Changes: Alzheimer’s disease

**Alzheimer’s disease**
ICD-10	G30, F00
ICD-9	331.0, 290.1
OMIM	104300
DiseasesDB	490
MedlinePlus	000760
eMedicine	neuro/13
MeSH	{{{MeshNumber}}}

Revision as of 04:33, 28 August 2014

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Alzheimer dementia (3) presenile onset.jpg|

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive deterioration together with declining activities of daily living and neuropsychiatric symptoms or behavioral changes. It is the most common type of dementia.

The most striking early symptom is loss of short term memory (amnesia), which usually manifests as minor forgetfulness that becomes steadily more pronounced with illness progression, with relative preservation of older memories. As the disorder progresses, cognitive (intellectual) impairment extends to the domains of language (aphasia), skilled movements (apraxia), recognition (agnosia), and those functions (such as decision-making and planning) closely related to the frontal and temporal lobes of the brain as they become disconnected from the limbic system, reflecting extension of the underlying pathological process. These changes make up the essential human qualities, and thus AD is sometimes described as a disease where the victims suffer the loss of qualities that define human existence.

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.

The ultimate cause of the disease is unknown. Genetic factors are known to be important, and dominant mutations in three different genes have been identified that account for a much smaller number of cases of familial, early-onset AD. For the more common form of late onset AD (LOAD), only one susceptibility gene has so far been identified called ApoE4.

Recent research ^[1] suggests that the plaques might be results of microhaemorrhages due to damage of the capillaries in the brain; if that proves to be true then the treatment of the disease might change dramatically.

History

In 1901, Dr. Alois Alzheimer, a German psychiatrist, interviewed a patient named Mrs. Auguste D age 51. He showed her several objects and later asked her what she had been shown. She could not remember. He would initially record her behavior as "amnestic 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 esteemed 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 would be 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, the name of the disease was well established among the specialist community. ^[2]

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. 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 22 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 behaviour often goes unnoticed even by the patients' immediate family.
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 may even lose the ability to walk or eat without assistance.

Diagnosis

The diagnosis is made primarily on the basis of history, clinical observation and tests of memory and intellectual functioning over a series of weeks or months, with various physical tests (blood tests and neuroimaging) being performed to rule out alternative diagnoses. 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).^[3]^[4] 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.^[5] However, when diagnosing individuals with a higher level of cognitive ability, in this study those with IQ's of 120 or more,^[6] 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

Main article: Biochemistry of Alzheimer's disease

Biochemical characteristics

Alzheimer's disease has been identified as a protein misfolding disease, or proteopathy, due to the accumulation of abnormally folded amyloid beta protein and tau protein in the brains of AD patients.^[7] Amyloid beta, also written Aβ, is a short peptide that is a proteolytic byproduct of the transmembrane protein amyloid precursor protein (APP), whose function is unclear but thought to be involved in neuronal development.^[8] The presenilins are components of proteolytic complex involved in APP processing and degradation.^[9] Although amyloid beta monomers are soluble and harmless, they undergo a dramatic conformational change at sufficiently high concentration to form a beta sheet-rich tertiary structure that aggregates to form amyloid fibrils^[10] that deposit outside neurons in dense formations known as senile plaques or neuritic plaques, in less dense aggregates as diffuse plaques, and sometimes in the walls of small blood vessels in the brain in a process called amyloid angiopathy or congophilic angiopathy.

AD is also considered a tauopathy due to abnormal aggregation of the tau protein, a microtubule-associated protein expressed in neurons that normally acts to stabilize microtubules in the cell cytoskeleton. Like most microtubule-associated proteins, tau is normally regulated by phosphorylation; however, in AD patients, hyperphosphorylated tau accumulates as paired helical filaments^[11] that in turn aggregate into masses inside nerve cell bodies known as neurofibrillary tangles and as dystrophic neurites associated with amyloid plaques.

Neuropathology

Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains.^[12] Through extremely fortunate circumstances the original microscope preparations on which Alzheimer based his description of the disease were rediscovered some years ago in Munich and his findings could thus be reevaluated.^[13] 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.^[14] Levels of the neurotransmitter acetylcholine are reduced. Levels of the neurotransmitters serotonin, norepinephrine, and somatostatin are also often reduced. Glutamate levels are usually elevated.^[15]

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. The medications that treat acetylcholine deficiency have served to only treat symptoms of the disease and have neither halted nor reversed it.^[16] The cholinergic hypothesis has not maintained widespread support in the face of this evidence, although cholingeric effects have been proposed to initiate large-scale aggregation^[17] leading to generalized neuroinflammation.^[14]

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 believes that beta amyloid deposits are the causative factor in the disease.^[18] The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques do not correlate well with neuron loss;^[19] however, a majority of researchers support the alternative hypothesis that amyloid is the primary causative agent.^[18]

The amyloid hypothesis is initially compelling because the gene for the amyloid beta precursor APP is located on chromosome 21, and patients with trisomy 21 - better known as Down syndrome - who thus have an extra gene copy almost universally exhibit AD-like disorders by 40 years of age.^[20]^[21] 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.^[22] A more recent and widely supported hypothesis suggests that the cytotoxic species is an intermediate misfolded form of amyloid beta, neither a soluble monomer nor a mature aggregated polymer but an oligomeric species.^[23] Relevantly, much early development work on lead compounds has focused on the inhibition of fibrillization,^[24]^[25]^[26] but the toxic-oligomer theory would imply that prevention of oligomeric assembly is the more important process^[27] or that a better target lies upstream, for example in the inhibition of APP processing to amyloid beta.^[28]

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, beta-amyloid deposition precedes clinical AD.^[29] Another strong support for the amyloid hypothesis, which looks at the beta-amyloid as the common initiating factor for the Alzheimer's disease, is that transgenic mice solely expressing a mutant human APP gene develop first diffuse and then fibrillar beta-amyloid plaques, associated with neuronal and microglial damage.^[30]^[31]^[32]

Genetics

Rare cases of Alzheimer's are caused by dominant genes that run in families. These cases often have an early age of onset. Mutations in presenilin-1 or presenilin-2 genes have been documented in some families. Mutations of presenilin 1 (PS1) lead to the most aggressive form of familial Alzheimer's disease (FAD).^[33] Evidence from rodent studies suggests that the FAD mutation of PS1 results in impaired hippocampal-dependent learning which is correlated with reduced adult neurogenesis in the dentate gyrus.^[34] Mutations in the APP gene on chromosome 21 can also cause early onset disease. The presenilins have been identified as essential components of the proteolytic processing machinery that produces beta amyloid peptides through cleavage of APP.

Most cases identified are "sporadic" with no clear family history. Environmental factors sometimes claimed to increase risk of Alzheimer's including prior head injury,^[35] particularly repeated trauma,^[36] previous incidents of migraine headaches,^[37] exposure to defoliants,^[37] and low activity levels during adulthood.^[38] However, with the exception of previous concussion, none of these environmental risk factors are widely accepted.

Inheritance of the ε4 allele of the ApoE gene is regarded as a risk factor for development of disease, but large-scale genetic association studies raise the possibility that even this does not indicate susceptibility so much as how early one is likely to develop Alzheimer's. There is speculation among genetic experts that there are other risk and protective factor genes that may influence the development of late onset Alzheimer's disease (LOAD). Researchers are investigating the possibility that the regulatory regions of various Alzheimer's associated genes could be important in sporadic Alzheimer's, especially inflammatory activation of these genes. These hypotheses include the amyloid-β precursor protein (APP),^[39] the beta secretase enzymes^[40] insulin-degrading enzyme^[41] endothelin-converting enzymes^[42] and inflammatory 5-lipoxygenase gene.^[43]

Genetic linkage

Alzheimer's disease is definitely linked to the 1st, 14th,^[44] and 21st chromosomes, but other linkages are controversial and not yet confirmed. While some genes predisposing to AD have been identified , such as ApoE4 on chromosome 19, sporadic AD also involves other risk and protective genes still awaiting confirmation.

Epidemiology

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.^[45] 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.^[46]

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.^[47] 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.

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. Therefore, prevention of these conditions can lower risk of developing Alzheimer's, as well as heart attack and stroke.

Risk reducers

Intellectual stimulation (e.g., playing chess or doing crosswords)^[48]
Regular physical exercise^[49]
Regular social interaction [9]. Lonely individuals may be twice as likely to develop the type of dementia linked to Alzheimer’s disease in late life as those who are not lonely.
A Mediterranean diet with fruits and vegetables and low in saturated fat,^[50] supplemented in particular with:
- B vitamins^[51] in particular, folic acid.^[52]^[53]^[54]^[55]
- Curry^[56]
- Omega-3 fatty acids, especially Docosahexaenoic acid^[57]^[58]
- Fruit and vegetable juice^[59]^[60]
- 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^[61]^[62]
- The moderate consumption of alcohol (beer, wine or distilled spirits) ^[63]
Cholesterol-lowering drugs (statins) reduce Alzheimer's risk in observational studies but so far not in randomized controlled trials^[64]
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.^[65]^[66] The risks appear to outweigh the drugs' benefit as a method of primary prevention.^[67]

Risk factors

Advancing age
ApoE epsilon 4 genotype (in some populations) [ ]
Environmental exposure to aluminum [10]
Head injury^[68]
Poor cardiovascular health (including diabetes,^[69] hypertension,^[70] high cholesterol^[71] and strokes)^[72]
Smoking^[73]

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.^[67]

Drug treatments

Main article: Antidementia drugs

Acetylcholinesterase inhibitors

Acetylcholinesterase inhibitors were 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.^[74]^[75]^[76]

Examples include:

tacrine - no longer clinically used (formerly marketed as Cognex)
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)

The three currently marketed products each comes in an oral form taken once or twice a day. Rivastigmine is also available as a once-daily transdermal patch.

There is some question 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.^[77]^[78] The pharmaceutical companies, but also some independent clinicians, dispute the conclusions of these articles.

Ginkgo biloba

Examining over 52 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. ^[79] The AAGP review^[67] 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. ^[80]

NMDA antagonists

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.^[81] 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 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.^[82]^[83]

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.^[84] 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.^[85]^[86] Leuprolide has also been studied for Alzheimer’s. It is hypothesized to work by reducing luteinizing hormone levels which may be causing damage in the brain as one ages.^[87]

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.^[88] Work is continuing on less toxic Aβ vaccines.

The statin simvastatin has been found to reduce the incidence of Alzheimer's disease and Parkinsons disease by almost 50 percent by resarchers from Boston University School of Medicine (BUSM).^[89]

Proposed alternative treatments for Alzheimer's include a range of herbal compounds and dietary supplements. In the AAGP review from 2006,^[67] 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^[90] 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.^[91] 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.^[92]

Social issues

Alzheimer's is a major public health challenge since the median age of the industrialized world's population is increasing gradually.^[93] 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.^[94]

Statistics on Alzheimer's disease

In the United States of America, AD was the 7th leading cause of death in 2004, with 65,829 number of deaths (and rising).^[95]
At over $100 billion per year, AD is the third most costly disease in the U.S., after heart disease and cancer.^[96]
There are an estimated 24 million people with dementia worldwide.^[97] By 2040, it is projected that this figure will have increased to 81 million.
More than 5 million Americans are estimated to have Alzheimer’s disease.^[98] It is projected that 14.3 million Americans will have the disease by mid-century: a 350 percent increase from 2000.^[99]
The federal government estimates spending approximately $647 million for Alzheimer’s disease research in fiscal year 2005.^[98]

Journals

Alzheimer Disease and Associated Disorders
Alzheimer's & Dementia

Journals

- Alzheimer Disease and Associated Disorders
- Journal of Alzheimer's Disease

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↑ Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, Niinistö L, Halonen P, Kontula K (1995). Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein.. N Engl J Med 333 (19): 1242-7. PMID 7566000.
↑ Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F (1995). Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein.. Nature 373 (6514): 523-7. PMID 7845465.
↑ Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D (1996). Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimer's disease.. J Neurosci 16 (18): 5795-811. PMID 8795633.
↑ Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996). Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice.. Science 274 (5284): 99-102. PMID 8810256.
↑ Vetrivel KS, Zhang YW, Xu H, Thinakaran G. (2006). Pathological and physiological functions of presenilins.. Mol Neurodegener 12: 1-4. PMID 16930451.
↑ Wang R, Dineley K, Sweatt J, Zheng H (2004). Presenilin 1 familial Alzheimer's disease mutation leads to defective associative learning and impaired adult neurogenesis.. Neuroscience 126 (2): 305-12. PMID 15207348.
↑ Jellinger KA (2006). Head injury and dementia.. Curr Opin Neurol 17 (6): 719-23. PMID 15542981.
↑ Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Cantu RC, Randolph C, Jordan BD (2006). Association between recurrent concussion and late-life cognitive impairment in retired professional football players.. Neurosurgery 57 (4): 719-26. PMID 16239884.
↑ ^37.0 ^37.1 Tyas SL, Manfreda J, Strain LA, Montgomery PR. (2001). Risk factors for Alzheimer's disease: a population-based, longitudinal study in Manitoba, Canada.. Int J Epidemiol 30 (3): 590-7. PMID 11416089.
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↑ Lahiri D, Ghosh C, Ge Y. A proximal gene promoter region for the beta-amyloid precursor protein provides a link between development, apoptosis, and Alzheimer's disease.. Ann N Y Acad Sci 1010: 643-7. PMID 15033805.
↑ Cacabelos R, Fernandez-Novoa L, Lombardi V, Kubota Y, Takeda M. Molecular genetics of Alzheimer's disease and aging.. Methods Find Exp Clin Pharmacol 27 Suppl A: 1-573. PMID 16470248.
↑ Nowotny P, Hinrichs A, Smemo S, Kauwe J, Maxwell T, Holmans P, Hamshere M, Turic D, Jehu L, Hollingworth P, Moore P, Bryden L, Myers A, Doil L, Tacey K, Gibson A, McKeith I, Perry R, Morris C, Thal L, Morris J, O'Donovan M, Lovestone S, Grupe A, Hardy J, Owen M, Williams J, Goate A (2005). Association studies between risk for late-onset Alzheimer's disease and variants in insulin degrading enzyme.. Am J Med Genet B Neuropsychiatr Genet 136 (1): 62-8. PMID 15858813.
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↑ Van Broeckhoven C, Backhovens H, Cruts M, De Winter G, Bruyland M, Cras P, Martin JJ., Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3, Nat Genet. 1992 Dec;2(4):335-9.
↑ Gorelick P (2004). Risk factors for vascular dementia and Alzheimer disease.. Stroke 35 (11 Suppl 1): 2620-2. PMID 15375299.
↑ Hebert L, Scherr P, Bienias J, Bennett D, Evans D (2003). Alzheimer disease in the US population: prevalence estimates using the 2000 census.. Arch Neurol 60 (8): 1119-22. PMID 12925369.
↑ Small, Gary W (2002-06-22). What we need to know about age related memory loss. British Medical Journal: 1502-1507.
↑ Verghese J, Lipton R, Katz M, Hall C, Derby C, Kuslansky G, Ambrose A, Sliwinski M, Buschke H (2003). Leisure activities and the risk of dementia in the elderly.. N Engl J Med 348 (25): 2508-16. PMID 12815136.
↑ Larson E, Wang L, Bowen J, McCormick W, Teri L, Crane P, Kukull W (2006). Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older.. Ann Intern Med 144 (2): 73-81. PMID 16418406.
↑ Scarmeas N, Stern Y, Mayeux R, Luchsinger J (2006). Mediterranean diet, Alzheimer disease, and vascular mediation.. Arch Neurol 63 (12): 1709-17. PMID 17030648.
↑ Morris M, Schneider J, Tangney C (2006). Thoughts on B-vitamins and dementia.. J Alzheimers Dis 9 (4): 429-33. PMID 16917152.
↑ Inna I. Kruman1, T. S. Kumaravel2, Althaf Lohani2, Ward A. Pedersen1, Roy G. Cutler1, Yuri Kruman1, Norman Haughey1, Jaewon Lee1, Michele Evans2, and Mark P. Mattson1, 3 (March 1, 2002). Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Them to Amyloid Toxicity in Experimental Models of Alzheimer's Disease .. The Journal of Neuroscience, 22 (5). A simplified report can be found at: www.alzheimers.org.uk
↑ CBS news, reporting from WebMD Folate May Lower Alzheimer's Risk
↑ National Institute of Health - Folic Acid Possibly A Key Factor In Alzheimer's Disease Prevention
↑ Alzheimer's and Dementia journal, reported at USA today[1]
↑ Giselle P. Lim1, Teresa Chu1, Fusheng Yang, Walter Beech1, Sally A. Frautschy1, and Greg M. Cole1 (2001). The Curry Spice Curcumin Reduces Oxidative Damage and Amyloid Pathology in an Alzheimer Transgenic Mouse. The Journal of Neuroscience 21 (4): 8370-8377. PMID 11606625.
↑ Lim W, Gammack J, Van Niekerk J, Dangour A. Omega 3 fatty acid for the prevention of dementia.. Cochrane Database Syst Rev: CD005379. PMID 16437528.
↑ Morris M, Evans D, Tangney C, Bienias J, Wilson R (2005). Fish consumption and cognitive decline with age in a large community study.. Arch Neurol 62 (12): 1849-53. PMID 16216930.
↑ Dai Q, Borenstein A, Wu Y, Jackson J, Larson E (2006). Fruit and vegetable juices and Alzheimer's disease: the Kame Project.. Am J Med 119 (9): 751-9. PMID 16945610.
↑ Joseph J, Fisher D, Carey A (2004). Fruit extracts antagonize Abeta- or DA-induced deficits in Ca2+ flux in M1-transfected COS-7 cells.. J Alzheimers Dis 6 (4): 403-11; discussion 443-9. PMID 15345811.
↑ Petersen R, Thomas R, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck C, Thal L (2005). Vitamin E and donepezil for the treatment of mild cognitive impairment.. N Engl J Med 352 (23): 2379-88. PMID 15829527.
↑ Zandi P, Anthony J, Khachaturian A, Stone S, Gustafson D, Tschanz J, Norton M, Welsh-Bohmer K, Breitner J (2004). Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study.. Arch Neurol 61 (1): 82-8. PMID 14732624.
↑ Scarmeas, N., et al. Mediterranean diet and risk for Alzheimer’s disease. Annals of Neurology, 2006 (published online April 18, 2006). Other research is consistent with the finding that moderate alcohol consumption is associated with lower risk of Alzheimer’s and other forms of dementia: Mulkamal, K.J., et al. Prospective study of alcohol consumption and risk of dementia in older adults. Journal of the American Medical Association, 2003 (March 19), 289, 1405-1413; Ganguli, M., et al. Alcohol consumption and cognitive function in late life: A longitudinal community study. Neurology, 2005, 65, 1210-12-17; Huang, W., et al. Alcohol consumption and incidence of dementia in a community sample aged 75 years and older. Journal of Clinical Epidemiology, 2002, 55(10), 959-964; Rodgers, B., et al. Non-linear relationships between cognitive function and alcohol consumption in young, middle-aged and older adults: The PATH Through Life Project. Addiction, 2005, 100(9), 1280-1290; Anstey, K. J., et al. Lower cognitive test scores observed in alcohol are associated with demographic, personality, and biological factors: The PATH Through Life Project. Addiction, 2005, 100(9), 1291-1301; Espeland, M., et al. Association between alcohol intake and domain-specific cognitive function in older women. Neuroepidemiology, 2006, 1(27), 1-12; Stampfer, M.J., et al. Effects of moderate alcohol consumption on cognitive function in women. New England Journal of Medicine, 2005, 352, 245-253; Ruitenberg, A., et al. Alcohol consumption and risk of dementia: the Rotterdam Study. Lancet, 2002, 359(9303), 281-286.
↑ Rockwood K. Epidemiological and clinical trials evidence about a preventive role for statins in Alzheimer's disease.. Acta Neurol Scand Suppl 185: 71-7. PMID 16866914.
↑ Zandi P, Anthony J, Hayden K, Mehta K, Mayer L, Breitner J (2002). Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study. Neurology 59 (6): 880-6. PMID 12297571.
↑ in t' Veld B, Ruitenberg A, Hofman A, Launer L, van Duijn C, Stijnen T, Breteler M, Stricker B (2001). Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med 345 (21): 1515-21. PMID 11794217.
↑ ^67.0 ^67.1 ^67.2 ^67.3 Lyketsos C, Colenda C, Beck C, Blank K, Doraiswamy M, Kalunian D, Yaffe K (2006). Position statement of the American Association for Geriatric Psychiatry (AAGP) regarding principles of care for patients with dementia resulting from Alzheimer disease.. Am J Geriatr Psychiatry 14 (7): 561-72. PMID 16816009. [2]
↑ Mayeux R, Ottman R, Tang M, Noboa-Bauza L, Marder K, Gurland B, Stern Y (1993). Genetic susceptibility and head injury as risk factors for Alzheimer's disease among community-dwelling elderly persons and their first-degree relatives. Ann. Neurol. 33 (5): 494-501.
↑ Kofman OS, MacMillan VH (1970). Diffuse Cerebral Atrophy.. Applied Therapeutics 12 (4): 24-26.
↑ Kehoe P, Wilcock G (2007). Is inhibition of the renin-angiotensin system a new treatment option for Alzheimer's disease?. Lancet neurology 6 (4): 373-8.
↑ Crisby M, Carlson L, Winblad B (2002). Statins in the prevention and treatment of Alzheimer disease. Alzheimer disease and associated disorders 16 (3): 131-6.
↑ BBC Why stroke ups Alzheimer's risk 4 June 2007
↑ Anstey KJ, von Sanden C, Salim A, O'kearney R (2007). Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies. Am. J. Epidemiol. 166 (4): 367-78.
↑ Ortho-McNeil Neurologics, “Razadyne ER US Product Insert”, May 2006. [3]
↑ Novartis Pharmaceuticals Corporation “Exelon Product Insert” June 2006. [4]
↑ Eisai Inc, “Aricept and Aricept ODT Product Insert”, March 2005. [5]
↑ Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, Edwards S, Hardyman W, Raftery J, Crome P, Lendon C, Shaw H, Bentham P (2004). Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial.. Lancet 363 (9427): 2105-15. PMID 15220031.
↑ Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt H, van den Bussche H (2005). Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials.. BMJ 331 (7512): 321-7. PMID 16081444.
↑ Birks J, Grimley E, Van Dongen M. Ginkgo biloba for cognitive impairment and dementia.. Cochrane Database Syst Rev: CD003120. PMID 12519586..
↑ DeKosky S, Fitzpatrick A, Ives D, Saxton J, Williamson J, Lopez O, Burke G, Fried L, Kuller L, Robbins J, Tracy R, Woolard N, Dunn L, Kronmal R, Nahin R, Furberg C (2006). The Ginkgo Evaluation of Memory (GEM) study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia.. Contemp Clin Trials 27 (3): 238-53. PMID 16627007..
↑ Areosa Sastre A, McShane R, Sherriff F. Memantine for dementia.. Cochrane Database Syst Rev: CD003154. PMID 15495043.
↑ Olazarán J, Muñiz R, Reisberg B, Peña-Casanova J, del Ser T, Cruz-Jentoft A, Serrano P, Navarro E, García de la Rocha M, Frank A, Galiano M, Fernández-Bullido Y, Serra J, González-Salvador M, Sevilla C (2004). Benefits of cognitive-motor intervention in MCI and mild to moderate Alzheimer disease.. Neurology 63 (12): 2348-53. PMID 15623698.
↑ Clare L, Woods R, Moniz Cook E, Orrell M, Spector A. Cognitive rehabilitation and cognitive training for early-stage Alzheimer's disease and vascular dementia.. Cochrane Database Syst Rev: CD003260. PMID 14583963.
↑ Lemaire L, Fournier J, Ponthus C, Le Fur Y, Confort-Gouny S, Vion-Dury J, Keane P, Cozzone P (2002). Magnetic resonance imaging of the neuroprotective effect of xaliproden in rats.. Invest Radiol 37 (6): 321-7. PMID 12021588.
↑ Zamrini E (2006). Emerging Drug Therapies for Dementia.. Geriatrics Aging 9 (2): 107,110-113. [6].
↑ Eriksen J, Sagi S, Smith T, Weggen S, Das P, McLendon D, Ozols V, Jessing K, Zavitz K, Koo E, Golde T (2003). NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo.. J Clin Invest 112 (3): 440-9. PMID 12897211..
↑ Casadesus G, Garrett M, Webber K, Hartzler A, Atwood C, Perry G, Bowen R, Smith M (2006). The estrogen myth: potential use of gonadotropin-releasing hormone agonists for the treatment of Alzheimer's disease.. Drugs R D 7 (3): 187-93. PMID 16752944..
↑ Alzheimer’s Association Fact Sheet: AN-1792 (2006, on ALZ.org). URL accessed on 2006-11-06..
↑ Researchers Find Specific Statin Significantly Reduces Alzheimer's and Parkinson's Disease Risk. URL accessed on 2007-08-06..
↑ Landreth G (2006). PPARgamma agonists as new therapeutic agents for treatment of Alzheimer's disease.. Exp Neurol 199 (2): 245-8. PMID 16733054.
↑ Treating behavioral and psychiatric symptoms. Alzheimer's Association. Accessed Oct. 15, 2006.[7]
↑ Dunne TE, Neargarder SA, Cipolloni PB, Cronin-Golomb A. (2004). Visual contrast enhances food and liquid intake in advanced Alzheimer's disease. Clin Nutr 23 (4): 533-8. PMID 15297089.
↑ Sloane P, Zimmerman S, Suchindran C, Reed P, Wang L, Boustani M, Sudha S. The public health impact of Alzheimer's disease, 2000-2050: potential implication of treatment advances.. Annu Rev Public Health 23: 213-31. PMID 11910061.
↑ The MetLife Study of Alzheimer’s Disease: The Caregiving Experience. MetLife Mature Market Institute ® (August 2006). [8]
↑ Faststats – Alzheimer's Disease National Center for Health Statistics
↑ Alzheimer's Drug Discovery Foundation 2005 Annual Report
↑ Statistics - Alzheimer's Disease International
↑ ^98.0 ^98.1 Alzheimer's Facts and Figures Alzheimer's Association
↑ Diagnostic Center for Alzheimer's Disease

Snowdon DA, Nun Study (2003) Healthy aging and dementia: findings from the Nun Study. Ann Intern Med 139: 450-4
Riley KP, Snowdon DA, Markesbery WR (2002) Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study. Ann Neurol 51: 567-77
Gosche KM, Mortimer JA, Smith CD, Markesbery WR, Snowdon DA (2002) Hippocampal volume as an index of Alzheimer neuropathology: findings from the Nun Study. Neurology 58: 1476-82
Snowdon DA, Greiner LH, Mortimer JA, et al. (1997) Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 277: 813-7
Snowdon DA, Kemper SJ, Mortimer JA, et al. (1996) Linguistic ability in early life and cognitive function and Alzheimer’s disease in late life: Findings from the Nun Study. JAMA 275: 528-32

External links

Alzheimer's Association - The major Alzheimer's support and advocacy group in the United States provides excellent information on topics ranging from basics of diagnosis and caregiving to the disease's legal implications and ways to talk to children about the disease. Similar groups provide country-specific information in Australia and Canada.
Alzheimer's Research Forum - A website intended to provide information to and foster collaboration among scientists and physicians conducting research on Alzheimer's. Features debates between and article annotations by many top Alzheimer's researchers
National Institute on Aging - Substantial website by a division of the U.S. National Institutes of Health with links to information about ongoing clinical studies
Alzheimerseurope.org - European Site for physicians dedicated to Alzheimers
Alzheimer's Disease Research Centers - Links to each of the NIH-funded centers of excellence for Alzheimer's disease located at academic medical centers scattered throughout the U.S.
OMIM - Running, highly technical synopsis of research on Alzheimer's disease maintained by the NIH
Can marijuana help treat Alzheimer's Disease? Pro, con, and neutral views on the utility of cannabis in treating Alzheimer's
Journal of Alzheimer's Disease - Subscription required for full text
eMedicine - Well-organized article on Alzheimer's
100 years of Alzheimer’s Disease

This page uses Creative Commons Licensed content from Wikipedia (view authors).

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Changes: Alzheimer’s disease

Revision as of 04:33, 28 August 2014

Contents

History

Clinical features

Stages and symptoms

Diagnosis

Pathology

Biochemical characteristics

Neuropathology

Disease mechanism

Genetics

Genetic linkage

Epidemiology

Prevention

Risk reducers

Risk factors

Treatment

Drug treatments

Acetylcholinesterase inhibitors

Ginkgo biloba

NMDA antagonists

Psychosocial interventions

Treatments in clinical development

Occupational and lifestyle therapies

Social issues

Statistics on Alzheimer's disease

Journals

See also

Journals

References

External links

@@ Line 1: / Line 1: @@
 {{ClinPsy}}
+{{PsyPerspective}}
 {{Infobox_Disease |
   Name           = {{PAGENAME}} |
@@ Line 23: / Line 23: @@
 This pathological process consists principally of [[neuron]]al loss or [[atrophy]], principally in the temporoparietal cortex, but also in the frontal cortex, together with an inflammatory response to the deposition of [[amyloid|amyloid plaques]] and [[neurofibrillary tangles]].
-The ultimate cause of the disease is unknown. Genetic factors are known to be important, and dominant [[mutations]] in three different genes have been identified that account for a much smaller number of cases of [[Familial Alzheimer disease|familial, early-onset AD]]. For the more common form of late onset AD (LOAD), only one susceptibility gene has so far been identified called [[Apolipoprotein E | ApoE4]].
+The ultimate cause of the disease is unknown. Genetic factors are known to be important, and dominant [[mutations]] in three different genes have been identified that account for a much smaller number of cases of [[Familial Alzheimer disease|familial, early-onset AD]]. For the more common form of [[Late onset Alzheimer's disease|late onset AD]] (LOAD), only one susceptibility gene has so far been identified called [[Apolipoprotein E | ApoE4]].
 Recent research <ref> {{cite journal | author = Cullen KM, Kócsi Z, Stone J | title = Microvascular pathology in the aging human brain: Evidence that senile plaques are sites of microhaemorrhages | journal = Neurobiology of Aging | volume = 27 | issue = 12 | year = 2006 | id = PMID 17063559 }} </ref> suggests that the plaques might be results of microhaemorrhages due to damage of the capillaries in the brain; if that proves to be true then the treatment of the disease might change dramatically.
@@ Line 30: / Line 30: @@
 In 1901, Dr. [[Alois Alzheimer]], a German psychiatrist, interviewed a patient named Mrs. Auguste D age 51. He showed her several objects and later asked her what she had been shown.  She could not remember. He would initially record her behavior as "amnestic 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 esteemed [[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 would be 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, the name of the disease was well established among the specialist community.
+Alzheimer would later work  in the laboratory of the esteemed [[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 would be 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, the name of the disease was well established among the specialist community.
 <ref> {{cite book | last =Maurer | first =Konrad | coauthors =Maurer, Ulrike | title = Alzheimer: the life of a physician and the career of a disease | publisher = Columbia University Press  | date =2003 | location =New York | id=  ISBN 0-231-11896-1}}</ref>
@@ Line 66: / Line 66: @@
 }}</ref>
 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==
 {{main|Biochemistry of Alzheimer's disease}}
 ===Biochemical characteristics===
-Alzheimer's disease has been identified as a [[protein folding|protein misfolding]] disease due to the accumulation of abnormally folded [[amyloid beta]] protein in the brains of AD patients.<ref name="Hashimoto"> {{cite journal | author = Hashimoto M, Rockenstein E, Crews L, Masliah E | title = Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases. | journal = Neuromolecular Med | volume = 4 | issue = 1-2 | pages = 21-36 | year = 2003 | id = PMID 14528050}}</ref> Amyloid beta, also written Aβ, is a short [[peptide]] that is an abnormal [[proteolysis|proteolytic]] byproduct of the [[transmembrane protein]] [[amyloid precursor protein]] (APP), whose function is unclear but thought to be involved in neuronal development.<ref name="Kerr">{{cite journal | author = Kerr M, Small D | title = Cytoplasmic domain of the beta-amyloid protein precursor of Alzheimer's disease: function, regulation of proteolysis, and implications for drug development. | journal = J Neurosci Res | volume = 80 | issue = 2 | pages = 151-9 | year = 2005 | id = PMID 15672415}} </ref>  The [[presenilin]]s are components of proteolytic complex involved in APP processing and degradation.<ref name="Cai"> {{cite journal | author = Cai D, Netzer W, Zhong M, Lin Y, Du G, Frohman M, Foster D, Sisodia S, Xu H, Gorelick F, Greengard P | title = Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation. | journal = Proc Natl Acad Sci U S A | volume = 103 | issue = 6 | pages = 1941-6 | year = 2006 | id = PMID 16449386}}</ref> Although amyloid beta [[monomer]]s are soluble and harmless, they undergo a dramatic [[conformational change]] at sufficiently high concentration to form a [[beta sheet]]-rich [[tertiary structure]] that aggregates to form [[amyloid|amyloid fibrils]]<ref name="Ohnishi">{{cite journal | author = Ohnishi S, Takano K | title = Amyloid fibrils from the viewpoint of protein folding. | journal = Cell Mol Life Sci | volume = 61 | issue = 5 | pages = 511-24 | year = 2004 | id = PMID 15004691}}</ref> that deposit outside neurons in dense formations known as ''senile plaques'' or ''neuritic plaques'', in less dense aggregates as ''diffuse plaques'', and sometimes in the walls of small blood vessels in the brain in a process called amyloid angiopathy or [[congophilic angiopathy]].
+Alzheimer's disease has been identified as a [[protein folding|protein misfolding]] disease, or [[proteopathy]], due to the accumulation of abnormally folded [[amyloid beta]] protein and [[tau protein]] in the brains of AD patients.<ref name="Hashimoto"> {{cite journal | author = Hashimoto M, Rockenstein E, Crews L, Masliah E | title = Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases. | journal = Neuromolecular Med | volume = 4 | issue = 1-2 | pages = 21-36 | year = 2003 | id = PMID 14528050}}</ref> Amyloid beta, also written Aβ, is a short [[peptide]] that is a [[proteolysis|proteolytic]] byproduct of the [[transmembrane protein]] [[amyloid precursor protein]] (APP), whose function is unclear but thought to be involved in neuronal development.<ref name="Kerr">{{cite journal | author = Kerr M, Small D | title = Cytoplasmic domain of the beta-amyloid protein precursor of Alzheimer's disease: function, regulation of proteolysis, and implications for drug development. | journal = J Neurosci Res | volume = 80 | issue = 2 | pages = 151-9 | year = 2005 | id = PMID 15672415}} </ref>  The [[presenilin]]s are components of proteolytic complex involved in APP processing and degradation.<ref name="Cai"> {{cite journal | author = Cai D, Netzer W, Zhong M, Lin Y, Du G, Frohman M, Foster D, Sisodia S, Xu H, Gorelick F, Greengard P | title = Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation. | journal = Proc Natl Acad Sci U S A | volume = 103 | issue = 6 | pages = 1941-6 | year = 2006 | id = PMID 16449386}}</ref> Although amyloid beta [[monomer]]s are soluble and harmless, they undergo a dramatic [[conformational change]] at sufficiently high concentration to form a [[beta sheet]]-rich [[tertiary structure]] that aggregates to form [[amyloid|amyloid fibrils]]<ref name="Ohnishi">{{cite journal | author = Ohnishi S, Takano K | title = Amyloid fibrils from the viewpoint of protein folding. | journal = Cell Mol Life Sci | volume = 61 | issue = 5 | pages = 511-24 | year = 2004 | id = PMID 15004691}}</ref> that deposit outside neurons in dense formations known as ''senile plaques'' or ''neuritic plaques'', in less dense aggregates as ''diffuse plaques'', and sometimes in the walls of small blood vessels in the brain in a process called amyloid angiopathy or [[congophilic angiopathy]].
-AD is also considered a [[tauopathy]] due to abnormal aggregation of the [[tau protein]], a [[microtubule-associated protein]] expressed in neurons that normally acts to stabilize [[microtubules]] in the cell [[cytoskeleton]]. Like most microtubule-associated proteins, tau is normally regulated by [[phosphorylation]]; however, in AD patients, hyperphosphorylated tau accumulated as paired helical filaments<ref name="Goedert">{{cite journal | author = Goedert M, Klug A, Crowther R | title = Tau protein, the paired helical filament and Alzheimer's disease. | journal = J Alzheimers Dis | volume = 9 | issue = 3 Suppl | pages = 195-207 | year = 2006 | id = PMID 16914859}}</ref> that in turn aggregate into masses inside nerve cell bodies known as ''neurofibrillary tangles'' and as dystrophic [[neurite]]s associated with amyloid plaques.
+AD is also considered a [[tauopathy]] due to abnormal aggregation of the [[tau protein]], a [[microtubule-associated protein]] expressed in neurons that normally acts to stabilize [[microtubules]] in the cell [[cytoskeleton]]. Like most microtubule-associated proteins, tau is normally regulated by [[phosphorylation]]; however, in AD patients, hyperphosphorylated tau accumulates as paired helical filaments<ref name="Goedert">{{cite journal | author = Goedert M, Klug A, Crowther R | title = Tau protein, the paired helical filament and Alzheimer's disease. | journal = J Alzheimers Dis | volume = 9 | issue = 3 Suppl | pages = 195-207 | year = 2006 | id = PMID 16914859}}</ref> that in turn aggregate into masses inside nerve cell bodies known as ''neurofibrillary tangles'' and as dystrophic [[neurite]]s associated with amyloid plaques.
 ===Neuropathology===
-Both amyloid plaques and neurofibrillary tangles are clearly visible by [[microscopy]] in AD brains.<ref name="Tiraboschi">{{cite journal | author = Tiraboschi P, Hansen L, Thal L, Corey-Bloom J | title = The importance of neuritic plaques and tangles to the development and evolution of AD. | journal = Neurology | volume = 62 | issue = 11 | pages = 1984-9 | year = 2004 | id = PMID 15184601}}</ref> 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]].<ref name="Wenk">{{cite journal | author = Wenk G | title = Neuropathologic changes in Alzheimer's disease. | journal = J Clin Psychiatry | volume = 64 Suppl 9 | issue = | pages = 7-10 | year = | id = PMID 12934968}}</ref> Levels of the neurotransmitter [[acetylcholine]] are reduced. Levels  of the neurotransmitters [[serotonin]], [[norepinephrine]], and [[somatostatin]] are also often reduced. [[Glutamate]] levels are usually elevated.<ref>
+Both amyloid plaques and neurofibrillary tangles are clearly visible by [[microscopy]] in AD brains.<ref name="Tiraboschi">{{cite journal | author = Tiraboschi P, Hansen L, Thal L, Corey-Bloom J | title = The importance of neuritic plaques and tangles to the development and evolution of AD. | journal = Neurology | volume = 62 | issue = 11 | pages = 1984-9 | year = 2004 | id = PMID 15184601}}</ref> Through extremely fortunate circumstances the original microscope preparations on which Alzheimer based his description of the disease were rediscovered some years ago in Munich and his findings could thus be reevaluated.<ref name="Graeber">{{cite journal | author = Graeber MB, Koesel S, Egensperger R, Banati RB, Mueller U, Bise K, Hoff P, Moeller HJ, Fujisawa K, Mehraein P | title = Rediscovery of the case described by Alois Alzheimer in 1911: historical, histological and molecular genetic analysis.  journal = Neurogenetics | volume = 1 | pages = 73-80 | year = 1997}}</ref> 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]].<ref name="Wenk">{{cite journal | author = Wenk G | title = Neuropathologic changes in Alzheimer's disease. | journal = J Clin Psychiatry | volume = 64 Suppl 9 | issue = | pages = 7-10 | year = | id = PMID 12934968}}</ref> Levels of the neurotransmitter [[acetylcholine]] are reduced. Levels  of the neurotransmitters [[serotonin]], [[norepinephrine]], and [[somatostatin]] are also often reduced. [[Glutamate]] levels are usually elevated.<ref>
 {{cite web
   | last = Baskys
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 ===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 begins as a deficiency in the production of the [[neurotransmitter]] [[acetylcholine]]. The medications that treat acetylcholine deficiency have served to only treat symptoms of the disease and have neither halted nor reversed it. The cholinergic hypothesis has not maintained widespread support in the face of this evidence, although cholingeric effects have been proposed to initiate large-scale aggregation<ref name="Shen">{{cite journal | author = Shen Z | title = Brain cholinesterases: II. The molecular and cellular basis of Alzheimer's disease. | journal = Med Hypotheses | volume = 63 | issue = 2 | pages = 308-21 | year = 2004 | id = PMID 15236795}} </ref> leading to generalized neuroinflammation.<ref name="Wenk" />
+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]]. The medications that treat acetylcholine deficiency have served to only treat symptoms of the disease and have neither halted nor reversed it.<ref name="Rosen">{{cite journal | author = Walker LC, Rosen RF | title = Alzheimer therapeutics: What after the cholinesterase inhibitors? | journal = Age Ageing | volume = 35 | pages = 332-335 | year = 2006 | id = PMID 16644763}}</ref> The cholinergic hypothesis has not maintained widespread support in the face of this evidence, although cholingeric effects have been proposed to initiate large-scale aggregation<ref name="Shen">{{cite journal | author = Shen Z | title = Brain cholinesterases: II. The molecular and cellular basis of Alzheimer's disease. | journal = Med Hypotheses | volume = 63 | issue = 2 | pages = 308-21 | year = 2004 | id = PMID 15236795}} </ref> leading to generalized neuroinflammation.<ref name="Wenk" />
-Research after 2000 includes hypotheses centered on the effects of the misfolded and aggregated proteins, amyloid beta and tau. The two positions are lightheartedly described as "ba-ptist" and "tau-ist" viewpoints in scientific publications by Alzheimer's disease researchers.  "Tau-ists" believe that the [[tau protein]] abnormalities initiate the disease cascade, while "ba-ptists" believe that [[beta amyloid]] deposits are the causative factor in the disease.<ref name="Mudher">{{cite journal | author = Mudher A, Lovestone S | title = Alzheimer's disease-do tauists and baptists finally shake hands? | journal = Trends Neurosci | volume = 25 | issue = 1 | pages = 22-6 | year = 2002 | id = PMID 11801334}}</ref> The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques do not correlate well with neuron loss;<ref name="Schmitz"> {{cite journal | author = Schmitz C, Rutten B, Pielen A, Schäfer S, Wirths O, Tremp G, Czech C, Blanchard V, Multhaup G, Rezaie P, Korr H, Steinbusch H, Pradier L, Bayer T | title = Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease. | journal = Am J Pathol | volume = 164 | issue = 4 | pages = 1495-502 | year = 2004 | id = PMID 15039236}}</ref> however, a majority of researchers support the alternative hypothesis that amyloid is the primary causative agent.<ref name="Mudher" />
+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 believes that [[beta amyloid]] deposits are the causative factor in the disease.<ref name="Mudher">{{cite journal | author = Mudher A, Lovestone S | title = Alzheimer's disease-do tauists and baptists finally shake hands? | journal = Trends Neurosci | volume = 25 | issue = 1 | pages = 22-6 | year = 2002 | id = PMID 11801334}}</ref> The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques do not correlate well with neuron loss;<ref name="Schmitz"> {{cite journal | author = Schmitz C, Rutten B, Pielen A, Schäfer S, Wirths O, Tremp G, Czech C, Blanchard V, Multhaup G, Rezaie P, Korr H, Steinbusch H, Pradier L, Bayer T | title = Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease. | journal = Am J Pathol | volume = 164 | issue = 4 | pages = 1495-502 | year = 2004 | id = PMID 15039236}}</ref> however, a majority of researchers support the alternative hypothesis that amyloid is the primary causative agent.<ref name="Mudher" />
-The amyloid hypothesis is initially compelling because the gene for the amyloid beta precursor APP is located on [[chromosome 21]], and patients with [[trisomy 21]] - better known as Down syndrome - who thus have an extra [[gene dosage|gene copy]] almost universally exhibit AD-like disorders by 40 years of age.<ref name="Nistor">{{cite journal | author =Nistor M, Don M, Parekh M, Sarsoza F, Goodus M, Lopez GE, Kawas C, Leverenz J, Doran E, Lott IT, Hill M, Head E | title = Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain. | journal = Neurobiol Aging | volume = | issue =epub | pages = | year =2006 | id = PMID 16904243}}</ref><ref name="Lott">{{cite journal | author = Lott I, Head E | title = Alzheimer disease and Down syndrome: factors in pathogenesis. | journal = Neurobiol Aging | volume = 26 | issue = 3 | pages = 383-9 | year = 2005 | id = PMID 15639317}} </ref> 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]].<ref name="Yankner">{{cite journal | author = Yankner B, Duffy L, Kirschner D | title = Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. | journal = Science | volume = 250 | issue = 4978 | pages = 279-82 | year = 1990 | id = PMID 2218531}}</ref> A more recent and widely supported hypothesis suggests that the cytotoxic species is an intermediate misfolded form of amyloid beta, neither a soluble monomer nor a mature aggregated polymer but an [[oligomer]]ic species.<ref name="Blanchard1">{{cite journal | author =Blanchard BJ, Hiniker AE, Lu CC, Margolin Y, Yu AS, Ingram VM | title = Elimination of Amyloid beta Neurotoxicity. | journal = J Alzheimers Dis | volume = 2 | issue = 2 | pages = 137-149 | year = 2000 | id = PMID 12214104}} </ref> Relevantly, much early development work on lead compounds has focused on the inhibition of fibrillization,<ref name="Blanchard2">{{cite journal | author = Blanchard B, Chen A, Rozeboom L, Stafford K, Weigele P, Ingram V | title = Efficient reversal of Alzheimer's disease fibril formation and elimination of neurotoxicity by a small molecule. | journal = Proc Natl Acad Sci U S A | volume = 101 | issue = 40 | pages = 14326-32 | year = 2004 | id = PMID 15388848}}</ref><ref name="Porat">{{cite journal | author = Porat Y, Abramowitz A, Gazit E | title = Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. | journal = Chem Biol Drug Des | volume = 67 | issue = 1 | pages = 27-37 | year = 2006 | id = PMID 16492146}}</ref><ref name="Kanapathipillai">{{cite journal | author = Kanapathipillai M, Lentzen G, Sierks M, Park C | title = Ectoine and hydroxyectoine inhibit aggregation and neurotoxicity of Alzheimer's beta-amyloid. | journal = FEBS Lett | volume = 579 | issue = 21 | pages = 4775-80 | year = 2005 | id = PMID 16098972}}</ref> but the toxic-oligomer theory would imply that prevention of oligomeric assembly is the more important process<ref name="Lee">{{cite journal | author = Lee K, Shin B, Shin K, Kim D, Yu J | title = A hybrid molecule that prohibits amyloid fibrils and alleviates neuronal toxicity induced by beta-amyloid (1-42). | journal = Biochem Biophys Res Commun | volume = 328 | issue = 4 | pages = 816-23 | year = 2005 | id = PMID 15707952}}</ref> or that a better target lies upstream, for example in the inhibition of APP processing to amyloid beta.<ref name="Espeseth">{{cite journal | author = Espeseth A, Xu M, Huang Q, Coburn C, Jones K, Ferrer M, Zuck P, Strulovici B, Price E, Wu G, Wolfe A, Lineberger J, Sardana M, Tugusheva K, Pietrak B, Crouthamel M, Lai M, Dodson E, Bazzo R, Shi X, Simon A, Li Y, Hazuda D | title = Compounds that bind APP and inhibit Abeta processing in vitro suggest a novel approach to Alzheimer disease therapeutics. | journal = J Biol Chem | volume = 280 | issue = 18 | pages = 17792-7 | year = 2005 | id = PMID 15737955}}</ref>
+The amyloid hypothesis is initially compelling because the gene for the amyloid beta precursor APP is located on [[chromosome 21]], and patients with [[trisomy 21]] - better known as Down syndrome - who thus have an extra [[gene dosage|gene copy]] almost universally exhibit AD-like disorders by 40 years of age.<ref name="Nistor">{{cite journal | author =Nistor M, Don M, Parekh M, Sarsoza F, Goodus M, Lopez GE, Kawas C, Leverenz J, Doran E, Lott IT, Hill M, Head E | title = Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain. | journal = Neurobiol Aging | volume = | issue =epub | pages = | year =2006 | id = PMID 16904243}}</ref><ref name="Lott">{{cite journal | author = Lott I, Head E | title = Alzheimer disease and Down syndrome: factors in pathogenesis. | journal = Neurobiol Aging | volume = 26 | issue = 3 | pages = 383-9 | year = 2005 | id = PMID 15639317}} </ref> 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]].<ref name="Yankner">{{cite journal | author = Yankner B, Duffy L, Kirschner D | title = Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. | journal = Science | volume = 250 | issue = 4978 | pages = 279-82 | year = 1990 | id = PMID 2218531}}</ref> A more recent and widely supported hypothesis suggests that the cytotoxic species is an intermediate misfolded form of amyloid beta, neither a soluble monomer nor a mature aggregated polymer but an [[oligomer]]ic species.<ref name="Blanchard1">{{cite journal | author =Blanchard BJ, Hiniker AE, Lu CC, Margolin Y, Yu AS, Ingram VM | title = Elimination of Amyloid beta Neurotoxicity. | journal = J Alzheimers Dis | volume = 2 | issue = 2 | pages = 137-149 | year = 2000 | id = PMID 12214104}} </ref> Relevantly, much early development work on [[lead compound]]s has focused on the inhibition of fibrillization,<ref name="Blanchard2">{{cite journal | author = Blanchard B, Chen A, Rozeboom L, Stafford K, Weigele P, Ingram V | title = Efficient reversal of Alzheimer's disease fibril formation and elimination of neurotoxicity by a small molecule. | journal = Proc Natl Acad Sci U S A | volume = 101 | issue = 40 | pages = 14326-32 | year = 2004 | id = PMID 15388848}}</ref><ref name="Porat">{{cite journal | author = Porat Y, Abramowitz A, Gazit E | title = Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. | journal = Chem Biol Drug Des | volume = 67 | issue = 1 | pages = 27-37 | year = 2006 | id = PMID 16492146}}</ref><ref name="Kanapathipillai">{{cite journal | author = Kanapathipillai M, Lentzen G, Sierks M, Park C | title = Ectoine and hydroxyectoine inhibit aggregation and neurotoxicity of Alzheimer's beta-amyloid. | journal = FEBS Lett | volume = 579 | issue = 21 | pages = 4775-80 | year = 2005 | id = PMID 16098972}}</ref> but the toxic-oligomer theory would imply that prevention of oligomeric assembly is the more important process<ref name="Lee">{{cite journal | author = Lee K, Shin B, Shin K, Kim D, Yu J | title = A hybrid molecule that prohibits amyloid fibrils and alleviates neuronal toxicity induced by beta-amyloid (1-42). | journal = Biochem Biophys Res Commun | volume = 328 | issue = 4 | pages = 816-23 | year = 2005 | id = PMID 15707952}}</ref> or that a better target lies upstream, for example in the inhibition of APP processing to amyloid beta.<ref name="Espeseth">{{cite journal | author = Espeseth A, Xu M, Huang Q, Coburn C, Jones K, Ferrer M, Zuck P, Strulovici B, Price E, Wu G, Wolfe A, Lineberger J, Sardana M, Tugusheva K, Pietrak B, Crouthamel M, Lai M, Dodson E, Bazzo R, Shi X, Simon A, Li Y, Hazuda D | title = Compounds that bind APP and inhibit Abeta processing ''in vitro'' suggest a novel approach to Alzheimer disease therapeutics. | journal = J Biol Chem | volume = 280 | issue = 18 | pages = 17792-7 | year = 2005 | id = PMID 15737955}}</ref>
-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, beta-amyloid deposition precedes clinical AD. <ref>{{cite journal | author = Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, Niinistö L, Halonen P, Kontula K | title = Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. | journal = N Engl J Med | volume = 333 | issue = 19 | pages = 1242-7 | year = 1995 | id = PMID 7566000}}</ref> Another strong support for the amyloid hypothesis, which looks at the beta-amyloid as the common initiating factor for the Alzheimer's disease, is that transgenic mice solely expressing a mutant human APP gene develop first diffuse and then fibrillar beta-amyloid plaques, associated with neuronal and microglial damage. <ref>{{cite journal | author = Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F | title = Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. | journal = Nature | volume = 373 | issue = 6514 | pages = 523-7 | year = 1995 | id = PMID 7845465}}</ref> <ref>{{cite journal | author = Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D | title = Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimer's disease. | journal = J Neurosci | volume = 16 | issue = 18 | pages = 5795-811 | year = 1996 | id = PMID 8795633}}</ref>
+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, beta-amyloid deposition precedes clinical AD.<ref>{{cite journal | author = Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, Niinistö L, Halonen P, Kontula K | title = Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. | journal = N Engl J Med | volume = 333 | issue = 19 | pages = 1242-7 | year = 1995 | id = PMID 7566000}}</ref> Another strong support for the amyloid hypothesis, which looks at the beta-amyloid as the common initiating factor for the Alzheimer's disease, is that transgenic mice solely expressing a mutant human APP gene develop first diffuse and then fibrillar beta-amyloid plaques, associated with neuronal and microglial damage.<ref>{{cite journal | author = Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F | title = Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. | journal = Nature | volume = 373 | issue = 6514 | pages = 523-7 | year = 1995 | id = PMID 7845465}}</ref><ref>{{cite journal | author = Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D | title = Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimer's disease. | journal = J Neurosci | volume = 16 | issue = 18 | pages = 5795-811 | year = 1996 | id = PMID 8795633}}</ref><ref>{{cite journal | author = Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G | title = Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. | journal = Science | volume = 274 | issue = 5284 | pages = 99-102 | year = 1996 | id = PMID 8810256}}</ref>
-<ref>{{cite journal | author = Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G | title = Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. | journal = Science | volume = 274 | issue = 5284 | pages = 99-102 | year = 1996 | id = PMID 8810256}}</ref>
-And yet another support for the amyloid hypothesis comes from the knowledge of other amyloid diseases. Humans get many amyloid diseases, generally referred to as amyloidosis. Blocking the production of the responsible amyloid protein ( e.g., beta-amyloid in AD) can successfully treat these diseases <ref> Amyloid and Amyloidosis 1993: The VIIth International Symposium on Amyloidosis, Kingston, Ontario. Kissilevsky, et al., eds. (Parthenon Publishing, New York, NY, 1993)</ref> .
 ===Genetics===
 Rare cases of Alzheimer's are caused by dominant genes that run in families. These cases often have an early age of onset. Mutations in presenilin-1 or presenilin-2 genes have been documented in some families. Mutations of presenilin 1 (PS1) lead to the most aggressive form of [[familial Alzheimer's disease]] (FAD).<ref name="Vetrivel">{{cite journal | author = Vetrivel KS, Zhang YW, Xu H, Thinakaran G. | title = Pathological and physiological functions of presenilins. | journal = Mol Neurodegener | volume = 12 | issue = | pages = 1-4 | year = 2006 | id = PMID 16930451}}</ref>  Evidence from rodent studies suggests that the FAD mutation of PS1 results in impaired [[Hippocampus|hippocampal]]-dependent learning which is correlated with reduced [[Adult Neurogenesis|adult neurogenesis]] in the [[Hippocampus|dentate gyrus]].<ref>{{cite journal | author = Wang R, Dineley K, Sweatt J, Zheng H | title = Presenilin 1 familial Alzheimer's disease mutation leads to defective associative learning and impaired adult neurogenesis. | journal = Neuroscience | volume = 126 | issue = 2 | pages = 305-12 | year = 2004 | id = PMID 15207348}}</ref>  Mutations in the APP gene on [[chromosome]] 21 can also cause early onset disease. The presenilins have been identified as essential components of the proteolytic processing machinery that produces beta amyloid peptides through cleavage of APP.
-Most cases identified are "sporadic" with no clear family history. Environmental factors sometimes claimed to increase risk of Alzheimer's include prior head injury<ref name="Jellinger">{{cite journal | author = Jellinger KA | title = Head injury and dementia. | journal = Curr Opin Neurol | volume = 17 | issue = 6 | pages = 719-23 | year = 2006 | id = PMID 15542981}}</ref>, particularly repeated trauma<ref name="Guskiewicz">{{cite journal | author = Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Cantu RC, Randolph C, Jordan BD | title = Association between recurrent concussion and late-life cognitive impairment in retired professional football players. | journal = Neurosurgery | volume = 57 | issue = 4 | pages = 719-26 | year = 2006 | id = PMID 16239884}}</ref>, previous incidents of [[migraine]] headaches<ref name="Tyas">{{cite journal | author = Tyas SL, Manfreda J, Strain LA, Montgomery PR. | title = Risk factors for Alzheimer's disease: a population-based, longitudinal study in Manitoba, Canada. | journal = Int J Epidemiol | volume = 30 | issue = 3 | pages = 590-7 | year = 2001 | id = PMID 11416089}}</ref>, exposure to [[defoliant]]s<ref name="Tyas" />, and low activity levels during adulthood.<ref name="Munoz">{{cite journal | author = Munoz DG, Feldman H. | title = Causes of Alzheimer's disease. | journal = CMAJ | volume = 162 | issue = 1 | pages = 65-72 | year = 2000 | id = PMID 11216203}}</ref> <!--In addition, small cranial diameter has been shown to correlate well with early onset of recognizable symptoms. ... I can't find any evidence of this.-->
+Most cases identified are "sporadic" with no clear family history. Environmental factors sometimes claimed to increase risk of Alzheimer's including prior head injury,<ref name="Jellinger">{{cite journal | author = Jellinger KA | title = Head injury and dementia. | journal = Curr Opin Neurol | volume = 17 | issue = 6 | pages = 719-23 | year = 2006 | id = PMID 15542981}}</ref> particularly repeated trauma,<ref name="Guskiewicz">{{cite journal | author = Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Cantu RC, Randolph C, Jordan BD | title = Association between recurrent concussion and late-life cognitive impairment in retired professional football players. | journal = Neurosurgery | volume = 57 | issue = 4 | pages = 719-26 | year = 2006 | id = PMID 16239884}}</ref> previous incidents of [[migraine]] headaches,<ref name="Tyas">{{cite journal | author = Tyas SL, Manfreda J, Strain LA, Montgomery PR. | title = Risk factors for Alzheimer's disease: a population-based, longitudinal study in Manitoba, Canada. | journal = Int J Epidemiol | volume = 30 | issue = 3 | pages = 590-7 | year = 2001 | id = PMID 11416089}}</ref> exposure to [[defoliant]]s,<ref name="Tyas" /> and low activity levels during adulthood.<ref name="Munoz">{{cite journal | author = Munoz DG, Feldman H. | title = Causes of Alzheimer's disease. | journal = CMAJ | volume = 162 | issue = 1 | pages = 65-72 | year = 2000 | id = PMID 11216203}}</ref> <!--In addition, small cranial diameter has been shown to correlate well with early onset of recognizable symptoms. ... I can't find any evidence of this.--> However, with the exception of previous concussion, none of these environmental risk factors are widely accepted.
-Inheritance of the epsilon 4 allele of the ApoE gene is regarded as a risk factor for development of disease, but large-scale genetic association studies raise the possibility that even this does not indicate susceptibility so much as how early one is likely to develop Alzheimer's. There is speculation among genetic experts that there are other risk and protective factor genes that may influence the development of late onset Alzheimer's disease (LOAD). Researchers are investigating the possibility that the regulatory regions of various Alzheimer's associated genes could be important in sporadic Alzheimer's, especially inflammatory activation of these genes. These hypotheses include the amyloid beta precursor protein<ref>{{cite journal | author = Lahiri D, Ghosh C, Ge Y | title = A proximal gene promoter region for the beta-amyloid precursor protein provides a link between development, apoptosis, and Alzheimer's disease. | journal = Ann N Y Acad Sci | volume = 1010 | issue = | pages = 643-7 | year = | id = PMID 15033805}}</ref>, the beta secretase enzymes <ref>{{cite journal | author = Cacabelos R, Fernandez-Novoa L, Lombardi V, Kubota Y, Takeda M | title = Molecular genetics of Alzheimer's disease and aging. | journal = Methods Find Exp Clin Pharmacol | volume = 27 Suppl A | issue = | pages = 1-573 | year = | id = PMID 16470248}}</ref> insulin-degrading enzyme<ref>{{cite journal | author = Nowotny P, Hinrichs A, Smemo S, Kauwe J, Maxwell T, Holmans P, Hamshere M, Turic D, Jehu L, Hollingworth P, Moore P, Bryden L, Myers A, Doil L, Tacey K, Gibson A, McKeith I, Perry R, Morris C, Thal L, Morris J, O'Donovan M, Lovestone S, Grupe A, Hardy J, Owen M, Williams J, Goate A | title = Association studies between risk for late-onset Alzheimer's disease and variants in insulin degrading enzyme. | journal = Am J Med Genet B Neuropsychiatr Genet | volume = 136 | issue = 1 | pages = 62-8 | year = 2005 | id = PMID 15858813}} </ref> endothelin-converting enzymes<ref> {{cite journal | author = Funalot B, Ouimet T, Claperon A, Fallet C, Delacourte A, Epelbaum J, Subkowski T, Léonard N, Codron V, David J, Amouyel P, Schwartz J, Helbecque N | title = Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease. | journal = Mol Psychiatry | volume = 9 | issue = 12 | pages = 1122-8, 1059 | year = 2004 | id = PMID 15340356}} </ref> and inflammatory 5-lipoxygenase gene.<ref> {{cite journal | author = Manev H, Manev R | title = 5-Lipoxygenase (ALOX5) and FLAP (ALOX5AP) gene polymorphisms as factors in vascular pathology and Alzheimer's disease. | journal = Med Hypotheses | volume = 66 | issue = 3 | pages = 501-3 | year = 2006 | id = PMID 16278051}} </ref>
+Inheritance of the ε4 allele of the ApoE gene is regarded as a risk factor for development of disease, but large-scale genetic association studies raise the possibility that even this does not indicate susceptibility so much as how early one is likely to develop Alzheimer's. There is speculation among genetic experts that there are other risk and protective factor genes that may influence the development of late onset Alzheimer's disease (LOAD). Researchers are investigating the possibility that the regulatory regions of various Alzheimer's associated genes could be important in sporadic Alzheimer's, especially inflammatory activation of these genes. These hypotheses include the amyloid-β precursor protein (APP),<ref>{{cite journal | author = Lahiri D, Ghosh C, Ge Y | title = A proximal gene promoter region for the beta-amyloid precursor protein provides a link between development, apoptosis, and Alzheimer's disease. | journal = Ann N Y Acad Sci | volume = 1010 | issue = | pages = 643-7 | year = | id = PMID 15033805}}</ref> the beta secretase enzymes<ref>{{cite journal | author = Cacabelos R, Fernandez-Novoa L, Lombardi V, Kubota Y, Takeda M | title = Molecular genetics of Alzheimer's disease and aging. | journal = Methods Find Exp Clin Pharmacol | volume = 27 Suppl A | issue = | pages = 1-573 | year = | id = PMID 16470248}}</ref> insulin-degrading enzyme<ref>{{cite journal | author = Nowotny P, Hinrichs A, Smemo S, Kauwe J, Maxwell T, Holmans P, Hamshere M, Turic D, Jehu L, Hollingworth P, Moore P, Bryden L, Myers A, Doil L, Tacey K, Gibson A, McKeith I, Perry R, Morris C, Thal L, Morris J, O'Donovan M, Lovestone S, Grupe A, Hardy J, Owen M, Williams J, Goate A | title = Association studies between risk for late-onset Alzheimer's disease and variants in insulin degrading enzyme. | journal = Am J Med Genet B Neuropsychiatr Genet | volume = 136 | issue = 1 | pages = 62-8 | year = 2005 | id = PMID 15858813}} </ref> endothelin-converting enzymes<ref> {{cite journal | author = Funalot B, Ouimet T, Claperon A, Fallet C, Delacourte A, Epelbaum J, Subkowski T, Léonard N, Codron V, David J, Amouyel P, Schwartz J, Helbecque N | title = Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease. | journal = Mol Psychiatry | volume = 9 | issue = 12 | pages = 1122-8, 1059 | year = 2004 | id = PMID 15340356}} </ref> and inflammatory 5-lipoxygenase gene.<ref> {{cite journal | author = Manev H, Manev R | title = 5-Lipoxygenase (ALOX5) and FLAP (ALOX5AP) gene polymorphisms as factors in vascular pathology and Alzheimer's disease. | journal = Med Hypotheses | volume = 66 | issue = 3 | pages = 501-3 | year = 2006 | id = PMID 16278051}} </ref>
 ===Genetic linkage===
-Alzheimer's disease is definitely linked to the 1st, 14th, and 21st chromosomes, but other linkages are controversial and not, as yet, confirmed.  While some genes predisposing to AD have been identified , such as ApoE4 on chromosome 19, sporadic AD also involves other risk and protective genes still awaiting confirmation.
+Alzheimer's disease is definitely linked to the 1st, 14th,<ref>Van Broeckhoven C, Backhovens H, Cruts M, De Winter G, Bruyland M, Cras P, Martin JJ., Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3, Nat Genet. 1992 Dec;2(4):335-9.</ref> and 21st chromosomes, but other linkages are controversial and not yet confirmed.  While some genes predisposing to AD have been identified , such as [[Apolipoprotein E|ApoE4]] on chromosome 19, sporadic AD also involves other risk and protective genes still awaiting confirmation.
-==Epidemiology and prevention==
+==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.<ref> {{cite journal | author = Gorelick P | title = Risk factors for vascular dementia and Alzheimer disease. | journal = Stroke | volume = 35 | issue = 11 Suppl 1 | pages = 2620-2 | year = 2004 | id = PMID 15375299}} </ref> 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.<ref> {{cite journal | author = Hebert L, Scherr P, Bienias J, Bennett D, Evans D | title = Alzheimer disease in the US population: prevalence estimates using the 2000 census. | journal = Arch Neurol | volume = 60 | issue = 8 | pages = 1119-22 | year = 2003 | id = PMID 12925369}}</ref>
+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&ndash;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.<ref> {{cite journal | author = Gorelick P | title = Risk factors for vascular dementia and Alzheimer disease. | journal = Stroke | volume = 35 | issue = 11 Suppl 1 | pages = 2620-2 | year = 2004 | id = PMID 15375299}} </ref> 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.<ref> {{cite journal | author = Hebert L, Scherr P, Bienias J, Bennett D, Evans D | title = Alzheimer disease in the US population: prevalence estimates using the 2000 census. | journal = Arch Neurol | volume = 60 | issue = 8 | pages = 1119-22 | year = 2003 | id = PMID 12925369}}</ref>
+==Prevention==
-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.<ref>{{cite journal | last = Small | first = Gary W | title = What we need to know about age related memory loss | journal = British Medical Journal | pages = 1502-1507 | date = [[2002-06-22]] | url = http://bmj.bmjjournals.com/cgi/content/full/324/7352/1502#B21 | accessdate = 2006-11-05}}</ref> 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 [[study design|design]], studies examining disease risk factors are often at risk from [[confounding]] variables. Several recent large, [[randomized controlled trial]]s—in particular the [[Women's Health Initiative]]—have called into question preventive mesasures based on [[cross-sectional studies]].  Some proposed preventive measures are even based on studies conducted solely in animals.
+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.<ref>{{cite journal | last = Small | first = Gary W | title = What we need to know about age related memory loss | journal = British Medical Journal | pages = 1502-1507 | date = [[2002-06-22]] | url = http://bmj.bmjjournals.com/cgi/content/full/324/7352/1502#B21 | accessdate = 2006-11-05}}</ref> 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 [[study design|design]], studies examining disease risk factors are often at risk from [[confounding variable]]s. Several recent large, [[randomized controlled trial]]s—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.
+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. Therefore, prevention of these conditions can lower risk of developing Alzheimer's, as well as [[heart attack]] and [[stroke]].
 ===Risk reducers===
-*Intellectual stimulation (e.g., playing [[chess]] or doing a [[crossword]])<ref> {{cite journal | author = Verghese J, Lipton R, Katz M, Hall C, Derby C, Kuslansky G, Ambrose A, Sliwinski M, Buschke H | title = Leisure activities and the risk of dementia in the elderly. | journal = N Engl J Med | volume = 348 | issue = 25 | pages = 2508-16 | year = 2003 | id = PMID 12815136}} </ref>
+*Intellectual stimulation (e.g., playing [[chess]] or doing  [[crosswords]])<ref> {{cite journal | author = Verghese J, Lipton R, Katz M, Hall C, Derby C, Kuslansky G, Ambrose A, Sliwinski M, Buschke H | title = Leisure activities and the risk of dementia in the elderly. | journal = N Engl J Med | volume = 348 | issue = 25 | pages = 2508-16 | year = 2003 | id = PMID 12815136}} </ref>
 *Regular physical exercise<ref>{{cite journal | author = Larson E, Wang L, Bowen J, McCormick W, Teri L, Crane P, Kukull W | title = Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. | journal = Ann Intern Med | volume = 144 | issue = 2 | pages = 73-81 | year = 2006 | id = PMID 16418406}}</ref>
+*Regular social interaction [http://news.bbc.co.uk/2/hi/health/6332883.stm]. Lonely individuals may be twice as likely to develop the type of dementia linked to Alzheimer’s disease in late life as those who are not lonely.
-*Regular social interaction
+*A [[Mediterranean diet]] with fruits and vegetables and low in saturated fat,<ref> {{cite journal | author = Scarmeas N, Stern Y, Mayeux R, Luchsinger J | title = Mediterranean diet, Alzheimer disease, and vascular mediation. | journal = Arch Neurol | volume = 63 | issue = 12 | pages = 1709-17 | year = 2006 | id = PMID 17030648}} </ref> supplemented in particular with:
-*A generally healthy diet low in saturated fat, supplemented in particular with:
+**[[B vitamins]]<ref> {{cite journal | author = Morris M, Schneider J, Tangney C | title = Thoughts on B-vitamins and dementia. | journal = J Alzheimers Dis | volume = 9 | issue = 4 | pages = 429-33 | year = 2006 | id = PMID 16917152}}</ref> in particular, [[folic acid]].<ref> {{cite journal | author = Inna I. Kruman1, T. S. Kumaravel2, Althaf Lohani2, Ward A. Pedersen1, Roy G. Cutler1, Yuri Kruman1, Norman Haughey1, Jaewon Lee1, Michele Evans2, and Mark P. Mattson1, 3  | title = Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Them to Amyloid Toxicity in Experimental Models of Alzheimer's Disease . | journal = The Journal of Neuroscience, | volume = 22 | issue = 5 | year = March 1, 2002 | website = http://www.jneurosci.org/cgi/content/abstract/22/5/1752?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&author1=Kruman&titleabstract=folic%2Bacid&searchid=1056979885583_2657&stored_search=&FIRSTINDEX=0&journalcode=jneuro}} A simplified report can be found at: [http://www.alzheimers.org.uk/Mind_your_head/Common_questions/Medicines_and_supplements/folate.htm www.alzheimers.org.uk]</ref><ref>CBS news, reporting from WebMD [http://www.cbsnews.com/stories/2005/08/15/health/webmd/main779484.shtml Folate May Lower Alzheimer's Risk]</ref><ref>[http://www.nih.gov/news/pr/mar2002/nia-01.htm National Institute of Health - Folic Acid Possibly A Key Factor In Alzheimer's Disease Prevention]</ref><ref>Alzheimer's and Dementia journal, reported at USA today[http://www.usatoday.com/news/health/2005-08-14-alzheimers-folate_x.htm]</ref>
-**[[B vitamins]]
+**[[Curry]]<ref> {{cite journal | author = Giselle P. Lim1, Teresa Chu1, Fusheng Yang, Walter Beech1, Sally A. Frautschy1, and Greg M. Cole1 | title = The Curry Spice Curcumin Reduces Oxidative Damage and Amyloid Pathology in an Alzheimer Transgenic Mouse | journal = The Journal of Neuroscience | volume = 21 | issue = 4 | pages = 8370-8377
+ | year = 2001 | id = PMID 11606625}}</ref>
 **[[Omega-3 fatty acids]], especially [[Docosahexaenoic acid]]<ref>{{cite journal | author = Lim W, Gammack J, Van Niekerk J, Dangour A | title = Omega 3 fatty acid for the prevention of dementia. | journal = Cochrane Database Syst Rev | volume = | issue = | pages = CD005379 | year = | id = PMID 16437528}}</ref><ref>{{cite journal | author = Morris M, Evans D, Tangney C, Bienias J, Wilson R | title = Fish consumption and cognitive decline with age in a large community study. | journal = Arch Neurol | volume = 62 | issue = 12 | pages = 1849-53 | year = 2005 | id = PMID 16216930}} </ref>
 **Fruit and vegetable juice<ref> {{cite journal | author = Dai Q, Borenstein A, Wu Y, Jackson J, Larson E | title = Fruit and vegetable juices and Alzheimer's disease: the Kame Project. | journal = Am J Med | volume = 119 | issue = 9 | pages = 751-9 | year = 2006 | id = PMID 16945610}}</ref><ref>{{cite journal | author = Joseph J, Fisher D, Carey A | title = Fruit extracts antagonize Abeta- or DA-induced deficits in Ca2+ flux in M1-transfected COS-7 cells. | journal = J Alzheimers Dis | volume = 6 | issue = 4 | pages = 403-11; discussion 443-9 | year = 2004 | id = PMID 15345811}} </ref>
-**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 [[preventative medicine|preventive measure]] because of observed increases in overall mortality<ref>{{cite journal | author = Petersen R, Thomas R, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck C, Thal L | title = Vitamin E and donepezil for the treatment of mild cognitive impairment. | journal = N Engl J Med | volume = 352 | issue = 23 | pages = 2379-88 | year = 2005 | id = PMID 15829527}}</ref> <ref>{{cite journal | author = Zandi P, Anthony J, Khachaturian A, Stone S, Gustafson D, Tschanz J, Norton M, Welsh-Bohmer K, Breitner J | title = Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. | journal = Arch Neurol | volume = 61 | issue = 1 | pages = 82-8 | year = 2004 | id = PMID 14732624}} </ref>
+**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 [[preventative medicine|preventive measure]] because of observed increases in overall mortality<ref>{{cite journal | author = Petersen R, Thomas R, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck C, Thal L | title = Vitamin E and donepezil for the treatment of mild cognitive impairment. | journal = N Engl J Med | volume = 352 | issue = 23 | pages = 2379-88 | year = 2005 | id = PMID 15829527}}</ref><ref>{{cite journal | author = Zandi P, Anthony J, Khachaturian A, Stone S, Gustafson D, Tschanz J, Norton M, Welsh-Bohmer K, Breitner J | title = Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. | journal = Arch Neurol | volume = 61 | issue = 1 | pages = 82-8 | year = 2004 | id = PMID 14732624}} </ref>
+**The moderate consumption of alcohol (beer, wine or distilled spirits) <ref> Scarmeas, N., et al. Mediterranean diet and risk for Alzheimer’s disease. Annals of Neurology, 2006 (published online April 18, 2006).  Other research is consistent with the finding that moderate alcohol consumption is associated with lower risk of Alzheimer’s and other forms of dementia: Mulkamal, K.J., et al. Prospective study of alcohol consumption and risk of dementia in older adults. Journal of the American Medical Association, 2003 (March 19), 289, 1405-1413; Ganguli, M., et al. Alcohol consumption and cognitive function in late life: A longitudinal community study. Neurology, 2005, 65, 1210-12-17; Huang, W., et al. Alcohol consumption and incidence of dementia in a community sample aged 75 years and older. Journal of Clinical Epidemiology, 2002, 55(10), 959-964; Rodgers, B., et al. Non-linear relationships between cognitive function and alcohol consumption in young, middle-aged and older adults: The PATH Through Life Project. Addiction, 2005, 100(9), 1280-1290; Anstey, K. J., et al. Lower cognitive test scores observed in alcohol are associated with demographic, personality, and biological factors: The PATH Through Life Project. Addiction, 2005, 100(9), 1291-1301; Espeland, M., et al. Association between alcohol intake and domain-specific cognitive function in older women. Neuroepidemiology, 2006, 1(27), 1-12; Stampfer, M.J., et al. Effects of moderate alcohol consumption on cognitive function in women. New England Journal of Medicine, 2005, 352, 245-253; Ruitenberg, A., et al. Alcohol consumption and risk of dementia: the Rotterdam Study. Lancet, 2002, 359(9303), 281-286.</ref>
-*[[Cholesterol]]-lowering drugs ([[statins]]) reduce Alzheimer's risk in observational studies but so far not in randomized controlled trials
+*[[Cholesterol]]-lowering drugs ([[statins]]) reduce Alzheimer's risk in observational studies but so far not in randomized controlled trials<ref>{{cite journal | author = Rockwood K | title = Epidemiological and clinical trials evidence about a preventive role for statins in Alzheimer's disease. | journal = Acta Neurol Scand Suppl | volume = 185 | issue = | pages = 71-7 | year = | id = PMID 16866914}}</ref>
-*[[Hormone replacement therapy]] is no longer thought to prevent dementia based on data from the [[Women's Health Initiative]]
+*Female [[Hormone replacement therapy]] is no longer thought to prevent dementia based on data from the [[Women's Health Initiative]]
-*Regular use of [[non-steroidal anti-inflammatory drugs]] like [[ibuprofen]] and [[aspirin]] reduces the chance of dementia but the risks appear to outweigh the drugs' benefit as a method of [[primary prevention]]
+*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.<ref> {{cite journal |author=Zandi P, Anthony J, Hayden K, Mehta K, Mayer L, Breitner J |title=Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study |journal=Neurology |volume=59 |issue=6 |pages=880-6 |year=2002 |id=PMID 12297571}} </ref><ref> {{cite journal |author=in t' Veld B, Ruitenberg A, Hofman A, Launer L, van Duijn C, Stijnen T, Breteler M, Stricker B |title=Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease |journal=N Engl J Med |volume=345 |issue=21 |pages=1515-21 |year=2001 |id=PMID 11794217}} </ref>  The risks appear to outweigh the drugs' benefit as a method of [[primary prevention]].<ref name="2006AAGP"> {{cite journal | author = Lyketsos C, Colenda C, Beck C, Blank K, Doraiswamy M, Kalunian D, Yaffe K | title = Position statement of the American Association for Geriatric Psychiatry (AAGP) regarding principles of care for patients with dementia resulting from Alzheimer disease. | journal = Am J Geriatr Psychiatry | volume = 14 | issue = 7 | pages = 561-72 | year = 2006 | id = PMID 16816009}} [http://ajgp.org/cgi/content/full/14/7/561]</ref>
 ===Risk factors===
-*Advancing age
+* Advancing age
-*ApoE epsilon 4 genotype (in some populations)
+* ApoE epsilon 4 genotype (in some populations) [  ]
+* Environmental exposure to aluminum [http://aje.oxfordjournals.org/cgi/content/full/154/3/288-a]
-*[[Head injury]]
+* [[Head injury]]<ref> {{cite journal |author=Mayeux R, Ottman R, Tang M, Noboa-Bauza L, Marder K, Gurland B, Stern Y |title=Genetic susceptibility and head injury as risk factors for Alzheimer's disease among community-dwelling elderly persons and their first-degree relatives |journal=Ann. Neurol. |volume=33 |issue=5 |pages=494-501 |year=1993 |pmid=8498827}} </ref>
-*Poor cardiovascular health (including [[tobacco smoking|smoking]], [[diabetes]], [[hypertension]], [[high cholesterol]])
+* Poor cardiovascular health (including [[diabetes]],<ref>{{cite journal | author = Kofman OS, MacMillan VH | title = Diffuse Cerebral Atrophy. | journal =  Applied Therapeutics | volume = 12 | issue = 4 | pages = 24-26 | year = 1970}}</ref> [[hypertension]],<ref> {{cite journal |author=Kehoe P, Wilcock G |title=Is inhibition of the renin-angiotensin system a new treatment option for Alzheimer's disease? |journal=Lancet neurology |volume=6 |issue=4 |pages=373-8 |year=2007 |pmid=17362841}}</ref> [[high cholesterol]]<ref> {{cite journal |author=Crisby M, Carlson L, Winblad B |title=Statins in the prevention and treatment of Alzheimer disease |journal=Alzheimer disease and associated disorders |volume=16 |issue=3 |pages=131-6 |year=2002 |pmid=12218642}}</ref> and [[stroke]]s)<ref>BBC [http://news.bbc.co.uk/1/hi/health/6713163.stm Why stroke ups Alzheimer's risk] 4 June 2007</ref>
-*Exposure to light metals is a proposed but not widely-accepted risk factor.<ref>{{cite web | title=Alzheimer's Disease and Aluminum - NIEHS Alphabetical Listing of Health Topics | url=http://www.niehs.nih.gov/external/faq/aluminum.htm | accessdate=9/20/2006 }}</ref><ref>{{cite journal | author = Squitti R, Barbati G, Rossi L, Ventriglia M, Dal Forno G, Cesaretti S, Moffa F, Caridi I, Cassetta E, Pasqualetti P, Calabrese L, Lupoi D, Rossini P | title = Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF [beta]-amyloid, and h-tau. | journal = Neurology | volume = 67 | issue = 1 | pages = 76-82 | year = 2006 | id = PMID 16832081}}</ref>  [[Aluminium]], a neurotoxin, is often present in higher quantities in brains of Alzheimers patients, but no causal relationship has yet been found.<ref>{{cite web | title=Exposure to aluminium and the subsequent development of a disorder with features of Alzheimer’s disease | url=http://jnnp.bmjjournals.com/cgi/content/extract/77/7/811}}</ref>  [[Copper]] is another candidate.<ref>{{cite web | title=Copper link to Alzheimer's disease | url=http://www.newscientist.com/article.ns?id=dn4045}}</ref>
+*Smoking<ref>{{cite journal |author=Anstey KJ, von Sanden C, Salim A, O'kearney R |title=Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies |journal=Am. J. Epidemiol. |volume=166 |issue=4 |pages=367-78 |year=2007 |pmid=17573335 |doi=10.1093/aje/kwm116}}</ref>
 ==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. The American Association for Geriatric Psychiatry published a consensus statement on Alzheimer's treatment in 2006.<ref name="2006AAGP"> {{cite journal | author = Lyketsos C, Colenda C, Beck C, Blank K, Doraiswamy M, Kalunian D, Yaffe K | title = Position statement of the American Association for Geriatric Psychiatry (AAGP) regarding principles of care for patients with dementia resulting from Alzheimer disease. | journal = Am J Geriatr Psychiatry | volume = 14 | issue = 7 | pages = 561-72 | year = 2006 | id = PMID 16816009}} [http://ajgp.org/cgi/content/full/14/7/561]</ref>
+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.<ref name="2006AAGP"/>
+==Drug treatments==
+{{main|Antidementia drugs}}
 ===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.<ref> Ortho-McNeil Neurologics, “Razadyne ER US Product Insert”, May 2006. [http://www.razadyne.com/active/janus/en_US/assets/common/company/pi/razadyne.pdf] </ref><ref name=”ProductInsert”> Novartis Pharmaceuticals Corporation “Exelon Product Insert” June 2006. [http://www.pharma.us.novartis.com/product/pi/pdf/exelon.pdf] </ref><ref> Eisai Inc, “Aricept and Aricept ODT Product Insert”, March 2005. [http://www.aricept.com/content/pi.pdf] </ref>
+[[Acetylcholinesterase inhibitor]]s were 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.<ref> Ortho-McNeil Neurologics, “Razadyne ER US Product Insert”, May 2006. [http://www.razadyne.com/active/janus/en_US/assets/common/company/pi/razadyne.pdf] </ref><ref name=”ProductInsert”> Novartis Pharmaceuticals Corporation “Exelon Product Insert” June 2006. [http://www.pharma.us.novartis.com/product/pi/pdf/exelon.pdf] </ref><ref> Eisai Inc, “Aricept and Aricept ODT Product Insert”, March 2005. [http://web.archive.org/web/20060709031607/http://www.aricept.com/content/pi.pdf] </ref>
 Examples include:
-* [[tacrine]] - no longer clinically used
+* [[tacrine]] - no longer clinically used (formerly marketed as Cognex)
 * [[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)
+The three currently marketed products each comes in an oral form taken once or twice a day.  Rivastigmine is also available as a once-daily [[transdermal patch]].
-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.<ref>{{cite journal | author = Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, Edwards S, Hardyman W, Raftery J, Crome P, Lendon C, Shaw H, Bentham P | title = Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. | journal = Lancet | volume = 363 | issue = 9427 | pages = 2105-15 | year = 2004 | id = PMID 15220031}}</ref><ref> {{cite journal | author = Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt H, van den Bussche H | title = Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. | journal = BMJ | volume = 331 | issue = 7512 | pages = 321-7 | year = 2005 | id = PMID 16081444}} </ref> 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.<ref>[http://www.medicalnewstoday.com/medicalnews.php?newsid=47681 Exelon Patch, The First Transdermal Therapy For Alzheimer's Disease, May Provide Promising New Approach To Treatment Of Dementia]</ref>
+There is some question 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.<ref>{{cite journal | author = Courtney C, '''Farrell D''', Gray R, Hills R, Lynch L, Sellwood E, Edwards S, Hardyman W, Raftery J, Crome P, Lendon C, Shaw H, Bentham P | title = Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. | journal = Lancet | volume = 363 | issue = 9427 | pages = 2105-15 | year = 2004 | id = PMID 15220031}}</ref><ref> {{cite journal | author = Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt H, van den Bussche H | title = Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. | journal = BMJ | volume = 331 | issue = 7512 | pages = 321-7 | year = 2005 | id = PMID 16081444}} </ref> The pharmaceutical companies, but also some independent clinicians, dispute the conclusions of these articles.
+===Ginkgo biloba===
+Examining over 52 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. <ref name="alzheim"> {{cite journal| author = Birks J, Grimley E, Van Dongen M | title = Ginkgo biloba for cognitive impairment and dementia. | journal = Cochrane Database Syst Rev | volume = | issue = | pages = CD003120 | year = | id = PMID 12519586}}.</ref>  The AAGP review<ref name="2006AAGP"/> 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. <ref> {{cite journal | author = DeKosky S, Fitzpatrick A, Ives D, Saxton J, Williamson J, Lopez O, Burke G, Fried L, Kuller L, Robbins J, Tracy R, Woolard N, Dunn L, Kronmal R, Nahin R, Furberg C | title = The Ginkgo Evaluation of Memory (GEM) study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia. | journal = Contemp Clin Trials | volume = 27 | issue = 3 | pages = 238-53 | year = 2006 | id = PMID 16627007}}.</ref>
 ===NMDA antagonists===
-Recent evidence of the involvement of [[Glutamate|glutamatergic]] neuronal [[excitotoxicity]] in the [[aetiology]] of Alzheimer's disease led to the development and introduction of [[memantine]]. Memantine is a novel [[NMDA receptor]] [[receptor antagonist|antagonist]], and has been shown to be moderately clinically efficacious.<ref name="Areosa">{{cite journal | author = Areosa Sastre A, McShane R, Sherriff F | title = Memantine for dementia. | journal = Cochrane Database Syst Rev | volume = | issue = | pages = CD003154 | year = | id = PMID 15495043}}</ref>
+Recent evidence of the involvement of [[glutamate]]rgic neuronal [[excitotoxicity]] in Alzheimer's disease led to the development and introduction of [[memantine]]. [[Memantine]] is a novel [[NMDA receptor]] [[receptor antagonist|antagonist]], and has been shown to be moderately clinically efficacious.<ref name="Areosa">{{cite journal | author = Areosa Sastre A, McShane R, Sherriff F | title =  Memantine for dementia. | journal = Cochrane Database Syst Rev | volume = | issue = | pages = CD003154 | year = | id = PMID 15495043}}</ref> 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.<ref>{{cite journal | author = Olazarán J, Muñiz R, Reisberg B, Peña-Casanova J, del Ser T, Cruz-Jentoft A, Serrano P, Navarro E, García de la Rocha M, Frank A, Galiano M, Fernández-Bullido Y, Serra J, González-Salvador M, Sevilla C | title = Benefits of cognitive-motor intervention in MCI and mild to moderate Alzheimer disease. | journal = Neurology | volume = 63 | issue = 12 | pages = 2348-53 | year = 2004 | id = PMID 15623698}}</ref><ref>{{cite journal | author = Clare L, Woods R, Moniz Cook E, Orrell M, Spector A | title = Cognitive rehabilitation and cognitive training for early-stage Alzheimer's disease and vascular dementia. | journal = Cochrane Database Syst Rev | volume = | issue = | pages = CD003260 | year = | id = PMID 14583963}}</ref>
+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.<ref>{{cite journal | author = Olazarán J, Muñiz R, Reisberg B, Peña-Casanova J, del Ser T, Cruz-Jentoft A, Serrano P, Navarro E, García de la Rocha M, Frank A, Galiano M, Fernández-Bullido Y, Serra J, González-Salvador M, Sevilla C | title = Benefits of cognitive-motor intervention in MCI and mild to moderate Alzheimer disease. | journal = Neurology | volume = 63 | issue = 12 | pages = 2348-53 | year = 2004 | id = PMID 15623698}}</ref><ref>{{cite journal | author = Clare L, Woods R, Moniz Cook E, Orrell M, Spector A | title = Cognitive rehabilitation and cognitive training for early-stage Alzheimer's disease and vascular dementia. | journal = Cochrane Database Syst Rev | volume = | issue = | pages = CD003260 | year = | id = PMID 14583963}}</ref>
 ===Treatments in clinical development===
-A large number of potential treatments for Alzheimer's disease are currently under investigation, including four compounds being studied in [[Regulatory requirement|phase 3]] clinical trials. Xaliproden had been shown to reduce neurodegeneration in animal studies.<ref>{{cite journal | author = Lemaire L,
+A large number of potential treatments for Alzheimer's disease are currently under investigation, including four compounds being studied in [[Regulatory requirement|phase 3]] clinical trials. [[Xaliproden]] had been shown to reduce neurodegeneration in animal studies.<ref>{{cite journal | author = Lemaire L,
      Fournier J, Ponthus C, Le Fur Y, Confort-Gouny S, Vion-Dury J, Keane P, Cozzone P
      | title = Magnetic resonance imaging of the neuroprotective effect of xaliproden in rats.
      | journal = Invest Radiol | volume = 37 | issue = 6 | pages = 321-7 | year = 2002
      | id = PMID 12021588}}
-</ref> 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. [[R-flurbiprofen]] (MPC-7869) 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.<ref> {{cite journal
+</ref> [[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.  [[R-flurbiprofen| 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.<ref> {{cite journal
      | author = Zamrini E | title = Emerging Drug Therapies for Dementia.
      | journal = Geriatrics Aging | volume = 9 | issue = 2 | pages = 107,110-113
@@ Line 165: / Line 180: @@
      | author = Eriksen J, Sagi S, Smith T, Weggen S, Das P, McLendon D, Ozols V,
        Jessing K, Zavitz K, Koo E, Golde T
-     | title = NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo.
+     | title = NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 ''in vivo''.
      | journal = J Clin Invest | volume = 112 | issue = 3 | pages = 440-9 | year = 2003
      | id = PMID 12897211}}.
-</ref> [[Leuprolide]] is 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.<ref> {{cite journal | author
+</ref> [[Leuprolide]] has also been studied for Alzheimer’s.  It is hypothesized to work by reducing luteinizing hormone levels which may be causing damage in the brain as one ages.<ref> {{cite journal | author
      = Casadesus G, Garrett M, Webber K, Hartzler A, Atwood C, Perry G, Bowen R, Smith M
      | title = The estrogen myth: potential use of gonadotropin-releasing hormone agonists for the treatment of Alzheimer's disease.
@@ Line 174: / Line 189: @@
      | id = PMID 16752944}}.</ref>
-*'''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 human-trials of drug AN-1792 showed results in 20% of patients; however, 6% of multi-dosed participants (18 of 300) developed [[encephalitis]] in 2002, 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.<ref>{{cite web
+*'''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.<ref>{{cite web
      | title=Alzheimer’s Association Fact Sheet: AN-1792 (2006, on ALZ.org)
      | url=http://www.alz.org/Resources/TopicIndex/AN1792.asp
      | accessdate=2006-11-06}}.
-</ref>  Work is continuing on less toxic [[amyloid beta|Aβ]] vaccines, such as a [[DNA]]-based therapy that recently showed promise in mice.
+</ref>  Work is continuing on less toxic [[amyloid beta|Aβ]] vaccines.
+*'''The statin simvastatin''' has been found to reduce the incidence of Alzheimer's disease and [[Parkinsons]] disease by almost 50 percent by resarchers from Boston University School of Medicine (BUSM).<ref>{{cite web
-*'''Proposed alternative treatments''' for Alzheimer's include a range of herbal compounds and [[dietary supplements]]. In general, research on the efficacy of these substances is either non-existent or far too weak to support therapeutic claims of improved memory or slowed disease progression.
+     | title=Researchers Find Specific Statin Significantly Reduces Alzheimer's and Parkinson's Disease Risk
+     | url=http://www.michaeljfox.org/newsEvents_parkinsonsInTheNews_article.cfm?ID=227
+     | accessdate=2007-08-06}}.
+</ref>
+*'''Proposed alternative treatments''' for Alzheimer's include a range of herbal compounds and [[dietary supplements]]. In the AAGP review from 2006,<ref name="2006AAGP"/> [[Tocopherol|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.
-In the AAGP review from 2006,<ref name="2006AAGP"/>
-[[Tocopherol | 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. [[Ginkgo|Ginkgo biloba]] did not show enough long-term efficacy to recommend its use, but it is being studied in a large randomized clinical study in the US.<ref>{{cite journal
-     | author = Birks J, Grimley E, Van Dongen M
-     | title = Ginkgo biloba for cognitive impairment and dementia.
-     | journal = Cochrane Database Syst Rev | volume = | issue = | pages = CD003120
-     | year = | id = PMID 12519586}}.</ref><ref>
-{{cite journal
-     | author = DeKosky S, Fitzpatrick A, Ives D, Saxton J, Williamson J, Lopez O,
-       Burke G, Fried L, Kuller L, Robbins J, Tracy R, Woolard N, Dunn L,
-       Kronmal R, Nahin R, Furberg C
-     | title = The Ginkgo Evaluation of Memory (GEM) study: design and baseline data
-       of a randomized trial of Ginkgo biloba extract in prevention of dementia.
-     | journal = Contemp Clin Trials | volume = 27 | issue = 3 | pages = 238-53
-     | year = 2006 | id = PMID 16627007}}.</ref>
 Laboratory studies with cells and animals continually fuel the pipeline of potential treatments.  Some currently approved drugs such as [[statin]]s and [[thiazolidinedione]]s<ref> {{cite journal
@@ Line 206: / Line 212: @@
 ===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 agitiation, whereas well-lit rooms, adquate rest, and avoidance of excess stimulation all help prevent such episodes.<ref>Treating behavioral and psychiatric symptoms.  Alzheimer's Association.  Accessed Oct. 15, 2006.[http://www.alz.org/Health/Treating/agitation.asp#behavioral]</ref> 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.<ref> {{cite journal | author = Dunne TE, Neargarder SA, Cipolloni PB, Cronin-Golomb A. | title = Visual contrast enhances food and liquid intake in advanced Alzheimer's disease | journal = Clin Nutr | volume = 23 | issue = 4 | pages = 533-8 | year = 2004 | id = PMID 15297089}} </ref>
+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.<ref>Treating behavioral and psychiatric symptoms.  Alzheimer's Association.  Accessed Oct. 15, 2006.[http://www.alz.org/Health/Treating/agitation.asp#behavioral]</ref> 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.<ref> {{cite journal | author = Dunne TE, Neargarder SA, Cipolloni PB, Cronin-Golomb A. | title = Visual contrast enhances food and liquid intake in advanced Alzheimer's disease | journal = Clin Nutr | volume = 23 | issue = 4 | pages = 533-8 | year = 2004 | id = PMID 15297089}} </ref>
 ==Social issues==
 Alzheimer's is a major public health challenge since the median age of the industrialized world's population is increasing gradually.<ref> {{cite journal | author = Sloane P, Zimmerman S, Suchindran C, Reed P, Wang L, Boustani M, Sudha S | title = The public health impact of Alzheimer's disease, 2000-2050: potential implication of treatment advances. | journal = Annu Rev Public Health | volume = 23 | issue = | pages = 213-31 | year = | id = PMID 11910061}} </ref>  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 [[caregiver]]s 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.  Family caregivers often give up time from work and foregoing 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.<ref>{{cite journal |author = | title= The MetLife Study of Alzheimer’s Disease: The Caregiving Experience | journal= MetLife Mature Market Institute ® | issue= August 2006 | }} [http://www.metlife.com/WPSAssets/14050063731156260663V1FAlzheimerCaregivingExperience.pdf]  </ref>
+The role of family [[caregiver]]s 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.<ref>{{cite journal |author = | title= The MetLife Study of Alzheimer’s Disease: The Caregiving Experience | journal= MetLife Mature Market Institute ® | issue= August 2006 | }} [http://www.metlife.com/WPSAssets/14050063731156260663V1FAlzheimerCaregivingExperience.pdf]  </ref>
 == Statistics on Alzheimer's disease ==
-* In the USA, AD was the 7th leading cause of death in 2004, with 65,829 number of deaths (and rising).<ref>[http://www.cdc.gov/nchs/fastats/alzheimr.htm], National Vital Statistics Report. </ref>
+* In the United States of America, AD was the 7th leading cause of death in 2004, with 65,829 number of deaths (and rising).<ref>[http://www.cdc.gov/nchs/fastats/alzheimr.htm  Faststats – Alzheimer's Disease] National Center for Health Statistics</ref>
-* At over $100 billion per year, AD is the third most costly disease in the U.S., after heart disease and cancer.<ref>[http://www.aging-institute.org/about/annualrp.html] Alzheimer's Drug Discovery Foundation 2005 Annual Report</ref>
+* At over $100 billion per year, AD is the third most costly disease in the U.S., after heart disease and cancer.<ref>[http://www.aging-institute.org/about/annualrp.html Alzheimer's Drug Discovery Foundation 2005 Annual Report] </ref>
-* There are an estimated 24 million people with dementia worldwide.<ref>[http://www.alz.co.uk/research/statistics.html], Alzheimer's Disease International.</ref>
+* There are an estimated 24 million people with dementia worldwide.<ref>[http://www.alz.co.uk/research/statistics.html Statistics - Alzheimer's Disease International]</ref> By 2040, it is projected that this figure will have increased to 81 million.
+* More than 5 million Americans are estimated to have Alzheimer’s disease.<ref name="AboutAD">[http://www.alz.org/AboutAD/statistics.asp Alzheimer's Facts and Figures] Alzheimer's Association</ref> It is projected that 14.3 million Americans will have the disease by mid-century: a 350 percent increase from 2000.<ref>
-* By 2040, it is projected that this figure will have increased to 81 million.
+[http://w3.uokhsc.edu/pathology/DeptLabs/diagnostic_center_for_alzheimer.htm Diagnostic Center for Alzheimer's Disease]</ref>
-* An estimated 4.5 million Americans have Alzheimer’s disease.<ref name="AboutAD"> [http://www.alz.org/AboutAD/statistics.asp], Alzheimer's Association </ref>
+* The federal government estimates spending approximately $647 million for Alzheimer’s disease research in fiscal year 2005.<ref name="AboutAD"/>
-* It is projected that 14.3 million Americans will have the disease by mid-century: a 350 percent increase from 2000.<ref>
-     [http://w3.uokhsc.edu/pathology/DeptLabs/diagnostic_center_for_alzheimer.htm]
-     Diagnostic Center for Alzheimer’s Disease - website: w3.uokhsc.edu.</ref>
-* The federal government estimates spending approximately $647 million for Alzheimer’s disease research in fiscal year 2005. <ref name="AboutAD"/>
-* The average lifetime cost of care for an individual with Alzheimer’s is $174,000.
-==Notable cases==
+==Journals==
+*[[Alzheimer Disease and Associated Disorders]]
-[[List of famous Alzheimer's disease sufferers|Notable cases]] of Alzheimer's disease have included President [[Ronald Reagan]], [[Charlton Heston]], [[Ralph Waldo Emerson]], and [[Rita Hayworth]]. <ref> {{cite book | last =Shenk | first =David | title = The Forgetting  Alzheimer’s:  Portrait of an Epidemic | publisher = Anchor Books| date =2003 | location =New York | id=  ISBN 0-385-49838-1}} </ref> For a more comprehensive list, see [[List of famous Alzheimer's disease sufferers]].
+*[[Alzheimer's & Dementia]]
 ==See also==
+* [[Dementia]]
-*[[Familial Alzheimer disease]]
 * Other major [[neurodegenerative disease]]s including [[Parkinson's disease]], [[Huntington's disease]], and [[amyotrophic lateral sclerosis]]
-* Diseases included in the [[differential diagnosis]] of Alzheimer's, including [[dementia with Lewy bodies]], [[frontotemporal dementia]], [[familial Alzheimer disease]], and [[multi-infarct dementia]]
+* Diseases included in the [[differential diagnosis]] of Alzheimer's, including [[dementia with Lewy bodies]], [[frontotemporal dementia]], [[familial Alzheimer disease]], [[multi-infarct dementia]], [[presenile dementia]], [[senile dementia]] and [[Pick's disease]]
+* [[Proteopathy]]
 * Information on the molecular pathogenesis of Alzheimer's disease, including [[amyloid beta]], [[beta-secretase]], and [[tau protein]]
 * Articles related to [[memory]], including [[memory and aging]], [[dementia]], and [[amnesia]]
-* Article concerning a [[QPNC-PAGE|new approach]] for elucidating the structure-function relationships of important metallo[[chaperone]] proteins relevant to [[diagnosis]] and [[therapy]] of [[protein folding|protein-misfolding diseases]].
+* [[QPNC-PAGE|New approach]] concerning the diagnosis and therapy of protein-misfolding diseases
+* [[Alzheimer's disease researchers]]
+* Related societies and organizations:
+**[[Alzheimer's Association]], based in the United States
+**[[Alzheimer Disease International]], based in the United Kingdom
+**[[Alzheimer's Society]], based in the United Kingdom
+**[[Alzheimer Society of Ontario]], based in Ontario, Canada
+**[[National Institute on Aging]], a division of the U.S. National Institutes of Health
+==Journals==
+**[[Alzheimer Disease and Associated Disorders]]
+**[[Journal of Alzheimer's Disease]]
 ==References==
@@ Line 263: / Line 278: @@
 [[Category:Unsolved problems in neuroscience]]
 [[Category:Pathology]]
+[[Category:Organic brain syndromes]]
+<!--
-Ǔ
 [[af:Alzheimer se siekte]]
@@ Line 300: / Line 315: @@
 [[yi:אלטסהיימערס]]
 [[zh:阿兹海默病]]
+-->
+{{enWP|Alzheimer’s disease}}

ICD-10	G 30, F 00
ICD-9	331.0, 290.1
OMIM	104300
DiseasesDB	490
MedlinePlus	000760
eMedicine	neuro/13
MeSH	{{{MeshNumber}}}