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Alzheimer's disease

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Alzheimer's disease
SpecialtyNeurology Edit this on Wikidata
Frequency5.05% (Europe)

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

The most striking early symptom is the loss of memory (amnesia), which usually manifests as minor forgetfulness that becomes steadily more pronounced with 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. 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), ApoE is the only repeatibly confirmed susceptibility genes for AD. In 2007, evidence suggested a possible association between SORL1 alleles and AD.[1]

History

Auguste D.

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

Alzheimer would later work in the laboratory of the preeminent Emil Kraepelin in Munich, Germany. Kraepelin was the author of a leading textbook in psychiatry and was a strong believer that neuropathology could be linked to clinical psychiatric function. Early in April 1906, Auguste D. died, and Alzheimer worked with two Italian physicians to examine her anatomy and neuropathology. On November 3, 1906, he presented Auguste D.'s case to the 37th Assembly of Southwest German Psychiatrists and described the neurofibrillary tangles and amyloid plaques that have come to be considered the hallmark of the disease. Kraepelin would later write about this case and others in his "Textbook for Students and Doctors" and index them under "Alzheimer's disease." By 1910, this denomination for the disease was well established among the specialist community.[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. Since family members are often the first to notice changes that might indicate the onset of the disease they should learn the early warning signs.[3] 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 is death from some external cause (e.g. heart attack or pneumonia) does not intervene. Average duration of the disease is approximately 7–10 years, although cases are known where reaching the final stage occurs within 4–5 years, or in some reported cases up to 21 years.

Stages and symptoms

  • Mild — At the early stage of the disease, patients have a tendency to become less energetic or spontaneous, though changes in their behavior often go unnoticed even by the patients' immediate family. This stage of the disease has also been termed Mild Cognitive Impairment (MCI) although this term remains somewhat controversial.[4]
  • 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. They might forget to eat and starve.

Diagnosis

The diagnosis is made primarily on the basis of history, clinical observation, memory tests and intellectual functioning over a series of weeks or months, with various physical tests (blood tests and neuroimaging) being performed to rule out alternative diagnoses. No medical tests are available to diagnose Alzheimer's disease conclusively pre-mortem. Expert clinicians who specialize in memory disorders can now diagnose AD with an accuracy of 85–90%, but a definitive diagnosis of Alzheimer's disease must await microscopic examination of brain tissue, generally at autopsy. Functional neuroimaging studies such as PET and SPECT scans can provide a supporting role where dementia is clearly present, but the type of dementia is questioned. Recent studies suggest that SPECT neuroimaging approaches clinical exam in diagnostic accuracy and may outperform exam at differentiating types of dementia (Alzheimer's disease vs. vascular dementia).[5][6] However, Alzheimer's disease remains a primarily clinical diagnosis based on the presence of characteristic neurological features and the absence of alternative diagnoses, with possible neuroimaging assistance. Interviews with family members and/or caregivers are extremely important in the initial assessment, as the sufferer him/herself may tend to minimize his symptomatology or may undergo evaluation at a time when his/her symptoms are less apparent, as quotidian fluctuations ("good days and bad days") are a fairly common feature. Such interviews also provide important information on the affected individual's functional abilities, which are a key indicator of the significance of the symptoms and the stage of dementia.

Initial suspicion of dementia may be strengthened by performing the mini mental state examination, after excluding clinical depression. Psychological testing generally focuses on memory, attention, abstract thinking, the ability to name objects, visuospatial abilities, and other cognitive functions. Results of psychological tests may not readily distinguish Alzheimer's disease from other types of dementia, but can be helpful in establishing the presence of and severity of dementia. They can also be useful in distinguishing true dementia from temporary (and more treatable) cognitive impairment due to depression or psychosis, which has sometimes been termed "pseudodementia". In addition, a 2004 study by Cervilla and colleagues showed that tests of cognitive ability provide useful predictive information up to a decade before the onset of dementia.[7] However, when diagnosing individuals with a higher level of cognitive ability, in this study those with IQs of 120 or more,[8] patients should not be diagnosed from the standard norm but from an adjusted high-I.Q norm that measured changes against the individual's higher ability level.

Pathology

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 in the brains of AD patients.[9] 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.[10] The presenilins are components of proteolytic complex involved in APP processing and degradation.[11] 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[12] 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[13] 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.[14] 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.[15] Levels of the neurotransmitter acetylcholine are reduced. Levels of the neurotransmitters serotonin, norepinephrine, and somatostatin are also often reduced. Glutamate levels are usually elevated.[16]

An emerging line of evidence suggests that abnormally low levels of endogenous S-adenosyl methionine (SAM-e) may play an important role in the development of AD. Severely low levels of SAM-e have been found in the cerebrospinal fluid[17] and in all brain regions of AD patients examined.[18] Preliminary research suggests SAM-e may have therapeutic potential in treating AD patients[19] and a recent study using a mouse model of AD found that supplementary SAM-e prevented oxidative damage and cognitive impairment.[20] In that study (available online), Tchantchou et al also explain the biomechanics that in addition to the above findings make low SAM-e a likely causal component of AD pathology.

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.[21] 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[22] leading to generalized neuroinflammation.[15]

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.[23] The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques do not correlate well with neuron loss;[24] however, a majority of researchers support the alternative hypothesis that amyloid is the primary causative agent.[23]

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.[25][26] 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.[27] 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.[28] Relevantly, much early development work on lead compounds has focused on the inhibition of fibrillization,[29][30][31] but the toxic-oligomer theory would imply that prevention of oligomeric assembly is the more important process[32] or that a better target lies upstream, for example in the inhibition of APP processing to amyloid beta.[33]

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.[34] 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.[35][36][37]

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).[38] 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.[39] 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,[40] particularly repeated trauma,[41] previous incidents of migraine headaches,[42] exposure to defoliants,[42] and low activity levels during adulthood.[43] 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),[44] the beta secretase enzymes[45] insulin-degrading enzyme[46] endothelin-converting enzymes[47] and inflammatory 5-lipoxygenase gene.[48]

Genetic linkage

Alzheimer's disease is definitely linked to the 1st, 14th,[49] 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 and prevention

Alzheimer's disease is the most frequent type of dementia in the elderly and affects almost half of all patients with dementia. Correspondingly, advancing age is the primary risk factor for Alzheimer's. Among people aged 65, 2-3% show signs of the disease, while 25–50% of people aged 85 have symptoms of Alzheimer's and an even greater number have some of the pathological hallmarks of the disease without the characteristic symptoms. Every five years after the age of 65, the probability of having the disease doubles.[50] 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.[51]

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.[52] 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.

Risk reducers

Risk factors

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.[66]

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.[71][72][73]

Examples include:

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

There is significant doubt as to the effectiveness of cholinesterase inhibitors. A number of recent articles have criticized the design of studies reporting benefit from these drugs, concluding that they have doubtful clinical utility, are costly, and confer many side effects.[74][75] 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.[76]

Ginkgo biloba

Examining over 50 studies conducted on Ginkgo for the treatment of "cognitive impairment and dementia," a Cochrane Review concludes that "there is promising evidence of improvement in cognition and function associated with Ginkgo." According to this review the two randomized controlled studies that focused on Alzheimer's patients both showed significant improvement in these areas. [77] The AAGP review[66] 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.[78]

NMDA antagonists

Recent evidence of the involvement of glutamatergic neuronal excitotoxicity causes Alzheimer's disease led to the development and introduction of memantine. Memantine is a novel NMDA receptor antagonist, and has been shown to be moderately clinically efficacious.[79] 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.[80][81]

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.[82] 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.[83][84] Leuprolide has also been studied for Alzheimer’s. It is hypothesized to work by reducing leutenizing hormone levels which may be causing damage in the brain as one ages.[85]

  • 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.[86] Work is continuing on less toxic Aβ vaccines, such as a DNA-based therapy that recently showed promise in mice.[87] Researchers from University of South Florida announced a patch version of the drug was shown to be safe and effective when tested on mice.[88]
  • Proposed alternative treatments for Alzheimer's include a range of herbal compounds and dietary supplements. In the AAGP review from 2006,[66] 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[89] 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.[90] 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.[91]

Social issues

Alzheimer's is a major public health challenge since the median age of the industrialized world's population is increasing gradually.[92] 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.[93]

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).[94]
  • At over $100 billion per year, AD is the third most costly disease in the U.S., after heart disease and cancer.[95]
  • There are an estimated 24 million people with dementia worldwide.[96] 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.[97] It is projected that 14.3 million Americans will have the disease by mid-century: a 350 percent increase from 2000.[98]
  • The federal government estimates spending approximately $647 million for Alzheimer’s disease research in fiscal year 2005.[97]

Notable cases

Notable cases of Alzheimer's disease have included former United States President Ronald Reagan, Harold Wilson, Iris Murdoch, Eddie Robinson, Denny Crane, Charlton Heston, Ferenc Puskas, Rita Hayworth,[99] Eddie Albert, James Doohan, and Australia's Hazel Hawke.

See also

References

  1. ^ "Study Detects a Gene Linked to Alzheimer’s". N. Wade, New York Times, January 15, 2007.
  2. ^ Maurer, Konrad (2003). Alzheimer: the life of a physician and the career of a disease. New York: Columbia University Press. ISBN 0-231-11896-1. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  3. ^ "Alzheimer's 10 Possible Early Warning Signs"
  4. ^ [http://www.nature.com/ncpneuro/journal/v3/n2/full/ncpneuro0402.html "The current status of mild cognitive impairment�what do we tell our patients?"]. Ronald C Petersen, Nature Clinical Practice Neurology (2007) 3, 60-61.
  5. ^ Dougall N, Bruggink S, Ebmeier K. "Systematic review of the diagnostic accuracy of 99mTc-HMPAO-SPECT in dementia". Am J Geriatr Psychiatry. 12 (6): 554–70. PMID 15545324.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Bonte F, Harris T, Hynan L, Bigio E, White C (2006). "Tc-99m HMPAO SPECT in the differential diagnosis of the dementias with histopathologic confirmation". Clin Nucl Med. 31 (7): 376–8. PMID 16785801.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Cervilla; et al. (2004). "Premorbid cognitive testing predicts the onset of dementia and Alzheimer's disease better than and independently of APOE genotype". Psychiatry 2004;75:1100-1106. {{cite web}}: Explicit use of et al. in: |author= (help); Unknown parameter |accessmonthday= ignored (help); Unknown parameter |accessyear= ignored (|access-date= suggested) (help)
  8. ^ Dorene Rentz, Brigham and Women's Hospital's Department of Neurology and Harvard Medical School. "More Sensitive Test Norms Better Predict Who Might Develop Alzheimer's Disease". Neuropsychology, published by the American Psychological Association. {{cite web}}: Unknown parameter |accessmonthday= ignored (help); Unknown parameter |accessyear= ignored (|access-date= suggested) (help)
  9. ^ Hashimoto M, Rockenstein E, Crews L, Masliah E (2003). "Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases". Neuromolecular Med. 4 (1–2): 21–36. PMID 14528050.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Kerr M, Small D (2005). "Cytoplasmic domain of the beta-amyloid protein precursor of Alzheimer's disease: function, regulation of proteolysis, and implications for drug development". J Neurosci Res. 80 (2): 151–9. PMID 15672415.
  11. ^ Cai D, Netzer W, Zhong M, Lin Y, Du G, Frohman M, Foster D, Sisodia S, Xu H, Gorelick F, Greengard P (2006). "Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation". Proc Natl Acad Sci U S A. 103 (6): 1941–6. PMID 16449386.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Ohnishi S, Takano K (2004). "Amyloid fibrils from the viewpoint of protein folding". Cell Mol Life Sci. 61 (5): 511–24. PMID 15004691.
  13. ^ Goedert M, Klug A, Crowther R (2006). "Tau protein, the paired helical filament and Alzheimer's disease". J Alzheimers Dis. 9 (3 Suppl): 195–207. PMID 16914859.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ Tiraboschi P, Hansen L, Thal L, Corey-Bloom J (2004). "The importance of neuritic plaques and tangles to the development and evolution of AD". Neurology. 62 (11): 1984–9. PMID 15184601.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ a b Wenk G. "Neuropathologic changes in Alzheimer's disease". J Clin Psychiatry. 64 Suppl 9: 7–10. PMID 12934968.
  16. ^ Baskys. "Receptor found that could lead to better treatments for stroke, alzheimer's disease". UCI Medical Center. Retrieved 2006-11-04.
  17. ^ Bottiglieri T, Godfrey P, Flynn T, Carney MW, Toone BK, Reynolds EH. (1990). "Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine". J Neurol Neurosurg Psychiatry. 53 (12): 1096–8. PMID 2292704.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Morrison LD, Smith DD, Kish SJ. (1996). "Brain S-adenosylmethionine levels are severely decreased in Alzheimer's disease". J Neurochem. 67 (3): 1328–31. PMID 8752143.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ Bottiglieri T. (1997). "Ademetionine (S-adenosylmethionine) neuropharmacology: implications for drug therapies in psychiatric and neurological disorders". Expert Opin Investig Drugs. 6 (4): 417-26. PMID 15989609.
  20. ^ Tchantchou F, Graves M, Ortiz D, Chan A, Rogers E, Shea TB. (2006). "S-adenosyl methionine: A connection between nutritional and genetic risk factors for neurodegeneration in Alzheimer's disease". J Nutr Health Aging. 10 (6): 541–4. PMID 17183426.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ Walker LC, Rosen RF (2006). "Alzheimer therapeutics: What after the cholinesterase inhibitors?". Age Ageing. 35: 332–335. PMID 16644763.
  22. ^ Shen Z (2004). "Brain cholinesterases: II. The molecular and cellular basis of Alzheimer's disease". Med Hypotheses. 63 (2): 308–21. PMID 15236795.
  23. ^ a b Mudher A, Lovestone S (2002). "Alzheimer's disease-do tauists and baptists finally shake hands?". Trends Neurosci. 25 (1): 22–6. PMID 11801334.
  24. ^ 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 (2004). "Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease". Am J Pathol. 164 (4): 1495–502. PMID 15039236.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ^ Nistor M, Don M, Parekh M, Sarsoza F, Goodus M, Lopez GE, Kawas C, Leverenz J, Doran E, Lott IT, Hill M, Head E (2006). "Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain". Neurobiol Aging (epub). PMID 16904243.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  26. ^ Lott I, Head E (2005). "Alzheimer disease and Down syndrome: factors in pathogenesis". Neurobiol Aging. 26 (3): 383–9. PMID 15639317.
  27. ^ Yankner B, Duffy L, Kirschner D (1990). "Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides". Science. 250 (4978): 279–82. PMID 2218531.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ^ Blanchard BJ, Hiniker AE, Lu CC, Margolin Y, Yu AS, Ingram VM (2000). "Elimination of Amyloid beta Neurotoxicity". J Alzheimers Dis. 2 (2): 137–149. PMID 12214104.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ^ Blanchard B, Chen A, Rozeboom L, Stafford K, Weigele P, Ingram V (2004). "Efficient reversal of Alzheimer's disease fibril formation and elimination of neurotoxicity by a small molecule". Proc Natl Acad Sci U S A. 101 (40): 14326–32. PMID 15388848.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  30. ^ Porat Y, Abramowitz A, Gazit E (2006). "Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism". Chem Biol Drug Des. 67 (1): 27–37. PMID 16492146.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  31. ^ Kanapathipillai M, Lentzen G, Sierks M, Park C (2005). "Ectoine and hydroxyectoine inhibit aggregation and neurotoxicity of Alzheimer's beta-amyloid". FEBS Lett. 579 (21): 4775–80. PMID 16098972.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  32. ^ Lee K, Shin B, Shin K, Kim D, Yu J (2005). "A hybrid molecule that prohibits amyloid fibrils and alleviates neuronal toxicity induced by beta-amyloid (1-42)". Biochem Biophys Res Commun. 328 (4): 816–23. PMID 15707952.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  33. ^ 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 (2005). "Compounds that bind APP and inhibit Abeta processing in vitro suggest a novel approach to Alzheimer disease therapeutics". J Biol Chem. 280 (18): 17792–7. PMID 15737955.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  34. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  35. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  36. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  37. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  38. ^ Vetrivel KS, Zhang YW, Xu H, Thinakaran G. (2006). "Pathological and physiological functions of presenilins". Mol Neurodegener. 12: 1–4. PMID 16930451.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  39. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  40. ^ Jellinger KA (2006). "Head injury and dementia". Curr Opin Neurol. 17 (6): 719–23. PMID 15542981.
  41. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  42. ^ a b 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  43. ^ Munoz DG, Feldman H. (2000). "Causes of Alzheimer's disease". CMAJ. 162 (1): 65–72. PMID 11216203.
  44. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  45. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  46. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  47. ^ 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 (2004). "Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease". Mol Psychiatry. 9 (12): 1122–8, 1059. PMID 15340356.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  48. ^ Manev H, Manev R (2006). "5-Lipoxygenase (ALOX5) and FLAP (ALOX5AP) gene polymorphisms as factors in vascular pathology and Alzheimer's disease". Med Hypotheses. 66 (3): 501–3. PMID 16278051.
  49. ^ 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.
  50. ^ Gorelick P (2004). "Risk factors for vascular dementia and Alzheimer disease". Stroke. 35 (11 Suppl 1): 2620–2. PMID 15375299.
  51. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  52. ^ Small, Gary W (2002-06-22). "What we need to know about age related memory loss". British Medical Journal: 1502–1507. Retrieved 2006-11-05. {{cite journal}}: Check date values in: |date= (help)
  53. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  54. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  55. ^ Scarmeas N, Stern Y, Mayeux R, Luchsinger J (2006). "Mediterranean diet, Alzheimer disease, and vascular mediation". Arch Neurol. 63 (12): 1709–17. PMID 17030648.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  56. ^ Morris M, Schneider J, Tangney C (2006). "Thoughts on B-vitamins and dementia". J Alzheimers Dis. 9 (4): 429–33. PMID 16917152.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  57. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  58. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  59. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  60. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  61. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  62. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  63. ^ 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.
  64. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  65. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  66. ^ a b c d 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.{{cite journal}}: CS1 maint: multiple names: authors list (link) [1]
  67. ^ 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. PMID 8498827.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  68. ^ Kofman OS, MacMillan VH (1970). "Diffuse Cerebral Atrophy". Applied Therapeutics. 12 (4): 24–26.
  69. ^ 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. PMID 17362841.
  70. ^ 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. PMID 12218642.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  71. ^ Ortho-McNeil Neurologics, “Razadyne ER US Product Insert”, May 2006. [2]
  72. ^ Novartis Pharmaceuticals Corporation “Exelon Product Insert” June 2006. [3]
  73. ^ Eisai Inc, “Aricept and Aricept ODT Product Insert”, March 2005. [4]
  74. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  75. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  76. ^ Potential Of Exelon® Patch As Promising Treatment Approach For Alzheimer's Disease Patients And Their Families
  77. ^ Birks J, Grimley E, Van Dongen M. "Ginkgo biloba for cognitive impairment and dementia". Cochrane Database Syst Rev: CD003120. PMID 12519586.{{cite journal}}: CS1 maint: multiple names: authors list (link).
  78. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link).
  79. ^ Areosa Sastre A, McShane R, Sherriff F. "Memantine for dementia". Cochrane Database Syst Rev: CD003154. PMID 15495043.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  80. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  81. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  82. ^ 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. {{cite journal}}: line feed character in |author= at position 11 (help)CS1 maint: multiple names: authors list (link)
  83. ^ Zamrini E (2006). "Emerging Drug Therapies for Dementia". Geriatrics Aging. 9 (2): 107, 110–113. [5].
  84. ^ 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. {{cite journal}}: line feed character in |author= at position 66 (help)CS1 maint: multiple names: authors list (link).
  85. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link).
  86. ^ "Alzheimer's Association Fact Sheet: AN-1792 (2006, on ALZ.org)". Retrieved 2006-11-06..
  87. ^ Okura Y, Miyakoshi A, Kohyama K, Park, I-K, Staufenbiel M, Matsumoto, Y (2006). "Nonviral Aβ vaccine therapy against Alzheimer's disease: Long-term effects and safety". PNAS. 103 (25): 9619–24. PMID 16769900.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  88. ^ http://news.bbc.co.uk/2/hi/health/6286689.stm
  89. ^ Landreth G (2006). "PPARgamma agonists as new therapeutic agents for treatment of Alzheimer's disease". Exp Neurol. 199 (2): 245–8. PMID 16733054.
  90. ^ Treating behavioral and psychiatric symptoms. Alzheimer's Association. Accessed Oct. 15, 2006.[6]
  91. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  92. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  93. ^ "The MetLife Study of Alzheimer's Disease: The Caregiving Experience". MetLife Mature Market Institute ® (August 2006). {{cite journal}}: Cite has empty unknown parameter: |1= (help) [7]
  94. ^ Faststats – Alzheimer's Disease National Center for Health Statistics
  95. ^ Alzheimer's Drug Discovery Foundation 2005 Annual Report
  96. ^ Statistics - Alzheimer's Disease International
  97. ^ a b Alzheimer's Facts and Figures Alzheimer's Association
  98. ^ Diagnostic Center for Alzheimer's Disease
  99. ^ Shenk, David (2003). The Forgetting Alzheimer’s: Portrait of an Epidemic. New York: Anchor Books. ISBN 0-385-49838-1.
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