Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative disease. Characterized by progressive cognitive deterioration, together with declining activities of daily living and by neuropsychiatry symptoms or behavioral changes, it is the most common type of dementia.

The most striking early symptom is the loss of memory (amnesia), which usually manifests as minor forgetfulness that becomes steadily more pronounced with the progression of the illness, 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 closely related to the frontal and temporal lobes of the brain (such as decision-making and planning) as they become disconnected from the limbic system, reflecting extension of the underlying pathological process. This pathological process consists principally of neuronal loss or atrophy, principally in the temporoparietal cortex, but also in the frontal cortex, together with an inflammatory response to the deposition of amyloid plaques and neurofibrillary tangles.

History

Auguste D.

In 1901, Dr. Alois Alzheimer, a German psychiatrist, interviewed a patient named Mrs. Auguste D., age 51. She was brought in by her husband, Karl Deter, who could not care for her declining mental health any longer. Dr. Alzheimer showed her several objects and later asked her what she had been shown. She could not recall. He would initially record her behavior as "amnesic writing disorder," but Mrs. Auguste D would be the first patient to be identified with Alzheimer's disease.

Alzheimer would later work in the laboratory of the preeminent Emil Kraepelin in Munich, Germany. Kraepelin was the author of a leading textbook in psychiatry and was a strong believer that neuropathology could be linked to clinical psychiatric function. Early in April 1906, Auguste D. died, and Alzheimer worked with two Italian physicians to examine her anatomy and neuropathology. On November 3, 1906, he presented Auguste D.'s case to the 37th Assembly of Southwest German Psychiatrists and described the neurofibrillary tangles and amyloid plaques that have come to be considered the hallmark of the disease. Kraepelin would later write about this case and others in his "Textbook for Students and Doctors" and index them under "Alzheimer's disease." By 1910, this denomination for the disease was well established among the specialist community.

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 due to the histopathologic process discovered by Dr. Alzheimer (see below for description of brain tissue changes). During this time senile dementia itself (as a set of symptoms) was considered to be a more or less normal outcome of the aging process, and thought to be due to age-related brain arterial "hardening." In the 1970s and early-1980s, because the symptoms and brain pathology were identical for Alzheimer victims older and younger than age 65, the name "Alzheimer's disease" began to be used, within and outside the medical profession, equally for afflicted individuals of all ages, although in this period the term senile dementia of the Alzheimer type (SDAT) was often used to distinguish those over 65 who did not fit the classical age criterion. Eventually, the term Alzheimer's disease was adopted formally in the psychiatric and neurological nomenclature to describe individuals of all ages with the characteristic common symptom pattern, disease course, and neuropathology. The term Alzheimer disease (without the apostrophe and s) also continues to be used commonly in the literature.

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. Since family members are often the first to notice changes that might indicate the onset of the disease they should learn the early warning signs. 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 in some reported cases up to 21 years.

Stages and symptoms

• Mild — At the early stage of the disease, patients have a tendency to become less energetic or spontaneous, though changes in their behavior often go unnoticed even by the patients' immediate family. This stage of the disease has also been termed Mild Cognitive Impairment (MCI) although this term remains somewhat controversial.
• Moderate — As the disease progresses to the middle stage, the patient might still be able to perform tasks independently, but may need assistance with more complicated activities.
• Severe — As the disease progresses from the middle to late stage, the patient will undoubtedly not be able to perform even the simplest of tasks on their own and will need constant supervision. They become incontinent of bladder and then incontinent of bowel. They will eventually lose the ability to walk and eat without assistance. Language becomes severely disorganized, and then is lost altogether. They may eventually lose the ability to swallow food and fluid and this can ultimately lead to death.

Diagnosis

The diagnosis is made primarily on the basis of history, clinical observation, memory tests 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. No medical tests are available to diagnose Alzheimer's disease conclusively pre-mortem. Expert clinicians who specialize in memory disorders can now diagnose AD with an accuracy of 85–90%, but a definitive diagnosis of Alzheimer's disease must await microscopic examination of brain tissue, generally at autopsy. Functional neuroimaging studies such as PET and SPECT scans can provide a supporting role where dementia is clearly present, but the type of dementia is questioned. Recent studies suggest that SPECT neuroimaging approaches clinical exam in diagnostic accuracy and may outperform exam at differentiating types of dementia (Alzheimer's disease vs. vascular dementia). However, Alzheimer's disease remains a primarily clinical diagnosis based on the presence of characteristic neurological features and the absence of alternative diagnoses, with possible neuroimaging assistance. 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". In addition, a 2004 study by Cervilla and colleagues showed that tests of cognitive ability provide useful predictive information up to a decade before the onset of dementia.^[7] However, when diagnosing individuals with a higher level of cognitive ability, in this study those with IQs of 120 or more,^[8] patients should not be diagnosed from the standard norm but from an adjusted high-I.Q norm that measured changes against the individual's higher ability level.

Pathology

Neuropathology

Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains. At an anatomical level, AD is characterized by gross diffuse atrophy of the brain 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, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.Levels of the neurotransmitter acetylcholine are reduced. Levels of the neurotransmitters serotonin, norepinephrine, and somatostatin are also often reduced. Glutamate levels are usually elevated.

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 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.^[46] 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.^[47]

Prevention

Ageing itself can not be prevented, but the senescence of it can be mitigated. However, 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.^[48] 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 preventive measures based on cross-sectional studies. Some proposed preventive measures are even based on studies conducted solely in animals or in cell cultures but are not listed here.

Risk reducers

• Intellectual stimulation (e.g., playing chess or doing crosswords)^[49]
• Regular physical exercise^[50]
• Regular social interaction [8]
• A Mediterranean diet with fruits and vegetables and low in saturated fat,^[51] supplemented in particular with:
  • B vitamins^[52]
  • Omega-3 fatty acids, especially Docosahexaenoic acid^[53][54]
  • Fruit and vegetable juice^[55][56]
  • High doses of the antioxidant Vitamin E (in combination with vitamin C) seem to reduce Alzheimer's risk in cross sectional studies but not in a randomized trial and so are not currently a recommended preventive measure because of observed increases in overall mortality^[57][58]
  • The moderate consumption of alcohol (beer, wine or distilled spirits) ^[59]
• Cholesterol-lowering drugs (statins) reduce Alzheimer's risk in observational studies but so far not in randomized controlled trials^[60]
• Female Hormone replacement therapy is no longer thought to prevent dementia based on data from the Women's Health Initiative
• 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.^[61][62] The risks appear to outweigh the drugs' benefit as a method of primary prevention.^[63]

Risk factors

• Advancing age
• ApoE epsilon 4 genotype (in some populations)
• Head injury
• Poor cardiovascular health (including smoking, diabetes, hypertension, high cholesterol and strokes)

Treatment

There is currently no cure for Alzheimer's disease. Currently available medications offer relatively small symptomatic benefit for some patients but do not slow disease progression. It helps a little for the memory. The American Association for Geriatric Psychiatry published a consensus statement on Alzheimer's treatment in 2006.

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 alter the course of the underlying dementing process

Examples include:

• tacrine - no longer clinically used
• donepezil - (marketed as Aricept)
• galantamine - (marketed as Razadyne in the U.S.A. Marketed as Reminyl or Nivalin in the rest of the world)
• rivastigmine - (marketed as Exelon)

There is significant doubt as to the effectiveness of cholinesterase inhibitors. A number of recent 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. The pharmaceutical companies, but also some independent clinicians, dispute the conclusions of these articles. A transdermal patch is under development that may ease administration of rivastigmine.

Ginkgo biloba

Examining over 50 studies conducted on Ginkgo for the treatment of "cognitive impairment and dementia," a Cochrane Review concludes that "there is promising evidence of improvement in cognition and function associated with Ginkgo." According to this review the two randomized controlled studies that focused on Alzheimer's patients both showed significant improvement in these areas. The AAGP review did not recommend Ginkgo neither did it warn against its use. A large, randomized clinical study in the US called the GEM study is underway (fully enrolled) and examining the effect of Ginkgo to prevent dementia. Results are expected in late 2007 or early 2008.

Tobacco

Information in this article or section has not been verified against sources and may not be reliable.
Please check for inaccuracies and modify as needed, citing the sources against which it was checked.

There is limited evidence that tobacco reduces the risk of Alzheimer's disease.The overall evidence, however, is not convincing, the research is very limited and the results are mixed. In some cases, tobacco actually increases the risk of Alzheimer's disease. A study was done saying tobacco users were much less likely to get Alzheimer's than non-users. But the authors of the study admitted that this might just be because most people do not get Alzheimer's until they are 75 and most tobacco users do not live to be that old. Some scientists are studying the possibility of using nicotine to treat Alzheimer's, believing that it acts as an anti-inflamatory agent in the central nervous system.

NMDA antagonists

Recent evidence of the involvement of glutamatergic neuronal excitotoxicity causes 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. Memantine is marketed as Akatinol, Axura, Ebixa and Namenda.

Psychosocial interventions

Cognitive and behavioral interventions and rehabilitation strategies may be used as an adjunct to pharmacologic 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.

Treatments in clinical development

A large number of potential treatments for Alzheimer's disease are currently under investigation, including four compounds being studied in phase 3 clinical trials. Xaliproden had been shown to reduce neurodegeneration in animal studies. Tramiprosate (3APS or Alzhemed) is a GAG-mimetic molecule that is believed to act by binding to soluble amyloid beta to prevent the accumulation of the toxic plaques. 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. Leuprolide has also been studied for Alzheimer’s. It is hypothesized to work by reducing leutenizing hormone levels which may be causing damage in the brain as one ages.

• 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. However, 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. Microcerebral haemorrhages with passive immunisation and meningoencephalitis with active immunisation still remains to be potent threats to this strategy Work is continuing on less toxic Aβ vaccines, such as a DNA-based therapy that recently showed promise in mice. Researchers from University of South Florida announced a patch version of the drug was shown to be safe and effective when tested on mice.

• Proposed alternative treatments for Alzheimer's include a range of herbal compounds and dietary supplements. In the AAGP review from 2006, Vitamin E in doses below 400 IU was mentioned as having conflicting evidence in efficacy to prevent AD. Higher doses were discouraged as these may be linked with higher mortality related to cardiac events.

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. Recent clinical trials for Phase 2 and Phase 3 in this category have taken 12 to 18 months under study drug, plus additional months for patient enrollment and analysis. Compounds that are just entering into human trials or are in pre-clinical trials would be at least 4 years from being available to the public and would be available only if they can demonstrate safety and efficacy in human trials.

Occupational and lifestyle therapies

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 and guns 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. Appropriate social and visual stimulation, however, 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.

Social issues

Alzheimer's is a major public health challenge since the median age of the industrialized world's population is increasing gradually. 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. However, 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.

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