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Alzheimer's disease
(redirected from Alzheimer's)

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Alzheimer's disease
Classification & external resources
Histopathologic image of senile plaques seen in the cerebral cortex in a patient with Alzheimer disease of presenile onset. Silver impregnation.
ICD-10G30., F00.
ICD-9331.0, 290.1
OMIM104300
DiseasesDB.htm 490
MedlinePlus.htm 000760
eMedicine/topic13 .htm neuro /13  
MeSH |]


Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative disease that, in its most common form, is found in people over age 65. Approximately 24 million people worldwide have dementia of which the majority (~60%) is due to Alzheimer's.[1]

Clinical signs of Alzheimer's disease are characterized by progressive cognitive deterioration, together with declining activities of daily living and by neuropsychiatric symptoms or behavioral changes. It is the most common type of dementia. Plaques which contain misfolded peptides called amyloid beta (Aβ) are formed in the brain many years before the clinical signs of Alzheimer's are observed. Together, these plaques and neurofibrillary tangles form the pathological hallmarks of the disease. These features can only be discovered at autopsy and help to confirm the clinical diagnosis. Medications can help reduce the symptoms of the disease, but they cannot change the course of the underlying pathology.

The ultimate cause of Alzheimer's is unknown. Genetic factors are clearly indicated as evidenced by dominant mutations in three different genes have been identified that account for the small number of cases of familial, early-onset AD. For the more common form of late onset AD (LOAD), ApoE is the only clearly established susceptibility gene. All four genes can contain mutations or variants that confer increased risk for AD, but account for only 30% of the genetic picture of AD. These four genes have in common the fact that mutations in each lead to the excessive accumulation in the brain of Aβ, the main component of the senile plaques that litter the brains of AD patients.[2].

History

Enlarge picture
Auguste D.
In 1901, Dr. Alois Alzheimer, a German psychiatrist, identified the first case of what became known as Alzheimer's disease, in a 50 year-old patient Auguste D. and followed her to her death in 1906, when he first reported the case publicly.[3]

For most of the twentieth century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of presenile dementia. Senile dementia, as a set of symptoms, was considered to be a relatively 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 any age, the name "Alzheimer's disease" became used equally for afflicted individuals of all ages; however, the term senile dementia of the Alzheimer type (SDAT) was often used to describe the condition in those over 65. Eventually, the term Alzheimer's disease was formally adopted in medical 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) is also sometimes used in literature for learning.

Etiology

Most cases of Alzheimer's disease are sporadic, i.e., do not exhibit familial inheritance requiring the patient to have two or more first-degree relatives with the disease. Nonetheless, at least 80% of sporadic AD cases most likely involve genetic risk factors based on twin studies. 5-10% of AD cases involve a clear familial pattern of inheritance in which the patient has at least two first-degree relatives with a history of AD [4] The relative contribution of genetics and environment to the sporadic cases is unclear, but are accepted to be of multifactorial origin. In early-onset (<60 years) familial AD, genetic defects identified include mutations in the presenlin 1 gene on chromosome 14, the presenilin 2 gene on chromosome 1, and the amyloid precursor protein (APP) gene on chromosome 21. ApoE is contributes to risk in roughly half of all late-onset sporadic AD cases which comprise 90-95% of total AD. .

Clinical features

The first readily identified symptoms of Alzheimer's disease are usually short-term memory loss and visual-spatial confusion. These initial symptoms progress from seemingly simple and often fluctuating forgetfulness and difficulty orienting oneself in space such as in a traffic lane while driving, to a more pervasive loss of short-term memory and difficulty navigating through familiar areas such as one's neighborhood, then to loss of other familiar and well-known skills as well as recognition of objects and persons.[6][7]

Since family members are often the first to notice changes that might indicate the onset of Alzheimer's they should learn the early warning signs and serve as informants during initial evaluation of patients clinically.[8] Aphasia, disorientation and disinhibition often accompany the loss of memory. Alzheimer's disease (AD) 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 of the disease, 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. Once identified, the average lifespan of patients living with Alzheimer's disease is approximately 7-10 years, although cases are known where reaching the final stage occurs within 4-5 years or at the other extreme they may survive up to 21 years.

Stages and symptoms

  • Mild — In 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 Minor Cognitive Impairment (MCI), when the patient does not meet the criteria for a diagnosis of dementia.[9]
  • Moderate — As the disease progresses to the middle stage, patients might still be able to perform tasks independently (such as using the bathroom), but may need assistance with more complicated activities (such as paying bills).
  • Severe — As the disease progresses from the middle to the late stage, patients will not be able to perform even simple tasks independently and will require constant supervision. They become incontinent of bladder and then incontinent of bowel. They will eventually lose the ability to walk and eat without assistance. Language becomes severely disorganized, and then is lost altogether. They may eventually lose the ability to swallow food and fluid, and this can ultimately lead to death.

Diagnosis

Alzheimer's disease (AD) is primarily a clinically diagnosed condition based on the presence of characteristic neurological and neuropsychological features and the absence of alternative diagnoses. Determination of neurological characteristics is made utilizing patient history and clinical observation, while neuropsychological evaluation includes memory testing and assessment of intellectual functioning over a series of weeks or months. Supplemental physical testing, including blood tests and neuroimaging, is utilized to rule out other diagnoses. Psychological testing, to include screening for depression and a mini mental state examination, can be helpful in establishing the presence and severity of dementia. Although certain clues from history may suggest a diagnosis of vascular dementias instead of, or in addition to, AD (for example, see the Hachinski scale [1]), the ability of certain neuroimaging modalities such as SPECT to differentiate vascular type from Alzheimer disease types of dementias, appears to be superior to clinical exam (PMID 15545324).

Interviews with family members and/or caregivers are also utilized in the initial assessment of the disease, as a patient with Alzheimer's may tend to minimize his or her symptoms, or may undergo evaluation at a time when his or her symptoms are less apparent, as quotidian fluctuations ("good days and bad days") are a common feature of the disease. Observations noting that a patient's good memory function decreases over time plays a critical role in the diagnosis of Alzheimer's.

Brain imaging

New imaging technologies have revolutionized our understanding of the structure and function of the living brain. Structural imaging provides information about the shape, position or volume of brain tissue. Structural techniques include magnetic resonance imaging (MRI) and computed tomography (CT Scan). Functional imaging reveals how well cells in various brain regions are working by showing how actively the cells use sugar or oxygen. Functional techniques include positron emission tomography (PET Scan) and functional MRI (fMRI).

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%. However, a definitive diagnosis of Alzheimer's disease must await microscopic examination of brain tissue which generally occurs at autopsy.

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 A-beta and tau proteins in the brains of AD patients.[10] A-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. The presenilins are components of a proteolytic complex involved in APP processing and degradation.[12] 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[13] 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[14] 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.[15] 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.[16] Levels of the neurotransmitter acetylcholine are reduced. Levels of the neurotransmitters serotonin, norepinephrine, and somatostatin are also often reduced. Glutamate levels are usually elevated.[17]

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.[18] 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[19] 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 differ with one stating that the tau protein abnormalities initiate the disease cascade, while the other states that amyloid beta (Aβ) deposits are the causative factor in the disease.[20] The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques do not correlate well with neuron loss;[21] however, a majority of researchers support the alternative hypothesis that Aβ 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 (Down Syndrome) who thus have an extra gene copy almost universally exhibit AD-like disorders by 40 years of age.[22][23] 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.[24] A more recent and widely supported hypothesis suggests that the cytotoxic species is an intermediate misfolded form of Aβ, neither a soluble monomer nor a mature aggregated polymer but an oligomeric species.[25] Relevantly, much early development work on lead compounds has focused on the inhibition of fibrillization,[26][27][28] but the toxic-oligomer theory would imply that prevention of oligomeric assembly is the more important process[29] or that a better target lies upstream, for example in the inhibition of APP processing to amyloid beta.[30]

It should be noted further that ApoE4, the major genetic risk factor for AD, leads to excess amyloid build up in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD.[31] Another strong support for the amyloid hypothesis, which looks at Aβ as the common initiating factor for Alzheimer's disease, is that transgenic mice solely expressing a mutant human APP gene develop first diffuse and then fibrillar amyloid plaques, associated with neuronal and microglial damage.[32][33][34]

Genetics

Rare cases of Alzheimer's are caused by dominant genes that run in families. These cases often have an early age of onset (usually <60 years). Nearly 200 different mutations in the presenilin-1 or presenilin-2 genes have been documented in over 500 families. Mutations of presenilin 1 (PS1) lead to the most aggressive form of familial Alzheimer's disease (FAD). Over 20 different mutations in the APP gene on chromosome 21 can also cause early onset disease. APP was the first AD gene to be discovered in 1987. The presenilins have been identified as essential components of the proteolytic processing machinery that produces beta amyloid peptides through cleavage of APP. Most mutations in the APP and presenilin genes increase the production of a small protein (peptide) called Abeta42, the main component of senile plaques in brains of AD patients. Inheritance of the ε4 allele of the ApoE gene is regarded as a risk factor for development of up to 50% of late-onset sporadic Alzheimer's. However, genetic experts agree that there are other risk and protective factor genes that influence the development of late onset Alzheimer's disease (LOAD). Over 400 genes have been tested for association with late-onset sproadic AD. The full list of these genes along with which genes exhibit the strongest association with AD are updated weekly and available at AlzGene.org <http://alzgene.org>.

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.[36] 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.[37]

Prevention

Aging itself cannot 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 Alzheimer's varies in quality and its acceptance by the medical community.[38] 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

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.[59]

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.[66][67][68]

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.[69][70] 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. [71] The AAGP review[59] did not recommend Ginkgo, nor did it warn against its use. A large, randomized clinical study in the US called the GEM study is now underway (fully enrolled), which examines the effect (or effects) of Ginkgo to prevent dementia. Results are expected in late 2007 or early 2008. [72]

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.[73] 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.[74][75]

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.[76] 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.[77][78] 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.[79]
  • 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 remain potent threats to this strategy.[80] 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).[81][82]
      • Proposed alternative treatments for Alzheimer's include a range of herbal compounds and dietary supplements. In the AAGP review from 2006,[59] 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[83] 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.[84] 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.[85]

      Social issues

      Alzheimer's is a major public health challenge since the median age of the industrialized world's population is increasing gradually.[86] 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.[87]

      Statistics on Alzheimer's disease

      Enlarge picture
      Ronald Reagan, former President of the United States was diagnosed in 1994
      • In the United States of America, AD was the 7th leading cause of death in 2004, with 65,829 number of deaths (and rising).[88]
      • At over $100 billion per year, AD is the third most costly disease in the U.S., after heart disease and cancer.[89]
      • There are an estimated 24 million people with dementia worldwide.[90] 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.[91] It is projected that 14.3 million Americans will have the disease by mid-century: a 350 percent increase from 2000.[92]
        • The federal government estimates spending approximately $647 million for Alzheimer’s disease research in fiscal year 2005.[91]

        Notable cases

        Notable cases of Alzheimer's disease have included Ronald Reagan, Harold Wilson, Iris Murdoch, Eddie Robinson, Ferenc Puskas, Rita Hayworth,[93] Eddie Albert, James Doohan, Claude Shannon, A.E. van Vogt, and Australia's Hazel Hawke.

        Alzheimer's in the media

        TV documentaries Malcolm and Barbara - A Love Story(1999) and Malcolm and Barbara: Love’s Farewell (2007), featured Malcolm Pointon who was diagnosed with Alzheimer's at the age of 51. Over a period of 14 years Paul Watson followed Malcolm and Barbara Pointon's lives. The documentary follows the couple as Malcolm succumbs to the disease and shows the harsh reality faced by caregivers. The 2007 programme was the target of controversy when initial media claims that the finale purported to show Malcolm's death from the disease, but insider sources revealed that in the closing shots of the documentary actually show Malcolm slipping into a coma from which he never recovered. The argument overshadowed the importance of the documentary, and when it aired on 8th August 2007 the narrator informs us that "Malcolm is in a coma, and dies three days later."[94]

        Thanmathra (Malayalam:Molecule) (2005) is a Malayalam film directed by Blessy which portrays the effects of Alzheimer's disease on the life of an individual and his family.

        Iris is a 2001 film that tells the story of Irish novelist Iris Murdoch and her relationship with John Bayley. The film contrasts the start of their relationship and their later life, when Murdoch (played by Dame Judi Dench) was suffering from Alzheimer's disease. The film is based on Bayley's memoir Elegy for Iris.

        In the popular television show Grey's Anatomy the mother of the main character Meredith Grey dies after battling Alzheimer's disease.

        Away From Her is the feature-length directorial debut of English Canadian actor Sarah Polley. The film is based on Alice Munro's short story "The Bear Came Over the Mountain", from the 2001 collection Hateship, Friendship, Courtship, Loveship, Marriage. The film stars Gordon Pinsent and Julie Christie as a couple whose marriage is tested when Christie's character begins to suffer from Alzheimer's and moves into a nursing home, where she loses virtually all memory of her husband and begins to develop a romance with another nursing home resident.

        See also

        References

        1. ^ Ferri CP, Prince M, Brayne C, et al (2005). "Global prevalence of dementia: a Delphi consensus study". Lancet 366 (9503): 2112-7. DOI:10.1016/S0140-6736(05)67889-0. PMID 16360788. 
        2. ^ "Decoding Darkness: The Search for the Genetics Causes of Alzheimer's Disease", Rudolph Tanzi and Ann Parson, Perseus Press, 2000
        3. ^ Maurer, Konrad; Maurer, Ulrike (2003). Alzheimer: the life of a physician and the career of a disease. New York: Columbia University Press. ISBN 0-231-11896-1. 
        4. ^ Alzheimer's Disease Genetics Fact Sheet. From the National Institute of Health
        6. ^ Kumru, Liz. Getting Lost in Alzheimer's UNMC. Accessed 22 July 2007.
        7. ^ Rickey, Tom. (31 January 2002) Road Skills Hint at "Motion Blindness" of Alzheimer's Accessed 21 July 2007.
        8. ^ "Alzheimer's 10 Possible Early Warning Signs"
        9. ^ "The current status of mild cognitive impairment�what do we tell our patients?". Ronald C Petersen, Nature Clinical Practice Neurology (2007) 3, 60-61.
        10. ^ 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. 
        12. ^ 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. 
        13. ^ Ohnishi S, Takano K (2004). "Amyloid fibrils from the viewpoint of protein folding.". Cell Mol Life Sci 61 (5): 511-24. PMID 15004691. 
        14. ^ 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. 
        15. ^ 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. 
        16. ^ Wenk G. "Neuropathologic changes in Alzheimer's disease.". J Clin Psychiatry 64 Suppl 9: 7-10. PMID 12934968. 
        17. ^ Baskys. Receptor found that could lead to better treatments for stroke, alzheimer's disease. UCI Medical Center. Retrieved on 2006-11-04.
        18. ^ Walker LC, Rosen RF (2006). "Alzheimer therapeutics: What after the cholinesterase inhibitors?". Age Ageing 35: 332-335. PMID 16644763. 
        19. ^ Shen Z (2004). "Brain cholinesterases: II. The molecular and cellular basis of Alzheimer's disease.". Med Hypotheses 63 (2): 308-21. PMID 15236795. 
        20. ^ Mudher A, Lovestone S (2002). "Alzheimer's disease-do tauists and baptists finally shake hands?". Trends Neurosci 25 (1): 22-6. PMID 11801334. 
        21. ^ 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. 
        22. ^ 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 Aβ in Down syndrome and normal brain.". Neurobiol Aging (epub). PMID 16904243. 
        23. ^ Lott I, Head E (2005). "Alzheimer disease and Down syndrome: factors in pathogenesis.". Neurobiol Aging 26 (3): 383-9. PMID 15639317. 
        24. ^ 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. 
        25. ^ 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. 
        26. ^ 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. 
        27. ^ 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. 
        28. ^ 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. 
        29. ^ 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. 
        30. ^ 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. 
        31. ^ 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. 
        32. ^ 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. 
        33. ^ 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. 
        34. ^ 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. 
        36. ^ Gorelick P (2004). "Risk factors for vascular dementia and Alzheimer disease.". Stroke 35 (11 Suppl 1): 2620-2. PMID 15375299. 
        37. ^ 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. 
        38. ^ Small, Gary W (2002-06-22). "What we need to know about age related memory loss". British Medical Journal: 1502-1507. Retrieved on 2006-11-05. 
        39. ^ 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. 
        40. ^ 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. 
        41. ^ Scarmeas N, Stern Y, Mayeux R, Luchsinger J (2006). "Mediterranean diet, Alzheimer disease, and vascular mediation.". Arch Neurol 63 (12): 1709-17. PMID 17030648. 
        42. ^ Morris M, Schneider J, Tangney C (2006). "Thoughts on B-vitamins and dementia.". J Alzheimers Dis 9 (4): 429-33. PMID 16917152. 
        43. ^ 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
        44. ^ CBS news, reporting from WebMD Folate May Lower Alzheimer's Risk
        45. ^ National Institute of Health - Folic Acid Possibly A Key Factor In Alzheimer's Disease Prevention
        46. ^ Alzheimer's and Dementia journal, reported at USA today[2]
        47. ^ 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. 
        48. ^ 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. 
        49. ^ 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. 
        50. ^ 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. 
        51. ^ 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. 
        52. ^ 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. 
        53. ^ 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. 
        54. ^ Lonn E, Bosch J, Yusuf S, et al (2005). "Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial". JAMA 293 (11): 1338–47. DOI:10.1001/jama.293.11.1338. PMID 15769967. 
        55. ^ 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.
        56. ^ 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. 
        57. ^ 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. 
        58. ^ 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. 
        59. ^ 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.  [3]
        60. ^ 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. 
        61. ^ Kofman OS, MacMillan VH (1970). "Diffuse Cerebral Atrophy.". Applied Therapeutics 12 (4): 24-26. 
        62. ^ 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. 
        63. ^ 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. 
        64. ^ BBC Why stroke ups Alzheimer's risk 4 June 2007
        65. ^ 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. DOI:10.1093/aje/kwm116. PMID 17573335. 
        66. ^ Ortho-McNeil Neurologics, “Razadyne ER US Product Insert”, May 2006. [4]
        67. ^ Novartis Pharmaceuticals Corporation “Exelon Product Insert” June 2006. [5]
        68. ^ Eisai Inc, “Aricept and Aricept ODT Product Insert”, March 2005. [6]
        69. ^ 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. 
        70. ^ 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. 
        71. ^ Birks J, Grimley E, Van Dongen M. "Ginkgo biloba for cognitive impairment and dementia.". Cochrane Database Syst Rev: CD003120. PMID 12519586. .
        72. ^ 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. .
        73. ^ Areosa Sastre A, McShane R, Sherriff F. "Memantine for dementia.". Cochrane Database Syst Rev: CD003154. PMID 15495043. 
        74. ^ 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. 
        75. ^ 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. 
        76. ^ 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. 
        77. ^ Zamrini E (2006). "Emerging Drug Therapies for Dementia.". Geriatrics Aging 9 (2): 107,110-113.  [7].
        78. ^ 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. .
        79. ^ 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. .
        80. ^ Alzheimer’s Association Fact Sheet: AN-1792 (2006, on ALZ.org). Retrieved on 2006-11-06..

      81. ^
    Researchers Find Specific Statin Significantly Reduces Alzheimer's and Parkinson's Disease Risk. Retrieved on 2007-08-06..
    82. ^ Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease. Retrieved on 2007-09-10..
    83. ^ Landreth G (2006). "PPARgamma agonists as new therapeutic agents for treatment of Alzheimer's disease.". Exp Neurol 199 (2): 245-8. PMID 16733054. 
    84. ^ Treating behavioral and psychiatric symptoms. Alzheimer's Association. Accessed Oct. 15, 2006.[8]
    85. ^ 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. 
    86. ^ 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. 
    87. ^ "The MetLife Study of Alzheimer’s Disease: The Caregiving Experience". MetLife Mature Market Institute ® (August 2006 |).  [9]
    88. ^ Faststats – Alzheimer's Disease National Center for Health Statistics
    89. ^ Alzheimer's Drug Discovery Foundation 2005 Annual Report
    90. ^ Statistics - Alzheimer's Disease International
    91. ^ Alzheimer's Facts and Figures Alzheimer's Association
    92. ^
Diagnostic Center for Alzheimer's Disease
93. ^ Shenk, David (2003). The Forgetting Alzheimer’s: Portrait of an Epidemic. New York: Anchor Books. ISBN 0-385-49838-1. 
94. ^ Alzheimer's film-maker to face ITV lawyers.

External links

 •  • [ e]
WHO ICD-10 Mental and behavioural disorders (, )
Neurological/symptomaticDementia (Alzheimer's disease, Multi-infarct dementia, Pick's disease, Creutzfeldt-Jakob disease, Huntington's disease, Parkinson's disease, AIDS dementia complex) - Delirium - Post-concussion syndrome
Psychoactive substanceIntoxication (Drunkenness) - Physical dependence (Alcohol dependence, Opioid dependency) - Withdrawal (Benzodiazepine withdrawal, Delirium tremens) - Amnesic (Korsakoff's syndrome)
Psychotic disorderSchizophrenia (Disorganized schizophrenia) - Schizotypal personality disorder - Delusional disorder - Folie deux - Schizoaffective disorder
Mood (affective)Mania - Bipolar disorder - Clinical depression - Cyclothymia - Dysthymia
Neurotic, stress-related
and somatoform		Agoraphobia - Anxiety disorder - Panic disorder - Generalized anxiety disorder - Social Anxiety Disorder - OCD - Acute stress reaction - PTSD - Adjustment disorder - Conversion disorder (Ganser syndrome) - Somatoform disorder - Somatization disorder - Neurasthenia
Physiological/physical
behavioural		Eating disorder (Anorexia nervosa, Bulimia nervosa) - Sleep disorder (Dyssomnia, Insomnia, Hypersomnia, Parasomnia, Night terror, Nightmare) - Sexual dysfunction (Erectile dysfunction, Premature ejaculation, Vaginismus, Dyspareunia, Hypersexuality) - Postpartum depression
Adult personality
and behaviour		Personality disorder - Passive-aggressive behavior - Kleptomania - Trichotillomania - Voyeurism - Factitious disorder - Munchausen syndrome
Mental retardationMental retardation
Psychological development
(developmental disorder)		Specific: speech and language (Expressive language disorder, Aphasia, Expressive aphasia, Receptive aphasia, Landau-Kleffner syndrome, Lisp) - scholastic skills (Dyslexia, Dysgraphia, Gerstmann syndrome) - motor function (Developmental Dyspraxia)
Pervasive: Autism - Rett syndrome - Asperger syndrome
Behaviou