Alzheimer's disease 50610 226148007 2008-07-17T01:10:55Z Orangemarlin 114927 /* Causes */ Copyedit for clarity of which hypothesis was which. {{redirect6|Alzheimer|the German neuropathologist|Alois Alzheimer}} {{DiseaseDisorder infobox | Name = Alzheimer's disease | Image = Alzheimer dementia (3) presenile onset.jpg | Caption = [[Histopathology|Histopathologic]] image of senile plaques seen in the cerebral cortex in a patient with Alzheimer disease of presenile onset. Silver impregnation. | DiseasesDB = 490 | ICD10 = {{ICD10|G|30||g|30}}, {{ICD10|F|00||f|00}} | ICD9 = {{ICD9|331.0}}, {{ICD9|290.1}} | ICDO = | OMIM = 104300 | MedlinePlus = 000760 | eMedicineSubj = neuro | eMedicineTopic = 13 | MeshID = D000544 |}} '''Alzheimer's disease''' ('''AD'''), also called '''Alzheimer disease''' or simply '''Alzheimer's''', is the most common type of [[dementia]]. Alzheimer's is a [[degenerative disease|degenerative]] and [[Terminal illness|terminal disease]] for which there is no known cure. In its most common form, it afflicts individuals over 65&nbsp;years old, although a less prevalent [[Familial Alzheimer disease|early-onset form]] also exists. It is estimated that 26.6&nbsp;million people worldwide were afflicted by AD in 2006, which could quadruple by 2050,<ref name="Brookmeyer2007"/> although estimates vary greatly.<ref name"789241563369">{{cite book | last = World Health Organization | title = Neurological Disorders: Public Health Challenges | publisher = World Health Organization | date = 2006 | location = Switzerland | pages = 204-207 | url = http://www.who.int/mental_health/neurology/neurodiso/en/index.html | isbn = 789241563369 }}</ref> Each individual experiences the symptoms of Alzheimer's disease in unique ways.<ref name="alzheimers.org"> {{cite web | title=What is Alzheimer’s disease? | url=http://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=100 | publisher=www.alzheimers.org.uk | date=August 2007 | accessdate=2008-02-21 }}</ref> Generally, the symptoms are reported to a [[physician]] when memory loss becomes apparent. If Alzheimer's is suspected as the cause, the physician or healthcare specialist will confirm the diagnosis with behavioral assessments and [[cognitive tests]], often followed by a [[brain scan]], if available.<ref name="alzres"> {{cite web | title=Alzheimer's Diagnosis of AD | url=http://www.alzheimers-research.org.uk/info/diagnosis/ | publisher=Alzheimer's Research Trust | accessdate=2008-02-29 }}</ref> The [[prognosis]] for an individual Alzheimer's patient is difficult to assess, as the duration of the disease varies per individual, and the disease can develop for an indeterminate time before becoming fully apparent. The disease can be misdiagnosed for years. On average, the survival time after diagnosis of AD is between 5 and 20&nbsp;years.<ref name="NINDS Prognosis"> {{cite web |url=http://www.ninds.nih.gov/disorders/alzheimersdisease/alzheimersdisease.htm#What_is_the_prognosis |title=Alzheimer's Disease Information Page |publisher= National Institute of Neurological Disorders and Stroke (NINDS) |date=2008-02-07 |accessdate=2008-02-12 }}</ref><ref name="healthlink"> {{cite web | title=Alzheimer's Disease Treatment and Prognosis | url=http://healthlink.mcw.edu/article/921383587.html | publisher=Healthlink | accessdate=2008-02-15 }}</ref> In the early stages, the most widely accepted symptom is memory loss, such as the difficulty to remember recently learned facts. Earliest occurring symptoms are often mistaken as being noncritical age-related complaints, or forms of [[Stress (medicine)|stress]].<ref name="alzdiag">{{cite journal |author=Waldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, Scheltens P, Tariska P, Winblad B |title=Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline |journal=European Journal of Neurology |volume=14 |issue=1 |pages=E1–26 |year=2007 |pmid=17222085 |doi=10.1111/j.1468-1331.2006.01605.x }}</ref> As the disease advances, progressive symptoms include [[Mental confusion|confusion]], [[anger]], [[mood swing]]s, language breakdown, [[long-term memory]] loss, and the general withdrawal of the sufferer as his or her senses decline in mental abilities.<ref name="alzdiag"/><ref name="pmid17823840">{{cite journal |author=Tabert MH, Liu X, Doty RL, Serby M, Zamora D, Pelton GH, Marder K, Albers MW, Stern Y, Devanand DP |title=A 10-item smell identification scale related to risk for Alzheimer's disease |journal=Ann. Neurol. |volume=58 |issue=1 |pages=155–160 |year=2005 |pmid=15984022 |doi=10.1002/ana.20533 }}</ref> Gradually, minor and major bodily functions are lost, leading ultimately to death.<ref name="nihstages"> {{cite web | title=Understanding Stages and Symptoms of Alzheimer's Disease | url=http://www.nia.nih.gov/Alzheimers/Publications/stages.htm | publisher=National Institute on Aging | date=2007-10-26 | accessdate=2008-02-21 }}</ref> The cause and progression of Alzheimer's disease are not well understood. Research indicates that the disease is associated with [[Senile plaques|plaques]] and [[neurofibrillary tangles|tangles]] in the [[brain]].<ref name="pmid15184601"/> No treatment has been found to stop or reverse the disease, and it is not known whether current treatments slow the progression, or simply manage the symptoms. Many preventive measures have been suggested for Alzheimer's disease, but their value is unproven in reducing the course and severity of the disease. [[Mental exercise|Mental stimulation]], [[exercise]] and a [[balanced diet]] are often recommended, both as a possible prevention and as a sensible way of managing the disease.<ref name="prevention1"> {{cite web | title=The Search for AD Prevention Strategies | url=http://www.nia.nih.gov/Alzheimers/Publications/ADPrevented/chap03.htm.htm | publisher=National Institute on Aging | accessdate=2008-02-29 | date =2006-08-29 }}</ref> Because AD cannot be cured and is degenerative, management of the Alzheimer's patient is essential. The role of the main [[Caregiving and dementia|caregiver]] is often taken by the spouse or a close relative.<ref> {{cite web | title= The MetLife Study of Alzheimer’s Disease: The Caregiving Experience | date= August 2006 | url=http://www.metlife.com/WPSAssets/14050063731156260663V1FAlzheimerCaregivingExperience.pdf | publisher=MetLife Mature Market Institute | format=PDF | accessdate=2008-02-12 }}</ref> Caregivers may themselves suffer from [[stress]], over-work, [[Clinical depression|depression]], and being physically hit or struck.<ref name="violence1"> {{cite web | title=http://healthlink.mcw.edu/article/1031002313.html | publisher=Medical College of Wisconsin HealthLink }}</ref><ref name="violence2"> {{cite web | title=Dementia patients aware of losing grasp suffer breakdowns most | url=http://www.eurekalert.org/pub_releases/2001-08/uorm-dpa083001.php | publisher=University of Rochester Medical Center }}</ref><ref name="violence3"> {{cite web | title=What about aggressiveness, combativeness or violence? | url=http://alzheimers.factsforhealth.org/what/faq.asp | publisher=Madison Institute of Medicine }}</ref> World Alzheimer's Day takes place annually on the 21st September. ==Characteristics== The disease course is divided into four stages, with a progressive pattern of cognitive and [[functional]] [[impairment]] expressed from one stage to the next and during each stage. ===Predementia=== Detailed [[neuropsychology|neuropsychological]] testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria of [[diagnosis]] of AD.<ref>Preclinical phase * {{cite journal |author=Linn RT, Wolf PA, Bachman DL, Knoefel JE, Cobb JL, Belanger AJ, Kaplan EF, D'Agostino RB |title=The 'preclinical phase' of probable Alzheimer's disease. A 13-year prospective study of the Framingham cohort |journal=Archives of Neurology |volume=52 |issue=5 |pages=485–490 |year=1995 |pmid=7733843 |doi= }} * {{cite journal |author=Saxton J, Lopez OL, Ratcliff G, Dulberg C, Fried LP, Carlson MC, Newman AB, Kuller L |title=Preclinical Alzheimer disease: neuropsychological test performance 1.5 to 8&nbsp;years prior to onset |journal=Neurology |volume=63 |issue=12 |pages=2341–2347 |year=2004 |pmid=15623697 |doi= }} * {{cite journal |author=Twamley EW, Ropacki SA, Bondi MW |title=Neuropsychological and neuroimaging changes in preclinical Alzheimer's disease |journal=J Int Neuropsychol Soc |volume=12 |issue=5 |pages=707–735 |year=2006 |pmid=16961952 |doi=10.1017/S1355617706060863 }} </ref> These early symptoms can have an effect on the most complex [[Activities of daily living|daily living activities]].<ref name="pmid16513677">{{cite journal |author=Perneczky R, Pohl C, Sorg C, Hartmann J, Komossa K, Alexopoulos P, Wagenpfeil S, Kurz A |title=Complex activities of daily living in mild cognitive impairment: conceptual and diagnostic issues |journal=Age Ageing |volume=35 |issue=3 |pages=240–245 |year=2006 |pmid=16513677 |doi=10.1093/ageing/afj054 }}</ref> The most noticeable deficit is memory loss, shown as a difficulty to remember recently learned facts and an inability to acquire new information.<ref name="pmid12603249">{{cite journal |author=Arnáiz E, Almkvist O |title=Neuropsychological features of mild cognitive impairment and preclinical Alzheimer's disease |journal=Acta Neurol. Scand., Suppl. |volume=179 |issue= |pages=34–41 |year=2003 |pmid=12603249 |doi=10.1034/j.1600-0404.107.s179.7.x |url= |accessdate=2008-06-12 }}</ref><ref name="pmid15785034">{{cite journal |author=Kazui H, Matsuda A, Hirono N, ''et al'' |title=Everyday memory impairment of patients with mild cognitive impairment |journal=Dement Geriatr Cogn Disord |volume=19 |issue=5-6 |pages=331–7 |year=2005 |pmid=15785034 |doi=10.1159/000084559 |url=http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=DEM20050195_6331 |accessdate=2008-06-12 }}</ref> Subtle [[executive function]] problems ([[attention|attentiveness]], [[planning]], [[flexibility]], or [[abstraction|abstract thinking]]) or impairments in [[semantic memory]] (memory of meanings and concept relationships) can also occur.<ref name="pmid15703322"> {{cite journal |author=Rapp MA, Reischies FM |title=Attention and executive control predict Alzheimer disease in late life: results from the Berlin Aging Study (BASE) |journal=American Journal of Geriatric Psychiatry |volume=13 |issue=2 |pages=134–141 |year=2005 |pmid=15703322 |doi=10.1176/appi.ajgp.13.2.134 }} </ref><ref name="pmid12754679"> {{cite journal |author=Spaan PE, Raaijmakers JG, Jonker C |title=Alzheimer's disease versus normal ageing: a review of the efficiency of clinical and experimental memory measures |journal=Journal of Clinical Experimental Neuropsychology |volume=25 |issue=2 |pages=216–233 |year=2003 |pmid=12754679 |doi= }} </ref> [[Apathy]] can be observed at this stage and is the most persistent [[neuropsychiatry|neuropsychiatric]] symptom throughout the course of the disease.<ref name="pmid15956265">{{cite journal |author=Craig D, Mirakhur A, Hart DJ, McIlroy SP, Passmore AP |title=A cross-sectional study of neuropsychiatric symptoms in 435 patients with Alzheimer's disease |journal=American Journal of Geriatric Psychiatry |volume=13 |issue=6 |pages=460–468 |year=2005 |pmid=15956265 |doi=10.1176/appi.ajgp.13.6.460 }}</ref><ref name="pmid16567037">{{cite journal |author=Robert PH, Berr C, Volteau M, Bertogliati C, Benoit M, Sarazin M, Legrain S, Dubois B |title=Apathy in patients with mild cognitive impairment and the risk of developing dementia of Alzheimer's disease: a one-year follow-up study |journal=Clin Neurol Neurosurg |volume=108 |issue=8 |pages=733–736 |year=2006 |pmid=16567037 |doi=10.1016/j.clineuro.2006.02.003 }}</ref><ref name="pmid17485646"> {{cite journal |author=Palmer K, Berger AK, Monastero R, Winblad B, Bäckman L, Fratiglioni L |title=Predictors of progression from mild cognitive impairment to Alzheimer disease |journal=Neurology |volume=68 |issue=19 |pages=1596–1602 |year=2007 |pmid=17485646 |doi=10.1212/01.wnl.0000260968.92345.3f }}</ref> This stage of the disease has also been termed [[mild cognitive impairment]],<ref name="pmid17408315"> {{cite journal |author=Small BJ, Gagnon E, Robinson B |title=Early identification of cognitive deficits: preclinical Alzheimer's disease and mild cognitive impairment |journal=Geriatrics |volume=62 |issue=4 |pages=19–23 |year=2007 |pmid=17408315 |doi= }}</ref> but there is still a debate on whether this term corresponds to a different diagnostic entity by itself or just a first step of the disease.<ref name="pmid17279076"> {{cite journal |author=Petersen RC |title=The current status of mild cognitive impairment—what do we tell our patients? |journal=Nat Clin Pract Neurol |volume=3 |issue=2 |pages=60–61 |year=2007 |pmid=17279076 |doi=10.1038/ncpneuro0402 }}</ref> ===Early dementia=== [[Image:Portion of Reagan's Alzheimer's letter.png‎|right|thumb|In 1994 the former United States president [[Ronald Reagan|R. Reagan]] informed the country of his AD diagnosis via a [[Ronald Reagan's Alzheimer's letter|hand-written letter]]. Writing is usually affected in the first stages of the disease.]] In patients with AD, the increasing impairment of learning and memory will lead to a definitive diagnosis. In a small proportion of these patients, difficulties with language, executive functions, recognition of [[perception]]s ([[agnosia]]) or execution of movements ([[apraxia]]) will be prominent.<ref name="pmid10653284"> {{cite journal |author=Förstl H, Kurz A |title=Clinical features of Alzheimer's disease |journal=European Archives of Psychiatry and Clinical Neuroscience |volume=249 |issue=6 |pages=288–290 |year=1999 |pmid=10653284 |doi= }}</ref> AD does not affect all memory subcapacities equally. [[long-term memory|Older memories]] of the patient's life ([[episodic memory]]), facts learned ([[semantic memory]]), and [[implicit memory]] (the memory of the body on how to do things, such as using a fork to eat) are affected to a much lesser degree than the capacities needed to learn new facts or make new memories.<ref name="pmid1300219"> {{cite journal |author=Carlesimo GA, Oscar-Berman M |title=Memory deficits in Alzheimer's patients: a comprehensive review |journal=Neuropsychology Review |volume=3 |issue=2 |pages=119–169 |year=1992 | pmid=1300219 | doi = 10.1007/BF01108841 }}</ref><ref name="pmid8821346"> {{cite journal |author=Jelicic M, Bonebakker AE, Bonke B |title=Implicit memory performance of patients with Alzheimer's disease: a brief review |journal=International Psychogeriatrics |volume=7 |issue=3 |pages=385–392 |year=1995 |pmid=8821346 | doi = 10.1017/S1041610295002134 }}</ref> [[semantic memory|Language problems]] are mainly characterised by a shrinking [[vocabulary]] and a decreased word [[fluency]] which leads to a general impoverishment of oral and written language. The Alzheimer's patient is usually capable of adequately communicating basic ideas.<ref name="pmid7967534">{{cite journal |author=Frank EM |title=Effect of Alzheimer's disease on communication function |journal=J S C Med Assoc |volume=90 |issue=9 |pages=417–23 |year=1994 |month=September |pmid=7967534 |doi= |url= |accessdate=2008-06-17 }}</ref><ref name="pmid12402233">{{cite journal |author=Becker JT, Overman AA |title=[The semantic memory deficit in Alzheimer's disease] |language=Spanish; Castilian |journal=Rev Neurol |volume=35 |issue=8 |pages=777–83 |year=2002 |pmid=12402233 |doi= |url= |accessdate=2008-06-17 }}</ref><ref name="pmid7617154">{{cite journal |author=Hodges JR, Patterson K |title=Is semantic memory consistently impaired early in the course of Alzheimer's disease? Neuroanatomical and diagnostic implications |journal=Neuropsychologia |volume=33 |issue=4 |pages=441–59 |year=1995 |month=April |pmid=7617154 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/0028-3932(94)00127-B |accessdate=2008-06-17 }}</ref> While performing [[fine motor skill|fine motor tasks]] such as writing, drawing or dressing, certain visoconstructional difficulties, or [[apraxia]], may be present, which may appear as [[clumsiness]].<ref name="pmid8124945">{{cite journal |author=Benke T |title=Two forms of apraxia in Alzheimer's disease |journal=Cortex |volume=29 |issue=4 |pages=715–25 |year=1993 |month=December |pmid=8124945 |doi= |url= |accessdate=2008-06-17 }}</ref> As the disease progresses to the middle stage, patients can perform tasks independently, but may need assistance or supervision with the most complicated activities.<ref name="pmid10653284">{{cite journal |author=Förstl H, Kurz A |title=Clinical features of Alzheimer's disease |journal=Eur Arch Psychiatry Clin Neurosci |volume=249 |issue=6 |pages=288–90 |year=1999 |pmid=10653284 |doi= |url=http://link.springer.de/link/service/journals/00406/bibs/9249006/92490288.htm |accessdate=2008-06-17 }}</ref> ===Moderate dementia=== During the early stage, people with Alzheimer's can usually care for themselves, but progressive deterioration seriously hinders the possibility of independence.<ref name="pmid10653284" /> Speech difficulties become clearly noticeable, due inability to recall vocabulary. The patient makes frequent incorrect substitutions ([[paraphasia]]s). Reading and writing skills are also progressively lost.<ref name="pmid7967534"> {{cite journal |author=Frank EM |title=Effect of Alzheimer's disease on communication function |journal=J S C Med Assoc |volume=90 |issue=9 |pages=417–423 |year=1994 |pmid=7967534 |doi= }}</ref><ref name="pmid15121235"> {{cite journal |author=Forbes KE, Shanks MF, Venneri A |title=The evolution of dysgraphia in Alzheimer's disease |journal=Brain Research Bulletin |volume=63 |issue=1 |pages=19–24 |year=2004 |pmid=15121235 |doi=10.1016/j.brainresbull.2003.11.005 |url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6SYT-4BKGCFP-1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=1b9b6a46fe45ef2bc0d872a8921f48c3 }}</ref> As time passes, complex motor sequences become less coordinated, costing the patient most of their daily-living abilities.<ref name="pmid16209425"> {{cite journal |author=Galasko D, Schmitt F, Thomas R, Jin S, Bennett D |title=Detailed assessment of activities of daily living in moderate to severe Alzheimer's disease |journal=Journal of the International Neuropsychology Society |volume=11 |issue=4 |pages=446–453 |year=2005 |pmid=16209425 |doi= }}</ref> Memory problems worsen, and the person may not recognize close relatives.<ref name="pmid1737981"> {{cite journal |author=Mendez MF, Martin RJ, Smyth KA, Whitehouse PJ |title=Disturbances of person identification in Alzheimer's disease. A retrospective study |journal=Journal of Nervous and Mental Disease |volume=180 |issue=2 |pages=94–96 |year=1992 |pmid=1737981 |doi= }}</ref> [[Long-term memory]], which was previously left intact, is now also impaired.<ref name="pmid15288331">{{cite journal |author=Sartori G, Snitz BE, Sorcinelli L, Daum I |title=Remote memory in advanced Alzheimer's disease |journal=Archives of Clinical Neuropsychology |volume=19 |issue=6 |pages=779–789 |year=2004 |pmid=15288331 |doi=10.1016/j.acn.2003.09.007 |url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VDJ-4BDM22D-2&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=2cbc823139b40b199d78461411ddd37e }}</ref> At this stage, behavior changes are more prevalent. Common [[neuropsychiatric]] manifestations are [[irritability]] and [[labile affect]], leading to crying or outbursts of unpremeditated [[aggression]] and physical violence, even in patients whose life-long behavior has been peaceful. Approximately 30% of the patients also develop [[Delusional misidentification syndrome|illusionary misidentifications]] and other [[delusion]]al symptoms.<ref name="pmid15956265">{{cite journal |author=Craig D, Mirakhur A, Hart DJ, McIlroy SP, Passmore AP |title=A cross-sectional study of neuropsychiatric symptoms in 435 patients with Alzheimer's disease |journal=American Journal of Geriatric Psychiatry |volume=13 |issue=6 |pages=460–468 |year=2005 |pmid=15956265 |doi=10.1176/appi.ajgp.13.6.460 |url=http://ajgponline.org/cgi/pmidlookup?view=long&pmid=15956265 }}</ref><ref name="pmid16670248">{{cite journal |author=Tatsch MF, Bottino CM, Azevedo D, Hototian SR, Moscoso MA, Folquitto JC, Scalco AZ, Louzã MR |title=Neuropsychiatric symptoms in Alzheimer disease and cognitively impaired, nondemented elderly from a community-based sample in Brazil: prevalence and relationship with dementia severity |journal=American Journal of Geriatric Psychiatry |volume=14 |issue=5 |pages=438–45 |year=2006 |pmid=16670248 |doi=10.1097/01.JGP.0000218218.47279.db |url=http://ajgponline.org/cgi/pmidlookup?view=long&pmid=16670248 }}</ref> Often urinary incontinence develops.<ref name="pmid11442300">{{cite journal |author=Honig LS, Mayeux R |title=Natural history of Alzheimer's disease |journal=Aging (Milano) |volume=13 |issue=3 |pages=171–182 |year=2001 |pmid=11442300 |doi= }}</ref> Because of the communication deficit along with delusions, patients often resist when caregivers attempt to provide care.<ref name="pmid17931577">{{cite journal |author=Volicer L, Bass EA, Luther SL |title=Agitation and resistiveness to care are two separate behavioral syndromes of dementia |journal=J Am Med Dir Assoc. 2007 Oct;8(8):527-32 |volume=8 |issue=8 |pages=527–532 |year=2007 |pmid=17931577 |doi= }}</ref> All these symptoms create [[stress (medicine)|stress]] for relatives and caretakers, increasing the likelihood of moving the patient from [[home care]] to other long-term care facilities.<ref name="pmid10653284">{{cite journal |author=Förstl H, Kurz A |title=Clinical features of Alzheimer's disease |journal=European Archives of Psychiatry and Clinical Neuroscience |volume=249 |issue=6 |pages=288–290 |year=1999 |pmid=10653284 |doi= |url=http://www.springerlink.com/home/main.mpx }}</ref><ref name="pmid7806732">{{cite journal |author=Gold DP, Reis MF, Markiewicz D, Andres D |title=When home caregiving ends: a longitudinal study of outcomes for caregivers of relatives with dementia |journal=Journal of the American Geriatric Society |volume=43 |issue=1 |pages=10–16 |year=1995 |pmid=7806732 |doi= }}</ref> ===Advanced=== During this last stage of AD, the patient is completely dependent upon caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech.<ref name="pmid7967534">{{ cite journal |author=Frank EM |title=Effect of Alzheimer's disease on communication function |journal=J S C Med Assoc |volume=90 |issue=9 |pages=417–423 |year=1994 |pmid=7967534 |doi=}}</ref> Many patients can receive and return emotional signals long after the loss of verbal language.<ref name="pmid14685735">{{ cite journal |author=Bär M, Kruse A, Re S |title=Situations of emotional significance in residents suffering from dementia |language={{de icon}} |journal=Z Gerontol Geriatr |volume=36 |issue=6 |pages=454–462 |year=2003 |pmid=14685735 |doi=10.1007/s00391-003-0191-0}}</ref> Although aggressiveness can still be present, extreme apathy and [[exhaustion]] are much more common.<ref name="pmid10653284"> {{cite journal |author=Förstl H, Kurz A |title=Clinical features of Alzheimer's disease |journal=European Archives of Psychiatry and Clinical Neuroscience |volume=249 |issue=6 |pages=288–290 |year=1999 |pmid=10653284 |doi=}}</ref> Patients will ultimately not be able to perform even the most simple tasks independently. Eventually, [[musculature|muscle]] and mobility will deteriorate to the point where the patient is bedridden.<ref name="pmid7775724">{{ cite journal |author=Souren LE, Franssen EH, Reisberg B |title=Contractures and loss of function in patients with Alzheimer's disease |journal=Journal of the American Geriatric Society |volume=43 |issue=6 |pages=650–655 |year=1995 |pmid=7775724 |doi=}}</ref> The AD sufferer will also lose the ability to feed themselves.<ref name="pmid12675103">{{ cite journal |author=Berkhout AM, Cools HJ, van Houwelingen HC |title=The relationship between difficulties in feeding oneself and loss of weight in nursing-home patients with dementia |journal=Age Ageing |volume=27 |issue=5 |pages=637–641 |year=1998 |pmid=12675103 |doi=}}</ref> Death usually occurs from some external factor such as [[bedsore|pressure ulcers]] or [[pneumonia]].<ref name="pmid11490146">{{ cite journal |author=Wada H, Nakajoh K, Satoh-Nakagawa T, Suzuki T, Ohrui T, Arai H, Sasaki H |title=Risk factors of aspiration pneumonia in Alzheimer's disease patients |journal=Gerontology |volume=47 |issue=5 |pages=271–276 |year=2001 |pmid=11490146 |doi=}}</ref><ref name="pmid10369823">{{ cite journal |author=Gambassi G, Landi F, Lapane KL, Sgadari A, Mor V, Bernabei R |title=Predictors of mortality in patients with Alzheimer's disease living in nursing homes |journal=J Neurol Neurosurg Psychiatr |volume=67 |issue=1 |pages=59–65 |year=1999 |pmid=10369823 |doi=}}</ref> ==Causes== 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 only affect symptoms of the disease and neither halt nor reverse it.<ref name="pmid16644763">{{cite journal |author=Walker LC, Rosen RF |title=Alzheimer therapeutics-what after the cholinesterase inhibitors? |journal=Age Ageing |volume=35 |issue=4 |pages=332–335 |year=2006 |pmid=16644763 |doi=10.1093/ageing/afl009}}</ref> The cholinergic hypothesis has not maintained widespread support in the face of this evidence, although cholinergic effects have been proposed to initiate large-scale aggregation,<ref name="pmid15236795">{{cite journal |author=Shen ZX |title=Brain cholinesterases: II. The molecular and cellular basis of Alzheimer's disease |journal=Medical Hypotheses |volume=63 |issue=2 |pages=308–321 |year=2004 |pmid=15236795 |doi=10.1016/j.mehy.2004.02.031}}</ref> leading to generalised neuroinflammation.<ref name="pmid12934968">{{cite journal |author=Wenk GL |title=Neuropathologic changes in Alzheimer's disease |journal=Journal of Clinical Psychiatry |volume=64 Suppl 9 |issue= |pages=7–10 |year=2003 |pmid=12934968 |doi=}}</ref> In 1991 the [[amyloid beta|amyloid]] hypothesis was proposed,<ref name="pmid1763432">{{cite journal |author=Hardy J, Allsop D |title=Amyloid deposition as the central event in the aetiology of Alzheimer's disease |journal=Trends Pharmacol. Sci. |volume=12 |issue=10 |pages=383–8 |year=1991 |pmid=1763432 |doi=10.1016/0165-6147(91)90609-V }}</ref> which states states that amyloid beta (Aβ) deposits are the causative factor in the disease.<ref name="pmid11801334">{{cite journal |author=Mudher A, Lovestone S |title=Alzheimer's disease-do tauists and baptists finally shake hands? |journal=Trends in Neuroscience |volume=25 |issue=1 |pages=22–26 |year=2002 |pmid=11801334 | doi=10.1016/S0166-2236(00)02031-2 }}</ref> Current research has focused on [[tau protein]] abnormalities that initiate the disease cascade.<ref name="pmid11801334"/> The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques do not correlate well with neuron loss.<ref name="pmid15039236">{{cite journal |author=Schmitz C, Rutten BP, Pielen A, Schäfer S, Wirths O, Tremp G, Czech C, Blanchard V, Multhaup G, Rezaie P, Korr H, Steinbusch HW, Pradier L, Bayer TA |title=Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease |journal=Am. J. Pathol. |volume=164 |issue=4 |pages=1495–502 |year=2004 |pmid=15039236 |doi= }}</ref> In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they become tangled inside nerve cell bodies and known as [[neurofibrillary tangles]].<ref name="pmid1669718">{{cite journal |author=Goedert M, Spillantini MG, Crowther RA |title=Tau proteins and neurofibrillary degeneration |journal=Brain Pathology |volume=1 |issue=4 |pages=279–286 |year=1991 |pmid=1669718 | doi=10.1111/j.1750-3639.1991.tb00671.x }}</ref> When this occurs, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in communication between neurons and later in the death of the cells.<ref name="pmid17127334">{{cite journal |author=Chun W, Johnson GV |title=The role of tau phosphorylation and cleavage in neuronal cell death |journal=Frontiers of Bioscience |volume=12 |pages=733–756 |year=2007 |pmid=17127334 |doi=10.2741/2097}}</ref> A majority of researchers support the alternative hypothesis that Aβ is the primary causative agent.<ref name="pmid11801334">{{cite journal |author=Mudher A, Lovestone S |title=Alzheimer's disease-do tauists and baptists finally shake hands? |journal=Trends in Neuroscience |volume=25 |issue=1 |pages=22–26 |year=2002 |pmid=11801334 | doi=10.1016/S0166-2236(00)02031-2}}</ref> The amyloid hypothesis is compelling because the gene for the amyloid beta precursor (APP) is located on [[chromosome 21]], and patients with [[trisomy 21]] (Down Syndrome) who thus have an extra [[gene dosage|gene copy]] almost universally exhibit AD-like disorders by 40&nbsp;years of age.<ref name="pmid16904243">{{cite journal |author=Nistor M, Don M, Parekh M, Sarsoza F, Goodus M, Lopez GE, Kawas C, Leverenz J, Doran E, Lott IT, Hill M, Head E |title=Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain |journal=Neurobiol. Aging |volume=28 |issue=10 |pages=1493–506 |year=2007 |pmid=16904243 |doi=10.1016/j.neurobiolaging.2006.06.023 }}</ref><ref name="pmid15639317">{{cite journal |author=Lott IT, Head E |title=Alzheimer disease and Down syndrome: factors in pathogenesis |journal=Neurobiology of Aging |volume=26 |issue=3 |pages=383–389 |year=2005 |pmid=15639317 |doi=10.1016/j.neurobiolaging.2004.08.005}}</ref> It should be noted further that [[APOE4]], the major genetic risk factor for AD, leads to excess amyloid build-up in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD.<ref name="pmid7566000">{{cite journal |author=Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, Niinistö L, Halonen P, Kontula K |title=Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein |journal=New England Journal of Medicine |volume=333 |issue=19 |pages=1242–1247 |year=1995 |pmid=7566000 |doi=10.1056/NEJM199511093331902 }}</ref> It is known that some types of inherited AD involve only mutations in the APP gene (although this is not the most common type—others involve genes for "pre-senilin" proteins which process APP and may also have still-unknown functions).<ref>{{cite web |url=http://ghr.nlm.nih.gov/condition=alzheimerdisease |title=Alzheimer disease |publisher=US National Library of Medicine |date=2008-04-25 |accessdate=2008-05-02}}</ref> However, another strong support for the amyloid hypothesis, which looks at Aβ as the common initiating factor for Alzheimer's disease, is that [[Genetically modified organism|transgenic]] mice solely expressing a mutant human APP gene develop fibrillar amyloid plaques.<ref>Beta-amyloid precursor protein * {{cite journal |author=Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F |title=Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein |journal=Nature |volume=373 |issue=6514 |pages=523–527 |year=1995 |pmid=7845465 |doi=10.1038/373523a0 }} * {{cite journal |author=Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D |title=Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimer's disease |journal=Journal of Neuroscience |volume=16 |issue=18 |pages=5795–5811 |year=1996 |pmid=8795633 |doi=}} * {{cite journal |author=Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G |title=Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice |journal=Science |volume=274 |issue=5284 |pages=99–102 |year=1996 |pmid=8810256 |doi = 10.1126/science.274.5284.99 }}</ref> ==Pathophysiology== {{main|Biochemistry of Alzheimer's disease}} ===Neuropathology=== [[Image:Alzheimer's disease - MRI.jpg|thumb|[[MRI]] images of a normal aged brain (right) and an Alzheimer's patient's brain (left). In the Alzheimer brain, atrophy is clearly seen.]] At a [[macroscopic]] level, AD is characterised by loss of [[neuron]]s and [[synapse]]s in the [[cerebral cortex]] and certain subcortical regions. This results in gross [[atrophy]] of the affected regions, including degeneration in the [[temporal lobe]] and [[parietal lobe]], and parts of the [[frontal cortex]] and [[cingulate gyrus]].<ref name="pmid12934968">{{cite journal |author=Wenk GL |title=Neuropathologic changes in Alzheimer's disease |journal=Journal of Clinical Psychiatry |volume=64 Suppl 9 |issue= |pages=7–10 |year=2003 |pmid=12934968 |doi=}}</ref> Both [[amyloid plaques]] and [[neurofibrillary tangle]]s are clearly visible by [[microscopy]] in AD brains.<ref name="pmid15184601">{{cite journal |author=Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J |title=The importance of neuritic plaques and tangles to the development and evolution of AD |journal=Neurology |volume=62 |issue=11 |pages=1984–1989 |year=2004 |pmid=15184601 |doi=}}</ref> Plaques are dense, mostly [[insoluble]] deposits of amyloid-beta [[protein]] and [[cell]]ular material outside and around neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. Though many older people develop some plaques and tangles, the brains of AD patients have them to a much greater extent and in different brain locations.<ref name="pmid8038565">{{cite journal |author=Bouras C, Hof PR, Giannakopoulos P, Michel JP, Morrison JH |title=Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: a quantitative evaluation of a one-year autopsy population from a geriatric hospital |journal=Cerebral Cortex |volume=4 |issue=2 |pages=138–150 |year=1994 |pmid=8038565 |doi =10.1093/cercor/4.2.138 }}</ref> ===Biochemical characteristics=== Alzheimer's disease has been identified as a [[protein folding|protein misfolding]] disease, or [[proteopathy]], due to the accumulation of abnormally folded A-beta and tau proteins in the brains of AD patients.<ref name="pmid14528050">{{cite journal |author=Hashimoto M, Rockenstein E, Crews L, Masliah E |title=Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases |journal=Neuromolecular Medicine |volume=4 |issue=1–2 |pages=21–36 |year=2003 |pmid=14528050 |doi=10.1385/NMM:4:1-2:21}}</ref> Plaques are made of a small [[peptide]] (39 to 43 amino acid residues) called [[beta-amyloid]] (also A-beta or Aβ), a [[protein]] fragment snipped from a larger protein called [[amyloid precursor protein]] (APP). APP is a [[transmembrane protein]]; which means that it sticks through the neuron's membrane; and is believed to help neurons grow, survive and repair themselves after injury.<ref name="pmid16822978">{{cite journal |author=Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J |title=Synapse formation and function is modulated by the amyloid precursor protein |journal=Journal of Neuroscience |volume=26 |issue=27 |pages=7212–7221 |year=2006 |pmid=16822978 |doi=10.1523/JNEUROSCI.1450-06.2006}}</ref><ref name="pmid12927332">{{cite journal |author=Turner PR, O'Connor K, Tate WP, Abraham WC |title=Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory |journal=Prog. Neurobiology |volume=70 |issue=1 |pages=1–32 |year=2003 |pmid=12927332 |doi=}}</ref> In AD, something causes APP to be divided by [[enzymes]] through a mechanism called [[proteolysis]].<ref name="pmid15787600">{{cite journal |author=Hooper NM |title=Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein |journal=Biochemical Society Transactions |volume=33 |issue=Pt 2 |pages=335–338 |year=2005 |pmid=15787600 |doi=10.1042/BST0330335}}</ref> One of these fragments is [[beta-amyloid]]. Beta-amyloid fragments (amyloid fibrils) outside the cell form clumps that deposit outside neurons in dense formations known as [[senile plaques]].<ref name="pmid15004691">{{cite journal |author=Ohnishi S, Takano K |title=Amyloid fibrils from the viewpoint of protein folding |journal=Cellular Molecular Life Sciences |volume=61 |issue=5 |pages=511–524 |year=2004 |pmid=15004691 |doi=10.1007/s00018-003-3264-8}}</ref><ref name="pmid15184601">{{cite journal |author=Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J |title=The importance of neuritic plaques and tangles to the development and evolution of AD |journal=Neurology |volume=62 |issue=11 |pages=1984–1989 |year=2004 |pmid=15184601 |doi=}}</ref> AD is also considered a [[tauopathy]] due to abnormal aggregation of the [[tau protein]]. Healthy neurons have an internal support structure, or [[cytoskeleton]], partly made up of structures called [[microtubules]]. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell down to the ends of the [[axon]] and back. A protein called tau makes the microtubules stable when [[phosphorylation|phosphorylated]], and is therefore called a [[microtubule-associated protein]].<ref name="pmid17604998">{{cite journal |author=Hernández F, Avila J |title=Tauopathies |journal=Cellular Molecular Life Sciences |volume=64 |issue=17 |pages=2219–2233 |year=2007 |pmid=17604998 |doi=10.1007/s00018-007-7220-x}}</ref> In AD, tau is changed chemically, becoming phosphate saturated ([[Hyperphosphorylation|hyperphosphorylated]]). ===Disease mechanism=== If the production and aggregation of the amyloid beta peptide plays a key role in AD, the exact mechanism has not been elucidated.<ref name="pmid17622778">{{cite journal |author=Van Broeck B, Van Broeckhoven C, Kumar-Singh S |title=Current insights into molecular mechanisms of Alzheimer disease and their implications for therapeutic approaches |journal=Neurodegener Dis |volume=4 |issue=5 |pages=349–65 |year=2007 |pmid=17622778 |doi=10.1159/000105156 |url=http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=000105156 |accessdate=2008-06-30 }}</ref> The traditional formulation of the amyloid hypothesis points to the accumulation of beta-amyloid [[peptide]]s as the central event triggering neurons degeneration. Accumulation of aggregated [[amyloid]] [[fibril]]s, which are believed to be the toxic form of the protein responsible for disrupting the [[cell]]'s [[calcium]] [[ion]] [[homeostasis]], induces [[apoptosis]] (programmed cell death).<ref name="pmid2218531">{{cite journal |author=Yankner BA, Duffy LK, Kirschner DA |title=Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides |journal=Science |volume=250 |issue=4978 |pages=279–282 |year=1990 |pmid=2218531 |doi=10.1126/science.2218531 }}</ref> It is also known that Aβ selectively builds up in the cells [[Mitochondrion|mitochondria]] of brains with AD and inhibits certain [[enzyme]] functions and the utilization of [[glucose]] by neurons. This process may also lead to the formation of damaging reactive [[oxygen]] species, [[calcium]] influx, and apoptosis.<ref name="pmid17424907">{{cite journal |author=Chen, X, Yan, SD |title=Mitochondrial Aβ: A Potential Cause of Metabolic Dysfunction in Alzheimer's Disease |journal=IUBMB Life |volume=58 |issue=12 |pages=686–694 |year=2006 |pmid=17424907 |doi=10.1080/15216540601047767}}</ref> Various inflammatory processes and inflammatory [[cytokine]]s may also have a role in the pathology of Alzheimer's disease. However, these are general markers of [[Tissue (biology)|tissue]] damage in any disease, and may also be either secondary causes of tissue damage in AD, or else bystander "marker" effects.<ref name="pmid15681814">{{cite journal |author=Greig NH, Mattson MP, Perry T, ''et al'' |title=New therapeutic strategies and drug candidates for neurodegenerative diseases: p53 and TNF-alpha inhibitors, and GLP-1 receptor agonists |journal=Ann. N. Y. Acad. Sci. |volume=1035 |issue= |pages=290–315 |year=2004 |month=December |pmid=15681814 |doi=10.1196/annals.1332.018 |url=http://www.annalsnyas.org/cgi/pmidlookup?view=long&pmid=15681814 |accessdate=2008-06-30 }}</ref> ===Genetic=== While [[Familial Alzheimer disease|earlier disease familial onset]] is mainly explained by three [[gene]]s, later age of disease onset representing most cases of AD has yet to be explained by a purely genetic model. In the second case the [[Apolipoprotein E|APOE]] gene is the strongest genetic [[risk factor]] discovered but it is far from explaining all occurrences of the disease.<ref name="pmid18332245">{{cite journal |author=Waring SC, Rosenberg RN |title=Genome-wide association studies in Alzheimer disease |journal=Arch. Neurol. |volume=65 |issue=3 |pages=329–34 |year=2008 |month=March |pmid=18332245 |doi=10.1001/archneur.65.3.329 |url=http://archneur.ama-assn.org/cgi/pmidlookup?view=long&pmid=18332245 |accessdate=2008-06-10 }}</ref> Only 10% of AD cases occurring before 60 years of age are due to [[autosomal dominant]] (familial) mutations, which represents less than 0,01 of all patients.<ref name="pmid18332245" /><ref name="pmid10441572">{{cite journal |author=Campion D, Dumanchin C, Hannequin D, ''et al'' |title=Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum |journal=Am. J. Hum. Genet. |volume=65 |issue=3 |pages=664–70 |year=1999 |month=September |pmid=10441572 |pmc=1377972 |doi=10.1086/302553 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)62317-9 |accessdate=2008-06-12 }}</ref> These mutations have been discovered in three different genes: [[amyloid precursor protein]] or APP,<ref name="pmid1671712">{{cite journal |author=Goate A, Chartier-Harlin MC, Mullan M, ''et al'' |title=Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease |journal=Nature |volume=349 |issue=6311 |pages=704–6 |year=1991 |month=February |pmid=1671712 |doi=10.1038/349704a0 |accessdate=2008-06-10 }}</ref> and [[presenilin]]s 1,<ref name="pmid7596406">{{cite journal |author=Sherrington R, Rogaev EI, Liang Y, ''et al'' |title=Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease |journal=Nature |volume=375 |issue=6534 |pages=754–60 |year=1995 |month=June |pmid=7596406 |doi=10.1038/375754a0 |accessdate=2008-06-10 }}</ref> and 2<ref name="pmid7651536">{{cite journal |author=Rogaev EI, Sherrington R, Rogaeva EA, ''et al'' |title=Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene |journal=Nature |volume=376 |issue=6543 |pages=775–8 |year=1995 |month=August |pmid=7651536 |doi=10.1038/376775a0 |accessdate=2008-06-10 }}</ref>. Most mutations in the APP and presenilin genes increase the production of a small protein called [[Abeta]]42, which is the main component of [[senile plaques]] in brains of AD patients.<ref name="pmid10392577">{{cite journal |author=Selkoe DJ |title=Translating cell biology into therapeutic advances in Alzheimer's disease |journal=Nature |volume=399 |issue=6738 Suppl |pages=A23–31 |year=1999 |month=June |pmid=10392577 |doi= |url= |accessdate=2008-06-12 }}</ref> Most cases of Alzheimer's disease do not exhibit familial inheritance. In this case genes may act as risk factors. The best known genetic risk factor is the inheritance of the ε4 [[allele]] of the [[apolipoprotein E]] (APOE). This gene is regarded as a risk factor for development of up to 50% of late-onset sporadic Alzheimer's.<ref name="pmid8446617">{{cite journal |author=Strittmatter WJ, Saunders AM, Schmechel D, ''et al'' |title=Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue=5 |pages=1977–81 |year=1993 |month=March |pmid=8446617 |pmc=46003 |doi= |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8446617 |accessdate=2008-06-11 }}</ref> Genetic experts agree that there are other risk and protective factor genes that influence the development of late onset Alzheimer's disease.<ref name="pmid18332245" /> Over 400 genes have been tested for association with late-onset sporadic AD.<ref> {{cite journal |author=Waring SC, Rosenberg RN |title=Genome-wide association studies in Alzheimer disease |journal=Arch. Neurol. |volume=65 |issue=3 |pages=329–34 |year=2008 |pmid=18332245 |doi=10.1001/archneur.65.3.329 }}</ref> ==Diagnosis== [[Dementia]] is by definition a clinical condition but not an exact diagnosis. Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic [[Neurology|neurological]] and [[neuropsychology|neuropsychological]] features and the [[Diagnosis of exclusion|absence of alternative conditions]].<ref name="pmid17407994">{{cite journal |author=Mendez MF |title=The accurate diagnosis of early-onset dementia |journal=International Journal of Psychiatry Medicine |volume=36 |issue=4 |pages=401–412 |year=2006 |pmid=17407994 |doi= }}</ref><ref name="pmid17018549">{{cite journal |author=Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J |title=Therapeutic approaches to Alzheimer's disease |journal=Brain |volume=129 |issue=Pt 11 |pages=2840–2855 |year=2006 |pmid=17018549 |doi=10.1093/brain/awl280 }}</ref> Advanced [[medical imaging]] with [[Computed tomography|CT]] or [[Magnetic resonance imaging|MRI]], and with [[SPECT]] or [[PET]] are generally used to help to diagnose the subtype of dementia and exclude other cerebral pathology.<ref> {{cite web |url = http://www.nice.org.uk/nicemedia/pdf/CG042quickrefguide.pdf |format = PDF |title = Dementia: Quick reference guide |publisher = [[National Institute for Health and Clinical Excellence]] |month = November |year = 2006 |isbn = 1-84629-312-X |accessdate = 2008-02-22 }}</ref> Neuropsychological evaluation including memory testing and assessment of intellectual functioning can further characterize the dementia.<ref name="pmid17222085"> {{cite journal |author=Waldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, Scheltens P, Tariska P, Winblad B |title=Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline |journal=European Journal of Neurology |volume=14 |issue=1 |pages=e1–26 |year=2007 |pmid=17222085 |doi=10.1111/j.1468-1331.2006.01605.x }}</ref> Medical organizations have created diagnostic criteria to ease and standardize the process for practicing physicians. Sometimes the diagnosis can be confirmed or made at postmortem when brain material is available and can be examined histologically and histochemically.<ref name="pmid6610841"> {{ cite journal |author=McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM |title=Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease |journal=Neurology |volume=34 |issue=7 |pages=939–44 |year=1984 |pmid=6610841 |doi= }} </ref> ===Diagnostic criteria=== [[NINCDS-ADRDA Alzheimer's Criteria|The diagnostic criteria for Alzheimer of the NINCDS-ADRDA]] ([[National Institute of Neurological and Communicative Disorders and Stroke|NINCDS]] and the [[Alzheimer's Disease and Related Disorders Association|ADRDA]]) are among the most used.<ref name="pmid17616482">{{cite journal |author=Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P |title=Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria |journal=Lancet Neurology |volume=6 |issue=8 |pages=734–746 |year=2007 |pmid=17616482 |doi=10.1016/S1474-4422(07)70178-3 }}</ref> These criteria require that the presence of cognitive impairment and a suspected dementia syndrome be confirmed by [[Neuropsychological assessment|neuropsychological testing]] for a clinical diagnosis of possible or probable AD while they need [[histopathologic]] confirmation ([[microscopic]] examination of [[brain tissue]]) for the definitive diagnosis. They have shown good [[Reliability (statistics)|reliability]] and [[Validity (statistics)|validity]].<ref name="pmid7986174"> {{ cite journal |author=Blacker D, Albert MS, Bassett SS, Go RC, Harrell LE, Folstein MF |title=Reliability and validity of NINCDS-ADRDA criteria for Alzheimer's disease. The National Institute of Mental Health Genetics Initiative |journal=Archives of Neurology |volume=51 |issue=12 |pages=1198–1204 |year=1994 |pmid=7986174 |doi= }} </ref> They specify as well eight cognitive domains that may be impaired in AD (i.e., [[memory]], [[language]], [[perception|perceptual skills]], [[attention]], constructive abilities, [[orientation (mental)|orientation]], [[problem solving]] and functional abilities). Similar to the NINCDS-ADRDA Alzheimer's Criteria are the ''[[Diagnostic and Statistical Manual of Mental Disorders]]'' (DSM-IV-TR) criteria published by the [[American Psychiatric Association]].<ref> {{ cite book | last=American Psychiatric Association | title=Diagnostic and Statistical Manual of Mental disorders, 4th Edition Text Revision | date=2000 | location=Washington DC | }} </ref><ref name="pmid8752526"> {{ cite journal |author=Ito N |title=Clinical aspects of dementia |language=Japanese |journal=Hokkaido Igaku Zasshi |volume=71 |issue=3 |pages=315–320 |year=1996 |pmid=8752526 |doi= }} </ref> ===Diagnostic tools=== [[Image:InterlockingPentagons.svg|right|framed|Neuropsychological screening tests can help in the diagnosis of AD. In them patients have to copy drawings similar to the one shown in the picture, remember words, read or sum.]] Neuropsychological [[Screening (medicine)|screening]] [[Neuropsychological test|tests]] such as the [[Mini mental state examination]] (MMSE) are widely used to evaluate the cognitive impairments needed for diagnosis, but more comprehensive tests arrays are necessary for high reliability by this method, especially in the earliest stages of the disease.<ref name="pmid1512391"> {{ cite journal |author=Tombaugh TN, McIntyre NJ |title=The mini-mental state examination: a comprehensive review |journal=J Am Geriatr Soc |volume=40 |issue=9 |pages=922–935 |year=1992 |pmid=1512391 |doi= }} </ref><ref name="pmid9987708"> {{ cite journal |author=Pasquier F |title=Early diagnosis of dementia: neuropsychology |journal=J. Neurol. |volume=246 |issue=1 |pages=6–15 |year=1999 |pmid=9987708 |doi= }} </ref> [[Neurological examination]] in early AD will usually be normal, independent of cognitive impairment; but for many of the other dementing disorders is key for diagnosis. Therefore, neurological examination is crucial in the [[differential diagnosis]] of Alzheimer and other diseases.<ref name="pmid17222085">{{cite journal |author=Waldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, Scheltens P, Tariska P, Winblad B |title=Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline |journal=European Journal of Neurology |volume=14 |issue=1 |pages=e1–26 |year=2007 |pmid=17222085 |doi=10.1111/j.1468-1331.2006.01605.x }}</ref> In addition, interviews with family members are also utilized in the assessment of the disease. Caregivers can supply important information on the daily living abilities, as well as on the decrease over time of the patient's mental function.<ref name="pmid16327345">{{cite journal |author=Harvey PD, Moriarty PJ, Kleinman L, Coyne K, Sadowsky CH, Chen M, Mirski DF |title=The validation of a caregiver assessment of dementia: the Dementia Severity Scale |journal=Alzheimer Disease and Associated Disorders |volume=19 |issue=4 |pages=186–194 |year=2005 |pmid=16327345 |doi= }}</ref> This is especially important since a patient with AD is commonly unaware of his or her own deficits ([[anosognosia]]).<ref name="pmid15738860"> {{ cite journal |author=Antoine C, Antoine P, Guermonprez P, Frigard B |title=Awareness of deficits and anosognosia in Alzheimer's disease. |language=French |journal=Encephale |volume=30 |issue=6 |pages=570–577 |year=2004 |pmid=15738860 |doi= }} </ref> Many times families also have difficulties in the detection of initial dementia symptoms and in adequately communicating them to a physician.<ref name="pmid16197855"> {{ cite journal |author=Cruz VT, Pais J, Teixeira A, Nunes B |title=The initial symptoms of Alzheimer disease: caregiver perception |language=Portuguese |journal=Acta Med Port |volume=17 |issue=6 |pages=435–444 |year=2004 |pmid=16197855 |doi= }} </ref> Finally, supplemental testing provides extra information on some features of the disease or are used to rule out other diagnoses. Examples are [[blood test]]s, which can identify other causes for dementia different than AD,<ref name="pmid17222085"> {{ cite journal |author=Waldemar G, Dubois B, Emre M, ''et al'' |title=Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline |journal=European Journal of Neurology |volume=14 |issue=1 |pages=e1–26 |year=2007 |pmid=17222085 |doi=10.1111/j.1468-1331.2006.01605.x }} </ref> which rarely may even be reversible;<ref>{{cite journal |author=Clarfield AM |title=The decreasing prevalence of reversible dementias: an updated meta-analysis |journal=Arch. Intern. Med. |volume=163 |issue=18 |pages=2219–29 |year=2003 |pmid=14557220 |doi=10.1001/archinte.163.18.2219 }}</ref> or [[psychological testing|psychological tests]] for [[clinical depression|depression]], as depression can both co-occur with AD or, on the contrary, be at the origin of the patient's cognitive impairment.<ref name="pmid9153154"> {{ cite journal |author=Geldmacher DS, Whitehouse PJ |title=Differential diagnosis of Alzheimer's disease |journal=Neurology |volume=48 |issue=5 Suppl 6 |pages=S2–9 |year=1997 |pmid=9153154 |doi= }} </ref><ref name="pmid17495754"> {{ cite journal |author=Potter GG, Steffens DC |title=Contribution of depression to cognitive impairment and dementia in older adults |journal=Neurologist |volume=13 |issue=3 |pages=105–117 |year=2007 |pmid=17495754 |doi=10.1097/01.nrl.0000252947.15389.a9 }} </ref> Increasingly, the [[functional neuroimaging]] modalities of [[single photon emission computed tomography]] (SPECT) and [[positron emission tomography]] (PET) are being used to diagnose Alzheimer's, as they have shown similar ability to diagnose Alzheimer's disease as methods involving [[mental status examination]].<ref name="pmid16785801"> {{ cite journal |author=Bonte FJ, Harris TS, Hynan LS, Bigio EH, White CL |title=Tc-99m HMPAO SPECT in the differential diagnosis of the dementias with histopathologic confirmation |journal=Clinical nuclear medicine |volume=31 |issue=7 |pages=376–378 |year=2006 |pmid=16785801 |doi=10.1097/01.rlu.0000222736.81365.63 }} </ref> Furthermore, the ability of SPECT to differentiate Alzheimer's disease from other possible causes, in a patient already known to be suffering from dementia, appears to be superior to attempts to differentiate the cause of dementia cause by mental testing and history.<ref name="pmid15545324">{{cite journal |author=Dougall NJ, Bruggink S, Ebmeier KP |title=Systematic review of the diagnostic accuracy of 99mTc-HMPAO-SPECT in dementia |journal=American Journal of Geriatric Psychiatry |volume=12 |issue=6 |pages=554–570 |year=2004 |pmid=15545324 |doi=10.1176/appi.ajgp.12.6.554 }}</ref> A new technique known as "PiB [[Positron emission tomography|PET]]" has been developed for directly and clearly imaging beta-amyloid deposits [[in vivo]] using a [[Contrast medium|contrasting]] [[Radioactive tracer|tracer]] that [[Binding (molecular)|binds]] selectively to the Abeta deposits.<ref>{{cite journal |author=Kemppainen NM, Aalto S, Karrasch M, Någren K, Savisto N, Oikonen V, Viitanen M, Parkkola R, Rinne JO |title=Cognitive reserve hypothesis: Pittsburgh Compound B and fluorodeoxyglucose positron emission tomography in relation to education in mild Alzheimer's disease |journal=Ann. Neurol. |volume=63 |issue=1 |pages=112–8 |year=2008 |pmid=18023012 |doi=10.1002/ana.21212 }}</ref><ref> {{cite journal |author=Ikonomovic MD, Klunk WE, Abrahamson EE, Mathis CA, Price JC, Tsopelas ND, Lopresti BJ, Ziolko S, Bi W, Paljug WR, Debnath ML, Hope CE, Isanski BA, Hamilton RL, Dekosky ST |title=Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease |journal=Brain |url=http://brain.oxfordjournals.org/cgi/reprint/awn016?ijkey=KksjlncuMZm8LuP&keytype=ref |date= March 2008 |doi=10.1093/brain/awn016 |pmid=18339640 |volume=131 |pages=1630 }}</ref><ref name="pmid18263627">{{cite journal |author=Jack CR, Lowe VJ, Senjem ML, ''et al'' |title=11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment |journal=Brain |volume=131 |issue=Pt 3 |pages=665–80 |year=2008 |pmid=18263627 |doi=10.1093/brain/awm336 }}</ref> Another recent objective marker of the disease is the analysis of [[cerebrospinal fluid]] for [[amyloid beta]] or [[tau protein]]s.<ref name="pmid17612711"> {{ cite journal |author=Marksteiner J, Hinterhuber H, Humpel C |title=Cerebrospinal fluid biomarkers for diagnosis of Alzheimer's disease: beta-amyloid(1-42), tau, phospho-tau-181 and total protein |journal=Drugs Today |volume=43 |issue=6 |pages=423–431 |year=2007 |pmid=17612711 |doi=10.1358/dot.2007.43.6.1067341 }} </ref> Both advances (neuroimaging and cerebrospinal fluid analysis) have led to the proposal of new diagnostic criteria.<ref name="pmid17616482">{{cite journal |author=Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P |title=Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria |journal=Lancet Neurology |volume=6 |issue=8 |pages=734–746 |year=2007 |pmid=17616482 |doi=10.1016/S1474-4422(07)70178-3 }}</ref><ref name="pmid17222085">{{cite journal |author=Waldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, Scheltens P, Tariska P, Winblad B |title=Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline |journal=European Journal of Neurology |volume=14 |issue=1 |pages=e1–26 |year=2007 |pmid=17222085 |doi=10.1111/j.1468-1331.2006.01605.x }}</ref> ==Prevention== [[Image:Honoré Daumier 032.jpg|left|thumb|Intellectual activities such as playing chess or regular social interaction have been linked to a reduced risk of AD in epidemiological studies, although no causal relationship has been found.]] At present contradictory results in global studies, incapacity to prove causal relationships between risk factors and the disease, and possible secondary effects indicate a lack of specific measures to prevent or delay the onset of AD.<ref>Prevention recommendations not supported: * {{cite journal |author=Kawas CH |title=Medications and diet: protective factors for AD? |journal=Alzheimer Dis Assoc Disord |volume=20 |issue=3 Suppl 2 |pages=S89–96 |year=2006 |pmid=16917203 |doi=}} * {{cite journal |author=Luchsinger JA, Mayeux R |title=Dietary factors and Alzheimer's disease |journal=Lancet Neurol |volume=3 |issue=10 |pages=579–87 |year=2004 |pmid=15380154 |doi=10.1016/S1474-4422(04)00878-6}} * {{cite journal |author=Luchsinger JA, Noble JM, Scarmeas N |title=Diet and Alzheimer's disease |journal=Curr Neurol Neurosci Rep |volume=7 |issue=5 |pages=366–72 |year=2007 |pmid=17764625 |doi=10.1007/s11910-007-0057-8 }} </ref> Different epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing AD. Only further research, including clinical trials, will reveal whether, in fact, these factors can help to prevent AD.<ref> {{cite journal |author=Szekely CA, Breitner JC, Zandi PP |title=Prevention of Alzheimer's disease |journal=Int Rev Psychiatry |volume=19 |issue=6 |pages=693–706 |year=2007 |pmid=18092245 |doi=10.1080/09540260701797944 }}</ref> The components of a [[Mediterranean diet]], which include fruit and vegetables, [[bread]], [[wheat]] and other [[cereal]]s, [[olive oil]], [[fish]], and [[red wine]], may all individually or together reduce the risk and course of Alzheimer's disease.<ref> Mediterranean diet: * {{cite journal |author=Scarmeas N, Stern Y, Mayeux R, Luchsinger JA |title=Mediterranean diet, Alzheimer disease, and vascular mediation |journal=Arch. Neurol. |volume=63 |issue=12 |pages=1709–1717 |year=2006 |pmid=17030648 |doi=10.1001/archneur.63.12.noc60109 }} * {{cite journal |author=Scarmeas N, Luchsinger JA, Mayeux R, Stern Y |title=Mediterranean diet and Alzheimer disease mortality |journal=Neurology |volume=69 |issue=11 |pages=1084–93 |year=2007 |pmid=17846408 |doi=10.1212/01.wnl.0000277320.50685.7c }} * {{cite journal |author=Barberger-Gateau P, Raffaitin C, Letenneur L, Berr C, Tzourio C, Dartigues JF, Alpérovitch A |title=Dietary patterns and risk of dementia: the Three-City cohort study |journal=Neurology |volume=69 |issue=20 |pages=1921–1930 |year=2007 |pmid=17998483 |doi=10.1212/01.wnl.0000278116.37320.52 }} * {{cite journal |author=Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB |title=Fruit and vegetable juices and Alzheimer's disease: the Kame Project |journal=American Journal of Medicine |volume=119 |issue=9 |pages=751–759 |year=2006 |pmid=16945610 |doi=10.1016/j.amjmed.2006.03.045 }} * {{cite journal |author=Savaskan E, Olivieri G, Meier F, Seifritz E, Wirz-Justice A, Müller-Spahn F |title=Red wine ingredient resveratrol protects from beta-amyloid neurotoxicity |journal=Gerontology |volume=49 |issue=6 |pages=380–383 |year=2003 |pmid=14624067 |doi=10.1159/000073766 }}</ref> [[B-vitamins|Vitamins B]] and [[vitamin C|C]], or [[folic acid]] have appeared to be related to a reduced risk of AD,<ref>Vitamins prevent: * {{cite journal |author=Morris MC, Schneider JA, Tangney CC |title=Thoughts on B-vitamins and dementia |journal=J. Alzheimers Dis. |volume=9 |issue=4 |pages=429–33 |year=2006 |pmid=16917152 |doi= }} * {{cite journal |author=Landmark K |title=[Could intake of vitamins C and E inhibit development of Alzheimer dementia?] |language=Norwegian |journal=Tidsskr. Nor. Laegeforen. |volume=126 |issue=2 |pages=159–61 |year=2006 |pmid=16415937 |doi= }} * {{cite journal |author=Luchsinger JA, Tang MX, Miller J, Green R, Mayeux R |title=Relation of higher folate intake to lower risk of Alzheimer disease in the elderly |journal=Arch. Neurol. |volume=64 |issue=1 |pages=86–92 |year=2007 |pmid=17210813 |doi=10.1001/archneur.64.1.86 }}</ref> but other studies indicate that they do not have any significant effect on the onset or course of the disease and may have important secondary effects.<ref>Vitamins do not prevent: * {{cite journal |author=Morris MC, Evans DA, Schneider JA, Tangney CC, Bienias JL, Aggarwal NT |title=Dietary folate and vitamins B-12 and B-6 not associated with incident Alzheimer's disease |journal=J. Alzheimers Dis. |volume=9 |issue=4 |pages=435–43 |year=2006 |pmid=16917153 |doi= }} * {{cite journal |author=Malouf M, Grimley EJ, Areosa SA |title=Folic acid with or without vitamin B12 for cognition and dementia |journal=Cochrane Database Syst Rev |volume= |issue=4 |pages=CD004514 |year=2003 |pmid=14584018 |doi=10.1002/14651858.CD004514 }} * {{cite journal |author=Sun Y, Lu CJ, Chien KL, Chen ST, Chen RC |title=Efficacy of multivitamin supplementation containing vitamins B6 and B12 and folic acid as adjunctive treatment with a cholinesterase inhibitor in Alzheimer's disease: a 26-week, randomised, double-blind, placebo-controlled study in Taiwanese patients |journal=Clin Ther |volume=29 |issue=10 |pages=2204–14 |year=2007 |pmid=18042476 |doi=10.1016/j.clinthera.2007.10.012 }} * {{cite journal |author=Boothby LA, Doering PL |title=Vitamin C and vitamin E for Alzheimer's disease |journal=Ann Pharmacother |volume=39 |issue=12 |pages=2073–80 |year=2005 |pmid=16227450 |doi=10.1345/aph.1E495 }} * {{cite journal |author=Gray SL, Anderson ML, Crane PK, Breitner JC, McCormick W, Bowen JD, Teri L, Larson E |title=Antioxidant vitamin supplement use and risk of dementia or Alzheimer's disease in older adults |journal=J Am Geriatr Soc |volume=56 |issue=2 |pages=291–295 |year=2008 |pmid=18047492 |doi=10.1111/j.1532-5415.2007.01531.x }}</ref> [[Curcumin]] in [[curry]] has shown some effectiveness in preventing brain damage in [[mouse model]]s.<ref>Curcumin in diet: * {{cite journal |author=Garcia-Alloza M, Borrelli LA, Rozkalne A, Hyman BT, Bacskai BJ |title=Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model |journal=Journal of Neurochemistry |volume=102 |issue=4 |pages=1095–1104 |year=2007 |pmid=17472706 |doi=10.1111/j.1471-4159.2007.04613.x }} * {{cite journal |author=Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM |title=The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse |journal=Journal of Neuroscience |volume=21 |issue=21 |pages=8370–8377 |year=2001 |pmid=11606625 |doi= }}</ref> Although cardiovascular risk factors, such as [[hypercholesterolemia]], [[hypertension]], [[diabetes]], and smoking, are associated with a higher risk of onset and course of AD,<ref name="pmid17483665">{{cite journal |author=Rosendorff C, Beeri MS, Silverman JM |title=Cardiovascular risk factors for Alzheimer's disease |journal=Am J Geriatr Cardiol |volume=16 |issue=3 |pages=143–9 |year=2007 |pmid=17483665 |doi=10.1111/j.1076-7460.2007.06696.x}}</ref><ref name="obesity">{{cite journal |author=Gustafson D, Rothenberg E, Blennow K, Steen B, Skoog I |title=An 18-year follow-up of overweight and risk of Alzheimer disease |journal=Arch. Intern. Med. |volume=163 |issue=13 |pages=1524–1528 |year=2003 |pmid=12860573 |doi=10.1001/archinte.163.13.1524 }}</ref> [[statins]], which are [[cholesterol]] lowering drugs, have not been effective in preventing or improving the course of the disease.<ref name="pmid17927279">{{cite journal |author=Reiss AB, Wirkowski E |title=Role of HMG-CoA reductase inhibitors in neurological disorders : progress to date |journal=Drugs |volume=67 |issue=15 |pages=2111–2120 |year=2007 |pmid=17927279 |doi=}}</ref><ref name="pmid17877925">{{cite journal |author=Kuller LH |title=Statins and dementia |journal=Current Atherosclerosis Reports |volume=9 |issue=2 |pages=154–161 |year=2007 |pmid=17877925 |doi=10.1007/s11883-007-0012-9 }}</ref> However long-term usage of [[non-steroidal anti-inflammatory drug]] (NSAIDs), is associated with a reduced likelihood of developing AD in some individuals.<ref name="pmid18003940"> {{cite journal |author=Szekely CA, Breitner JC, Fitzpatrick AL, Rea TD, Psaty BM, Kuller LH, Zandi PP |title=NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type |journal=Neurology |volume=70 |issue=1 |pages=17–24 |year=2008 |pmid=18003940 |doi=10.1212/01.wnl.0000284596.95156.48 }}</ref> Other pharmaceutical therapies such as female [[hormone replacement therapy]] are no longer thought to prevent dementia,<ref name="pmid17882683">{{cite journal |author=Craig MC, Murphy DG |title=Estrogen: effects on normal brain function and neuropsychiatric disorders |journal=Climacteric |volume=10 Suppl 2 |issue= |pages=97–104 |year=2007 |pmid=17882683 |doi=10.1080/13697130701598746}}</ref><ref name="pmid17767023">{{cite journal |author=Mori K, Takeda M |title=Hormone replacement Up-to-date. Hormone replacement therapy and brain function|language=Japanese |journal=Clin Calcium |volume=17 |issue=9 |pages=1349–1354 |year=2007 |pmid=17767023 |doi=CliCa070913491354 |doi_brokendate=2008-06-25}}</ref> and a 2007 [[systematic review]] concluded that there was inconsistent and unconvincing evidence that [[Ginkgo Biloba|ginkgo]] has any positive effect on dementia or cognitive impairment.<ref>{{cite journal |author=Birks J, Grimley Evans J |title=Ginkgo biloba for cognitive impairment and dementia |journal=Cochrane Database Syst Rev |volume= |issue=2 |pages=CD003120 |year=2007 |pmid=17443523 |doi=10.1002/14651858.CD003120.pub2 |url= http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003120/frame.html |accessdate=2008-02-22 }}</ref> Intellectual activities such as playing [[chess]], completing [[crossword]] [[puzzle]]s or regular [[social interaction]], may also delay the onset or reduce the severity of Alzheimer's disease.<ref>{{cite journal | author=Verghese J, Lipton R, Katz M, Hall C, Derby C, Kuslansky G, Ambrose A, Sliwinski M, Buschke H | title=Leisure activities and the risk of dementia in the elderly |journal=N Engl J Med | volume=348 | issue=25 | pages=2508–2516 | year=2003 | pmid=12815136 |doi=10.1056/NEJMoa022252 }}</ref><ref name="pmid16632311">{{cite journal |author=Bennett DA, Schneider JA, Tang Y, Arnold SE, Wilson RS |title=The effect of social networks on the relation between Alzheimer's disease pathology and level of cognitive function in old people: a longitudinal cohort study |journal=Lancet Neurol |volume=5 |issue=5 |pages=406–412 |year=2006 |pmid=16632311 |doi=10.1016/S1474-4422(06)70417-3 }}</ref> [[Multilingualism|Bilingualism]] is also related to a later onset of Alzheimer.<ref>{{cite journal | author=Bialystok E, Craik FIM, Freedman M |title=Bilingualism as a protection against the onset of symptoms of dementia|journal=Neuropsychologia |volume=42 |issue=2 |pages=459–464 |year=2007|doi=10.1016/j.neuropsychologia.2006.10.009}}</ref> Some studies have shown a positive relationship between risk of developing AD and different occupational exposures such as [[magnetic field]] exposure,<ref>{{cite journal |author=Davanipour Z, Tseng CC, Lee PJ, Sobel E |title=A case-control study of occupational magnetic field exposure and Alzheimer's disease: results from the California Alzheimer's Disease Diagnosis and Treatment Centers |journal=BMC Neurol |volume=7 |issue= |pages=13 |year=2007 |pmid=17559686 |doi=10.1186/1471-2377-7-13 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1906833 |accessdate=2008-02-26 }}</ref><ref>{{cite journal |author=Qiu C, Fratiglioni L, Karp A, Winblad B, Bellander T |title=Occupational exposure to electromagnetic fields and risk of Alzheimer's disease |journal=Epidemiology |volume=15 |issue=6 |pages=687–694 |year=2004 |pmid=15475717 |doi=10.1097/01.ede.0000142147.49297.9d }}</ref>, [[metal]]s intake and specifically [[aluminium]],<ref name="pmid17522444">{{cite journal |author=Shcherbatykh I, Carpenter DO |title=The role of metals in the etiology of Alzheimer's disease |journal=J. Alzheimers Dis. |volume=11 |issue=2 |pages=191–205 |year=2007 |month=May |pmid=17522444 |doi= |url=http://iospress.metapress.com/openurl.asp?genre=article&issn=1387-2877&volume=11&issue=2&spage=191 |accessdate=2008-07-01 }}</ref><ref>{{cite journal |author=Rondeau V, Commenges D, Jacqmin-Gadda H, Dartigues JF |title=Relation between aluminum concentrations in drinking water and Alzheimer's disease: an 8-year follow-up study |journal=American Journal of Epidemiology |volume=152 |issue=1 |pages=59–66 |year=2000 |pmid=10901330 |url=http://aje.oxfordjournals.org/cgi/content/full/152/1/59 |doi=10.1093/aje/152.1.59 }}</ref> or [[solvent]]s.<ref name="pmid7771442">{{cite journal |author=Kukull WA, Larson EB, Bowen JD, ''et al'' |title=Solvent exposure as a risk factor for Alzheimer's disease: a case-control study |journal=Am. J. Epidemiol. |volume=141 |issue=11 |pages=1059–71; discussion 1072–9 |year=1995 |month=June |pmid=7771442 |doi= |url=http://aje.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7771442 |accessdate=2008-07-01 }}</ref> The quality of some of these studies has been criticized,<ref>{{cite journal |author=Santibáñez M, Bolumar F, García AM |title=Occupational risk factors in Alzheimer's disease: a review assessing the quality of published epidemiological studies |journal=Occupational and Environmental Medicine |volume=64 |issue=11 |pages=723–732 |year=2007 |pmid=17525096 |doi=10.1136/oem.2006.028209 }}</ref> and other research does not confirm this link.<ref>{{cite journal |author=Seidler A, Geller P, Nienhaus A, Bernhardt T, Ruppe I, Eggert S, Hietanen M, Kauppinen T, Frölich L |title=Occupational exposure to low frequency magnetic fields and dementia: a case-control study |journal=Occup Environ Med |volume=64 |issue=2 |pages=108–114 |year=2007 |pmid=17043077 |doi=10.1136/oem.2005.024190 |url=http://oem.bmj.com/cgi/content/full/64/2/108 }}</ref><ref name="pmid12222737">{{cite journal |author=Rondeau V |title=A review of epidemiologic studies on aluminum and silica in relation to Alzheimer's disease and associated disorders |journal=Rev Environ Health |volume=17 |issue=2 |pages=107–21 |year=2002 |pmid=12222737 |doi= |url= |accessdate=2008-07-01 }}</ref> <ref name="pmid9115023">{{cite journal |author=Martyn CN, Coggon DN, Inskip H, Lacey RF, Young WF |title=Aluminum concentrations in drinking water and risk of Alzheimer's disease |journal=Epidemiology |volume=8 |issue=3 |pages=281–6 |year=1997 |month=May |pmid=9115023 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1044-3983&volume=8&issue=3&spage=281 |accessdate=2008-07-01 }}</ref><ref name="pmid9861186">{{cite journal |author=Graves AB, Rosner D, Echeverria D, Mortimer JA, Larson EB |title=Occupational exposures to solvents and aluminium and estimated risk of Alzheimer's disease |journal=Occup Environ Med |volume=55 |issue=9 |pages=627–33 |year=1998 |month=September |pmid=9861186 |pmc=1757634 |doi= |url= |accessdate=2008-07-01 }}</ref> ==Management== There is no known cure for Alzheimer's disease. Available treatments offer relatively small symptomatic benefit but remain [[palliative care|palliative]] in nature. Current treatments can be divided into pharmaceutical, psychosocial and caregiving. ===Pharmaceutical=== [[Image:Donepezil3d.png‎|right|thumb|3d molecular spacefill of [[donepezil]], an [[acetylcholinesterase inhibitor]] used in the treatment of AD symptoms]] [[Image:Memantine-3d-sticks.png|right|thumb|Molecular structure of [[memantine]], a medication approved for advanced AD symptoms]] Four medications, to treat the cognitive manifestations of AD, are currently approved by regulatory agencies, including the U.S. [[Food and Drug Administration]] (FDA) and the [[European Medicines Agency]] (EMEA). Three are [[acetylcholinesterase inhibitor]]s and the other is [[memantine]], an [[NMDA receptor]] [[receptor antagonist|antagonist]]. No drug has an indication for delaying or halting the progression of the disease. Because reduction in the activity of the [[cholinergic]] neurons in the disease is well known,<ref name="pmid8534419">{{cite journal |author=Geula C, Mesulam MM |title=Cholinesterases and the pathology of Alzheimer disease |journal=Alzheimer Dis Assoc Disord |volume=9 Suppl 2 |issue= |pages=23–28 |year=1995 |pmid=8534419 |doi= }}</ref> [[acetylcholinesterase inhibitor]]s are employed to reduce the rate at which [[acetylcholine]] (ACh) is broken down and so to increase the concentration of ACh in the brain, thereby combatting the loss of ACh caused by the death of the cholinergin neurons.<ref name="pmid11105732">{{cite journal |author=Stahl SM |title=The new cholinesterase inhibitors for Alzheimer's disease, Part 2: illustrating their mechanisms of action |journal=J Clin Psychiatry |volume=61 |issue=11 |pages=813–814 |year=2000 |pmid=11105732 |doi= }}</ref> Cholinesterase inhibitors currently approved include [[donepezil]] (brand name ''Aricept''),<ref>{{cite web |url=http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a697032.html |title=Donepezil |accessdate=2008-03-20 |date=2007-01-08 |publisher= US National Library of Medicine (Medline Plus) }}</ref> [[galantamine]] (''Razadyne''),<ref>{{cite web |url=http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a699058.html |title=Galantamine |accessdate=2008-03-20 |date=2007-01-08 |publisher= US National Library of Medicine (Medline Plus) }}</ref> and [[rivastigmine]] (branded as ''Exelon'',<ref>{{cite web |url=http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a602009.html |title=Rivastigmine |accessdate=2008-03-20 |date=2007-01-08 |publisher= US National Library of Medicine (Medline Plus) }}</ref> and ''Exelon Patch''<ref>{{cite web |url=http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a607078.html |title=Rivastigmine Transdermal |accessdate=2008-03-20 |date=2007-01-08 |publisher= US National Library of Medicine (Medline Plus) }}</ref>). There is also evidence for the efficacy of these medications in mild to moderate Alzheimer’s disease,<ref name="pmid16437532">{{cite journal |author=Birks J |title=Cholinesterase inhibitors for Alzheimer's disease |journal=Cochrane Database Syst Rev |volume= |issue=1 |pages=CD005593 |year=2006 |pmid=16437532 |doi=10.1002/14651858.CD005593 }}</ref> and some evidence for their use in the advanced stage. Only donepezil is approved for treatment of advanced AD dementia.<ref name="pmid16437430">{{cite journal |author=Birks J, Harvey RJ |title=Donepezil for dementia due to Alzheimer's disease |journal=Cochrane Database Syst Rev |volume= |issue=1 |pages=CD001190 |year=2006 |pmid=16437430 |doi=10.1002/14651858.CD001190.pub2 }}</ref> The use of these drugs in [[mild cognitive impairment]] has not shown any effect in a delay of the onset of AD.<ref name="pmid18044984">{{cite journal |author=Raschetti R, Albanese E, Vanacore N, Maggini M |title=Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials |journal=PLoS Med |volume=4 |issue=11 |pages=e338 |year=2007 |pmid=18044984 |doi=10.1371/journal.pmed.0040338 }}</ref> Most common [[side effect]]s include [[nausea]] and [[vomiting]], both of which are linked to cholinergic excess. These side effects arise in approximately ten to twenty percent of users and are mild to moderate in [[severity]]. Less common secondary effects include [[muscle cramp]]s; decreased [[heart rate]] ([[bradycardia]]), decreased [[appetite]] and weight, and increased [[gastric acid]].<ref>{{cite web |url=http://www.aricept.com/content/pi.pdf |title=Aricept and Aricept ODT Product Insert |accessdate=2008-01-30 |format= PDF |publisher= Eisai and Pfizer }}</ref><ref>{{cite web |url=http://razadyneer.com/razadyneer/pages/pdf/razadyne_er.pdf |title=Razadyne ER U.S. Full Prescribing Information |accessdate=2008-02-19 |format=PDF |publisher=Ortho-McNeil Neurologics }}</ref><ref>{{cite web |url=http://www.pharma.us.novartis.com/product/pi/pdf/exelonpatch.pdf |title=Exelon ER U.S. Prescribing Information |accessdate=2008-02-19 |format=PDF |publisher=Novartis Pharmaceuticals }}</ref><ref>{{cite web |url=http://www.fda.gov/cder/foi/label/2006/020823s016,021025s008lbl.pdf |title=Exelon U.S. Prescribing Information |accessdate=2008-02-21 |format= PDF |publisher=Novartis Pharmaceuticals }}</ref> [[Glutamate]] is a useful excitatory [[neurotransmitter]] of the nervous system, although excessive amounts in the [[brain]] can lead to [[cell]] death through a process called [[excitotoxicity]] which consists of the overstimulation of glutamate [[Receptor (biochemistry)|receptors]]. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as [[Parkinson's disease]] and [[multiple sclerosis]].<ref name="pmid16424917">{{cite journal |author=Lipton SA |title=Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond |journal=Nat Rev Drug Discov |volume=5 |issue=2 |pages=160–170 |year=2006 |pmid=16424917 |doi=10.1038/nrd1958 }}</ref> [[Memantine]] (brand names ''Akatinol'', ''Axura'', ''Ebixa''/''Abixa'', ''Memox'' and ''Namenda''),<ref>{{cite web |url=http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a604006.html |title=Memantine |accessdate=2008-03-22 |date=2004-01-04 |publisher= US National Library of Medicine (Medline) }}</ref> is a noncompetitive [[NMDA receptor]] [[Receptor antagonist|antagonist]] first used as an anti-[[influenza]] agent. It acts on the [[glutamatergic system]] by blocking NMDA glutamate receptors and inhibits their overstimulation by glutamate.<ref name="pmid16424917" /> Memantine has been shown to be moderately efficacious in the treatment of moderate to severe Alzheimer’s disease. Its effects in the initial stages are unknown.<ref name="pmid15495043">{{cite journal |author=Areosa Sastre A, McShane R, Sherriff F |title=Memantine for dementia |journal=Cochrane Database Syst Rev |volume= |issue=4 |pages=CD003154 |year=2004 |pmid=15495043 |doi=10.1002/14651858.CD003154.pub2 }}</ref> Reported adverse events with memantine are infrequent and mild, including [[hallucination]]s, [[confusion]], [[dizziness]], [[headache]] and [[fatigue (medical)|fatigue]].<ref>{{cite web |url=http://www.frx.com/pi/namenda_pi.pdf |title=Namenda Prescribing Information |accessdate=2008-02-19 |format=PDF |publisher=Forest Pharmaceuticals }}</ref> Memantine used in combination with donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".<ref name="pmid18316756">{{cite journal |author=Raina P, Santaguida P, Ismaila A, ''et al'' |title=Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline |journal=Annals of Internal Medicine |volume=148 |issue=5 |pages=379–397 |year=2008 |pmid=18316756 |doi= }}</ref> [[Neuroleptic]] [[anti-psychotic]] drugs commonly given to Alzheimer's patients with behavioural problems are modestly useful in reducing [[aggression]] and [[psychosis]], but are associated with serious adverse effects, such as [[cerebrovascular]] events, [[extra-pyramidal|movement difficulties]] or cognitive decline, that do not permit their routine use.<ref name="pmid16437455">{{cite journal |author=Ballard C, Waite J |title=The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease |journal=Cochrane Database Syst Rev |volume= |issue=1 |pages=CD003476 |year=2006 |pmid=16437455 |doi=10.1002/14651858.CD003476.pub2 }}</ref><ref name="pmid18384230">{{cite journal |author=Ballard C, Lana MM, Theodoulou M, ''et al'' |title=A Randomised, Blinded, Placebo-Controlled Trial in Dementia Patients Continuing or Stopping Neuroleptics (The DART-AD Trial) |journal=PLoS Med. |volume=5 |issue=4 |pages=e76 |year=2008 |pmid=18384230 |doi=10.1371/journal.pmed.0050076 }}</ref><ref name="pmid15687315">{{cite journal |author=Sink KM, Holden KF, Yaffe K |title=Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence |journal=JAMA |volume=293 |issue=5 |pages=596–608 |year=2005 |pmid=15687315 |doi=10.1001/jama.293.5.596 }}</ref> ===Psychosocial intervention=== [[Image:Snoezelruimte.JPG|righ|thumb|A specifically designed room for sensory integration therapy, or snoezelen; an emotion-oriented psychosocial intervention for people with dementia]] [[Psychosocial]] interventions are used as an adjunct to pharmaceutical treatment and can be classified within behavior, emotion, cognition or stimulation oriented approaches. Research on efficacy is unavailable and rarely specific to the disease, focusing instead on dementia.<ref name="pracGuideAPA">{{cite web | url=http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=AlzPG101007 | format=PDF | title =Practice Guideline for the Treatment of Patients with Alzheimer's disease and Other Dementias | publisher =[[American Psychiatric Association]] | date=October 2007 | accessdate=2007-12-28 | doi=10.1176/appi.books.9780890423967.152139 }}</ref> [[Behavior modification|Behavioral interventions]] attempt to identify and reduce the antecedents and consequences of problem behaviors. This approach has not shown success in the overall functioning of patients,<ref name="pmid16323385">{{cite journal |author=Bottino CM, Carvalho IA, Alvarez AM, ''et al'' |title=Cognitive rehabilitation combined with drug treatment in Alzheimer's disease patients: a pilot study |journal=Clin Rehabil |volume=19 |issue=8 |pages=861–869 |year=2005 |pmid=16323385 |doi=10.1191/0269215505cr911oa }}</ref> but can help to reduce some specific problem behaviors, such as [[Urinary incontinence|incontinence]].<ref name="pmid11342679">{{cite journal |author=Doody RS, Stevens JC, Beck C, ''et al'' |title=Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology |journal=Neurology |volume=56 |issue=9 |pages=1154–1166 |year=2001 |pmid=11342679 |doi= }}</ref> There is still a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering.<ref name="pmid17253573">{{cite journal |author=Hermans DG, Htay UH, McShane R |title=Non-pharmacological interventions for wandering of people with dementia in the domestic setting |journal=Cochrane Database Syst Rev |volume= |issue=1 |pages=CD005994 |year=2007 |pmid=17253573 |doi=10.1002/14651858.CD005994.pub2 }}</ref><ref name="pmid17096455">{{cite journal |author=Robinson L, Hutchings D, Dickinson HO, ''et al'' |title=Effectiveness and acceptability of non-pharmacological interventions to reduce wandering in dementia: a systematic review |journal=Int J Geriatr Psychiatry |volume=22 |issue=1 |pages=9–22 |year=2007 |pmid=17096455 |doi=10.1002/gps.1643 }}</ref> Emotion-oriented interventions include [[reminiscence therapy]], [[validation therapy]], supportive [[psychotherapy]], sensory integration or [[snoezelen]], and [[simulated presence therapy]]. Supportive psychotherapy has received little or no formal scientific study, but some clinicians find it useful in helping mildly impaired patients adjust to their illness.<ref name="pracGuideAPA">{{{{cite web | url=http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=AlzPG101007 | format=PDF | title =Practice Guideline for the Treatment of Patients with Alzheimer's disease and Other Dementias | publisher =[[American Psychiatric Association]] | date=October 2007 | accessdate=2007-12-28 | doi=10.1176/appi.books.9780890423967.152139 }}</ref> Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, many times with the aid of photographs, household items, music and sound recordings, or other familiar items from the past. Although there are few quality studies on the effectiveness of RT it may be beneficial for [[cognition]] and [[Mood (psychology)|mood]].<ref name="pmid15846613">{{cite journal |author=Woods B, Spector A, Jones C, Orrell M, Davies S |title=Reminiscence therapy for dementia |journal=Cochrane Database Syst Rev |volume= |issue=2 |pages=CD001120 |year=2005 |pmid=15846613 |doi=10.1002/14651858.CD001120.pub2 }}</ref> Simulated presence therapy (SPT) is based on [[Attachment theory|attachment theories]] and is normally carried out playing a recording with voices of the closest relatives of the patient. There is preliminary evidence indicating that SPT may reduce [[anxiety]] and [[Challenging behaviour|challenging behaviors]].<ref name="pmid11827626">{{cite journal |author=Peak JS, Cheston RI |title=Using simulated presence therapy with people with dementia |journal=Aging Ment Health |volume=6 |issue=1 |pages=77–81 |year=2002 |pmid=11827626 |doi=10.1080/13607860120101095 }}</ref><ref name="pmid10203120">{{cite journal |author=Camberg L, Woods P, Ooi WL, ''et al'' |title=Evaluation of Simulated Presence: a personalised approach to enhance well-being in persons with Alzheimer's disease |journal=J Am Geriatr Soc |volume=47 |issue=4 |pages=446–452 |year=1999 |pmid=10203120 |doi= }}</ref> Finally, validation therapy is based on acceptance of the reality and personal truth of another's experience, while sensory integration is based on exercises aimed to stimulate [[sense]]s. There is little evidence to support the usefulness of these therapies.<ref name="pmid12917907">{{cite journal |author=Neal M, Briggs M |title=Validation therapy for dementia |journal=Cochrane Database Syst Rev |volume= |issue=3 |pages=CD001394 |year=2003 |pmid=12917907 |doi=10.1002/14651858.CD001394 }}</ref><ref name="pmid12519587">{{cite journal |author=Chung JC, Lai CK, Chung PM, French HP |title=Snoezelen for dementia |journal=Cochrane Database Syst Rev |volume= |issue=4 |pages=CD003152 |year=2002 |pmid=12519587 |doi=10.1002/14651858.CD003152 }}</ref> The aim of cognition-oriented treatments, which include reality orientation and [[Rehabilitation (neuropsychology)|cognitive retraining]] is the restoration of [[cognitive deficit]]s. Reality orientation consists in the presentation of information about time, place or person in order to ease the understanding of the person about its surroundings and his place in them. On the other hand cognitive retraining tries to improve impaired capacities by exercitation of mental abilities. Both have shown some efficacy improving cognitive capacities,<ref name="pmid17636652">{{cite journal |author=Spector A, Orrell M, Davies S, Woods B |title=WITHDRAWN: Reality orientation for dementia |journal=Cochrane Database Syst Rev |volume= |issue=3 |pages=CD001119 |year=2000 |pmid=17636652 |doi=10.1002/14651858.CD001119.pub2 }}</ref><ref name="pmid12948999">{{cite journal |author=Spector A, Thorgrimsen L, Woods B, ''et al'' |title=Efficacy of an evidence-based cognitive stimulation therapy programme for people with dementia: randomised controlled trial |journal=Br J Psychiatry |volume=183 |issue= |pages=248–254 |year=2003 |pmid=12948999 |doi=10.1192/bjp.183.3.248 }}</ref> although in some works these effects were transient and negative effects, such as frustration, have also been reported.<ref name="pracGuideAPA">{{{{cite web | url=http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=AlzPG101007 | format=PDF | title=Practice Guideline for the Treatment of Patients with Alzheimer's disease and Other Dementias | publisher=[[American Psychiatric Association]] | date=October 2007 | accessdate=2007-12-28 | doi=10.1176/appi.books.9780890423967.152139 }}</ref> Stimulation-oriented treatments include [[Art therapy|art]], [[Music therapy|music]] and [[Animal-assisted therapy|pet]] therapies, [[Physical therapy|exercise]], and any other kind of [[Recreational therapy|recreational activities]] for patients. Stimulation has modest support for improving behavior, mood, and, to a lesser extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation therapies is the improvement in the patient daily life routine they suppose.<ref name="pracGuideAPA">{{cite web | url=http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=AlzPG101007 | format=PDF | title =Practice Guideline for the Treatment of Patients with Alzheimer's disease and Other Dementias | publisher =[[American Psychiatric Association]] | date=October 2007 | accessdate=2007-12-28 | doi=10.1176/appi.books.9780890423967.152139 }}</ref> ===Caregiving=== {{Further|[[Caregiving and dementia]]}} Since there is no cure for Alzheimer's, caregiving is an essential part of the treatment. Due to the progressive inability for the sufferer to self-care, Alzheimer's has to be carefully care-managed. In the initial and moderate stages and specially if the patient is home cared; modifications to his living environment and lifestyle can ease daily living activities of the patient and the caretaker burden.<ref name="pmid11220813">{{cite journal |author=Gitlin LN, Corcoran M, Winter L, Boyce A, Hauck WW |title=A randomized, controlled trial of a home environmental intervention: effect on efficacy and upset in caregivers and on daily function of persons with dementia |journal=Gerontologist |volume=41 |issue=1 |pages=4–14 |year=2001 |month=February |pmid=11220813 |doi= |url=http://gerontologist.gerontologyjournals.org/cgi/pmidlookup?view=long&pmid=11220813 |accessdate=2008-07-15 }}</ref><ref name="pmid15860476">{{cite journal |author=Gitlin LN, Hauck WW, Dennis MP, Winter L |title=Maintenance of effects of the home environmental skill-building program for family caregivers and individuals with Alzheimer's disease and related disorders |journal=J. Gerontol. A Biol. Sci. Med. Sci. |volume=60 |issue=3 |pages=368–74 |year=2005 |month=March |pmid=15860476 |doi= |url=http://biomed.gerontologyjournals.org/cgi/pmidlookup?view=long&pmid=15860476 |accessdate=2008-07-15 }}</ref> Examples of such modifications are the adherence to simplified routines, the placing of safety locks, the labeling of household items to cue the patient or the use of modified daily life objects.<ref> {{cite web |url=http://web.archive.org/web/20060925112503/http://www.alz.org/Health/Treating/agitation.asp |title= Treating behavioral and psychiatric symptoms |date=2006 |accessdate=2006-09-25 |publisher = Alzheimer's Association }}</ref><ref name="pmid15297089"> {{cite journal | author = Dunne TE, Neargarder SA, Cipolloni PB, Cronin-Golomb A | title = Visual contrast enhances food and liquid intake in advanced Alzheimer's disease | journal = Clinical Nutrition | volume = 23 | issue = 4 | pages = 533–538 | year = 2004 | pmid = 15297089 | doi = 10.1016/j.clnu.2003.09.015 }}</ref> ==Prognosis== As the disease progresses, the patient will advance from mild cognitive impairment, when the suspected underlying pathology may or may not yet have been diagnosed, to mild and advanced stages of dementia, finally reaching a severe stage of dementia.<ref name="pmid10653284"> {{cite journal |author=Förstl H, Kurz A |title=Clinical features of Alzheimer's disease |journal=European Archives of Psychiatry and Clinical Neuroscience |volume=249 |issue=6 |pages=288–290 |year=1999 |pmid=10653284 |doi=10.1007/s004060050101 }}</ref> Once Alzheimer's has been diagnosed, the average [[life expectancy]] is approximately seven years, while less than three percent of the patients live more than fourteen years.<ref name="pmid3776457"> {{cite journal |author=Mölsä PK, Marttila RJ, Rinne UK |title=Survival and cause of death in Alzheimer's disease and multi-infarct dementia |journal=Acta Neurologica Scandinavica |volume=74 |issue=2 |pages=103–107 |year=1986 |pmid=3776457 }}</ref><ref name="pmid7793228"> {{cite journal |author=Mölsä PK, Marttila RJ, Rinne UK |title=Long-term survival and predictors of mortality in Alzheimer's disease and multi-infarct dementia |journal=Acta Neurologica Scandinavica |volume=91 |issue=3 |pages=159–164 |year=1995 |pmid=7793228 }}</ref><ref name="pmid15068977"> {{cite journal |author=Larson Eric B, Shadlen Marie-Florence, Wang Li, McCormick Wayne C, Bowen James D, Teri Linda, Kukull Walter A |title=Survival after initial diagnosis of Alzheimer disease |journal=Annals of Internal Medicine |volume=140 |issue=7 |pages=501–509 |date=2004-04-06 |pmid=15068977 |url=http://www.annals.org/cgi/reprint/140/7/501.pdf |format=PDF }}</ref><ref name="pmid15466779"> {{cite journal |author=Kaldjian Lauris C |title=Survival versus prognosis in Alzheimer disease |journal=Annals of Internal Medicine |volume=141 |issue=7 |date=2004-10-05 |pmid=15466779 |url=http://www.annals.org/cgi/reprint/141/7/575.pdf |format=PDF |pages=575 }}</ref><ref name="NINDS Prognosis"> {{cite web |url=http://www.ninds.nih.gov/disorders/alzheimersdisease/alzheimersdisease.htm#What_is_the_prognosis |title=Alzheimer's Disease Information Page |publisher=National Institute of Neurological Disorders and Stroke (NINDS) |date=2008-02-07 |accessdate=2008-02-12 }}</ref> ==Epidemiology== {| align="left" border="2"| class="wikitable" style="text-align:center" |+AD incidence rates after 65 years of age<ref name="pmid17727890"/> |- ! Age !! Incidence (new affected per 1000 and year) |- ! 65-69 | 2 |- ! 70-74 | 6 |- ! 75-79 | 9 |- ! 80-84 | 23 |- ! 85-89 | 40 |- ! Older than 90 | 69 |} Two main measures are used in [[epidemiology|epidemiological]] studies: incidence and prevalence.[[Incidence (epidemiology)|Incidence]] is the number of new cases per unit of person-time at risk (usually number of new cases per 1000 and year); while [[prevalence]] is the total number of cases of the disease in the population at a given time. Regarding incidence, [[cohort study|cohort]] [[longitudinal studies]] (studies where a disease free population is followed over the years) provide rates between 10-15 per 1000 and year for all dementias and 5-8 for AD;<ref name="pmid12028245">{{cite journal |author=Di Carlo A, Baldereschi M, Amaducci L, ''et al'' |title=Incidence of dementia, Alzheimer's disease, and vascular dementia in Italy. The ILSA Study |journal=J Am Geriatr Soc |volume=50 |issue=1 |pages=41–8 |year=2002 |month=January |pmid=12028245 |doi= |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0002-8614&date=2002&volume=50&issue=1&spage=41 |accessdate=2008-06-13 }}</ref><ref name="pmid17727890">{{cite journal |author=Bermejo-Pareja F, Benito-León J, Vega S, Medrano MJ, Román GC |title=Incidence and subtypes of dementia in three elderly populations of central Spain |journal=J. Neurol. Sci. |volume=264 |issue=1-2 |pages=63–72 |year=2008 |month=January |pmid=17727890 |doi=10.1016/j.jns.2007.07.021 |url=http://linkinghub.elsevier.com/retrieve/pii/S0022-510X(07)00491-1 |accessdate=2008-06-13 }}</ref> which means that half of new dementia cases each year are AD. Advancing age is a primary risk factor for the disease and incidence rates are not equal for all ages: every five years after the age of 65, the risk of acquiring the disease doubles increasing from 2 per 1000 to as much as 69 per 1000.<ref name="pmid12028245"/><ref name="pmid17727890"/> There are also sex differences in the incidence rates, having women a higher risk of developing AD specially in the population older than 85.<ref>{{cite journal |author=Andersen K, Launer LJ, Dewey ME, Letenneur L, Ott A, Copeland JR, Dartigues JF, Kragh-Sorensen P, Baldereschi M, Brayne C, Lobo A, Martinez-Lage JM, Stijnen T, Hofman A |title=Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. EURODEM Incidence Research Group |journal=Neurology |volume=53 |issue=9 |pages=1992–1997 |year=1999 |pmid=10599770 |doi= }}</ref><ref name="pmid12028245"/> Prevalence depends on different factors including incidence but also patient survival. Since the incidence of AD increases with age it is specially important the mean age of the population of interest. [[United States]] specific Alzheimer prevalence was estimated to be 1'6 % in the year 2000.In the age group between 65-74 around 5% of the U.S. population had AD, increasing almost to 20% in the 75-84 group and to 50% afterwards<ref> {{cite journal | author = Hebert L, Scherr P, Bienias J, Bennett D, Evans D | title = Alzheimer disease in the U.S. population: prevalence estimates using the 2000 census | journal = Archives of Neurology | volume = 60 | issue = 8 | pages = 1119–1122 | year = 2003 | pmid = 12925369 | url = http://archneur.ama-assn.org/cgi/content/full/60/8/1119 | doi = 10.1001/archneur.60.8.1119 }}</ref> Prevalence rates in less developed countries, such as [[India]] <ref name="pmid8773818">{{cite journal |author=Shaji S, Promodu K, Abraham T, Roy KJ, Verghese A |title=An epidemiological study of dementia in a rural community in Kerala, India |journal=Br J Psychiatry |volume=168 |issue=6 |pages=745–9 |year=1996 |month=June |pmid=8773818 |doi= |url= |accessdate=2008-06-14 }}</ref> or [[Taiwan]],<ref name="pmid9804120">{{cite journal |author=Lin RT, Lai CL, Tai CT, Liu CK, Yen YY, Howng SL |title=Prevalence and subtypes of dementia in southern Taiwan: impact of age, sex, education, and urbanization |journal=J. Neurol. Sci. |volume=160 |issue=1 |pages=67–75 |year=1998 |month=September |pmid=9804120 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0022510X98002251 |accessdate=2008-06-14 }}</ref> are usually lower. Few studies have tried to make world-wide estimations of Alzheimer's disease prevalence, being much more common estimations of dementia in general. The [[World Health Organization]] provided an estimation of approximately 24.5 millions of people affected with any kind of dementia in 2005, which was going to increase to 30 million in 2015 and reach 45 millions by 2030;<ref name"789241563369">{{cite book | last = World Health Organization | title = Neurological Disorders: Public Health Challenges | publisher = World Health Organization | date = 2006 | location = Switzerland | pages = 204-207 | url = http://www.who.int/mental_health/neurology/neurodiso/en/index.html | isbn = 789241563369 }}</ref> giving other studies similar numbers.<ref name="pmid16360788">{{cite journal |author=Ferri CP, Prince M, Brayne C, ''et al'' |title=Global prevalence of dementia: a Delphi consensus study |journal=Lancet |volume=366 |issue=9503 |pages=2112–7 |year=2005 |month=December |pmid=16360788 |doi=10.1016/S0140-6736(05)67889-0 |url=http://www.sbgg.org.br/profissional/artigos/pdf/demencia_mundo.pdf |accessdate=2008-06-13 |format=PDF}}</ref> Other study provided a worldwide estimation of Alzheimer in 2006 of 26.6 million which would multiply by four by the year 2050.<ref name="Brookmeyer2007">{{cite journal |author=Brookmeyer R, Johnson E, Ziegler-Graham K, MH Arrighi |title=Forecasting the global burden of Alzheimer’s disease |journal=Alzheimer's and Dementia |volume=3 |issue=3 |pages=186–91 |year=2007 |month=July |doi=10.1016/j.jalz.2007.04.381 |url=http://works.bepress.com/cgi/viewcontent.cgi?article=1022&context=rbrookmeyer |accessdate=2008-06-18 }}</ref> ==History== [[Image:Auguste D aus Marktbreit.jpg|thumb|[[Auguste D]], first described patient with AD by [[Alöis Alzheimer]] in [[1901]]]] Although the concept of [[dementia]] goes as far back as the [[Classical antiquity|ancient Greek and Roman]] [[philosopher]]s and [[physician]]s,<ref name="pmid9661992">{{cite journal |author=Berchtold NC, Cotman CW |title=Evolution in the conceptualization of dementia and Alzheimer's disease: Greco-Roman period to the 1960s |journal=Neurobiology of Aging |volume=19 |issue=3 |pages=173–189 |year=1998 |pmid=9661992 |doi=10.1016/S0197-4580(98)00052-9 }}</ref> it was in 1901 when [[Alöis Alzheimer]], a German [[psychiatry|psychiatrist]], identified the first case of what became known as Alzheimer's disease in a fifty-year-old woman he called [[Auguste D]]. Alöis Alzheimer followed her until she died in 1906, when he first reported the case publicly.<ref>Auguste D.: * {{ cite journal | author=Alzheimer Alöis | title=Uber eine eigenartige Erkrankung der Hirnrinde | journal= | volume=64 | issue=1—2 | pages=146—148 | year=1907 | language={{de icon}} }} *{{cite journal |author=Alzheimer Alöis |origdate=1907 |title=About a peculiar disease of the cerebral cortex. (Translated by L. Jarvik and H. Greenson) |journal=Alzheimer Disease and Associated Disorders |volume=1 |issue=1 |pages=3–8 |year=1987 |pmid=3331112 |doi= |issn= }} *{{cite book |author=Maurer Ulrike, Maurer Konrad |title=Alzheimer: the life of a physician and the career of a disease |publisher=Columbia University Press |location=New York |year=2003 |pages=270 |isbn=0-231-11896-1 |oclc= |doi= }} *{{cite book |author=Hochberg Fred H., Rottenberg David |title=Neurological classics in modern translation |publisher=Hafner Press |location=New York |year=1977 |pages=<!-- needed --> |isbn=0-02-851180-8 |oclc= |doi= }}</ref> In the following five years, eleven similar cases were reported in the [[medical literature]], some of them already using the term Alzheimer's disease.<ref name="pmid9661992">{{cite journal |author=Berchtold NC, Cotman CW |title=Evolution in the conceptualization of dementia and Alzheimer's disease: Greco-Roman period to the 1960s |journal=Neurobiology of Aging |volume=19 |issue=3 |pages=173–189 |year=1998 |pmid=9661992 |doi=10.1016/S0197-4580(98)00052-9 }}</ref> The official consideration of the disease as a distinctive entity is attributed to [[Emil Kraepelin]], who included ''Alzheimer’s disease'' or ''presenile'' [[dementia]] as a subtype of ''senile dementia'' in the eighth edition of his ''Textbook of Psychiatry'', published in 1910.<ref name="isbn1-4325-0833-4">{{cite book |author=Kraepelin Emil, Diefendorf A. Ross (translated by) |title=Clinical Psychiatry: A Textbook For Students And Physicians (Reprint) |publisher=Kessinger Publishing |location= |date=2007-01-17 |pages=568 |isbn=1-4325-0833-4 |oclc= |doi= }}</ref> For most of the twentieth century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a conference concluded that the clinical and [[pathological]] manifestations of presenile and senile dementia were almost identical, although the authors also added that this did not rule out the possibility of different [[etiology|etiologies]].<ref name="isbn0-89004-225-X">{{cite book |author=Katzman Robert, Terry Robert D, Bick Katherine L (editors) |title=Alzheimer's disease: senile dementia and related disorders |publisher=Raven Press |location=New York |year=1978 |pages=595 |isbn=0-89004-225-X |oclc= |doi= }}</ref> This eventually led to the use of ''Alzheimer's disease'' independently of onset age of the disease.<ref name="pmid9702682">{{cite journal |author=Boller F, Forbes MM |title=History of dementia and dementia in history: an overview |journal=Journal of Neurological Science |volume=158 |issue=2 |pages=125–133 |year=1998 |pmid=9702682 |doi=10.1016/S0022-510X(98)00128-2 }}</ref> The term ''senile dementia of the Alzheimer type'' (SDAT) was used for a time to describe the condition in those over 65, with classical Alzheimer's disease being used for those younger. Eventually, the term Alzheimer's disease was formally adopted in medical [[nomenclature]] to describe individuals of all ages with a characteristic common symptom pattern, disease course, and [[neuropathology]].<ref name="pmid3531918">{{cite journal |author=Amaducci LA, Rocca WA, Schoenberg BS |title=Origin of the distinction between Alzheimer's disease and senile dementia: how history can clarify nosology |journal=Neurology |volume=36 |issue=11 |pages=1497–1499 |year=1986 |pmid=3531918 |doi= }}</ref> ==Society and culture== ===Social costs=== Because the median age of the industrialised world's population is gradually increasing, AD is a public health challenge. The World Health Organization estimates that globally the total ''[[disability adjusted life years]] (DALYs)'' for AD and other dementias exceeded eleven million in 2005, with a projected 3.4% annual increase.<ref> {{cite web |url=http://www.who.int/mental_health/neurology/chapter_2_neuro_disorders_public_h_challenges.pdf |title=Neurological disorders: Public health challenges |format=PDF |publisher=World Health Organization |pages=27—41 |accessdate=2008-06-05 }}</ref> The DALYs are a measure for the overall disease burden that quantifies the impact of premature death and disability on a population by combining them into a single measure. The solvency of governmental social safety nets will be impacted by the increased aged population which may develop Alzheimer's in the same proportions as earlier generations.<ref name="pmid11910061"> {{cite journal |author=Sloane PD, Zimmerman S, Suchindran C, Reed P, Wang L, Boustani M, Sudha S |title=The public health impact of Alzheimer's disease, 2000–2050: potential implication of treatment advances |journal=Annual Review of Public Health |volume=23 |pages=213–231 |year=2002 |pmid=11910061 |doi=10.1146/annurev.publhealth.23.100901.140525 }}</ref> ===Caregiving burden=== {{Further|[[Caregiving and dementia]]}} Alzheimer's disease is known for placing a great burden on [[carer|caregivers]] which includes social, psychological, physical or economic aspects.<ref name="pmid17662119">{{cite journal |author=Thompson CA, Spilsbury K, Hall J, Birks Y, Barnes C, Adamson J |title=Systematic review of information and support interventions for caregivers of people with dementia |journal=BMC Geriatrics |volume=7 |issue= |pages=18 |year=2007 |pmid=17662119 |pmc=1951962 |doi=10.1186/1471-2318-7-18 |url=http://www.biomedcentral.com/1471-2318/7/18 |accessdate=2008-07-04 }}</ref><ref name="pmid10489656">{{cite journal |author=Schneider J, Murray J, Banerjee S, Mann A |title=EUROCARE: a cross-national study of co-resident spouse carers for people with Alzheimer's disease: I—Factors associated with carer burden |journal=International Journal of Geriatric Psychiatry |volume=14 |issue=8 |pages=651–661 |year=1999 |month=August |pmid=10489656 |doi=10.1002/(SICI)1099-1166(199908)14:8<651::AID-GPS992>3.0.CO;2-B |accessdate=2008-07-04 }}</ref><ref name="pmid10489657">{{cite journal |author=Murray J, Schneider J, Banerjee S, Mann A |title=EUROCARE: a cross-national study of co-resident spouse carers for people with Alzheimer's disease: II--A qualitative analysis of the experience of caregiving |journal=International Journal of Geriatric Psychiatry |volume=14 |issue=8 |pages=662–667 |year=1999 |month=August |pmid=10489657 |doi=10.1002/(SICI)1099-1166(199908)14:8<662::AID-GPS993>3.0.CO;2-4 }}</ref> Home care is usually preferred by patients and families.<ref name="pmid18044111">{{cite journal |author=Zhu CW, Sano M |title=Economic considerations in the management of Alzheimer's disease |journal=Clin Interv Aging |volume=1 |issue=2 |pages=143–54 |year=2006 |pmid=18044111 |doi= |url= |accessdate=2008-07-15 }}</ref> This option also delays or eliminates the need for more professional and costly levels of care.<ref>{{cite journal |author=Gaugler JE, Kane RL, Kane RA, Newcomer R |title=Early community-based service utilization and its effects on institutionalization in dementia caregiving |journal=Gerontologist |volume=45 |issue=2 |pages=177–85 |year=2005 |month=April |pmid=15799982 |doi= |url=http://gerontologist.gerontologyjournals.org/cgi/pmidlookup?view=long&pmid=15799982 |accessdate=2008-05-30 }}</ref><ref name="pmid18044111">{{cite journal |author=Zhu CW, Sano M |title=Economic considerations in the management of Alzheimer's disease |journal=Clin Interv Aging |volume=1 |issue=2 |pages=143–54 |year=2006 |pmid=18044111 |doi= |url= |accessdate=2008-07-15 }}</ref> Nevertheless two-thirds of nursing home residents have dementias.<ref> {{cite web | url=http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=AlzPG101007 | format=PDF | title =Practice Guideline for the Treatment of Patients with Alzheimer's disease and Other Dementias | publisher =[[American Psychiatric Association]] | date=October 2007 | accessdate=2007-12-28 | doi=10.1176/appi.books.9780890423967.152139 }}</ref>. Dementia caregivers are subject to high rates of physical and [[mental disorder|mental]] disorders.<ref name="pmid12480441">{{cite journal |author=Ritchie K, Lovestone S |title=The dementias |journal=Lancet |volume=360 |issue=9347 |pages=1759–1766 |year=2002 |month=November |pmid=12480441 |doi=10.1016/S0140-6736(02)11667-9 }}</ref> Factors associated with greater psychosocial problems of the primary caregivers include having an affected person at home, the carer being a spouse, demanding behaviors of the patient such as depression, behavioral disturbances, hallucinations, sleep problems or walking disruptions and [[social isolation]].<ref name="pmid2241719">{{cite journal |author=Brodaty H, Hadzi-Pavlovic D |title=Psychosocial effects on carers of living with persons with dementia |journal=Aust N Z J Psychiatry |volume=24 |issue=3 |pages=351–361 |year=1990 |month=September |pmid=2241719 |doi= |url= }}</ref><ref name="pmid9646153">{{cite journal |author=Donaldson C, Tarrier N, Burns A |title=Determinants of carer stress in Alzheimer's disease |journal=International Journal of Geriatric Psychiatry |volume=13 |issue=4 |pages=248–256 |year=1998 |month=April |pmid=9646153 |doi=10.1002/(SICI)1099-1166(199804)13:4<248::AID-GPS770>3.0.CO;2-0 }}</ref> Regarding economic problems, family caregivers often give up time from work to spend 47&nbsp;hours per week on average with the person with AD, while the costs of caring an Alzheimer's patient are high. Direct and indirect costs of caring for an Alzheimer's patient average between $18,000 and $77,500 per year and patient in the [[United States]], depending on the study.<ref> {{cite web | title= The MetLife Study of Alzheimer’s Disease: The Caregiving Experience | date=August 2006 | url=http://www.metlife.com/WPSAssets/14050063731156260663V1FAlzheimerCaregivingExperience.pdf | publisher=MetLife Mature Market Institute | format=PDF | accessdate=2008-02-12 }}</ref><ref name="pmid11445614">{{cite journal |author=Moore MJ, Zhu CW, Clipp EC |title=Informal costs of dementia care: estimates from the National Longitudinal Caregiver Study |journal=J Gerontol B Psychol Sci Soc Sci |volume=56 |issue=4 |pages=S219–28 |year=2001 |month=July |pmid=11445614 |doi= |url=http://psychsoc.gerontologyjournals.org/cgi/pmidlookup?view=long&pmid=11445614 |accessdate=2008-07-15 }}</ref> [[Cognitive behavioral therapy|Individual behavioral therapy]] and the teaching [[Coping (psychology)|coping strategies]] either individually or in group have both demonstrated their efficacy improving caregivers psychological health.<ref name="pmid17662119">{{cite journal |author=Thompson CA, Spilsbury K, Hall J, Birks Y, Barnes C, Adamson J |title=Systematic review of information and support interventions for caregivers of people with dementia |journal=BMC Geriatrics |volume=7 |issue= |pages=18 |year=2007 |pmid=17662119 |pmc=1951962 |doi=10.1186/1471-2318-7-18 |url=http://www.biomedcentral.com/1471-2318/7/18 |accessdate=2008-07-04 }}</ref><ref name="pmid11511058">{{cite journal |author=Pusey H, Richards D |title=A systematic review of the effectiveness of psychosocial interventions for carers of people with dementia |journal=Aging and Mental Health |volume=5 |issue=2 |pages=107–119 |year=2001 |month=May |pmid=11511058 |doi= |url= |accessdate=2008-07-04 }}</ref> Nevertheless caregiving can also have some positive effects in main carers.<ref name="pmid10489657">{{cite journal |author=Murray J, Schneider J, Banerjee S, Mann A |title=EUROCARE: a cross-national study of co-resident spouse carers for people with Alzheimer's disease: II--A qualitative analysis of the experience of caregiving |journal=International Journal of Geriatric Psychiatry |volume=14 |issue=8 |pages=662–667 |year=1999 |month=August |pmid=10489657 |doi=10.1002/(SICI)1099-1166(199908)14:8<662::AID-GPS993>3.0.CO;2-4 }}</ref><ref name="pmid15584791">{{cite journal |author=Boerner K, Schulz R, Horowitz A |title=Positive aspects of caregiving and adaptation to bereavement |journal=Psychol Aging |volume=19 |issue=4 |pages=668–675 |year=2004 |month=December |pmid=15584791 |doi=10.1037/0882-7974.19.4.668 }}</ref> ===Notable cases=== {{Further|[[Alzheimer's in the media]]}} As a result of the prevalence of the disease, many notable people have contracted it. Well-known examples are former [[United States President]] [[Ronald Reagan]] and Irish writer [[Iris Murdoch]], both of whom have scientific articles on how their cognitive capacities deteriorated with the disease.<ref name="pmid15574466"> {{cite journal |author=Garrard P, Maloney LM, Hodges JR, Patterson K |title=The effects of very early Alzheimer's disease on the characteristics of writing by a renowned author |journal=Brain |volume=128 |issue=Pt 2 |pages=250–260 |year=2005 |pmid=15574466 |doi=10.1093/brain/awh341}} </ref><ref name="pmid15461232"> {{cite journal |author=Sherman FT |title=Did President Reagan have mild cognitive impairment while in office? Living longer with Alzheimer's Disease |journal=Geriatrics |volume=59 |issue=9 |pages=11, 15 |year=2004 |pmid=15461232}} </ref> Other cases include the retired [[footballer]] [[Ferenc Puskas]],<ref> {{cite web | url=http://news.bbc.co.uk/sport1/hi/football/europe/6155766.stm |title=Hungary legend Puskas dies at 79 |publisher=BBC News |date=2006-11-17 |accessdate=2008-01-25}} </ref> the former British [[Prime Minister]] [[Harold Wilson]],<ref> {{cite web |url=http://www.pm.gov.uk/output/Page129.asp |title=Harold Wilson 1964-70 and 1974-76 Labour |publisher=10 Downing Street |accessdate=2008-03-08 }}</ref> the actress [[Rita Hayworth]],<ref> {{cite web |url=http://chicago2008.kintera.org/faf/home/default.asp?ievent=245601&lis=1&kntae245601=EC385A175E764E0CAD0814131A12797B |title=Chicago Rita Hayworth Gala |publisher=Alzheimer’s Association |date=2007 |accessdate=2008-01-25 }} </ref> the actor [[Charlton Heston]],<ref> {{cite web |url=http://archives.cnn.com/2002/US/08/09/heston.illness/ |title=Charlton Heston has Alzheimer's symptoms |publisher=CNN |date=2002-08-09 |accessdate=2008-01-25}} </ref> and the novelist [[Terry Pratchett]].<ref> {{cite news |url=http://books.guardian.co.uk/news/articles/0,,2226306,00.html |author=Pauli Michelle |title=Pratchett announces he has Alzheimer's|publisher=Guardian News and Media |date=2007-12-12|accessdate=2008-06-02 }}</ref> Alzheimers has also been portrayed in films such as: ''[[Iris (film)|Iris]]'' (2001),<ref> {{cite web |url=http://www.imdb.com/title/tt0280778/ |title=Iris |date=2002-01-18 |publisher=IMDB |accessdate=2008-01-24}}</ref> (based on [[John Bayley]]'s memoir of his wife [[Iris Murdoch]]);<ref> {{cite book |title=Iris: a memoir of Iris Murdoch |author=Bayley John |publisher=Abacus |location=London |year=2000 |isbn=9780349112152 |oclc=41960006 }}</ref> ''[[The Notebook]]'' (2004),<ref> {{cite web |url=http://www.imdb.com/title/tt0332280/ |title=The notebook |publisher=IMDB |accessdate=2008-02-22}}</ref> (based on [[Nicholas Sparks (author)|Nicholas Sparks]]' 1996 novel of the same name);<ref>{{cite book |title=The notebook |author=Sparks Nicholas |year=1996 |publisher=Thorndike Press |pages=268 |isbn=078620821X }} </ref> ''[[Thanmathra]]'' (2005);<ref> {{cite web |url=http://www.webindia123.com/movie/regional/thanmatra/index.htm |title=Thanmathra |publisher=Webindia123.com |accessdate=2008-01-24}} </ref> ''[[Memories of Tomorrow (Ashita no Kioku)]]'' (2006),<ref> {{cite web |url=http://www.imdb.com/title/tt0494640/ |title=Ashita no kioku |originallanguage={{jp icon}} |publisher=IMDB |accessdate=2008-01-24}}</ref> (based on Hiroshi Ogiwara's novel of the same name);<ref> {{cite book |author=Ogiwara Hiroshi |year=2004 |title=Ashita no Kioku |location=Tōkyō |publisher=Kōbunsha |isbn=9784334924461 |oclc=57352130 |language={{jp icon}} }}</ref> and ''[[Away from her]]'' (2006), (based on [[Alice Munro]]'s short story ''The bear came over the mountain'').<ref>{{cite book |title=Hateship, friendship, courtship, loveship, marriage : stories |author=Munro Alice |chaptertitle=The bear came over the mountain |location=New York |publisher=A.A. Knopf |year=2001 |isbn=9780375413001 |oclc=46929223}}</ref> Documentaries on AD include ''Malcolm and Barbara: A Love Story'' (1999) and ''Malcolm and Barbara: Love’s Farewell'' (2007), both featuring [[Malcolm Pointon]].<ref>Malcolm and Barbara: * {{cite web |url=http://www.dfgdocs.com/Directory/Titles/700.aspx |title=Malcolm and Barbara: A love story |publisher=Dfgdocs |accessdate=2008-01-24}} * {{cite web |url=http://www.bbc.co.uk/cambridgeshire/content/articles/2007/08/06/pointon_audio_feature.shtml |title=Malcolm and Barbara: A love story |publisher=BBC Cambridgeshire |accessdate=2008-03-02}} * {{cite news |url=http://www.guardian.co.uk/media/2007/aug/07/broadcasting.itv |title=Alzheimer's film-maker to face ITV lawyers |publisher=Guardian Media |date=2007-08-07 |accessdate=2008-01-24}}</ref> In ''[[The Cider House Rules]]'' the affliction of a character with Alzheimer's is mistaken as [[alcoholism]].{{Fact|date=June 2008}} ==Research directions== {{Main|Alzheimer's disease clinical research}} As of 2008, the safety and efficacy of more than 400 pharmaceutical treatments are being investigated in [[clinical trial]]s worldwide, and approximately one-fourth of these compounds are in [[Phase III]] trials, which is the last step prior to review by regulatory agencies.<ref>{{cite web |url=http://www.clinicaltrials.gov/ct2/results?term=alzheimer |title= Clinical Trials. Found 459 studies with search of: alzheimer |accessdate= 2008-03-23 |publisher= US National Institutes of Health }}</ref> It is unknown as to whether any of these trials will ultimately prove successful in treating the disease. A critical area of clinical research is focused on treating the underlying disease pathology. Reduction of [[amyloid beta]] levels is a common target of compounds under investigation. [[Immunotherapy]] or [[vaccination]] for the amyloid protein is one treatment modality under study. Unlike vaccines which seek to prevent disease, this therapy would be used to treat diagnosed patients, and is based upon the concept of training the immune system to recognize, attack, and reverse deposition of amyloid, thereby altering the course of the disease.<ref>Vaccination: * {{cite journal |author=Hawkes CA, McLaurin J |title=Immunotherapy as treatment for Alzheimer's disease |journal=Expert Reviews of Neurotherapy |volume=7 |issue=11 |pages=1535–1548 |year=2007 |pmid=17997702 |doi=10.1586/14737175.7.11.1535 }} * {{cite journal |author=Solomon B |title=Clinical immunologic approaches for the treatment of Alzheimer's disease |journal=Expert Opin Investig Drugs |volume=16 |issue=6 |pages=819–828 |year=2007 |pmid=17501694 |doi=10.1517/13543784.16.6.819 }} * {{cite journal |author=Woodhouse A, Dickson TC, Vickers JC |title=Vaccination strategies for Alzheimer's disease: A new hope? |journal=Drugs Aging |volume=24 |issue=2 |pages=107–119 |year=2007 |pmid=17313199 |doi=10.2165/00002512-200724020-00003 }}</ref> An example of such a vaccine under investigation was ACC-001,<ref>{{cite web |url=http://www.clinicaltrials.gov/ct/show/NCT00498602 |title = Study Evaluating ACC-001 in Mild to Moderate Alzheimers Disease Subjects |work = Clinical Trial |publisher =US National Institutes of Health|accessdate=2008-06-05 |date = 2008-03-11}}</ref><ref>{{cite web |url=http://clinicaltrials.gov/ct2/show/NCT00479557 |title=Study Evaluating Safety, Tolerability, and Immunogenicity of ACC-001 in Subjects With Alzheimer's Disease|publisher=US National Institutes of Health|accessdate=2008-06-05}} }}</ref> although the trials were suspended in 2008.<ref>{{cite web |url=http://www.medpagetoday.com/MeetingCoverage/AAN/tb/9165|title = Alzheimer's Disease Vaccine Trial Suspended on Safety Concern |publisher =Medpage Today|accessdate=2008-06-14 |date = 2008-04-18}}</ref> Similar agents are [[bapineuzumab]], an antibody designed as identical to the naturally-induced anti-amyloid antibody,<ref>{{cite web |url=http://clinicaltrials.gov/ct2/show/NCT00574132 |title= Bapineuzumab in Patients With Mild to Moderate Alzheimer's Disease/ Apo_e4 non-carriers |work = Clinical Trial |accessdate=2008-03-23 |publisher= US National Institutes of Health |date= 2008-02-29 }}</ref> and [[Tarenflurbil|MPC-7869]], a selective amyloid beta-42 lowering agent.<ref>{{cite web |url = http://clinicaltrials.gov/ct2/show/NCT00105547 |title= Efficacy Study of MPC-7869 to Treat Patients With Alzheimer's |work = Clinical Trial |accessdate=2008-03-23 |publisher= US National Institutes of Health |date = 2007-12-11 }}</ref> Other approaches are neuroprotective agents, such as AL-108,<ref>{{cite web |url = http://clinicaltrials.gov/ct2/show/NCT00422981 |title = Safety, Tolerability and Efficacy Study to Evaluate Subjects With Mild Cognitive Impairment |work = Clinical Trial |accessdate=2008-03-23 |publisher= US National Institutes of Health |date = 2008-03-11 }}</ref> metal-protein interaction attenuation agents, such as PBT2,<ref>{{cite web |url = http://clinicaltrials.gov/ct2/show/NCT00471211 |title = Study Evaluating the Safety, Tolerability and Efficacy of PBT2 in Patients With Early Alzheimer's Disease |work = Clinical Trial |accessdate=2008-03-23 |publisher= US National Institutes of Health |date = 2008-01-13 }}</ref> or [[tumor necrosis factor-alpha]] [[receptor]] fusion proteins, such as [[etanercept]].<ref name="pmid16926764">Eternacept research: * {{cite journal |author=Tobinick E, Gross H, Weinberger A, Cohen H |title=TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study |journal=MedGenMed |volume=8 |issue=2 |pages=25 |year=2006 |pmid=16926764 |doi= }} * {{cite journal |author=Griffin WS |title=Perispinal etanercept: potential as an Alzheimer therapeutic |journal=J Neuroinflammation |volume=5 |issue= |pages=3 |year=2008 |pmid=18186919 |doi=10.1186/1742-2094-5-3 }} * {{cite journal |author=Tobinick E |title=Perispinal etanercept for treatment of Alzheimer's disease |journal=Curr Alzheimer Res |volume=4 |issue=5 |pages=550–552 |year=2007 |pmid=18220520 |doi=10.2174/156720507783018217 }}</ref> There are also many basic investigations attempting to increase the knowledge on the origin and mechanisms of the disease that may lead to new treatments. ==References == {{reflist|3}} ==Further reading== *{{cite journal |author=Cummings JL, Frank JC, Cherry D, Kohatsu ND, Kemp B, Hewett L, Mittman B |title=Guidelines for managing Alzheimer's disease: Part I. Assessment |journal=American Family Physician |volume=65 |issue=11 |pages=2263–2272 |year=2002 |pmid=12074525 |url=http://www.aafp.org/afp/20020601/2263.html }} *{{ cite journal |author= Cummings JL, Frank JC, Cherry D, Kohatsu ND, Kemp B, Hewett L, Mittman B |title=Guidelines for managing Alzheimer's disease: Part II. Treatment |journal=American Family Physician |volume=65 |issue=12 |pages=2525–2534 |year=2002 |pmid=12086242 |url=http://www.aafp.org/afp/20020615/2525.html }} *{{cite web |url=http://www.nia.nih.gov/NR/rdonlyres/63B5A29C-F943-4DB7-91B4-0296772973F3/0/CanADbePrevented.pdf |title= Genes, lifestyles, and crossword puzzles: Can Alzheimer's disease be prevented |publisher=US Department of Health and Human Services, National Institute of Aging |accessdate=2008-02-29 |format=PDF |work= }} *{{cite web | title=Alzheimer’s Behavior Management: Learn to manage common behavior problems | url=http://www.helpguide.org/elder/alzheimers_behavior_problems.htm | author=Russell D, Barston S, White M | publisher=helpguide.org | date=2007-12-19 | accessdate=2008-02-29 }} {{Mental and behavioural disorders}} {{Diseases of the nervous system}} {{Amyloidosis}} [[Category:Alzheimer's disease]] [[Category:Aging-associated diseases]] [[Category:Neurological disorders]] [[Category:Unsolved problems in neuroscience]] [[Category:Eponyms]] [[Category:Ailments of unknown etiology]] {{Link FA|ro}} [[af:Alzheimer se siekte]] [[ar:ألزهايمر]] [[ast:Alzheimer]] [[bs:Alzheimerova bolest]] [[bg:Болест на Алцхаймер]] [[ca:Malaltia d'Alzheimer]] [[cs:Alzheimerova choroba]] [[cy:Clefyd Alzheimer]] [[da:Alzheimers sygdom]] [[de:Alzheimer-Krankheit]] [[es:Enfermedad de Alzheimer]] [[eo:Alchajmero]] [[eu:Alzheimer]] [[fa:آلزایمر]] [[fr:Maladie d'Alzheimer]] [[gl:Alzheimer]] [[ko:알츠하이머병]] [[hy:Ալցհայմերի հիվանդություն]] [[hr:Alzheimerova bolest]] [[id:Alzheimer]] [[is:Alsheimer]] [[it:Morbo di Alzheimer]] [[he:אלצהיימר]] [[lb:Alzheimer]] [[lt:Alzheimerio liga]] [[hu:Alzheimer-kór]] [[ms:Alzheimer]] [[nl:Ziekte van Alzheimer]] [[ja:アルツハイマー型認知症]] [[no:Alzheimers sykdom]] [[pl:Choroba Alzheimera]] [[pt:Mal de Alzheimer]] [[ro:Boala Alzheimer]] [[ru:Болезнь Альцгеймера]] [[simple:Alzheimer's disease]] [[sk:Alzheimerova choroba]] [[sl:Alzheimerjeva bolezen]] [[sr:Алцхајмерова болест]] [[su:Panyakit Alzheimer]] [[fi:Alzheimerin tauti]] [[sv:Alzheimers sjukdom]] [[tr:Alzheimer hastalığı]] [[uk:Хвороба Альцгеймера]] [[yi:אלצהיימערס קרענק]] [[zh:阿兹海默病]]