitamins C and E, individually or in combination, from being correlated with the onset of AD.^[90] In addition, high intake of folate may be associated with cognitive decline in elderly individuals.^[91]

Curcumin in Curry (from the yellow spice Turmeric) may delay disease onset and severity through a possible interaction with metallic ions.^[92][93][94] A large clinical study is underway to determine if the compound has a significant effect in humans.^[95] Other foods or nutrients, such as Omega-3 fatty acids, especially Docosahexaenoic acid (DHA, often found in fish oil),^[96] fresh fruit and vegetables high in the Polyphenol antioxidant (for example, blueberries, apples, grapes, broccoli, and legumes).^[97][98] and the moderate consumption of red wine^[99][100] may all individually or together reduce the risk and development of Alzheimer’s disease.

[edit] Pharmaceuticals

Cholesterol-lowering drugs (statins) can reduce the cardiovascular risk, but have not shown much evidence that they have an effect in preventing or reducing the course of the disease.^[101][102] Other pharmaceutical therapies such as female Hormone replacement therapy is no longer thought to prevent dementia.^[103][104] Long-term usage of non-steroidal anti-inflammatory drugs (NSAIDs), used to reduce joint inflammation and pain, are associated with a reduced likelihood of developing AD, according to some observational studies.^[105]

A 2007 systematic review concluded that there was inconsistent and unconvincing evidence that Ginkgo has any positive effect on dementia or cognitive impairment.^[106] A large, randomized clinical study is now underway, which examines the effect of Ginkgo to prevent dementia. Results are expected in early 2008.^[107]

[edit] Treatment

There is currently no cure for Alzheimer’s disease. Currently available medications offer relatively small symptomatic benefit for some patients and some medications do slow disease progression.^[108]

[edit] Pharmaceutical

There is an observed reduction in activity of the cholinergic neurons in the disease. Acetylcholinesterase 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). AChE-inhibitors seem to modestly moderate symptoms but do not alter the course of the underlying dementing process.^[109] Examples currently marketed include donepezil (Trade name Aricept), galantamine (trade names Reminylin and Nivalin, U.S. trade name Razadyne) and rivastigmine (Exelon). The three products come in an oral form taken once or twice a day. Rivastigmine is also available as a once-daily transdermal patch.^{[110][111][112]}

There is some question as to the effectiveness of cholinesterase inhibitors. Different articles have criticized the design of studies reporting benefit from these drugs, concluding that they have doubtful clinical utility, are costly, and confer many side effects.^{[113][114][115]}

Recent evidence of the involvement of glutamatergic neuronal excitotoxicity in 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.^{[116][117][108]} Memantine is marketed as Akatinol, Axura, Ebixa and Namenda.

[edit] Psychosocial intervention

Cognitive and behavioral interventions and rehabilitation strategies may be used as an adjunct to pharmacological treatment, especially in the early to moderately advanced stages of disease. Treatment modalities include counseling, psychotherapy (if cognitive functioning is adequate), reminiscent therapy, reality orientation therapy, and behavioral reinforcements as well as cognitive rehabilitation training.^{[118][119][120]}

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.^[121] 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.^[122]

[edit] Treatments in clinical development

Several potential treatments for Alzheimer’s disease are currently under investigation, including two compounds being studied in phase 3 clinical trials. Tarenflurbil (MPC-7869, formerly R-flubiprofen) is a gamma secretase modulator sometimes called a selective amyloid beta 42 lowering agent. It is believed to reduce the production of the toxic amyloid beta in favor of shorter forms of the peptide.^{[123][124][125]}

Vaccines or immunotherapy for Alzheimer’s, unlike typical vaccines, would be used to treat diagnosed patients rather than for disease prevention. Ongoing efforts are based on the idea that, by training the immune system to recognize and attack beta-amyloid, the immune system might reverse deposition of amyloid and thus stop the disease. Initial results using this approach in animals were promising, and clinical trials of the drug candidate AN-1792 showed results in 20% of patients. In 2002 it was reported that 6% of multi-dosed participants (18 of 300) developed symptoms resembling meningoencephalitis, and the trials were stopped. Participants in the halted trials continued to be followed, and 20% “developed high levels of antibodies to beta-amyloid” and some showed slower progression of the disease, maintaining memory-test levels while placebo-patients worsened. Micro-cererebral hemorrhages during passive immunisation and meningoencephalitis with active immunisation still remain potent threats to this strategy.^{[126][127][128]}

Simvastatin, a statin, stimulates brain vascular endothelial cells to create a beta-amyloid ejector.^[129] The use of this statin may be have a causal relationship to decreased development of the disease.^[130]

Several other pharmaceuticals are under investigation to treat Alzheimer’s disease. A 2006 pilot study showed small but significant improvements in various cognitive rating scales in patients with Alzheimer’s disease after treatment with etanercept, Tumor necrosis factor-alpha receptor fusion protein, which binds to tumor necrosis factor-alpha, and decreases its role in inflammation of nervous tissue.^[131] A further study, administering to a single AD patient via perispinal infusion, showed rapid and significant improvement in Alzheimer’s symptoms.^[132] Laboratory studies with cells and animals continually fuel the pipeline of potential treatments. Some currently approved drugs such as statins and thiazolidinediones have also been under investigation for the treatment and prevention of Alzheimer’s.^[133]

[edit] Epidemiology

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, 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.^[134] The share of Alzheimer’s patients over the age of 85 is 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.^[135]

Adults with damaged blood vessels in the brain or atrophy in their temporal lobe are more likely to develop Alzheimer’s disease. It is known that blood vessel damage in the brain is more likely to occur in patients with high blood pressure, high cholesterol or diabetes. Prevention of these conditions can lower the risk of developing the disease, as well as heart attack and stroke,^{[136][137][138][139]} Head injury and smoking are also risk factors for AD;^[140][141] while the role of metals in the etiology of the disease is more controversial.^{[142][143][144]}

[edit] Prognosis

As the disease progresses the patient will advance from mild cognitive impairment, when the disease has not yet been diagnosed, to mild and advanced stages of dementia, finally reaching a severe stage of dementia.^[20] It is important to note there is also an important individual variability in the presentation and development of the symptoms; being sometimes difficult to classify the person in one of the described stages. Once Alzheimer’s has been diagnosed, the average life expectancy of patients living with the disease is approximately 7 years, while less than 3% of the patients live more than 14 years.^{[145][146][147][5]}

[edit] Social issues

Alzheimer’s is a major public health challenge since the median age of the industrialized world’s population is increasing gradually.^[148] Indeed, much of the concern about the solvency of governmental social safety nets 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. For this reason, money spent informing the public of available effective prevention methods may yield disproportionate benefits.

The role of family caregivers has also become more prominent, as 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. Home-based care may entail tremendous economic, emotional, and even psychological costs as well (see elderly care). Family caregivers often give up time from work and forego pay to spend 47 hours per week on average with an affected loved one who frequently cannot be left alone. From a survey of patients with long term care insurance, direct and indirect costs of caring for an Alzheimer’s patient average $77,500 per year.^[149]

[edit] History

Auguste D.

Although the origin of the concept of dementia goes as far back as the ancient Greek and Roman philosophers and physicians;^[150] it was in 1901 when Alois Alzheimer, a German psychiatrist, identified the first case of what became known as Alzheimer’s disease. The patient was a 50-year-old woman called Auguste D. Alois Alzheimer followed her until she died in 1906, when he first reported the case publicly.^{[151][152][153]} In the following five years eleven similar cases were reported in the medical literature; some of them already using the term Alzheimer’s disease.^[150] 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.^[154]

Accordingly; 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 held in that year 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.^[155][156] The term senile dementia of the Alzheimer type (SDAT) was often 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.^[157]

[edit] Cultural references

Further information: Alzheimer’s in the media

Since Alzheimer’s is such a prevalent disease, many notable people have lived with it. well-known examples are United States president Ronald Reagan and Irish writer Iris Murdoch, both of whom have articles focused on how their language deteriorated with the disease.^[158][159] Other cases are the retired footballer Ferenc Puskas,^[160] the former British Prime Minister Harold Wilson,^[161] the actress Rita Hayworth,^[162] the actor Charlton Heston,^[163] etc. The media attention to the cases of these prominent individuals has helped to make society even more aware of the problem of the disease.

Alzheimer has also been portrayed in many films such as Iris (2001),^[164] The Notebook (2004),^[165] Thanmathra (2005),^[166] or Memories of tomorrow (Ashita no Kioku) (2006);^[167] documentaries, such as Malcolm and Barbara…A Love Story (1999) and Malcolm and Barbara…Love’s Farewell (2007) both featuring Malcolm Pointon;^[168][169] or TV series; being either the center of the main plot or a secondary issue.