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Alzheimer's disease
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{{Redirect|Alzheimer}}{{pp-semi-indef}}{{pp-move-indef}}{{short description|Progressive, neurodegenerative disease characterized by memory loss}}{{bots|deny=Monkbot7}} {{EngvarB|date=May 2014}}{{Use British English|date=September 2016}}{{Use dmy dates|date=August 2018}}







factoids
Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a chronic neurodegenerative disease that usually starts slowly and gradually worsens over time. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events.JOURNAL, Burns A, Iliffe S, Alzheimer's disease, BMJ, 338, b158, February 2009, 19196745, 10.1136/bmj.b158, As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, not managing self care, and behavioural issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death.WEB, About Alzheimer's Disease: Symptoms,weblink National Institute on Aging, 28 December 2011, no,weblink" title="web.archive.org/web/20120115201854weblink">weblink 15 January 2012, Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years.JOURNAL, Querfurth HW, LaFerla FM, Alzheimer's disease, The New England Journal of Medicine, 362, 4, 329–44, January 2010, 20107219, 10.1056/NEJMra0909142, JOURNAL, Todd S, Barr S, Roberts M, Passmore AP, Survival in dementia and predictors of mortality: a review, International Journal of Geriatric Psychiatry, 28, 11, 1109–24, November 2013, 23526458, 10.1002/gps.3946, The cause of Alzheimer's disease is poorly understood. About 70% of the risk is believed to be inherited from a person's parents with many genes usually involved. Other risk factors include a history of head injuries, depression, and hypertension. The disease process is associated with plaques and neurofibrillary tangles in the brain.JOURNAL, Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E, Alzheimer's disease, Lancet, 377, 9770, 1019–31, March 2011, 21371747, 10.1016/S0140-6736(10)61349-9, A probable diagnosis is based on the history of the illness and cognitive testing with medical imaging and blood tests to rule out other possible causes.WEB, Dementia diagnosis and assessment,weblink National Institute for Health and Care Excellence (NICE), 30 November 2014, yes,weblink" title="web.archive.org/web/20141205184403weblink">weblink 5 December 2014, Initial symptoms are often mistaken for normal ageing. Examination of brain tissue is needed for a definite diagnosis. Mental and physical exercise, and avoiding obesity may decrease the risk of AD; however, evidence to support these recommendations is weak.WEB, So, What Can You Do?,weblink National Institute on Aging, en, 29 July 2016, yes,weblink 3 April 2017, There are no medications or supplements that have been shown to decrease risk.No treatments stop or reverse its progression, though some may temporarily improve symptoms. Affected people increasingly rely on others for assistance, often placing a burden on the caregiver. The pressures can include social, psychological, physical, and economic elements.JOURNAL, Thompson CA, Spilsbury K, Hall J, Birks Y, Barnes C, Adamson J, Systematic review of information and support interventions for caregivers of people with dementia, BMC Geriatrics, 7, 18, July 2007, 17662119, 1951962, 10.1186/1471-2318-7-18, Exercise programs may be beneficial with respect to activities of daily living and can potentially improve outcomes.JOURNAL, Forbes D, Forbes SC, Blake CM, Thiessen EJ, Forbes S, Exercise programs for people with dementia, The Cochrane Database of Systematic Reviews, 132, 4, CD006489, April 2015, 25874613, 10.1002/14651858.CD006489.pub4,weblink Submitted manuscript, Behavioural problems or psychosis due to dementia are often treated with antipsychotics, but this is not usually recommended, as there is little benefit with an increased risk of early death.WEB, National Institute for Health and Clinical Excellence, Low-dose antipsychotics in people with dementia,weblink National Institute for Health and Care Excellence (NICE), 29 November 2014, yes,weblink 5 December 2014, WEB, Information for Healthcare Professionals: Conventional Antipsychotics,weblink US Food and Drug Administration, 29 November 2014, 16 June 2008, no,weblink" title="web.archive.org/web/20141129015823weblink">weblink 29 November 2014, In 2015, there were approximately 29.8 million people worldwide with AD.WEB,weblink Dementia Fact sheet, 12 December 2017, World Health Organization, JOURNAL, GBD 2015 Disease Injury Incidence Prevalence Collaborators, Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015, Lancet, 388, 10053, 1545–1602, October 2016, 27733282, 5055577, 10.1016/S0140-6736(16)31678-6, It most often begins in people over 65 years of age, although 4–5% of cases are early-onset Alzheimer's.JOURNAL, Mendez MF, Early-onset Alzheimer's disease: nonamnestic subtypes and type 2 AD, Archives of Medical Research, 43, 8, 677–85, November 2012, 23178565, 3532551, 10.1016/j.arcmed.2012.11.009, It affects about 6% of people 65 years and older. In 2015, dementia resulted in about 1.9 million deaths.JOURNAL, GBD 2015 Mortality Causes of Death Collaborators, Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015, Lancet, 388, 10053, 1459–1544, October 2016, 27733281, 5388903, 10.1016/S0140-6736(16)31012-1, It was first described by, and later named after, German psychiatrist and pathologist Alois Alzheimer in 1906. In developed countries, AD is one of the most financially costly diseases.JOURNAL, Bonin-Guillaume S, Zekry D, Giacobini E, Gold G, Michel JP, [The economical impact of dementia], French, Presse Médicale, 34, 1, 35–41, January 2005, 15685097, 10.1016/s0755-4982(05)83882-5, JOURNAL, Meek PD, McKeithan K, Schumock GT, Economic considerations in Alzheimer's disease, Pharmacotherapy, 18, 2 Pt 2, 68–73; discussion 79–82, 1998, 9543467, 10.1002/j.1875-9114.1998.tb03880.x, 2019-02-24, {{TOC limit|3}}

Signs and symptoms

|
Effects of ageing on memory but not AD


Early stage Alzheimer's
  • Not remembering episodes of forgetfulness
  • Forgets names of family or friends
  • Changes may only be noticed by close friends or relatives
  • Some confusion in situations outside the familiar


Middle stage Alzheimer's
  • Greater difficulty remembering recently learned information
  • Deepening confusion in many circumstances
  • Problems with sleep
  • Trouble determining their location


Late stage Alzheimer's
  • Poor ability to think
  • Problems speaking
  • Repeats same conversations
  • More abusive, anxious, or paranoid
}}The disease course is divided into four stages, with a progressive pattern of cognitive and functional impairment.

Pre-dementia

The first symptoms are often mistakenly attributed to ageing or stress.JOURNAL, Waldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, Scheltens P, Tariska P, Winblad B, Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline, European Journal of Neurology, 14, 1, e1–26, January 2007, 17222085, 10.1111/j.1468-1331.2006.01605.x, Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfils the clinical criteria for diagnosis of AD.JOURNAL, Bäckman L, Jones S, Berger AK, Laukka EJ, Small BJ, Multiple cognitive deficits during the transition to Alzheimer's disease, Journal of Internal Medicine, 256, 3, 195–204, September 2004, 15324363, 10.1111/j.1365-2796.2004.01386.x, These early symptoms can affect the most complex activities of daily living.JOURNAL, Nygård L, Instrumental activities of daily living: a stepping-stone towards Alzheimer's disease diagnosis in subjects with mild cognitive impairment?, Acta Neurologica Scandinavica. Supplementum, 179, 179, 42–6, 2003, 12603250, 10.1034/j.1600-0404.107.s179.8.x, The most noticeable deficit is short term memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information.JOURNAL, Arnáiz E, Almkvist O, Neuropsychological features of mild cognitive impairment and preclinical Alzheimer's disease, Acta Neurologica Scandinavica. Supplementum, 179, 34–41, 2003, 12603249, 10.1034/j.1600-0404.107.s179.7.x, Subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and concept relationships) can also be symptomatic of the early stages of AD. Apathy can be observed at this stage, and remains the most persistent neuropsychiatric symptom throughout the course of the disease.JOURNAL, Landes AM, Sperry SD, Strauss ME, Geldmacher DS, Apathy in Alzheimer's disease, Journal of the American Geriatrics Society, 49, 12, 1700–7, December 2001, 11844006, 10.1046/j.1532-5415.2001.49282.x, Depressive symptoms, irritability and reduced awareness of subtle memory difficulties are also common.BOOK, Bradley's neurology in clinical practice, 2012, Elsevier/Saunders, Philadelphia, PA, 978-1-4377-0434-1, Murray ED, Buttner N, Price BH, 6th, Bradley WG, Daroff RB, Fenichel GM, Jankovic J, Depression and Psychosis in Neurological Practice, The preclinical stage of the disease has also been termed mild cognitive impairment (MCI). This is often found to be a transitional stage between normal ageing and dementia. MCI can present with a variety of symptoms, and when memory loss is the predominant symptom, it is termed "amnestic MCI" and is frequently seen as a prodromal stage of Alzheimer's disease.JOURNAL, Grundman M, Petersen RC, Ferris SH, Thomas RG, Aisen PS, Bennett DA, Foster NL, Jack CR, Galasko DR, Doody R, Kaye J, Sano M, Mohs R, Gauthier S, Kim HT, Jin S, Schultz AN, Schafer K, Mulnard R, van Dyck CH, Mintzer J, Zamrini EY, Cahn-Weiner D, Thal LJ, 6, Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials, Archives of Neurology, 61, 1, 59–66, January 2004, 14732621, 10.1001/archneur.61.1.59, Christopher H. van Dyck,

Early

In people with AD, the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small percentage, difficulties with language, executive functions, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems.JOURNAL, Förstl H, Kurz A, Clinical features of Alzheimer's disease, European Archives of Psychiatry and Clinical Neuroscience, 249, 6, 288–90, 1999, 10653284, 10.1007/s004060050101, AD does not affect all memory capacities equally. Older memories of the person'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 or how to drink from a glass) are affected to a lesser degree than new facts or memories.JOURNAL, Carlesimo GA, Oscar-Berman M, Memory deficits in Alzheimer's patients: a comprehensive review, Neuropsychology Review, 3, 2, 119–69, June 1992, 1300219, 10.1007/BF01108841, JOURNAL, Jelicic M, Bonebakker AE, Bonke B, Implicit memory performance of patients with Alzheimer's disease: a brief review, International Psychogeriatrics, 7, 3, 385–92, 1995, 8821346, 10.1017/S1041610295002134, Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, leading to a general impoverishment of oral and written language.JOURNAL, Taler V, Phillips NA, Language performance in Alzheimer's disease and mild cognitive impairment: a comparative review, Journal of Clinical and Experimental Neuropsychology, 30, 5, 501–56, July 2008, 18569251, 10.1080/13803390701550128, In this stage, the person with Alzheimer's is usually capable of communicating basic ideas adequately.JOURNAL, Frank EM, Effect of Alzheimer's disease on communication function, Journal of the South Carolina Medical Association, 90, 9, 417–23, September 1994, 7967534, While performing fine motor tasks such as writing, drawing or dressing, certain movement coordination and planning difficulties (apraxia) may be present, but they are commonly unnoticed. As the disease progresses, people with AD can often continue to perform many tasks independently, but may need assistance or supervision with the most cognitively demanding activities.

Moderate

Progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living. Speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also progressively lost. Complex motor sequences become less coordinated as time passes and AD progresses, so the risk of falling increases. During this phase, memory problems worsen, and the person may fail to recognise close relatives. Long-term memory, which was previously intact, becomes impaired.Behavioural and neuropsychiatric changes become more prevalent. Common manifestations are wandering, irritability and labile affect, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving. Sundowning can also appear.JOURNAL, Volicer L, Harper DG, Manning BC, Goldstein R, Satlin A, Sundowning and circadian rhythms in Alzheimer's disease, The American Journal of Psychiatry, 158, 5, 704–11, May 2001, 11329390, 10.1176/appi.ajp.158.5.704, Approximately 30% of people with AD develop illusionary misidentifications and other delusional symptoms. Subjects also lose insight of their disease process and limitations (anosognosia). Urinary incontinence can develop. These symptoms create stress for relatives and carers, which can be reduced by moving the person from home care to other long-term care facilities.JOURNAL, Gold DP, Reis MF, Markiewicz D, Andres D, When home caregiving ends: a longitudinal study of outcomes for caregivers of relatives with dementia, Journal of the American Geriatrics Society, 43, 1, 10–6, January 1995, 7806732, 10.1111/j.1532-5415.1995.tb06235.x,

Advanced

During the final stages, the patient is completely dependent upon caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal language abilities, people can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common symptoms. People with Alzheimer's disease will ultimately not be able to perform even the simplest tasks independently; muscle mass and mobility deteriorates to the point where they are bedridden and unable to feed themselves. The cause of death is usually an external factor, such as infection of pressure ulcers or pneumonia, not the disease itself.

Cause

The cause for most Alzheimer's cases is still mostly unknown except for 1% to 5% of cases where genetic differences have been identified.WEB,weblink What We Know Today About Alzheimer's Disease, Alzheimer's Association, 1 October 2011, While scientists know Alzheimer's disease involves progressive brain cell failure, the reason cells fail isn't clear., no,weblink" title="web.archive.org/web/20111007055341weblink">weblink 7 October 2011, JOURNAL, Reitz C, Mayeux R, Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers, Biochemical Pharmacology, 88, 4, 640–51, April 2014, 24398425, 3992261, 10.1016/j.bcp.2013.12.024, Several competing hypotheses exist trying to explain the cause of the disease.

Genetic

The genetic heritability of Alzheimer's disease (and memory components thereof), based on reviews of twin and family studies, ranges from 49% to 79%.JOURNAL, Wilson RS, Barral S, Lee JH, Leurgans SE, Foroud TM, Sweet RA, Graff-Radford N, Bird TD, Mayeux R, Bennett DA, Heritability of different forms of memory in the Late Onset Alzheimer's Disease Family Study, Journal of Alzheimer's Disease, 23, 2, 249–55, 2011, 20930268, 3130303, 10.3233/JAD-2010-101515, Around 0.1% of the cases are familial forms of autosomal (not sex-linked) dominant inheritance, which have an onset before age 65.JOURNAL, Blennow K, de Leon MJ, Zetterberg H, Alzheimer's disease, Lancet, 368, 9533, 387–403, July 2006, 16876668, 10.1016/S0140-6736(06)69113-7, This form of the disease is known as early onset familial Alzheimer's disease. Most of autosomal dominant familial AD can be attributed to mutations in one of three genes: those encoding amyloid precursor protein (APP) and presenilins 1 and 2.JOURNAL, Waring SC, Rosenberg RN, Genome-wide association studies in Alzheimer disease, Archives of Neurology, 65, 3, 329–34, March 2008, 18332245, 10.1001/archneur.65.3.329, Most mutations in the APP and presenilin genes increase the production of a small protein called Aβ42, which is the main component of senile plaques.JOURNAL, Selkoe DJ, Translating cell biology into therapeutic advances in Alzheimer's disease, Nature, 399, 6738 Suppl, A23–31, June 1999, 10392577, 10.1038/19866, Some of the mutations merely alter the ratio between Aβ42 and the other major forms—particularly Aβ40—without increasing Aβ42 levels.JOURNAL, Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M, Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS, 6, Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo, Neuron, 17, 5, 1005–13, November 1996, 8938131, 10.1016/S0896-6273(00)80230-5, Two other genes associated with autosomal dominant Alzheimer's disease are ABCA7 and SORL1.JOURNAL, Kim, JH, Genetics of Alzheimer's Disease., Dementia and neurocognitive disorders, December 2018, 17, 4, 131–136, 10.12779/dnd.2018.17.4.131, 30906402, Most cases of Alzheimer's disease do not exhibit autosomal-dominant inheritance and are termed sporadic AD, in which environmental and genetic differences may act as risk factors. The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (APOE).JOURNAL, Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD, Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease, Proceedings of the National Academy of Sciences of the United States of America, 90, 5, 1977–81, March 1993, 8446617, 46003, 10.1073/pnas.90.5.1977, JOURNAL, Mahley RW, Weisgraber KH, Huang Y, Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease, Proceedings of the National Academy of Sciences of the United States of America, 103, 15, 5644–51, April 2006, 16567625, 1414631, 10.1073/pnas.0600549103, 2006PNAS..103.5644M, Between 40 and 80% of people with AD possess at least one APOEε4 allele. The APOEε4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes. Like many human diseases, environmental effects and genetic modifiers result in incomplete penetrance. For example, certain Nigerian populations do not show the relationship between dose of APOEε4 and incidence or age-of-onset for Alzheimer's disease seen in other human populations.JOURNAL, Hall K, Murrell J, Ogunniyi A, Deeg M, Baiyewu O, Gao S, Gureje O, Dickens J, Evans R, Smith-Gamble V, Unverzagt FW, Shen J, Hendrie H, Cholesterol, APOE genotype, and Alzheimer disease: an epidemiologic study of Nigerian Yoruba, Neurology, 66, 2, 223–7, January 2006, 16434658, 2860622, 10.1212/01.wnl.0000194507.39504.17, JOURNAL, Gureje O, Ogunniyi A, Baiyewu O, Price B, Unverzagt FW, Evans RM, Smith-Gamble V, Lane KA, Gao S, Hall KS, Hendrie HC, Murrell JR, 6, APOE epsilon4 is not associated with Alzheimer's disease in elderly Nigerians, Annals of Neurology, 59, 1, 182–5, January 2006, 16278853, 2855121, 10.1002/ana.20694, Early attempts to screen up to 400 candidate genes for association with late-onset sporadic AD (LOAD) resulted in a low yield. More recent genome-wide association studies (GWAS) have found 19 areas in genes that appear to affect the risk.JOURNAL, Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thorton-Wells TA, Jones N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, Kamatani Y, Lin CF, Gerrish A, Schmidt H, Kunkle B, Dunstan ML, Ruiz A, Bihoreau MT, Choi SH, Reitz C, Pasquier F, Cruchaga C, Craig D, Amin N, Berr C, Lopez OL, De Jager PL, Deramecourt V, Johnston JA, Evans D, Lovestone S, Letenneur L, Morón FJ, Rubinsztein DC, Eiriksdottir G, Sleegers K, Goate AM, Fiévet N, Huentelman MW, Gill M, Brown K, Kamboh MI, Keller L, Barberger-Gateau P, McGuiness B, Larson EB, Green R, Myers AJ, Dufouil C, Todd S, Wallon D, Love S, Rogaeva E, Gallacher J, St George-Hyslop P, Clarimon J, Lleo A, Bayer A, Tsuang DW, Yu L, Tsolaki M, Bossù P, Spalletta G, Proitsi P, Collinge J, Sorbi S, Sanchez-Garcia F, Fox NC, Hardy J, Deniz Naranjo MC, Bosco P, Clarke R, Brayne C, Galimberti D, Mancuso M, Matthews F, Moebus S, Mecocci P, Del Zompo M, Maier W, Hampel H, Pilotto A, Bullido M, Panza F, Caffarra P, Nacmias B, Gilbert JR, Mayhaus M, Lannefelt L, Hakonarson H, Pichler S, Carrasquillo MM, Ingelsson M, Beekly D, Alvarez V, Zou F, Valladares O, Younkin SG, Coto E, Hamilton-Nelson KL, Gu W, Razquin C, Pastor P, Mateo I, Owen MJ, Faber KM, Jonsson PV, Combarros O, O'Donovan MC, Cantwell LB, Soininen H, Blacker D, Mead S, Mosley TH, Bennett DA, Harris TB, Fratiglioni L, Holmes C, de Bruijn RF, Passmore P, Montine TJ, Bettens K, Rotter JI, Brice A, Morgan K, Foroud TM, Kukull WA, Hannequin D, Powell JF, Nalls MA, Ritchie K, Lunetta KL, Kauwe JS, Boerwinkle E, Riemenschneider M, Boada M, Hiltuenen M, Martin ER, Schmidt R, Rujescu D, Wang LS, Dartigues JF, Mayeux R, Tzourio C, Hofman A, Nöthen MM, Graff C, Psaty BM, Jones L, Haines JL, Holmans PA, Lathrop M, Pericak-Vance MA, Launer LJ, Farrer LA, van Duijn CM, Van Broeckhoven C, Moskvina V, Seshadri S, Williams J, Schellenberg GD, Amouyel P, 6, Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease, Nature Genetics, 45, 12, 1452–8, December 2013, 24162737, 3896259, 10.1038/ng.2802, These genes include: CASS4, CELF1, FERMT2, HLA-DRB5, INPP5D, MEF2C, NME8, PTK2B, SORL1, ZCWPW1, SlC24A4, CLU, PICALM, CR1, BIN1, MS4A, ABCA7, EPHA1, and CD2AP.Alleles in the TREM2 gene have been associated with a 3 to 5 times higher risk of developing Alzheimer's disease.JOURNAL, Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K, 6, Variant of TREM2 associated with the risk of Alzheimer's disease, The New England Journal of Medicine, 368, 2, 107–16, January 2013, 23150908, 3677583, 10.1056/NEJMoa1211103, Original article, JOURNAL, Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, Hardy J, 6, TREM2 variants in Alzheimer's disease, The New England Journal of Medicine, 368, 2, 117–27, January 2013, 23150934, 3631573, 10.1056/NEJMoa1211851, Original article, A suggested mechanism of action is that in some variants in TREM2 white blood cells in the brain are no longer able to control the amount of beta amyloid present. Many SNPs are associated with Alzheimer's with a 2018 study adding 30 SNPs by differentiating AD into 6 categories, including memory, language, visuospatial, and executive functioning.JOURNAL, Mukherjee S, Mez J, Trittschuh EH, Saykin AJ, Gibbons LE, Fardo DW, Wessels M, Bauman J, Moore M, Choi SE, Gross AL, Rich J, Louden DK, Sanders RE, Grabowski TJ, Bird TD, McCurry SM, Snitz BE, Kamboh MI, Lopez OL, De Jager PL, Bennett DA, Keene CD, Larson EB, Crane PK, 6, Genetic data and cognitively defined late-onset Alzheimer's disease subgroups, Molecular Psychiatry, December 2018, 30514930, 10.1038/s41380-018-0298-8,

Cholinergic hypothesis

The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis,JOURNAL, Francis PT, Palmer AM, Snape M, Wilcock GK, The cholinergic hypothesis of Alzheimer's disease: a review of progress, Journal of Neurology, Neurosurgery, and Psychiatry, 66, 2, 137–47, February 1999, 10071091, 1736202, 10.1136/jnnp.66.2.137, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective.JOURNAL, Martorana A, Esposito Z, Koch G, Beyond the cholinergic hypothesis: do current drugs work in Alzheimer's disease?, CNS Neuroscience & Therapeutics, 16, 4, 235–45, August 2010, 20560995, 10.1111/j.1755-5949.2010.00175.x,

Amyloid hypothesis

In 1991, the amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease.JOURNAL, Hardy J, Allsop D, Amyloid deposition as the central event in the aetiology of Alzheimer's disease, Trends in Pharmacological Sciences, 12, 10, 383–8, October 1991, 1763432, 10.1016/0165-6147(91)90609-V, JOURNAL, Mudher A, Lovestone S, Alzheimer's disease-do tauists and baptists finally shake hands?, Trends in Neurosciences, 25, 1, 22–6, January 2002, 11801334, 10.1016/S0166-2236(00)02031-2, Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit at least the earliest symptoms of AD by 40 years of age.JOURNAL, Nistor M, Don M, Parekh M, Sarsoza F, Goodus M, Lopez GE, Kawas C, Leverenz J, Doran E, Lott IT, Hill M, Head E, Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain, Neurobiology of Aging, 28, 10, 1493–506, October 2007, 16904243, 3375834, 10.1016/j.neurobiolaging.2006.06.023, JOURNAL, Lott IT, Head E, Alzheimer disease and Down syndrome: factors in pathogenesis, Neurobiology of Aging, 26, 3, 383–9, March 2005, 15639317, 10.1016/j.neurobiolaging.2004.08.005, Also, a specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. While apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain.JOURNAL, Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, Niinistö L, Halonen P, Kontula K, Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein, The New England Journal of Medicine, 333, 19, 1242–7, November 1995, 7566000, 10.1056/NEJM199511093331902, Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology with spatial learning deficits.Transgenic mice:
  • JOURNAL, Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein, Nature, 373, 6514, 523–7, February 1995, 7845465, 10.1038/373523a0,
  • JOURNAL, Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D, Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimer's disease, The Journal of Neuroscience, 16, 18, 5795–811, September 1996, 8795633, 10.1523/JNEUROSCI.16-18-05795.1996,
  • JOURNAL, Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G, Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice, Science, 274, 5284, 99–102, October 1996, 8810256, 10.1126/science.274.5284.99,
  • JOURNAL, Lalonde R, Dumont M, Staufenbiel M, Sturchler-Pierrat C, Strazielle C, Spatial learning, exploration, anxiety, and motor coordination in female APP23 transgenic mice with the Swedish mutation, Brain Research, 956, 1, 36–44, November 2002, 12426044, 10.1016/S0006-8993(02)03476-5,
An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia.JOURNAL, Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA, Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial, Lancet, 372, 9634, 216–23, July 2008, 18640458, 10.1016/S0140-6736(08)61075-2, Researchers have been led to suspect non-plaque Aβ oligomers (aggregates of many monomers) as the primary pathogenic form of Aβ. These toxic oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the synapse, thereby disrupting neuronal communication.JOURNAL, Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL, 6, Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease, The Journal of Neuroscience, 27, 4, 796–807, January 2007, 17251419, 10.1523/JNEUROSCI.3501-06.2007, One receptor for Aβ oligomers may be the prion protein, the same protein that has been linked to mad cow disease and the related human condition, Creutzfeldt–Jakob disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of Alzheimer's disease.JOURNAL, Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM, Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers, Nature, 457, 7233, 1128–32, February 2009, 19242475, 2748841, 10.1038/nature07761, In 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. The theory holds that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by ageing-related processes in later life to cause the neuronal withering of Alzheimer's disease.JOURNAL, Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M, APP binds DR6 to trigger axon pruning and neuron death via distinct caspases, Nature, 457, 7232, 981–9, February 2009, 19225519, 2677572, 10.1038/nature07767, 2009Natur.457..981N, N-APP, a fragment of APP from the peptide's N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known as TNFRSF21). DR6 is highly expressed in the human brain regions most affected by Alzheimer's, so it is possible that the N-APP/DR6 pathway might be hijacked in the ageing brain to cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function.In early 2017, a trial of verubecestat, which inhibits the beta-secretase protein responsible for creating beta-amyloid protein was discontinued as an independent panel found "virtually no chance of finding a positive clinical effect".WEB,weblink Merck Alzheimer's Drug Study Halted Early for Futility, Feuerstein, Adam, 14 February 2017, TheStreet, Inc., New York City, NY, USA, no,weblink 16 February 2017, Merck Alzheimer's Drug Study Halted Early for Futility Independent study monitors concluded that there was "virtually no chance of finding a positive clinical effect." In 2018 and 2019, more trials, including aducanumab which reduce amyloid beta concentrations, failed leading some to question the validity of the amyloid hypothesis.NEWS, After A Big Failure, Scientists And Patients Hunt For A New Type Of Alzheimer's Drug,weblink 17 May 2019, NPR.org, en, NEWS, Gallagher, James, Dementia is 'greatest health challenge',weblink 17 May 2019, 2 May 2019,

Tau hypothesis

(File:TANGLES HIGH.jpg|upright=1.35|thumb|In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.)The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies.JOURNAL, Goedert M, Spillantini MG, Crowther RA, Tau proteins and neurofibrillary degeneration, Brain Pathology, 1, 4, 279–86, July 1991, 1669718, 10.1111/j.1750-3639.1991.tb00671.x, When this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system.JOURNAL, Iqbal K, Alonso A, Chen S, Chohan MO, El-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Iqbal I, Tau pathology in Alzheimer disease and other tauopathies, Biochimica et Biophysica Acta, 1739, 2–3, 198–210, January 2005, 15615638, 10.1016/j.bbadis.2004.09.008, This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.JOURNAL, Chun W, Johnson GV, The role of tau phosphorylation and cleavage in neuronal cell death, Frontiers in Bioscience, 12, 733–56, January 2007, 17127334, 10.2741/2097,

Other hypotheses

A neurovascular hypothesis has been proposed which states that poor functioning of the blood–brain barrier may be involved.JOURNAL, Deane R, Zlokovic BV, Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease, Current Alzheimer Research, 4, 2, 191–7, April 2007, 17430246, 10.2174/156720507780362245, Spirochete infections have also been linked to dementia.JOURNAL, Miklossy J, Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria, Journal of Neuroinflammation, 8, 1, 90, August 2011, 21816039, 3171359, 10.1186/1742-2094-8-90, JOURNAL, Allen, HB, Alzheimer's Disease: Assessing the Role of Spirochetes, Biofilms, the Immune System, and Amyloid-β with Regard to Potential Treatment and Prevention., Journal of Alzheimer's disease : JAD, 27 June 2016, 53, 4, 1271-6, 10.3233/JAD-160388, 27372648, The cellular homeostasis of biometals such as ionic copper, iron, and zinc is disrupted in AD, though it remains unclear whether this is produced by or causes the changes in proteins. These ions affect and are affected by tau, APP, and APOE,JOURNAL, Xu H, Finkelstein DI, Adlard PA, Interactions of metals and Apolipoprotein E in Alzheimer's disease, Frontiers in Aging Neuroscience, 6, 121, 12 June 2014, 24971061, 4054654, 10.3389/fnagi.2014.00121, Although we still do not know if the metal ion dyshomeostasis present in AD is a cause or consequence of the disease, there is a growing body of evidence showing a direct correlation between metal ions and key AD-related key proteins., and their dysregulation may cause oxidative stress that may contribute to the pathology.JOURNAL, Su B, Wang X, Nunomura A, Moreira PI, Lee HG, Perry G, Smith MA, Zhu X, Oxidative stress signaling in Alzheimer's disease, Current Alzheimer Research, 5, 6, 525–32, December 2008, 19075578, 2780015, 10.2174/156720508786898451, JOURNAL, Kastenholz B, Garfin DE, Horst J, Nagel KA, Plant metal chaperones: a novel perspective in dementia therapy, Amyloid, 16, 2, 81–3, 2009, 20536399, 10.1080/13506120902879392, WEB, Aluminium and Alzheimer's disease, Alzheimer's Society, Facts about dementia,weblink 14 October 2005, yes,weblink" title="web.archive.org/web/20051027165732weblink">weblink 27 October 2005, JOURNAL, Bondy SC, Low levels of aluminum can lead to behavioral and morphological changes associated with Alzheimer's disease and age-related neurodegeneration, Neurotoxicology, 52, 222–9, January 2016, 26687397, 10.1016/j.neuro.2015.12.002,weblink Submitted manuscript, JOURNAL, Kandimalla R, Vallamkondu J, Corgiat EB, Gill KD, Understanding Aspects of Aluminum Exposure in Alzheimer's Disease Development, Brain Pathology, 26, 2, 139–54, March 2016, 26494454, 10.1111/bpa.12333, The quality of some of these studies has been criticised,JOURNAL, Santibáñez M, Bolumar F, García AM, Occupational risk factors in Alzheimer's disease: a review assessing the quality of published epidemiological studies, Occupational and Environmental Medicine, 64, 11, 723–32, November 2007, 17525096, 2078415, 10.1136/oem.2006.028209, JOURNAL, Lidsky TI, Is the Aluminum Hypothesis dead?, Journal of Occupational and Environmental Medicine, 56, 5 Suppl, S73–9, May 2014, 24806729, 4131942, 10.1097/jom.0000000000000063, and the link remains controversial.JOURNAL, Yegambaram M, Manivannan B, Beach TG, Halden RU, Role of environmental contaminants in the etiology of Alzheimer's disease: a review, Current Alzheimer Research, 12, 2, 116–46, 2015, 25654508, 4428475, 10.2174/1567205012666150204121719, The majority of researchers do not support a causal connection with aluminium.Smoking is a significant AD risk factor.JOURNAL, Cataldo JK, Prochaska JJ, Glantz SA, Cigarette smoking is a risk factor for Alzheimer's Disease: an analysis controlling for tobacco industry affiliation, Journal of Alzheimer's Disease, 19, 2, 465–80, 2010, 20110594, 2906761, 10.3233/JAD-2010-1240, Systemic markers of the innate immune system are risk factors for late-onset AD.JOURNAL, Eikelenboom P, van Exel E, Hoozemans JJ, Veerhuis R, Rozemuller AJ, van Gool WA, Neuroinflammation - an early event in both the history and pathogenesis of Alzheimer's disease, Neuro-Degenerative Diseases, 7, 1–3, 38–41, 2010, 20160456, 10.1159/000283480, There is tentative evidence that exposure to air pollution may be a contributing factor to the development of Alzheimer's disease.JOURNAL, Moulton PV, Yang W, Air pollution, oxidative stress, and Alzheimer's disease, Journal of Environmental and Public Health, 2012, 1–9, 2012, 22523504, 3317180, 10.1155/2012/472751, Review, One hypothesis posits that dysfunction of oligodendrocytes and their associated myelin during aging contributes to axon damage, which then causes amyloid production and tau hyper-phosphorylation as a side effect.JOURNAL, Bartzokis G, Alzheimer's disease as homeostatic responses to age-related myelin breakdown, Neurobiology of Aging, 32, 8, 1341–71, August 2011, 19775776, 3128664, 10.1016/j.neurobiolaging.2009.08.007, JOURNAL, Cai Z, Xiao M, Oligodendrocytes and Alzheimer's disease, The International Journal of Neuroscience, 126, 2, 97–104, 2016, 26000818, 10.3109/00207454.2015.1025778, Retrogenesis is a medical hypothesis about the development and progress of Alzheimer's disease proposed by Barry Reisberg in the 1980s. The hypothesis is that just as the fetus goes through a process of neurodevelopment beginning with neurulation and ending with myelination, the brains of people with AD go through a reverse neurodegeneration process starting with demyelination and death of axons (white matter) and ending with the death of grey matter.JOURNAL, Alves GS, Oertel Knöchel V, Knöchel C, Carvalho AF, Pantel J, Engelhardt E, Laks J, Integrating retrogenesis theory to Alzheimer's disease pathology: insight from DTI-TBSS investigation of the white matter microstructural integrity, BioMed Research International, 2015, 291658, 2015, 25685779, 4320890, 10.1155/2015/291658, Likewise the hypothesis is, that as infants go through states of cognitive development, people with AD go through the reverse process of progressive cognitive impairment.JOURNAL, Reisberg B, Franssen EH, Hasan SM, Monteiro I, Boksay I, Souren LE, Kenowsky S, Auer SR, Elahi S, Kluger A, 6, Retrogenesis: clinical, physiologic, and pathologic mechanisms in brain aging, Alzheimer's and other dementing processes, European Archives of Psychiatry and Clinical Neuroscience, 249 Suppl 3, 3, 28–36, 1999, 10654097, 10.1007/pl00014170, dmy-all, Reisberg developed the caregiving assessment tool known as "FAST" (Functional Assessment Staging Tool) which he says allows those caring for people with AD to identify the stages of disease progression and that provides advice about the kind of care needed at each stage.BOOK, Brenner Carson, Verna, Caregiving for Alzheimer's Disease, 2015, Springer New York Academy of Sciences, New York, 978-1-4939-2406-6, 1–9, The association with celiac disease is unclear, with a 2019 study finding no increase in dementia overall in those with CD, while a 2018 review found an association with several types of dementia including AD.JOURNAL, Zis, Panagiotis, Hadjivassiliou, Marios, Treatment of Neurological Manifestations of Gluten Sensitivity and Coeliac Disease, Current Treatment Options in Neurology, 26 February 2019, 21, 3, 10.1007/s11940-019-0552-7, JOURNAL, Makhlouf S, Messelmani M, Zaouali J, Mrissa R, Cognitive impairment in celiac disease and non-celiac gluten sensitivity: review of literature on the main cognitive impairments, the imaging and the effect of gluten free diet., Acta Neurol Belg, 2018, 118, 1, 21–27, 29247390, 10.1007/s13760-017-0870-z, Review,

Pathophysiology

File:Alzheimer dementia (3) presenile onset.jpg|thumb|Histopathologic image of senile plaques seen in the cerebral cortex of a person with Alzheimer's disease of presenile onset. Silver impregnation.]]

Neuropathology

Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss 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.JOURNAL, Wenk GL, Neuropathologic changes in Alzheimer's disease, The Journal of Clinical Psychiatry, 64 Suppl 9, 7–10, 2003, 12934968, Degeneration is also present in brainstem nuclei like the locus coeruleus.JOURNAL, Braak H, Del Tredici K, Where, when, and in what form does sporadic Alzheimer's disease begin?, Current Opinion in Neurology, 25, 6, 708–14, December 2012, 23160422, 10.1097/WCO.0b013e32835a3432, Studies using MRI and PET have documented reductions in the size of specific brain regions in people with AD as they progressed from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from healthy older adults.JOURNAL, Desikan RS, Cabral HJ, Hess CP, Dillon WP, Glastonbury CM, Weiner MW, Schmansky NJ, Greve DN, Salat DH, Buckner RL, Fischl B, Automated MRI measures identify individuals with mild cognitive impairment and Alzheimer's disease, Brain, 132, Pt 8, 2048–57, August 2009, 19460794, 2714061, 10.1093/brain/awp123, JOURNAL, Moan R, MRI Software Accurately IDs Preclinical Alzheimer's Disease, Diagnostic Imaging, 20 July 2009,weblink 7 January 2013,weblink 16 May 2016, yes, Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD.JOURNAL, Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J, The importance of neuritic plaques and tangles to the development and evolution of AD, Neurology, 62, 11, 1984–9, June 2004, 15184601, 10.1212/01.WNL.0000129697.01779.0A, Plaques are dense, mostly insoluble deposits of beta-amyloid peptide and cellular material outside and around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves. Although many older individuals develop some plaques and tangles as a consequence of ageing, the brains of people with AD have a greater number of them in specific brain regions such as the temporal lobe.JOURNAL, Bouras C, Hof PR, Giannakopoulos P, Michel JP, Morrison JH, 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, Cerebral Cortex, 4, 2, 138–50, 1994, 8038565, 10.1093/cercor/4.2.138, Lewy bodies are not rare in the brains of people with AD.JOURNAL, Kotzbauer PT, Trojanowsk JQ, Lee VM, Lewy body pathology in Alzheimer's disease, Journal of Molecular Neuroscience, 17, 2, 225–32, October 2001, 11816795, 10.1385/JMN:17:2:225,

Biochemistry

{{Multiple image|footer = Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of senile plaques in AD.|image1 = Amyloid 01big1.jpg|image2 = Amyloid 02big1.jpg|image3 = Amyloid 03big1.jpg}}Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by plaque accumulation of abnormally folded amyloid beta protein and tau protein in the brain.JOURNAL, Hashimoto M, Rockenstein E, Crews L, Masliah E, Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases, Neuromolecular Medicine, 4, 1–2, 21–36, 2003, 14528050, 10.1385/NMM:4:1-2:21, Plaques are made up of small peptides, 39–43 amino acids in length, called amyloid beta (Aβ). Aβ is a fragment from the larger amyloid precursor protein (APP). APP is a transmembrane protein that penetrates through the neuron's membrane. APP is critical to neuron growth, survival, and post-injury repair.JOURNAL, Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J, Synapse formation and function is modulated by the amyloid precursor protein, The Journal of Neuroscience, 26, 27, 7212–21, July 2006, 16822978, 10.1523/JNEUROSCI.1450-06.2006, JOURNAL, Turner PR, O'Connor K, Tate WP, Abraham WC, Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory, Progress in Neurobiology, 70, 1, 1–32, May 2003, 12927332, 10.1016/S0301-0082(03)00089-3, In Alzheimer's disease, gamma secretase and beta secretase act together in a proteolytic process which causes APP to be divided into smaller fragments.JOURNAL, Hooper NM, Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein, Biochemical Society Transactions, 33, Pt 2, 335–8, April 2005, 15787600, 10.1042/BST0330335, One of these fragments gives rise to fibrils of amyloid beta, which then form clumps that deposit outside neurons in dense formations known as senile plaques.JOURNAL, Ohnishi S, Takano K, Amyloid fibrils from the viewpoint of protein folding, Cellular and Molecular Life Sciences, 61, 5, 511–524, March 2004, 15004691, 10.1007/s00018-003-3264-8, AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilises the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.JOURNAL, Hernández F, Avila J, Tauopathies, Cellular and Molecular Life Sciences, 64, 17, 2219–33, September 2007, 17604998, 10.1007/s00018-007-7220-x, Pathogenic tau can also cause neuronal death through transposable element dysregulation.JOURNAL, Sun W, Samimi H, Gamez M, Zare H, Frost B, Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies, Nature Neuroscience, 21, 8, 1038–1048, August 2018, 30038280, 6095477, 10.1038/s41593-018-0194-1,

Disease mechanism

Exactly how disturbances of production and aggregation of the beta-amyloid peptide give rise to the pathology of AD is not known.JOURNAL, Van Broeck B, Van Broeckhoven C, Kumar-Singh S, Current insights into molecular mechanisms of Alzheimer disease and their implications for therapeutic approaches, Neuro-Degenerative Diseases, 4, 5, 349–65, 2007, 17622778, 10.1159/000105156, JOURNAL, Huang Y, Mucke L, Alzheimer mechanisms and therapeutic strategies, Cell, 148, 6, 1204–22, March 2012, 22424230, 3319071, 10.1016/j.cell.2012.02.040, The amyloid hypothesis traditionally points to the accumulation of beta-amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces programmed cell death (apoptosis).JOURNAL, Yankner BA, Duffy LK, Kirschner DA, Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides, Science, 250, 4978, 279–82, October 1990, 2218531, 10.1126/science.2218531, 1990Sci...250..279Y, It is also known that Aβ selectively builds up in the mitochondria in the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilisation of glucose by neurons.JOURNAL, Chen X, Yan SD, Mitochondrial Abeta: a potential cause of metabolic dysfunction in Alzheimer's disease, IUBMB Life, 58, 12, 686–94, December 2006, 17424907, 10.1080/15216540601047767, Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer's disease. Inflammation is a general marker of tissue damage in any disease, and may be either secondary to tissue damage in AD or a marker of an immunological response.JOURNAL, Greig NH, Mattson MP, Perry T, Chan SL, Giordano T, Sambamurti K, Rogers JT, Ovadia H, Lahiri DK, New therapeutic strategies and drug candidates for neurodegenerative diseases: p53 and TNF-alpha inhibitors, and GLP-1 receptor agonists, Annals of the New York Academy of Sciences, 1035, 290–315, December 2004, 15681814, 10.1196/annals.1332.018, There is increasing evidence of a strong interaction between the neurons and the immunological mechanisms in the brain. Obesity and systemic inflammation may interfere with immunological processes which promote disease progression.JOURNAL, Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, Kummer MP, 6, Neuroinflammation in Alzheimer's disease, The Lancet. Neurology, 14, 4, 388–405, April 2015, 25792098, 5909703, 10.1016/S1474-4422(15)70016-5,weblink Nicolas Bazan, Alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as the brain-derived neurotrophic factor (BDNF) have been described in AD.JOURNAL, Tapia-Arancibia L, Aliaga E, Silhol M, Arancibia S, New insights into brain BDNF function in normal aging and Alzheimer disease, Brain Research Reviews, 59, 1, 201–20, November 2008, 18708092, 10.1016/j.brainresrev.2008.07.007, JOURNAL, Schindowski K, Belarbi K, Buée L, Neurotrophic factors in Alzheimer's disease: role of axonal transport, Genes, Brain, and Behavior, 7, Suppl 1, 43–56, February 2008, 18184369, 2228393, 10.1111/j.1601-183X.2007.00378.x,

Diagnosis

File:PET Alzheimer.jpg|thumb|left|upright|PET scan of the brain of a person with AD showing a loss of function in the temporal lobe]]Alzheimer's disease is usually diagnosed based on the person's medical history, history from relatives, and behavioural observations. The presence of characteristic neurological and neuropsychological features and the absence of alternative conditions is supportive.JOURNAL, Mendez MF, The accurate diagnosis of early-onset dementia, International Journal of Psychiatry in Medicine, 36, 4, 401–12, 2006, 17407994, 10.2190/Q6J4-R143-P630-KW41, JOURNAL, Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J, Therapeutic approaches to Alzheimer's disease, Brain, 129, Pt 11, 2840–55, November 2006, 17018549, 10.1093/brain/awl280, Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single-photon emission computed tomography (SPECT) or positron emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of dementia.BOOK,weblink Dementia: Quick Reference Guide, (UK) National Institute for Health and Clinical Excellence, London, November 2006, 978-1-84629-312-2, 22 February 2008,weblink" title="web.archive.org/web/20080227161412weblink">weblink 27 February 2008, yes, Moreover, it may predict conversion from prodromal stages (mild cognitive impairment) to Alzheimer's disease.JOURNAL, Schroeter ML, Stein T, Maslowski N, Neumann J, Neural correlates of Alzheimer's disease and mild cognitive impairment: a systematic and quantitative meta-analysis involving 1351 patients, NeuroImage, 47, 4, 1196–206, October 2009, 19463961, 2730171, 10.1016/j.neuroimage.2009.05.037, Assessment of intellectual functioning including memory testing can further characterise the state of the disease. Medical organisations have created diagnostic criteria to ease and standardise the diagnostic process for practising physicians. The diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be examined histologically.JOURNAL, McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM, 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, Neurology, 34, 7, 939–44, July 1984, 6610841, 10.1212/wnl.34.7.939,

Criteria

The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA, now known as the Alzheimer's Association) established the most commonly used NINCDS-ADRDA Alzheimer's Criteria for diagnosis in 1984, extensively updated in 2007.JOURNAL, 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, 6, Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria, The Lancet. Neurology, 6, 8, 734–46, August 2007, 17616482, 10.1016/S1474-4422(07)70178-3, These criteria require that the presence of cognitive impairment, and a suspected dementia syndrome, be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD. A histopathologic confirmation including a microscopic examination of brain tissue is required for a definitive diagnosis. Good statistical reliability and validity have been shown between the diagnostic criteria and definitive histopathological confirmation.JOURNAL, Blacker D, Albert MS, Bassett SS, Go RC, Harrell LE, Folstein MF, Reliability and validity of NINCDS-ADRDA criteria for Alzheimer's disease. The National Institute of Mental Health Genetics Initiative, Archives of Neurology, 51, 12, 1198–204, December 1994, 7986174, 10.1001/archneur.1994.00540240042014, Eight intellectual domains are most commonly impaired in AD—memory, language, perceptual skills, attention, motor skills, orientation, problem solving and executive functional abilities. These domains are equivalent to the NINCDS-ADRDA Alzheimer's Criteria as listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) published by the American Psychiatric Association.BOOK, American Psychiatric Association, Diagnostic and statistical manual of mental disorders: DSM-IV-TR, 4th Edition Text Revision, American Psychiatric Association, 2000, Washington, DC, 978-0-89042-025-6, JOURNAL, Ito N, [Clinical aspects of dementia], Japanese, [Hokkaido Igaku Zasshi] the Hokkaido Journal of Medical Science, 71, 3, 315–20, May 1996, 8752526,

Techniques

File:InterlockingPentagons.svg|right|thumb|Neuropsychological screening testscreening testNeuropsychological tests such as the mini–mental state examination (MMSE) are widely used to evaluate the cognitive impairments needed for diagnosis. More comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease.JOURNAL, Tombaugh TN, McIntyre NJ, The mini-mental state examination: a comprehensive review, Journal of the American Geriatrics Society, 40, 9, 922–35, September 1992, 1512391, 10.1111/j.1532-5415.1992.tb01992.x, JOURNAL, Pasquier F, Early diagnosis of dementia: neuropsychology, Journal of Neurology, 246, 1, 6–15, January 1999, 9987708, 10.1007/s004150050299, Neurological examination in early AD will usually provide normal results, except for obvious cognitive impairment, which may not differ from that resulting from other diseases processes, including other causes of dementia.Further neurological examinations are crucial in the differential diagnosis of AD and other diseases. Interviews with family members are also utilised 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 person's mental function.JOURNAL, Harvey PD, Moriarty PJ, Kleinman L, Coyne K, Sadowsky CH, Chen M, Mirski DF, The validation of a caregiver assessment of dementia: the Dementia Severity Scale, Alzheimer Disease and Associated Disorders, 19, 4, 186–94, 2005, 16327345, 10.1097/01.wad.0000189034.43203.60, A caregiver's viewpoint is particularly important, since a person with AD is commonly unaware of his own deficits.JOURNAL, Antoine C, Antoine P, Guermonprez P, Frigard B, [Awareness of deficits and anosognosia in Alzheimer's disease], French, L'Encephale, 30, 6, 570–7, 2004, 15738860, 10.1016/S0013-7006(04)95472-3, Many times, families also have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician.JOURNAL, Cruz VT, Pais J, Teixeira A, Nunes B, [The initial symptoms of Alzheimer disease: caregiver perception], Portuguese, Acta Medica Portuguesa, 17, 6, 435–44, 2004, 16197855, Supplemental testing provides extra information on some features of the disease or is used to rule out other diagnoses. Blood tests can identify other causes for dementia than AD—causes which may, in rare cases, be reversible.JOURNAL, Clarfield AM, The decreasing prevalence of reversible dementias: an updated meta-analysis, Archives of Internal Medicine, 163, 18, 2219–29, October 2003, 14557220, 10.1001/archinte.163.18.2219, It is common to perform thyroid function tests, assess B12, rule out syphilis, rule out metabolic problems (including tests for kidney function, electrolyte levels and for diabetes), assess levels of heavy metals (e.g. lead, mercury) and anaemia. (It is also necessary to rule out delirium).Psychological tests for depression are employed, since depression can either be concurrent with AD (see Depression of Alzheimer disease), an early sign of cognitive impairment,JOURNAL, Sun X, Steffens DC, Au R, Folstein M, Summergrad P, Yee J, Rosenberg I, Mwamburi DM, Qiu WQ, Amyloid-associated depression: a prodromal depression of Alzheimer disease?, Archives of General Psychiatry, 65, 5, 542–50, May 2008, 18458206, 3042807, 10.1001/archpsyc.65.5.542, dmy-all, or even the cause.JOURNAL, Geldmacher DS, Whitehouse PJ, Differential diagnosis of Alzheimer's disease, Neurology, 48, 5 Suppl 6, S2–9, May 1997, 9153154, 10.1212/WNL.48.5_Suppl_6.2S, JOURNAL, Potter GG, Steffens DC, Contribution of depression to cognitive impairment and dementia in older adults, The Neurologist, 13, 3, 105–17, May 2007, 17495754, 10.1097/01.nrl.0000252947.15389.a9, Due to low accuracy, the C-PIB-PET scan is not recommended to be used as an early diagnostic tool or for predicting the development of Alzheimer's disease when people show signs of mild cognitive impairment (MCI).JOURNAL, Zhang S, Smailagic N, Hyde C, Noel-Storr AH, Takwoingi Y, McShane R, Feng J, (11)C-PIB-PET for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI), The Cochrane Database of Systematic Reviews, 7, CD010386, July 2014, 25052054, 10.1002/14651858.CD010386.pub2, The use of ¹⁸F-FDG PET scans, as a single test, to identify people who may develop Alzheimer's disease is also not supported by evidence.JOURNAL, Smailagic N, Vacante M, Hyde C, Martin S, Ukoumunne O, Sachpekidis C, ¹⁸F-FDG PET for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI), The Cochrane Database of Systematic Reviews, 1, CD010632, January 2015, 25629415, 10.1002/14651858.CD010632.pub2,

Prevention

File:Honoré Daumier 032.jpg|right|thumb|Intellectual activities such as playing chesschessThere is no definitive evidence to support that any particular measure is effective in preventing AD.JOURNAL, Hsu D, Marshall GA, Primary and Secondary Prevention Trials in Alzheimer Disease: Looking Back, Moving Forward, Current Alzheimer Research, 14, 4, 426–440, 2017, 27697063, 5329133, 10.2174/1567205013666160930112125,
Global studies of measures to prevent or delay the onset of AD have often produced inconsistent results.
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 these factors can help to prevent AD.

Medication

Although cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD,JOURNAL, Patterson C, Feightner JW, Garcia A, Hsiung GY, MacKnight C, Sadovnick AD, Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease, CMAJ, 178, 5, 548–56, February 2008, 18299540, 2244657, 10.1503/cmaj.070796, JOURNAL, Rosendorff C, Beeri MS, Silverman JM, Cardiovascular risk factors for Alzheimer's disease, The American Journal of Geriatric Cardiology, 16, 3, 143–9, 2007, 17483665, 10.1111/j.1076-7460.2007.06696.x, statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease.JOURNAL, Reiss AB, Wirkowski E, Role of HMG-CoA reductase inhibitors in neurological disorders : progress to date, Drugs, 67, 15, 2111–20, 2007, 17927279, 10.2165/00003495-200767150-00001, JOURNAL, Kuller LH, Statins and dementia, Current Atherosclerosis Reports, 9, 2, 154–61, August 2007, 17877925, 10.1007/s11883-007-0012-9, JOURNAL, McGuinness B, Craig D, Bullock R, Malouf R, Passmore P, Statins for the treatment of dementia, The Cochrane Database of Systematic Reviews, 7, 7, CD007514, July 2014, 25004278, 10.1002/14651858.CD007514.pub3, Long-term usage of non-steroidal anti-inflammatory drugs (NSAIDs) were thought in 2007 to be associated with a reduced likelihood of developing AD.BOOK, Szekely CA, Town T, Zandi PP, NSAIDs for the chemoprevention of Alzheimer's disease, Sub-Cellular Biochemistry, 42, 229–48, 2007, 17612054, 10.1007/1-4020-5688-5_11, 978-1-4020-5687-1, Subcellular Biochemistry, Evidence also suggested the notion that NSAIDs could reduce inflammation related to amyloid plaques, but trials were suspended due to high adverse events. No prevention trial has been completed. They do not appear to be useful as a treatment, but {{as of|2011|lc=y}} were thought to be candidates as presymptomatic preventatives.JOURNAL, Hoozemans JJ, Veerhuis R, Rozemuller JM, Eikelenboom P, Soothing the inflamed brain: effect of non-steroidal anti-inflammatory drugs on Alzheimer's disease pathology, CNS & Neurological Disorders Drug Targets, 10, 1, 57–67, February 2011, 21143138, 10.2174/187152711794488665, Hormone replacement therapy in menopause, although previously used, may increase the risk of dementia.JOURNAL, Marjoribanks J, Farquhar C, Roberts H, Lethaby A, Lee J, Long-term hormone therapy for perimenopausal and postmenopausal women, The Cochrane Database of Systematic Reviews, 1, CD004143, January 2017, 28093732, 10.1002/14651858.CD004143.pub5,

Lifestyle

People who engage in intellectual activities such as reading, playing board games, completing crossword puzzles, playing musical instruments, or regular social interaction show a reduced risk for Alzheimer's disease.JOURNAL, Stern Y, Cognitive reserve and Alzheimer disease, Alzheimer Disease and Associated Disorders, 20, 3 Suppl 2, S69–74, July 2006, 16917199, 10.1097/01.wad.0000213815.20177.19, This is compatible with the cognitive reserve theory, which states that some life experiences result in more efficient neural functioning providing the individual a cognitive reserve that delays the onset of dementia manifestations. Education delays the onset of AD syndrome without changing the duration of the disease.JOURNAL, Paradise M, Cooper C, Livingston G, Systematic review of the effect of education on survival in Alzheimer's disease, International Psychogeriatrics, 21, 1, 25–32, February 2009, 19026089, 10.1017/S1041610208008053, Learning a second language even later in life seems to delay getting Alzheimer disease.NEWS,weblink The Denver Post, Associated Press, Speaking 2 Languages May Delay Getting Alzheimer's, 19 February 2011, Lauran, Neergaard, no,weblink" title="web.archive.org/web/20140502013633weblink">weblink 2 May 2014, Physical activity is also associated with a reduced risk of AD. Physical exercise is associated with decreased rate of dementia.JOURNAL, Cheng ST, Cognitive Reserve and the Prevention of Dementia: the Role of Physical and Cognitive Activities, Current Psychiatry Reports, 18, 9, 85, September 2016, 27481112, 4969323, 10.1007/s11920-016-0721-2, Physical exercise is also effective in reducing symptom severity in those with Alzheimer's disease.JOURNAL, Farina N, Rusted J, Tabet N, The effect of exercise interventions on cognitive outcome in Alzheimer's disease: a systematic review, International Psychogeriatrics, 26, 1, 9–18, January 2014, 23962667, 10.1017/S1041610213001385,weblink

Diet

People who maintain a healthy, Japanese, or Mediterranean diet have a reduced risk of AD.JOURNAL, Hu N, Yu JT, Tan L, Wang YL, Sun L, Tan L, Nutrition and the risk of Alzheimer's disease, BioMed Research International, 2013, 1–12, 2013, 23865055, 3705810, 10.1155/2013/524820, Review, A Mediterranean diet may improve outcomes in those with the disease.JOURNAL, Solfrizzi V, Panza F, Frisardi V, Seripa D, Logroscino G, Imbimbo BP, Pilotto A, Diet and Alzheimer's disease risk factors or prevention: the current evidence, Expert Review of Neurotherapeutics, 11, 5, 677–708, May 2011, 21539488, 10.1586/ern.11.56, Those who eat a diet high in saturated fats and simple carbohydrates (mono- and disaccharide) have a higher risk.JOURNAL, Kanoski SE, Davidson TL, Western diet consumption and cognitive impairment: links to hippocampal dysfunction and obesity, Physiology & Behavior, 103, 1, 59–68, April 2011, 21167850, 3056912, 10.1016/j.physbeh.2010.12.003, Review, The Mediterranean diet's beneficial cardiovascular effect has been proposed as the mechanism of action.JOURNAL, Solfrizzi V, Capurso C, D'Introno A, Colacicco AM, Santamato A, Ranieri M, Fiore P, Capurso A, Panza F, Lifestyle-related factors in predementia and dementia syndromes, Expert Review of Neurotherapeutics, 8, 1, 133–58, January 2008, 18088206, 10.1586/14737175.8.1.133, Conclusions on dietary components have at times been difficult to ascertain as results have differed between population-based studies and randomised controlled trials. There is limited evidence that light to moderate use of alcohol, particularly red wine, is associated with lower risk of AD. There is tentative evidence that caffeine may be protective.JOURNAL, Santos C, Costa J, Santos J, Vaz-Carneiro A, Lunet N, Caffeine intake and dementia: systematic review and meta-analysis, Journal of Alzheimer's Disease, 20 Suppl 1, S187–204, 2010, 20182026, 10.3233/JAD-2010-091387, A number of foods high in flavonoids such as cocoa, red wine, and tea may decrease the risk of AD.JOURNAL, Nehlig A, The neuroprotective effects of cocoa flavanol and its influence on cognitive performance, British Journal of Clinical Pharmacology, 75, 3, 716–27, March 2013, 22775434, 3575938, 10.1111/j.1365-2125.2012.04378.x, Review, JOURNAL, Stoclet JC, Schini-Kerth V, [Dietary flavonoids and human health], Annales Pharmaceutiques Francaises, 69, 2, 78–90, March 2011, 21440100, 10.1016/j.pharma.2010.11.004, Reviews on the use of vitamins and minerals have not found enough consistent evidence to recommend them. This includes vitamin A,JOURNAL, Ono K, Yamada M, Vitamin A and Alzheimer's disease, Geriatrics & Gerontology International, 12, 2, 180–8, April 2012, 22221326, 10.1111/j.1447-0594.2011.00786.x, Review, JOURNAL, Lerner AJ, Gustaw-Rothenberg K, Smyth S, Casadesus G, Retinoids for treatment of Alzheimer's disease, BioFactors, 38, 2, 84–9, March–April 2012, 22419567, 10.1002/biof.196, C,JOURNAL, Heo JH, Lee KM, The possible role of antioxidant vitamin C in Alzheimer's disease treatment and prevention, American Journal of Alzheimer's Disease and Other Dementias, 28, 2, 120–5, March 2013, 23307795, 10.1177/1533317512473193, Review, JOURNAL, Boothby LA, Doering PL, Vitamin C and vitamin E for Alzheimer's disease, The Annals of Pharmacotherapy, 39, 12, 2073–80, December 2005, 16227450, 10.1345/aph.1E495, the alpha-tocopherol form of vitamin E,JOURNAL, Farina N, Llewellyn D, Isaac MG, Tabet N, Vitamin E for Alzheimer's dementia and mild cognitive impairment, The Cochrane Database of Systematic Reviews, 4, CD002854, April 2017, 28418065, 10.1002/14651858.CD002854.pub5, selenium,JOURNAL, Loef M, Schrauzer GN, Walach H, Selenium and Alzheimer's disease: a systematic review, Journal of Alzheimer's Disease, 26, 1, 81–104, 2011, 21593562, 10.3233/JAD-2011-110414, Review, zinc,JOURNAL, Loef M, von Stillfried N, Walach H, Zinc diet and Alzheimer's disease: a systematic review, Nutritional Neuroscience, 15, 5, 2–12, September 2012, 22583839, 10.1179/1476830512Y.0000000010, Review, JOURNAL, Avan A, Hoogenraad TU, Zinc and Copper in Alzheimer's Disease, Journal of Alzheimer's Disease, 46, 1, 89–92, 2015, 25835420, 10.3233/JAD-150186, Review, and folic acid with or without vitamin B12.JOURNAL, Malouf R, Grimley Evans J, Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people, The Cochrane Database of Systematic Reviews, 4, CD004514, October 2008, 18843658, 10.1002/14651858.CD004514.pub2, Evidence from one randomized controlled trial indicated that the alpha-tocopherol form of vitamin E may slow cognitive decline, this evidence was judged to be "moderate" in quality. Trials examining folic acid (B9) and other B vitamins failed to show any significant association with cognitive decline.JOURNAL, Wald DS, Kasturiratne A, Simmonds M, Effect of folic acid, with or without other B vitamins, on cognitive decline: meta-analysis of randomized trials, The American Journal of Medicine, 123, 6, 522–527.e2, June 2010, 20569758, 10.1016/j.amjmed.2010.01.017, Omega-3 fatty acid supplements from plants and fish, and dietary docosahexaenoic acid (DHA), do not appear to benefit people with mild to moderate Alzheimer's disease.JOURNAL, Cunnane SC, Chouinard-Watkins R, Castellano CA, Barberger-Gateau P, Docosahexaenoic acid homeostasis, brain aging and Alzheimer's disease: Can we reconcile the evidence?, Prostaglandins, Leukotrienes, and Essential Fatty Acids, 88, 1, 61–70, January 2013, 22575581, 10.1016/j.plefa.2012.04.006, JOURNAL, Burckhardt M, Herke M, Wustmann T, Watzke S, Langer G, Fink A, Omega-3 fatty acids for the treatment of dementia, The Cochrane Database of Systematic Reviews, 4, CD009002, April 2016, 27063583, 10.1002/14651858.CD009002.pub3, Curcumin {{as of|2010|lc=y}} had not shown benefit in people even though there is tentative evidence in animals.JOURNAL, Hamaguchi T, Ono K, Yamada M, REVIEW: Curcumin and Alzheimer's disease, CNS Neuroscience & Therapeutics, 16, 5, 285–97, October 2010, 20406252, 10.1111/j.1755-5949.2010.00147.x, review, There was inconsistent and unconvincing evidence that ginkgo has any positive effect on cognitive impairment and dementia.JOURNAL, Birks J, Grimley Evans J, Ginkgo biloba for cognitive impairment and dementia, The Cochrane Database of Systematic Reviews, 1, CD003120, January 2009, 19160216, 10.1002/14651858.CD003120.pub3, {{as of|2008}} there was no concrete evidence that cannabinoids are effective in improving the symptoms of AD or dementia;JOURNAL, Krishnan S, Cairns R, Howard R, Cannabinoids for the treatment of dementia, The Cochrane Database of Systematic Reviews, 2, CD007204, April 2009, 19370677, 10.1002/14651858.CD007204.pub2, Krishnan, Sarada, however, some research into endocannabinoids looked promising.JOURNAL, Bilkei-Gorzo A, The endocannabinoid system in normal and pathological brain ageing, Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 367, 1607, 3326–41, December 2012, 23108550, 3481530, 10.1098/rstb.2011.0388,

Management

There is no cure for Alzheimer's disease; available treatments offer relatively small symptomatic benefit but remain palliative in nature. Current treatments can be divided into pharmaceutical, psychosocial and caregiving.

Medications

File:Donepezil 1EVE.png|right|thumb|Three-dimensional molecular model of donepezil, an acetylcholinesterase inhibitoracetylcholinesterase inhibitorFile:Memantine.svg|right|thumb|upright|Molecular structure of memantinememantineFive medications are currently used to treat the cognitive problems of AD: four are acetylcholinesterase inhibitors (tacrine, rivastigmine, galantamine and donepezil) and the other (memantine) is an NMDA receptor antagonist. The benefit from their use is small.JOURNAL, Commission de la transparence, Drugs for Alzheimer's disease: best avoided. No therapeutic advantage, Prescrire International, 21, 128, 150, June 2012, 22822592, Drugs for Alzheimer's disease: best avoided. No therapeutic advantage, JOURNAL, Birks JS, Grimley Evans J, Rivastigmine for Alzheimer's disease, The Cochrane Database of Systematic Reviews, 4, CD001191, April 2015, 25858345, 10.1002/14651858.CD001191.pub3, John Grimley Evans, No medication has been clearly shown to delay or halt the progression of the disease.Reduction in the activity of the cholinergic neurons is a well-known feature of Alzheimer's disease.JOURNAL, Geula C, Mesulam MM, Cholinesterases and the pathology of Alzheimer disease, Alzheimer Disease and Associated Disorders, 9 Suppl 2, 23–8, 1995, 8534419, 10.1097/00002093-199501002-00005, Acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (ACh) is broken down, thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the death of cholinergic neurons.JOURNAL, Stahl SM, The new cholinesterase inhibitors for Alzheimer's disease, Part 2: illustrating their mechanisms of action, The Journal of Clinical Psychiatry, 61, 11, 813–4, November 2000, 11105732, 10.4088/JCP.v61n1101, There is evidence for the efficacy of these medications in mild to moderate Alzheimer's disease,JOURNAL, Birks J, Cholinesterase inhibitors for Alzheimer's disease, The Cochrane Database of Systematic Reviews, 1, CD005593, January 2006, 16437532, 10.1002/14651858.CD005593, Birks, Jacqueline, JOURNAL, Birks JS, Harvey RJ, Donepezil for dementia due to Alzheimer's disease, The Cochrane Database of Systematic Reviews, 6, CD001190, June 2018, 29923184, 10.1002/14651858.CD001190.pub3, and some evidence for their use in the advanced stage. The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of AD.JOURNAL, Raschetti R, Albanese E, Vanacore N, Maggini M, Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials, PLoS Medicine, 4, 11, e338, November 2007, 18044984, 2082649, 10.1371/journal.pmed.0040338, The most common side effects are nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately 10–20% of users, are mild to moderate in severity, and can be managed by slowly adjusting medication doses.BOOK, al.], edited by Brian K. Alldredge ... [et, Applied therapeutics : the clinical use of drugs, 2013, Wolters Kluwer Health/Lippincott Williams & Wilkins, Baltimore, 978-1609137137, 2385, 10th, Less common secondary effects include muscle cramps, decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid production.Glutamate is an 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 receptors. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as Parkinson's disease and multiple sclerosis.JOURNAL, Lipton SA, Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond, Nature Reviews. Drug Discovery, 5, 2, 160–70, February 2006, 16424917, 10.1038/nrd1958, Memantine is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA receptors and inhibiting their overstimulation by glutamate.WEB,weblink Memantine, 3 February 2010, 4 January 2004, US National Library of Medicine (Medline),weblink 22 February 2010, no, Memantine has been shown to have a small benefit in the treatment of moderate to severe Alzheimer's disease.JOURNAL, McShane R, Westby MJ, Roberts E, Minakaran N, Schneider L, Farrimond LE, Maayan N, Ware J, Debarros J, Memantine for dementia, The Cochrane Database of Systematic Reviews, 3, CD003154, May 2019, 30891742, 10.1002/14651858.CD003154.pub6, Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue.WEB,weblink Namenda prescribing information, 19 February 2008, Forest Pharmaceuticals,weblink" title="web.archive.org/web/20080227161413weblink">weblink 27 February 2008, yes, (primary source) The combination of memantine and donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".JOURNAL, Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, Booker L, Oremus M, Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline, Annals of Internal Medicine, 148, 5, 379–97, March 2008, 18316756, 10.7326/0003-4819-148-5-200803040-00009, Atypical antipsychotics are modestly useful in reducing aggression and psychosis in people with Alzheimer's disease, but their advantages are offset by serious adverse effects, such as stroke, movement difficulties or cognitive decline.JOURNAL, Ballard C, Waite J, The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease, The Cochrane Database of Systematic Reviews, 1, CD003476, January 2006, 16437455, 10.1002/14651858.CD003476.pub2, Ballard, Clive G, When used in the long-term, they have been shown to associate with increased mortality.JOURNAL, Ballard C, Hanney ML, Theodoulou M, Douglas S, McShane R, Kossakowski K, Gill R, Juszczak E, Yu LM, Jacoby R, The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial, The Lancet. Neurology, 8, 2, 151–7, February 2009, 19138567, 10.1016/S1474-4422(08)70295-3,weblink Stopping antipsychotic use in this group of people appears to be safe.JOURNAL, Declercq T, Petrovic M, Azermai M, Vander Stichele R, De Sutter AI, van Driel ML, Christiaens T, Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia, The Cochrane Database of Systematic Reviews, 3, 3, CD007726, March 2013, 23543555, 10.1002/14651858.CD007726.pub2, 1854/LU-3109108, Huperzine A while promising, requires further evidence before its use can be recommended.JOURNAL, Li J, Wu HM, Zhou RL, Liu GJ, Dong BR, Huperzine A for Alzheimer's disease, The Cochrane Database of Systematic Reviews, 2, CD005592, April 2008, 18425924, 10.1002/14651858.CD005592.pub2,

Psychosocial intervention

Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behaviour-, emotion-, cognition- or stimulation-oriented approaches. Research on efficacy is unavailable and rarely specific to AD, focusing instead on dementia in general.JOURNAL, Rabins PV, Blacker D, Rovner BW, Rummans T, Schneider LS, Tariot PN, Blass DM, McIntyre JS, Charles SC, Anzia DJ, Cook IA, Finnerty MT, Johnson BR, Nininger JE, Schneidman B, Summergrad P, Woods SM, Berger J, Cross CD, Brandt HA, Margolis PM, Shemo JP, Blinder BJ, Duncan DL, Barnovitz MA, Carino AJ, Freyberg ZZ, Gray SH, Tonnu T, Kunkle R, Albert AB, Craig TJ, Regier DA, Fochtmann LJ, 6, American Psychiatric Association practice guideline for the treatment of patients with Alzheimer's disease and other dementias. Second edition, The American Journal of Psychiatry, 164, 12 Suppl, 5–56, December 2007, 18340692, Steering Committee on Practice Guidelines, Behavioural interventions attempt to identify and reduce the antecedents and consequences of problem behaviours. This approach has not shown success in improving overall functioning,JOURNAL, Bottino CM, Carvalho IA, Alvarez AM, Avila R, Zukauskas PR, Bustamante SE, Andrade FC, Hototian SR, Saffi F, Câmargo CH, 6, Cognitive rehabilitation combined with drug treatment in Alzheimer's disease patients: a pilot study, Clinical Rehabilitation, 19, 8, 861–9, December 2005, 16323385, 10.1191/0269215505cr911oa, but can help to reduce some specific problem behaviours, such as incontinence.JOURNAL, Doody RS, Stevens JC, Beck C, Dubinsky RM, Kaye JA, Gwyther L, Mohs RC, Thal LJ, Whitehouse PJ, DeKosky ST, Cummings JL, 6, Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology, Neurology, 56, 9, 1154–66, May 2001, 11342679, 10.1212/WNL.56.9.1154, There is a lack of high quality data on the effectiveness of these techniques in other behaviour problems such as wandering.JOURNAL, Hermans DG, Htay UH, McShane R, Non-pharmacological interventions for wandering of people with dementia in the domestic setting, The Cochrane Database of Systematic Reviews, 1, CD005994, January 2007, 17253573, 10.1002/14651858.CD005994.pub2, JOURNAL, Robinson L, Hutchings D, Dickinson HO, Corner L, Beyer F, Finch T, Hughes J, Vanoli A, Ballard C, Bond J, Effectiveness and acceptability of non-pharmacological interventions to reduce wandering in dementia: a systematic review, International Journal of Geriatric Psychiatry, 22, 1, 9–22, January 2007, 17096455, 10.1002/gps.1643, Music therapy is effective in reducing behavioural and psychological symptoms.JOURNAL, Abraha I, Rimland JM, Trotta FM, Dell'Aquila G, Cruz-Jentoft A, Petrovic M, Gudmundsson A, Soiza R, O'Mahony D, Guaita A, Cherubini A, Systematic review of systematic reviews of non-pharmacological interventions to treat behavioural disturbances in older patients with dementia. The SENATOR-OnTop series, BMJ Open, 7, 3, e012759, March 2017, 28302633, 5372076, 10.1136/bmjopen-2016-012759, Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration, also called snoezelen, and simulated presence therapy. A Cochrane review has found no evidence that this is effective.JOURNAL, Chung JC, Lai CK, Chung PM, French HP, Snoezelen for dementia, The Cochrane Database of Systematic Reviews, 4, CD003152, 2002, 12519587, 10.1002/14651858.CD003152, Supportive psychotherapy has received little or no formal scientific study, but some clinicians find it useful in helping mildly impaired people adjust to their illness. 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. A 2018 review of the effectiveness of RT found that effects were inconsistent, small in size and of doubtful clinical significance, and varied by setting.JOURNAL, Woods B, O'Philbin L, Farrell EM, Spector AE, Orrell M, Reminiscence therapy for dementia, The Cochrane Database of Systematic Reviews, 3, CD001120, March 2018, 29493789, 10.1002/14651858.CD001120.pub3,weblink Simulated presence therapy (SPT) is based on attachment theories and involves playing a recording with voices of the closest relatives of the person with Alzheimer's disease. There is partial evidence indicating that SPT may reduce challenging behaviours.JOURNAL, Zetteler J, Effectiveness of simulated presence therapy for individuals with dementia: a systematic review and meta-analysis, Aging & Mental Health, 12, 6, 779–85, November 2008, 19023729, 10.1080/13607860802380631, 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 senses. There is no evidence to support the usefulness of these therapies.JOURNAL, Neal M, Barton Wright P, Validation therapy for dementia, The Cochrane Database of Systematic Reviews, 3, CD001394, 2003, 12917907, 10.1002/14651858.CD001394, Neal, Martin, JOURNAL, Chung JC, Lai CK, Chung PM, French HP, Snoezelen for dementia, The Cochrane Database of Systematic Reviews, 4, CD003152, 2002, 12519587, 10.1002/14651858.CD003152, Chung, Jenny CC, (up to date as of 2009)The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining, is the reduction of cognitive deficits. Reality orientation consists in the presentation of information about time, place or person to ease the understanding of the person about its surroundings and his or her 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,JOURNAL, Spector A, Thorgrimsen L, Woods B, Royan L, Davies S, Butterworth M, Orrell M, Efficacy of an evidence-based cognitive stimulation therapy programme for people with dementia: randomised controlled trial, The British Journal of Psychiatry, 183, 3, 248–54, September 2003, 12948999, 10.1192/bjp.183.3.248, although in some studies these effects were transient and negative effects, such as frustration, have also been reported.Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind of recreational activities. Stimulation has modest support for improving behaviour, 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 change in the person's routine. The efficacy of non-invasive brain stimulation and invasive brain stimulation in AD remains uncertain.JOURNAL, Chang CH, Lane HY, Lin CH, Brain Stimulation in Alzheimer's Disease, Frontiers in Psychiatry, 9, 201, 2018, 29910746, 5992378, 10.3389/fpsyt.2018.00201, {{CC-notice|cc=by4|url=https://www.frontiersin.org/articles/10.3389/fpsyt.2018.00201/full|author(s)=Chun-Hung Chang, Hsien-Yuan Lane, and Chieh-Hsin Lin}}

Caregiving

{{further|Caregiving and dementia}}Since Alzheimer's has no cure and it gradually renders people incapable of tending for their own needs, caregiving is essentially the treatment and must be carefully managed over the course of the disease.During the early and moderate stages, modifications to the living environment and lifestyle can increase patient safety and reduce caretaker burden.JOURNAL, Gitlin LN, Corcoran M, Winter L, Boyce A, Hauck WW, A randomized, controlled trial of a home environmental intervention: effect on efficacy and upset in caregivers and on daily function of persons with dementia, The Gerontologist, 41, 1, 4–14, February 2001, 11220813, 10.1093/geront/41.1.4, JOURNAL, Gitlin LN, Hauck WW, Dennis MP, Winter L, Maintenance of effects of the home environmental skill-building program for family caregivers and individuals with Alzheimer's disease and related disorders, The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 60, 3, 368–74, March 2005, 15860476, 10.1093/gerona/60.3.368, Examples of such modifications are the adherence to simplified routines, the placing of safety locks, the labelling of household items to cue the person with the disease or the use of modified daily life objects.WEB,weblink Treating Behavioral and Psychiatric Symptoms, 2006, 25 September 2006, Alzheimer's Association,weblink" title="web.archive.org/web/20060925112503weblink">weblink 25 September 2006, JOURNAL, Dunne TE, Neargarder SA, Cipolloni PB, Cronin-Golomb A, Visual contrast enhances food and liquid intake in advanced Alzheimer's disease, Clinical Nutrition, 23, 4, 533–8, August 2004, 15297089, 10.1016/j.clnu.2003.09.015, If eating becomes problematic, food will need to be prepared in smaller pieces or even pureed.BOOK, Dudek, Susan G., vanc, Nutrition Essentials for Nursing Practice, Lippincott Williams & Wilkins, Hagerstown, Maryland, 2007, 360, 978-0-7817-6651-7,weblink 19 August 2008, When swallowing difficulties arise, the use of feeding tubes may be required. In such cases, the medical efficacy and ethics of continuing feeding is an important consideration of the caregivers and family members.JOURNAL, Dennehy C, Analysis of patients' rights: dementia and PEG insertion, British Journal of Nursing, 15, 1, 18–20, 2006, 16415742, 10.12968/bjon.2006.15.1.20303, JOURNAL, Chernoff R, Tube feeding patients with dementia, Nutrition in Clinical Practice, 21, 2, 142–6, April 2006, 16556924, 10.1177/0115426506021002142, The use of physical restraints is rarely indicated in any stage of the disease, although there are situations when they are necessary to prevent harm to the person with AD or their caregivers.As the disease progresses, different medical issues can appear, such as oral and dental disease, pressure ulcers, malnutrition, hygiene problems, or respiratory, skin, or eye infections. Careful management can prevent them, while professional treatment is needed when they do arise.JOURNAL, Gambassi G, Landi F, Lapane KL, Sgadari A, Mor V, Bernabei R, Predictors of mortality in patients with Alzheimer's disease living in nursing homes, Journal of Neurology, Neurosurgery, and Psychiatry, 67, 1, 59–65, July 1999, 10369823, 1736445, 10.1136/jnnp.67.1.59, Medical issues:
  • JOURNAL, Head B, Palliative care for persons with dementia, Home Healthcare Nurse, 21, 1, 53–60; quiz 61, January 2003, 12544465, 10.1097/00004045-200301000-00012,
  • JOURNAL, Friedlander AH, Norman DC, Mahler ME, Norman KM, Yagiela JA, Alzheimer's disease: psychopathology, medical management and dental implications, Journal of the American Dental Association, 137, 9, 1240–51, September 2006, 16946428, 10.14219/jada.archive.2006.0381


,
  • JOURNAL, Belmin J, Practical guidelines for the diagnosis and management of weight loss in Alzheimer's disease: a consensus from appropriateness ratings of a large expert panel, The Journal of Nutrition, Health & Aging, 11, 1, 33–7, 2007, 17315078,
  • JOURNAL, McCurry SM, Gibbons LE, Logsdon RG, Vitiello M, Teri L, Training caregivers to change the sleep hygiene practices of patients with dementia: the NITE-AD project, Journal of the American Geriatrics Society, 51, 10, 1455–60, October 2003, 14511168, 10.1046/j.1532-5415.2003.51466.x,
  • JOURNAL, Perls TT, Herget M, Higher respiratory infection rates on an Alzheimer's special care unit and successful intervention, Journal of the American Geriatrics Society, 43, 12, 1341–4, December 1995, 7490383, 10.1111/j.1532-5415.1995.tb06611.x, During the final stages of the disease, treatment is centred on relieving discomfort until death, often with the help of hospice.JOURNAL, Shega JW, Levin A, Hougham GW, Cox-Hayley D, Luchins D, Hanrahan P, Stocking C, Sachs GA, Palliative Excellence in Alzheimer Care Efforts (PEACE): a program description, Journal of Palliative Medicine, 6, 2, 315–20, April 2003, 12854952, 10.1089/109662103764978641,

Prognosis

File:Alzheimer and other dementias world map - DALY - WHO2004.svg|thumb|upright=1.2|#b3b3b3|No data}}{{legend|#ffff65|≤ 50}}{{legend|#fff200|50–70}}{{legend|#ffdc00|70–90}}{{legend|#ffc600|90–110}}{{legend|#ffb000|110–130}}{{legend|#ff9a00|130–150}}{{legend|#ff8400|150–170}}{{legend|#ff6e00|170–190}}{{legend|#ff5800|190–210}}{{legend|#ff4200|210–230}}{{legend|#ff2c00|230–250}}{{legend|#cb0000|≥ 250}}The early stages of Alzheimer's disease are difficult to diagnose. A definitive diagnosis is usually made once cognitive impairment compromises daily living activities, although the person may still be living independently. The symptoms will progress from mild cognitive problems, such as memory loss through increasing stages of cognitive and non-cognitive disturbances, eliminating any possibility of independent living, especially in the late stages of the disease.Life expectancy of people with AD is reduced.JOURNAL, Zanetti O, Solerte SB, Cantoni F, Life expectancy in Alzheimer's disease (AD), Archives of Gerontology and Geriatrics, 49 Suppl 1, 237–43, 2009, 19836639, 10.1016/j.archger.2009.09.035, Following diagnosis it typically ranges from three to ten years.Fewer than 3% of people live more than fourteen years.JOURNAL, Mölsä PK, Marttila RJ, Rinne UK, Long-term survival and predictors of mortality in Alzheimer's disease and multi-infarct dementia, Acta Neurologica Scandinavica, 91, 3, 159–64, March 1995, 7793228, 10.1111/j.1600-0404.1995.tb00426.x, Disease features significantly associated with reduced survival are an increased severity of cognitive impairment, decreased functional level, history of falls, and disturbances in the neurological examination. Other coincident diseases such as heart problems, diabetes or history of alcohol abuse are also related with shortened survival.JOURNAL, Bowen JD, Malter AD, Sheppard L, Kukull WA, McCormick WC, Teri L, Larson EB, Predictors of mortality in patients diagnosed with probable Alzheimer's disease, Neurology, 47, 2, 433–9, August 1996, 8757016, 10.1212/wnl.47.2.433, JOURNAL, Larson EB, Shadlen MF, Wang L, McCormick WC, Bowen JD, Teri L, Kukull WA, Survival after initial diagnosis of Alzheimer disease, Annals of Internal Medicine, 140, 7, 501–9, April 2004, 15068977, 10.7326/0003-4819-140-7-200404060-00008, JOURNAL, Jagger C, Clarke M, Stone A, Predictors of survival with Alzheimer's disease: a community-based study, Psychological Medicine, 25, 1, 171–7, January 1995, 7792352, 10.1017/S0033291700028191, While the earlier the age at onset the higher the total survival years, life expectancy is particularly reduced when compared to the healthy population among those who are younger.JOURNAL, Dodge HH, Shen C, Pandav R, DeKosky ST, Ganguli M, Functional transitions and active life expectancy associated with Alzheimer disease, Archives of Neurology, 60, 2, 253–9, February 2003, 12580712, 10.1001/archneur.60.2.253, Men have a less favourable survival prognosis than women.JOURNAL, Ganguli M, Dodge HH, Shen C, Pandav RS, DeKosky ST, Alzheimer disease and mortality: a 15-year epidemiological study, Archives of Neurology, 62, 5, 779–84, May 2005, 15883266, 10.1001/archneur.62.5.779, Pneumonia and dehydration are the most frequent immediate causes of death brought by AD, while cancer is a less frequent cause of death than in the general population.{{clear}}

Epidemiology{| class"wikitable" style"float:right; text-align:center;"|+Rates after age 65

! Age !! New affected per thousand person–years!65–69| 3!70–74| 6!75–79| 9!80–84|23!85–89|40!90–    |69Two main measures are used in epidemiological studies: incidence and prevalence. Incidence is the number of new cases per unit of person–time at risk (usually number of new cases per thousand person–years); while prevalence is the total number of cases of the disease in the population at any given time.Regarding incidence, cohort longitudinal studies (studies where a disease-free population is followed over the years) provide rates between 10 and 15 per thousand person–years for all dementias and 5–8 for AD,JOURNAL, Bermejo-Pareja F, Benito-León J, Vega S, Medrano MJ, Román GC, Incidence and subtypes of dementia in three elderly populations of central Spain, Journal of the Neurological Sciences, 264, 1–2, 63–72, January 2008, 17727890, 10.1016/j.jns.2007.07.021, JOURNAL, Di Carlo A, Baldereschi M, Amaducci L, Lepore V, Bracco L, Maggi S, Bonaiuto S, Perissinotto E, Scarlato G, Farchi G, Inzitari D, Incidence of dementia, Alzheimer's disease, and vascular dementia in Italy. The ILSA Study, Journal of the American Geriatrics Society, 50, 1, 41–8, January 2002, 12028245, 10.1046/j.1532-5415.2002.50006.x, 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 approximately doubles, increasing from 3 to as much as 69 per thousand person years. There are also sex differences in the incidence rates, women having a higher risk of developing AD particularly in the population older than 85.JOURNAL, 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, 6, Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. EURODEM Incidence Research Group, Neurology, 53, 9, 1992–7, December 1999, 10599770, 10.1212/wnl.53.9.1992, In the United States, the risk of dying from Alzheimer's disease is 26% higher among the non-Hispanic white population than among the non-Hispanic black population, whereas the Hispanic population has a 30% lower risk than the non-Hispanic white population.Tejada-Vera B. (2013). Mortality from Alzheimer's Disease in the United States: Data for 2000 and 2010. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics.(File:Alzheimer's disease and other dementias world map-Deaths per million persons-WHO2012.svg|thumb|left|upright=1.3|Deaths per million persons in 2012 due to dementias including Alzheimer's disease {{legend|#ffff20|0–4}}{{legend|#ffe820|5–8}}{{legend|#ffd820|9–10}}{{legend|#ffc020|11–13}}{{legend|#ffa020|14–17}}{{legend|#ff9a20|18–24}}{{legend|#f08015|25–45}}{{legend|#e06815|46–114}}{{legend|#d85010|115–375}}{{legend|#d02010|376–1266}})Prevalence of AD in populations is dependent upon different factors including incidence and survival. Since the incidence of AD increases with age, it is particularly important to include the mean age of the population of interest. In the United States, Alzheimer prevalence was estimated to be 1.6% in 2000 both overall and in the 65–74 age group, with the rate increasing to 19% in the 75–84 group and to 42% in the greater than 84 group.2000 U.S. estimates:
  • JOURNAL, Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA, Alzheimer disease in the US population: prevalence estimates using the 2000 census, Archives of Neurology, 60, 8, 1119–22, August 2003, 12925369, 10.1001/archneur.60.8.1119,
  • WEB, Profiles of General Demographic Characteristics, 2000 Census of Population and Housing, United States, 2001, U.S. Census Bureau,weblink 27 August 2008,weblink" title="web.archive.org/web/20080819203118weblink">weblink 19 August 2008, no, Prevalence rates in less developed regions are lower. The World Health Organization estimated that in 2005, 0.379% of people worldwide had dementia, and that the prevalence would increase to 0.441% in 2015 and to 0.556% in 2030.BOOK, World Health Organization, Neurological Disorders: Public Health Challenges, World Health Organization, 2006, Switzerland, 204–07,weblink 978-92-4-156336-9, no,weblink" title="web.archive.org/web/20100210144936weblink">weblink 10 February 2010, Other studies have reached similar conclusions.JOURNAL, Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, Rimmer E, Scazufca M, Global prevalence of dementia: a Delphi consensus study, Lancet, 366, 9503, 2112–7, December 2005, 16360788, 2850264, 10.1016/S0140-6736(05)67889-0, Another study estimated that in 2006, 0.40% of the world population (range 0.17–0.89%; absolute number {{Nowrap|26.6 million}}, range {{Nowrap|11.4–59.4 million}}) were afflicted by AD, and that the prevalence rate would triple and the absolute number would quadruple by 2050.
2006 prevalence estimate:
  • JOURNAL, Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM, Forecasting the global burden of Alzheimer's disease, Alzheimer's & Dementia, 3, 3, 186–91, July 2007, 19595937, 10.1016/j.jalz.2007.04.381,weblink 18 June 2008, dmy-all, no,weblink" title="web.archive.org/web/20081207025403weblink">weblink 7 December 2008, 10.1.1.729.847,
  • JOURNAL,weblink 27 August 2008, 2007, World population prospects: the 2006 revision, highlights, Population Division, Department of Economic and Social Affairs, United Nations, Working Paper No. ESA/P/WP.202, yes,weblink" title="web.archive.org/web/20080819191533weblink">weblink 19 August 2008, dmy-all,

History

{{see also|Timeline of Alzheimer's disease}}File:Auguste D aus Marktbreit.jpg|thumb|left|Alois Alzheimer's patient Auguste DeterAuguste DeterThe ancient Greek and Roman philosophers and physicians associated old age with increasing dementia. It was not until 1901 that German psychiatrist Alois Alzheimer identified the first case of what became known as Alzheimer's disease, named after him, in a fifty-year-old woman he called Auguste D. He followed her case until she died in 1906, when he first reported publicly on it.Auguste D.:
  • JOURNAL, Alzheimer, Alois, vanc, Ãœber eine eigenartige Erkrankung der Hirnrinde, About a peculiar disease of the cerebral cortex, Allgemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtlich Medizin, 64, 1–2, 146–48, 1907, de,
  • JOURNAL, Alzheimer A, About a peculiar disease of the cerebral cortex. By Alois Alzheimer, 1907 (Translated by L. Jarvik and H. Greenson), Alzheimer Disease and Associated Disorders, 1, 1, 3–8, 1987, 3331112, H. Greenson,
  • BOOK, Maurer, Ulrike, Maurer, Konrad, vanc, Alzheimer: The Life of a Physician and the Career of a Disease, Columbia University Press, New York, 2003, 270, 978-0-231-11896-5, During the next five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease.JOURNAL, Berchtold NC, Cotman CW, Evolution in the conceptualization of dementia and Alzheimer's disease: Greco-Roman period to the 1960s, Neurobiology of Aging, 19, 3, 173–89, 1998, 9661992, 10.1016/S0197-4580(98)00052-9, The disease was first described as a distinctive disease by Emil Kraepelin after suppressing some of the clinical (delusions and hallucinations) and pathological features (arteriosclerotic changes) contained in the original report of Auguste D.JOURNAL, Berrios GE, Alzheimer's Disease: A Conceptual History, Int. J. Geriatr. Psychiatry, 5, 6, 355–65, 1990, 10.1002/gps.930050603, He included Alzheimer's disease, also named presenile dementia by Kraepelin, as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published on {{nowrap|15 July,}} 1910.BOOK, Kraepelin Emil, Diefendorf A. Ross, Clinical Psychiatry: A Textbook For Students And Physicians (Reprint), Kessinger Publishing, 17 January 2007, 568, 978-1-4325-0833-3,
For most of the 20th 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 on AD 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 that they had different causes.BOOK, Katzman R, Terry RD, Bick KL, Alzheimer's Disease: Senile Dementia and Related Disorders, Raven Press, New York, 1978, 595, 978-0-89004-225-0, This eventually led to the diagnosis of Alzheimer's disease independent of age.JOURNAL, Boller F, Forbes MM, History of dementia and dementia in history: an overview, Journal of the Neurological Sciences, 158, 2, 125–33, June 1998, 9702682, 10.1016/S0022-510X(98)00128-2, 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 to describe those who were 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.JOURNAL, Amaducci LA, Rocca WA, Schoenberg BS, Origin of the distinction between Alzheimer's disease and senile dementia: how history can clarify nosology, Neurology, 36, 11, 1497–9, November 1986, 3531918, 10.1212/wnl.36.11.1497,

Society and culture

{{See also|Alzheimer's disease organisations}}

Social costs

Dementia, and specifically Alzheimer's disease, may be among the most costly diseases for society in Europe and the United States, while their costs in other countries such as Argentina,JOURNAL, Allegri RF, Butman J, Arizaga RL, Machnicki G, Serrano C, Taragano FE, Sarasola D, Lon L, Economic impact of dementia in developing countries: an evaluation of costs of Alzheimer-type dementia in Argentina, International Psychogeriatrics, 19, 4, 705–18, August 2007, 16870037, 10.1017/S1041610206003784, and South Korea,JOURNAL, Suh GH, Knapp M, Kang CJ, The economic costs of dementia in Korea, 2002, International Journal of Geriatric Psychiatry, 21, 8, 722–8, August 2006, 16858741, 10.1002/gps.1552, are also high and rising. These costs will probably increase with the ageing of society, becoming an important social problem. AD-associated costs include direct medical costs such as nursing home care, direct nonmedical costs such as in-home day care, and indirect costs such as lost productivity of both patient and caregiver. Numbers vary between studies but dementia costs worldwide have been calculated around $160 billion,JOURNAL, Wimo A, Jonsson L, Winblad B, An estimate of the worldwide prevalence and direct costs of dementia in 2003, Dementia and Geriatric Cognitive Disorders, 21, 3, 175–81, 2006, 16401889, 10.1159/000090733, while costs of Alzheimer's disease in the United States may be $100 billion each year.The greatest origin of costs for society is the long-term care by health care professionals and particularly institutionalisation, which corresponds to 2/3 of the total costs for society. The cost of living at home is also very high, especially when informal costs for the family, such as caregiving time and caregiver's lost earnings, are taken into account.JOURNAL, Moore MJ, Zhu CW, Clipp EC, Informal costs of dementia care: estimates from the National Longitudinal Caregiver Study, The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences, 56, 4, S219–28, July 2001, 11445614, 10.1093/geronb/56.4.S219, Costs increase with dementia severity and the presence of behavioural disturbances,JOURNAL, Jönsson L, Eriksdotter Jönhagen M, Kilander L, Soininen H, Hallikainen M, Waldemar G, Nygaard H, Andreasen N, Winblad B, Wimo A, 6, Determinants of costs of care for patients with Alzheimer's disease, International Journal of Geriatric Psychiatry, 21, 5, 449–59, May 2006, 16676288, 10.1002/gps.1489, and are related to the increased caregiving time required for the provision of physical care. Therefore, any treatment that slows cognitive decline, delays institutionalisation or reduces caregivers' hours will have economic benefits. Economic evaluations of current treatments have shown positive results.

Caregiving burden

{{further|Caregiving and dementia}}The role of the main caregiver is often taken by the spouse or a close relative.WEB, The MetLife study of Alzheimer's disease: The caregiving experience, August 2006, MetLife Mature Market Institute, 5 February 2011,weblinkweblink" title="web.archive.org/web/20110108073750weblink">weblink 8 January 2011, yes, Alzheimer's disease is known for placing a great burden on caregivers which includes social, psychological, physical or economic aspects.JOURNAL, Schneider J, Murray J, Banerjee S, Mann A, EUROCARE: a cross-national study of co-resident spouse carers for people with Alzheimer's disease: I--Factors associated with carer burden, International Journal of Geriatric Psychiatry, 14, 8, 651–61, August 1999, 10489656, 10.1002/(SICI)1099-1166(199908)14:83.0.CO;2-B, JOURNAL, Murray J, Schneider J, Banerjee S, Mann A, 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, International Journal of Geriatric Psychiatry, 14, 8, 662–7, August 1999, 10489657, 10.1002/(SICI)1099-1166(199908)14:83.0.CO;2-4, Home care is usually preferred by people with AD and their families.JOURNAL, Zhu CW, Sano M, Economic considerations in the management of Alzheimer's disease, Clinical Interventions in Aging, 1, 2, 143–54, 2006, 18044111, 2695165, 10.2147/ciia.2006.1.2.143, This option also delays or eliminates the need for more professional and costly levels of care.JOURNAL, Gaugler JE, Kane RL, Kane RA, Newcomer R, Early community-based service utilization and its effects on institutionalization in dementia caregiving, The Gerontologist, 45, 2, 177–85, April 2005, 15799982, 10.1093/geront/45.2.177, Nevertheless, two-thirds of nursing home residents have dementias.Dementia caregivers are subject to high rates of physical and mental disorders.JOURNAL, Ritchie K, Lovestone S, The dementias, Lancet, 360, 9347, 1759–66, November 2002, 12480441, 10.1016/S0140-6736(02)11667-9, Factors associated with greater psychosocial problems of the primary caregivers include having an affected person at home, the carer being a spouse, demanding behaviours of the cared person such as depression, behavioural disturbances, hallucinations, sleep problems or walking disruptions and social isolation.JOURNAL, Brodaty H, Hadzi-Pavlovic D, Psychosocial effects on carers of living with persons with dementia, The Australian and New Zealand Journal of Psychiatry, 24, 3, 351–61, September 1990, 2241719, 10.3109/00048679009077702, JOURNAL, Donaldson C, Tarrier N, Burns A, Determinants of carer stress in Alzheimer's disease, International Journal of Geriatric Psychiatry, 13, 4, 248–56, April 1998, 9646153, 10.1002/(SICI)1099-1166(199804)13:43.0.CO;2-0, Regarding economic problems, family caregivers often give up time from work to spend 47 hours per week on average with the person with AD, while the costs of caring for them are high. Direct and indirect costs of caring for an Alzheimer's patient average between $18,000 and $77,500 per year in the United States, depending on the study.Cognitive behavioural therapy and the teaching of coping strategies either individually or in group have demonstrated their efficacy in improving caregivers' psychological health.JOURNAL, Pusey H, Richards D, A systematic review of the effectiveness of psychosocial interventions for carers of people with dementia, Aging & Mental Health, 5, 2, 107–19, May 2001, 11511058, 10.1080/13607860120038302,

Media

AD has been portrayed in films such as: Iris (2001), based on John Bayley's memoir of his wife Iris Murdoch;BOOK, Iris: A Memoir of Iris Murdoch, Bayley, John, vanc, Abacus, London, 2000, 978-0-349-11215-2, 41960006, The Notebook (2004), based on Nicholas Sparks' 1996 novel of the same name;BOOK, The notebook, Sparks, Nicholas, vanc, 1996, Thorndike Press, Thorndike, Maine, 268, 978-0-7862-0821-0, A Moment to Remember (2004);Thanmathra (2005);WEB,weblink Thanmathra, Webindia123.com, 24 January 2008, no,weblink" title="web.archive.org/web/20071106105455weblink">weblink 6 November 2007, Memories of Tomorrow (Ashita no Kioku) (2006), based on Hiroshi Ogiwara's novel of the same name;BOOK, Ogiwara, Hiroshi, vanc, 2004, Ashita no Kioku, Tōkyō, Kōbunsha, 978-4-334-92446-1, 57352130, ja, Away from Her (2006), based on Alice Munro's short story "The Bear Came over the Mountain";BOOK, Hateship, Friendship, Courtship, Loveship, Marriage: Stories, Munro, Alice, vanc, New York, A.A. Knopf, 2001, 978-0-375-41300-1, 46929223, Hateship, Friendship, Courtship, Loveship, Marriage, Still Alice (2014), about a Columbia University professor who has early onset Alzheimer's disease, based on Lisa Genova's 2007 novel of the same name and featuring Julianne Moore in the title role. Documentaries on Alzheimer's disease include Malcolm and Barbara: A Love Story (1999) and Malcolm and Barbara: Love's Farewell (2007), both featuring Malcolm Pointon.WEB,weblink Malcolm and Barbara: A love story, Dfgdocs, 24 January 2008, yes,weblink" title="web.archive.org/web/20080524213821weblink">weblink 24 May 2008, WEB,weblink Malcolm and Barbara: A love story, BBC Cambridgeshire, 2 March 2008, no,weblink" title="web.archive.org/web/20121110084233weblink">weblink 10 November 2012, NEWS,weblink Alzheimer's film-maker to face ITV lawyers, Guardian Media, 7 August 2007, 24 January 2008, London, Plunkett J,weblink" title="web.archive.org/web/20080115132419weblink">weblink 15 January 2008, no,

Research directions

Medication

In the decade 2002–2012, 244 compounds were assessed in Phase I, Phase II, or Phase III trials, and only one of these (memantine) received FDA approval (though others were still in the pipeline).JOURNAL, Cummings JL, Morstorf T, Zhong K, Alzheimer's disease drug-development pipeline: few candidates, frequent failures, Alzheimer's Research & Therapy, 6, 4, 37, July 2014, 25024750, 4095696, 10.1186/alzrt269, Solanezumab and aducanumab failed to show effectiveness in people who already had Alzheimer's symptoms.NEWS, Gutis, Phillip S., An Alzheimer’s Drug Trial Gave Me Hope, and Then It Ended,weblink 25 March 2019, The New York Times, 22 March 2019, One area of clinical research is focused on treating the underlying disease pathology. Reduction of beta-amyloid levels is a common target of compoundsJOURNAL, Lashuel HA, Hartley DM, Balakhaneh D, Aggarwal A, Teichberg S, Callaway DJ, New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease, The Journal of Biological Chemistry, 277, 45, 42881–90, November 2002, 12167652, 10.1074/jbc.M206593200, dmy-all, (such as apomorphine) under investigation. Immunotherapy or vaccination for the amyloid protein is one treatment modality under study.JOURNAL, Dodel R, Neff F, Noelker C, Pul R, Du Y, Bacher M, Oertel W, Intravenous immunoglobulins as a treatment for Alzheimer's disease: rationale and current evidence, Drugs, 70, 5, 513–28, March 2010, 20329802, 10.2165/11533070-000000000-00000,weblink dmy-all, yes,weblink" title="web.archive.org/web/20110917191608weblink">weblink 17 September 2011, Unlike preventative vaccination, the putative therapy would be used to treat people already diagnosed. It is based upon the concept of training the immune system to recognise, attack, and reverse deposition of amyloid, thereby altering the course of the disease.Vaccination:
  • JOURNAL, Hawkes CA, McLaurin J, Immunotherapy as treatment for Alzheimer's disease, Expert Review of Neurotherapeutics, 7, 11, 1535–48, November 2007, 17997702, 10.1586/14737175.7.11.1535,
  • JOURNAL, Solomon B, Clinical immunologic approaches for the treatment of Alzheimer's disease, Expert Opinion on Investigational Drugs, 16, 6, 819–28, June 2007, 17501694, 10.1517/13543784.16.6.819,
  • JOURNAL, Woodhouse A, Dickson TC, Vickers JC, Vaccination strategies for Alzheimer's disease: A new hope?, Drugs & Aging, 24, 2, 107–19, 2007, 17313199, 10.2165/00002512-200724020-00003, An example of such a vaccine under investigation was ACC-001,WEB,weblink Study Evaluating ACC-001 in Mild to Moderate Alzheimers Disease Subjects, Clinical Trial, US National Institutes of Health, 5 June 2008, 11 March 2008, no,weblink" title="web.archive.org/web/20130730112226weblink">weblink 30 July 2013, WEB,weblink Study Evaluating Safety, Tolerability, and Immunogenicity of ACC-001 in Subjects with Alzheimer's Disease, US National Institutes of Health, 5 June 2008, no,weblink" title="web.archive.org/web/20081029135546weblink">weblink 29 October 2008, although the trials were suspended in 2008.WEB,weblink Alzheimer's Disease Vaccine Trial Suspended on Safety Concern, Medpage Today, 14 June 2008, 18 April 2008, no,weblink" title="web.archive.org/web/20080423230653weblink">weblink 23 April 2008, Another similar agent is bapineuzumab, an antibody designed as identical to the naturally induced anti-amyloid antibody.WEB,weblink Bapineuzumab in Patients with Mild to Moderate Alzheimer's Disease/ Apo_e4 Non-carriers, Clinical Trial, 23 March 2008, US National Institutes of Health, 29 February 2008,weblink" title="web.archive.org/web/20080322093853weblink">weblink 22 March 2008, no, However, immunotherapeutic agents have been found to cause some concerning adverse drug reactions, such as amyloid-related imaging abnormalities.JOURNAL, Sperling RA, Jack CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, Scheltens P, Carrillo MC, Thies W, Bednar MM, Black RS, Brashear HR, Grundman M, Siemers ER, Feldman HH, Schindler RJ, Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup, Alzheimer's & Dementia, 7, 4, 367–85, July 2011, 21784348, 3693547, 10.1016/j.jalz.2011.05.2351, Other approaches are neuroprotective agents, such as AL-108,WEB,weblink Safety, Tolerability and Efficacy Study to Evaluate Subjects with Mild Cognitive Impairment, Clinical Trial, 23 March 2008, US National Institutes of Health, 11 March 2008, no,weblink" title="web.archive.org/web/20081022200548weblink">weblink 22 October 2008, and metal-protein interaction attenuation agents, such as PBT2.WEB,weblink Study Evaluating the Safety, Tolerability and Efficacy of PBT2 in Patients with Early Alzheimer's Disease, Clinical Trial, 23 March 2008, US National Institutes of Health, 13 January 2008, no,weblink" title="web.archive.org/web/20080831021630weblink">weblink 31 August 2008, A TNFα receptor-blocking fusion protein, etanercept has showed encouraging results.Etanercept research:
  • JOURNAL, Tobinick E, Tumour necrosis factor modulation for treatment of Alzheimer's disease: rationale and current evidence, CNS Drugs, 23, 9, 713–25, September 2009, 19689163, 10.2165/11310810-000000000-00000,
  • JOURNAL, Tobinick E, Gross H, Weinberger A, Cohen H, TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study, MedGenMed, 8, 2, 25, April 2006, 16926764, 1785182,
  • JOURNAL, Griffin WS, Perispinal etanercept: potential as an Alzheimer therapeutic, Journal of Neuroinflammation, 5, 3, January 2008, 18186919, 2241592, 10.1186/1742-2094-5-3,
  • JOURNAL, Tobinick E, Perispinal etanercept for treatment of Alzheimer's disease, Current Alzheimer Research, 4, 5, 550–2, December 2007, 18220520, 10.2174/156720507783018217,
  • JOURNAL, Cheng X, Shen Y, Li R, Targeting TNF: a therapeutic strategy for Alzheimer's disease, Drug Discovery Today, 19, 11, 1822–1827, November 2014, 24998784, 10.1016/j.drudis.2014.06.029,
In 2008, two separate clinical trials showed positive results in modifying the course of disease in mild to moderate AD with methylthioninium chloride, a drug that inhibits tau aggregation,JOURNAL, Wischik CM, Bentham P, Wischik DJ, Seng KM, Tau aggregation inhibitor (TAI) therapy with remberTM arrests disease progression in mild and moderate Alzheimer's disease over 50 weeks, Alzheimer's & Dementia, July 2008, 4, 4, T167,weblink{E7C717CF-8D73-41E0-8DB0-FA92205978CD}&SKey={68E04DB5-AB1C-4F7B-9511-DA3173F4F755}&MKey={CFC5F7C6-CB6A-40C4-BC87-B30C9E64B1CC}&AKey={50E1744A-0C52-45B2-BF85-2A798BF24E02}, 30 July 2008, 10.1016/j.jalz.2008.05.438, JOURNAL, Harrington C, Rickard J, Horsley D, Methylthioninium chloride (MTC) acts as a tau aggregation inhibitor (TAI) in a cellular model and reverses tau pathology in transgenic mouse models of Alzheimer's disease, Alzheimer's & Dementia, July 2008, T120–T121, 10.1016/j.jalz.2008.05.259, 4, 4, and dimebon, an antihistamine.JOURNAL, Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D, Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study, Lancet, 372, 9634, 207–15, July 2008, 18640457, 10.1016/S0140-6736(08)61074-0, The consecutive phase-III trial of dimebon failed to show positive effects in the primary and secondary endpoints.JOURNAL, Bezprozvanny I, The rise and fall of Dimebon, Drug News & Perspectives, 23, 8, 518–23, October 2010, 21031168, 3922928, 10.1358/dnp.2010.23.8.1500435, Original article, PRESS RELEASE,weblink Pfizer And Medivation announce results from two phase 3 studies in Dimebon (latrepirdine*) Alzheimer's disease clinical development program (NASDAQ:MDVN), 16 November 2012, yes,weblink" title="web.archive.org/web/20120904163533weblink">weblink 4 September 2012, JOURNAL, Wendler A, Wehling M, Translatability scoring in drug development: eight case studies, Journal of Translational Medicine, 10, 10, 39, March 2012, 22397594, 3330010, 10.1186/1479-5876-10-39, Work with methylthioninium chloride showed that bioavailability of methylthioninium from the gut was affected by feeding and by stomach acidity, leading to unexpectedly variable dosing.JOURNAL, Baddeley TC, McCaffrey J, Storey JM, Cheung JK, Melis V, Horsley D, Harrington CR, Wischik CM, Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer's disease, The Journal of Pharmacology and Experimental Therapeutics, 352, 1, 110–8, January 2015, 25320049, 10.1124/jpet.114.219352, A new stabilised formulation, as the prodrug LMTX, is in phase-III trials (in 2014).JOURNAL, Wischik CM, Harrington CR, Storey JM, Tau-aggregation inhibitor therapy for Alzheimer's disease, Biochemical Pharmacology, 88, 4, 529–39, April 2014, 24361915, 10.1016/j.bcp.2013.12.008,

Behavioral prevention

Research on the effects of meditation on preserving memory and cognitive functions is at an early stage.JOURNAL, Marciniak R, Sheardova K, Cermáková P, Hudeček D, Sumec R, Hort J, Effect of meditation on cognitive functions in context of aging and neurodegenerative diseases, Frontiers in Behavioral Neuroscience, 8, 17, 2014, 24478663, 3903052, 10.3389/fnbeh.2014.00017, A 2015 review suggests that mindfulness-based interventions may prevent or delay the onset of mild cognitive impairment and Alzheimer's disease.JOURNAL, Larouche E, Hudon C, Goulet S, Potential benefits of mindfulness-based interventions in mild cognitive impairment and Alzheimer's disease: an interdisciplinary perspective, Behavioural Brain Research, 276, 276, 199–212, January 2015, 24893317, 10.1016/j.bbr.2014.05.058,

Possible transmission

Rare cases of possible transmission between people are being studied,JOURNAL, Jaunmuktane Z, Mead S, Ellis M, Wadsworth JD, Nicoll AJ, Kenny J, Launchbury F, Linehan J, Richard-Loendt A, Walker AS, Rudge P, Collinge J, Brandner S, 6, Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy, Nature, 525, 7568, 247–50, September 2015, 26354483, 10.1038/nature15369, dmy-all, 2015Natur.525..247J, e.g. to growth hormone patients.JOURNAL, Abbott A, Autopsies reveal signs of Alzheimer's in growth-hormone patients, Nature, 525, 7568, 165–6, September 2015, 26354460, 10.1038/525165a, 2015Natur.525..165A,

Infections

The herpes simplex virus HSV-1 has been found in the same areas as amyloid plaques.JOURNAL, Martin C, Solís L, Concha MI, Otth C, [Herpes simplex virus type 1 as risk factor associated to Alzheimer disease], Spanish, Revista Medica de Chile, 139, 6, 779–86, June 2011, 22051760, 10.4067/S0034-98872011000600013, Herpes Simplex Virus Type 1 as Risk Factor Associated to Alzheimer Disease, This suggested the possibility that AD could be treated or prevented with antiviral medication.JOURNAL, Wozniak MA, Mee AP, Itzhaki RF, Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques, The Journal of Pathology, 217, 1, 131–8, January 2009, 18973185, 10.1002/path.2449, Original study, Studies of antivirals in cell cultures have shown promising results.JOURNAL, Itzhaki RF, Herpes simplex virus type 1 and Alzheimer's disease: increasing evidence for a major role of the virus, Frontiers in Aging Neuroscience, 6, 202, 2014, 25157230, 4128394, 10.3389/fnagi.2014.00202, Fungal infection of AD brain has also been described.JOURNAL, Itzhaki RF, Lathe R, Balin BJ, Ball MJ, Bearer EL, Braak H, Bullido MJ, Carter C, Clerici M, Cosby SL, Del Tredici K, Field H, Fulop T, Grassi C, Griffin WS, Haas J, Hudson AP, Kamer AR, Kell DB, Licastro F, Letenneur L, Lövheim H, Mancuso R, Miklossy J, Otth C, Palamara AT, Perry G, Preston C, Pretorius E, Strandberg T, Tabet N, Taylor-Robinson SD, Whittum-Hudson JA, 6, Microbes and Alzheimer's Disease, Journal of Alzheimer's Disease, 51, 4, 979–84, 2016, 26967229, 5457904, 10.3233/JAD-160152,weblink dmy-all, no,weblink" title="web.archive.org/web/20161110115259weblink">weblink 10 November 2016, This hypothesis was proposed by the microbiologist L. Carrasco when his group found statistical correlation between disseminated mycoses and AD.JOURNAL, Alonso R, Pisa D, Rábano A, Carrasco L, Alzheimer's disease and disseminated mycoses, European Journal of Clinical Microbiology & Infectious Diseases, 33, 7, 1125–32, July 2014, 24452965, 10.1007/s10096-013-2045-z, Further work revealed that fungal infection is present in different brain regions of AD patients, but not in the control individuals.JOURNAL, Pisa D, Alonso R, Rábano A, Rodal I, Carrasco L, Different Brain Regions are Infected with Fungi in Alzheimer's Disease, Scientific Reports, 5, 15015, October 2015, 26468932, 4606562, 10.1038/srep15015, dmy-all, 2015NatSR...515015P, JOURNAL, Fungus, the bogeyman, The Economist,weblink no,weblink 8 August 2017, dmy-all, 2015-10-22, A fungal infection explains the symptoms observed in AD patients. The slow progression of AD fits with the chronic nature of some systemic fungal infections, which can be asymptomatic and thus, unnoticed and untreated.The fungal hypotheses are also compatible with some other established AD hypotheses, like the amyloid hypothesis, that can be explained as an immune system response to an infection in the CNS,JOURNAL, Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, Lefkowitz A, McColl G, Goldstein LE, Tanzi RE, Moir RD, Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease, Science Translational Medicine, 8, 340, 340ra72, May 2016, 27225182, 5505565, 10.1126/scitranslmed.aaf1059, NEWS, Could Alzheimer's Stem From Infections? It Makes Sense, Experts Say,weblink The New York Times, no,weblink 4 February 2017, dmy-all, The New York Times, 2016-05-25, Kolata, Gina, WEB, Alzheimer's culprit may fight other diseases,weblink Science News, no,weblink 26 May 2016, dmy-all, 2016-06-16, as found by R. Moir and R. Tanzi in mouse and worm models of AD.

Imaging

{{update|section|from {{PMID|28072381}} and {{PMID|28259856}}|date=April 2018}}Of the many medical imaging techniques available, single photon emission computed tomography (SPECT) appears to be superior in differentiating Alzheimer's disease from other types of dementia, and this has been shown to give a greater level of accuracy compared with mental testing and medical history analysis.JOURNAL, Dougall NJ, Bruggink S, Ebmeier KP, Systematic review of the diagnostic accuracy of 99mTc-HMPAO-SPECT in dementia, The American Journal of Geriatric Psychiatry, 12, 6, 554–70, 2004, 15545324, 10.1176/appi.ajgp.12.6.554, Advances have led to the proposal of new diagnostic criteria.PiB PET remains investigational, but a similar PET scanning radiopharmaceutical called florbetapir, containing the longer-lasting radionuclide fluorine-18, is a diagnostic tool in Alzheimer's disease.JOURNAL, Carpenter AP, Pontecorvo MJ, Hefti FF, Skovronsky DM, The use of the exploratory IND in the evaluation and development of 18F-PET radiopharmaceuticals for amyloid imaging in the brain: a review of one company's experience, The Quarterly Journal of Nuclear Medicine and Molecular Imaging, 53, 4, 387–93, August 2009, 19834448, WEB, Leung K,weblink (E)-4-(2-(6-(2-(2-(2-(18F-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl benzenamine 18F]AV-45], Molecular Imaging and Contrast Agent Database, 8 April 2010, 24 June 2010, no,weblink" title="web.archive.org/web/20100607233852weblink">weblink 7 June 2010, Amyloid imaging is likely to be used in conjunction with other markers rather than as an alternative.JOURNAL, Rabinovici GD, Jagust WJ, Amyloid imaging in aging and dementia: testing the amyloid hypothesis in vivo, Behavioural Neurology, 21, 1, 117–28, 2009, 19847050, 2804478, 10.3233/BEN-2009-0232,weblink dmy-all, yes,weblink" title="web.archive.org/web/20130730122115weblink">weblink 30 July 2013, Volumetric MRI can detect changes in the size of brain regions. Measuring those regions that atrophy during the progress of Alzheimer's disease is showing promise as a diagnostic indicator. It may prove less expensive than other imaging methods currently under study.JOURNAL, O'Brien JT, Role of imaging techniques in the diagnosis of dementia, The British Journal of Radiology, 80 Spec No 2, Spec No 2, S71–7, December 2007, 18445747, 10.1259/bjr/33117326, In 2011 An FDA panel voted unanimously to recommend approval of florbetapir. The imaging agent can help to detect Alzheimer's brain plaques.JOURNAL, Clark CM, Schneider JA, Bedell BJ, Beach TG, Bilker WB, Mintun MA, Pontecorvo MJ, Hefti F, Carpenter AP, Flitter ML, Krautkramer MJ, Kung HF, Coleman RE, Doraiswamy PM, Fleisher AS, Sabbagh MN, Sadowsky CH, Reiman EP, Reiman PE, Zehntner SP, Skovronsky DM, 6, Use of florbetapir-PET for imaging beta-amyloid pathology, JAMA, 305, 3, 275–83, January 2011, 21245183, 10.1001/jama.2010.2008,weblink A negative scan indicates sparse or no plaques, which is not consistent with a diagnosis of AD.WEB,weblink European Community, Amyvid, Community register of medicinal products for human use, 17 January 2013, 18 April 2018,

Diagnosis

Emphasis in Alzheimer's research has been placed on diagnosing the condition before symptoms begin.JOURNAL, Chong MS, Sahadevan S, Preclinical Alzheimer's disease: diagnosis and prediction of progression, The Lancet. Neurology, 4, 9, 576–9, September 2005, 16109364, 10.1016/s1474-4422(05)70168-x, A number of biochemical tests have been developed to enable earlier detection. Some such tests involve the analysis of cerebrospinal fluid for beta-amyloid, total tau protein and phosphorylated tau181P protein concentrations.JOURNAL, Sharma N, Singh AN, Exploring Biomarkers for Alzheimer's Disease, Journal of Clinical and Diagnostic Research, 10, 7, KE01–6, July 2016, 27630867, 5020308, 10.7860/JCDR/2016/18828.8166, Review, Because drawing CSF can be painful, repeated draws are avoided. A blood test for circulatory miRNA and inflammatory biomarkers is a potential alternative indicator.

References

{{Reflist}}

Further reading

{{Spoken Wikipedia|Alzheimer's Disease.ogg|2008-09-12}}{{Library resources box |by=no |onlinebooks=no |others=yes |about=yes |label=Alzheimer's Disease|lcheading=Alzheimers Disease}}
  • BOOK, Alzheimer's Disease: Unraveling the Mystery,weblink US Department of Health and Human Services, National Institute on Aging, NIH, 2008, yes,weblink" title="web.archive.org/web/20120108204115weblink">weblink 8 January 2012,
  • BOOK, Can Alzheimer's Disease Be Prevented?,weblink US Department of Health and Human Services, National Institute on Aging, NIH, 2009, yes,weblink" title="web.archive.org/web/20130502233551weblink">weblink 2 May 2013,
  • BOOK, Caring for a Person with Alzheimer's Disease: Your Easy-to-Use Guide from the National Institute on Aging,weblink US Department of Health and Human Services, National Institute on Aging, NIH, 2009, yes,weblink" title="web.archive.org/web/20120108193219weblink">weblink 8 January 2012,
  • WEB, Alzheimer's Behavior Management: Learn to Manage Common Behavior Problems,weblink Russell D, Barston S, White M, helpguide.org, 19 December 2007, 29 February 2008,weblink" title="web.archive.org/web/20080223082753weblink">weblink 23 February 2008, yes,
  • JOURNAL, Irvine K, Laws KR, Gale TM, Kondel TK, Keith Laws, Greater cognitive deterioration in women than men with Alzheimer's disease: a meta analysis, Journal of Clinical and Experimental Neuropsychology, 34, 9, 989–98, 2012, 22913619, 10.1080/13803395.2012.712676, Meta-analysis,

External links

{{Commons category|Alzheimer's disease}}{{Medical condition classification and resources|DiseasesDB=490G30}}, {{ICD1000f|00}}331.0}}, {{ICD9|290.1}}|ICDO=|OMIM=104300|MedlinePlus=000760|eMedicineSubj=neuro|eMedicineTopic=13|MeshID=D000544|GeneReviewsNBK=NBK1161|Scholia = Q11081}}
  • {{dmoz|Health/Conditions_and_Diseases/Neurological_Disorders/Alzheimer%27s/}}
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