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| Alzheimer\'s disease Classification & external resources | |
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| Histopathologic image of senile plaques seen in the cerebral cortex in a patient with Alzheimer disease of presenile onset. Silver impregnation. | |
| ICD-10 | G30., F00. |
| ICD-9 | 331.0, 290.1 |
| OMIM | 104300 |
| DiseasesDB | 490 |
| MedlinePlus | 000760 |
| eMedicine | neuro/13 |
| MeSH | D000544 |
Alzheimer\'s disease (AD), also called Alzheimer disease or simply Alzheimer\'s, is the most common cause of dementia, afflicting 24 million people worldwide. Alzheimer\'s is a degenerative and terminal disease for which there is currently no cure. In its most common form, it occurs in people over 65 years old although a less-prevalent early-onset form also exists. 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 (2005). "Global prevalence of dementia: a Delphi consensus study". Lancet 366 (9503): 2112–2117. doi:10.1016/S0140-6736(05)67889-0. PMID 16360788. The disease can begin many years before it is eventually diagnosed. In its early stages, short-term memory loss is the most common symptom, often initially thought to be caused by aging or stress by the sufferer.Waldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, Scheltens P, Tariska P, Winblad B (2007). "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. doi:10.1111/j.1468-1331.2006.01605.x. PMID 17222085. Later symptoms include confusion, anger, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as his or her senses decline.Tabert MH, Liu X, Doty RL, Serby M, Zamora D, Pelton GH, Marder K, Albers MW, Stern Y, Devanand DP (2005). "A 10-item smell identification scale related to risk for Alzheimer\'s disease". Ann. Neurol. 58 (1): 155–60. doi:10.1002/ana.20533. PMID 15984022. Gradually the sufferer loses minor, and then major bodily functions, until death occurs. Understanding Stages and Symptoms of Alzheimer\'s Disease. National Institute on Aging (2007-10-26). Retrieved on 2008-02-21. Although the symptoms are common, people commonly experience them in a unique way. What is Alzheimer’s disease?. www.alzheimers.org.uk (August 2007). Retrieved on 2008-02-21. The duration of the disease is estimated as being between 5 and 20 years. Alzheimer\'s Disease Information Page. National Institute of Neurological Disorders and Stroke (NINDS) (2008-02-07). Retrieved on 2008-02-12. Alzheimer\'s Disease Treatment and Prognosis. Healthlink. Retrieved on 2008-02-15.
The symptoms of Alzheimer\'s disease are generally reported to a doctor when memory-loss causes concern, and on suspecting Alzheimer’s disease, the physician or healthcare specialists will confirm the diagnosis with a behavioral assessment and cognitive tests, often followed by a brain scan. Alzheimer\'s Diagnosis of AD. Alzheimer\'s Reearch Trust. Retrieved on 2008-02-29.
The cause and progression of Alzheimer\'s disease is not well understood, but is associated with plaques and tangles in the brain. Possible causes and potential cures of the disease have been conjectured, with varying evidence supporting each claim. No treatment has been found to stop or reverse the disease, and it is not known whether current treatments slow the progression, or simply manage the symptoms. Many preventative measures have been suggested for Alzheimer\'s disease, but their value is often uncertain: mental stimulation, exercise and a balanced diet are usually recommended, both as a possible prevention and as a sensible way of managing the disease. The Search for AD Prevention Strategies. National Institute on Aging (2006-08-29). Retrieved on 2008-02-29.
Due to the incurable and degenerative nature of the disease care-management of Alzheimer\'s is essential. The role of the main caregiver is often taken by the spouse or a close relative. Carers may themselves suffer from stress, over-work, depression, and being physically hit or struck.
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The disease course is typically divided into four stages, with a different pattern of cognitive and functional impairment occurring at each stage.
Careful neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fullfils clinical criteria of diagnosis.Preclinical phase
It is not yet clear if these difficulties affect daily living activities. Recent studies show impairments in the most complex activities.Perneczky R, Pohl C, Sorg C, Hartmann J, Komossa K, Alexopoulos P, Wagenpfeil S, Kurz A (2006). "Complex activities of daily living in mild cognitive impairment: conceptual and diagnostic issues". Age Ageing 35 (3): 240–5. doi:10.1093/ageing/afj054. PMID 16513677. The most noticeable deficit for most people is short-term memory loss and the consequent problems to acquire new information, but subtle executive problems or semantic memory impairments can also occur. Rapp MA, Reischies FM (2005). "Attention and executive control predict Alzheimer disease in late life: results from the Berlin Aging Study (BASE)". American Journal of Geriatric Psychiatry 13 (2): 134–141. doi:10.1176/appi.ajgp.13.2.134. PMID 15703322. Spaan PE, Raaijmakers JG, Jonker C (2003). "Alzheimer\'s disease versus normal ageing: a review of the efficiency of clinical and experimental memory measures". Journal of Clinical Experimental Neuropsychology 25 (2): 216–233. PMID 12754679. Apathy can be seen at this stage, and is the most common and persistent neuropsychiatric symptom throughout the course of the disease.Craig D, Mirakhur A, Hart DJ, McIlroy SP, Passmore AP (2005). "A cross-sectional study of neuropsychiatric symptoms in 435 patients with Alzheimer\'s disease". American Journal of Geriatric Psychiatry 13 (6): 460–468. doi:10.1176/appi.ajgp.13.6.460. PMID 15956265. Robert PH, Berr C, Volteau M, Bertogliati C, Benoit M, Sarazin M, Legrain S, Dubois B (2006). "Apathy in patients with mild cognitive impairment and the risk of developing dementia of Alzheimer\'s disease: a one-year follow-up study". Clin Neurol Neurosurg 108 (8): 733–6. doi:10.1016/j.clineuro.2006.02.003. PMID 16567037. Palmer K, Berger AK, Monastero R, Winblad B, Bäckman L, Fratiglioni L (2007). "Predictors of progression from mild cognitive impairment to Alzheimer disease". Neurology 68 (19): 1596–1602. doi:10.1212/01.wnl.0000260968.92345.3f. PMID 17485646. This stage of the disease has also been termed mild cognitive impairment, Small BJ, Gagnon E, Robinson B (2007). "Early identification of cognitive deficits: preclinical Alzheimer\'s disease and mild cognitive impairment". Geriatrics 62 (4): 19–23. PMID 17408315. but there is still a debate on whether this term corresponds to a different diagnostic entity by itself or just a first step of the disease. Petersen RC (2007). "The current status of mild cognitive impairment—what do we tell our patients?". Nat Clin Pract Neurol 3 (2): 60–61. doi:10.1038/ncpneuro0402. PMID 17279076.
In most people with the disease the increasing impairments in learning and memory will lead to diagnosis, while in a small proportion of them language, executive or visuoconstructional difficulties will be more salient. Förstl H, Kurz A (1999). "Clinical features of Alzheimer\'s disease". European Archives of Psychiatry and Clinical Neuroscience 249 (6): 288–290. PMID 10653284. Nevertheless memory problems do not affect all memory subcapacities equally. Older memories of the patient\'s life (episodic memory) and facts he learned (declarative memory); or implicit memory (the memory of the body on how to do things, such as using a knife to eat) are affected to a much lesser degree than the capacities needed to learn new facts or make new memories. Carlesimo GA, Oscar-Berman M (1992). "Memory deficits in Alzheimer\'s patients: a comprehensive review". Neuropsychology Review 3 (2): 119–169. PMID 1300219. Jelicic M, Bonebakker AE, Bonke B (1995). "Implicit memory performance of patients with Alzheimer\'s disease: a brief review". International Psychogeriatrics 7 (3): 385–392. PMID 8821346. On the other hand, language problems are mainly characterized by a shrinking vocabulary and a decreased word fluency which leads to a general impoverishment of oral and written language but the person with the disease is usually capable of communicating ideas adequately. Frank EM (1994). "Effect of Alzheimer\'s disease on communication function". J S C Med Assoc 90 (9): 417–423. PMID 7967534. Becker JT, Overman AA (2002). "The semantic memory deficit in Alzheimer\'s disease" (in Spanish; Castilian). Reviews of Neurology 35 (8): 777–783. PMID 12402233. Hodges JR, Patterson K (1995). "Is semantic memory consistently impaired early in the course of Alzheimer\'s disease? Neuroanatomical and diagnostic implications". Neuropsychologia 33 (4): 441–459. PMID 7617154. While performing fine motor tasks such as writing, drawing or dressing, certain visoconstructional difficulties, or apraxia, may be present, which may appear as clumsiness. Benke T (1993). "Two forms of apraxia in Alzheimer\'s disease". Cortex 29 (4): 715–725. PMID 8124945. As the disease progresses to the middle stage, patients might still be able to live and perform tasks independently for most of the time, but may need assistance or supervision with the most complicated activities. Förstl H, Kurz A (1999). "Clinical features of Alzheimer\'s disease". European Archives of Psychiatry and Clinical Neuroscience 249 (6): 288–290. PMID 10653284.
In the early stage, people with Alzheimer\'s can usually care for themselves. At the moderate stage, progressive deterioration seriously hinders the possibility of independence. Förstl H, Kurz A (1999). "Clinical features of Alzheimer\'s disease". European Archives of Psychiatry and Clinical Neuroscience 249 (6): 288–290. PMID 10653284. Language difficulties become clearly noticeable: the person makes frequent paraphasias due to difficulties in finding words, and content is poor. Reading and writing are also progressively forgotten. Frank EM (1994). "Effect of Alzheimer\'s disease on communication function". J S C Med Assoc 90 (9): 417–423. PMID 7967534. Forbes KE, Shanks MF, Venneri A (2004). "The evolution of dysgraphia in Alzheimer\'s disease". Brain Research Bulletin 63 (1): 19–24. doi:10.1016/j.brainresbull.2003.11.005. PMID 15121235. As time passes, complex motor sequences become less coordinated, costing the patient most of their daily-living abilities. Galasko D, Schmitt F, Thomas R, Jin S, Bennett D (2005). "Detailed assessment of activities of daily living in moderate to severe Alzheimer\'s disease". Journal of the International Neuropsychology Society 11 (4): 446–53. PMID 16209425. Memory problems worsen, and the person may not recognize close relatives. Mendez MF, Martin RJ, Smyth KA, Whitehouse PJ (1992). "Disturbances of person identification in Alzheimer\'s disease. A retrospective study". Journal of Nervous and Mental Disease 180 (2): 94–96. PMID 1737981. Long-term memory, which was previously left intact, is now also impaired.Sartori G, Snitz BE, Sorcinelli L, Daum I (2004). "Remote memory in advanced Alzheimer\'s disease". Archives of Clinical Neuropsychology 19 (6): 779–789. doi:10.1016/j.acn.2003.09.007. PMID 15288331. Patients are usually almost completely unaware of their own deficits, and behavior changes are the norm. Common neuropsychiatric manifestations in this stage are irritability and labile affect, leading to crying or outbursts of unpremeditated aggression and physical violence, even in patients whose life-long behavior has been peaceful. Approximately 30% of the patients also develop illusionary misidentifications and other delusional symptoms.Craig D, Mirakhur A, Hart DJ, McIlroy SP, Passmore AP (2005). "A cross-sectional study of neuropsychiatric symptoms in 435 patients with Alzheimer\'s disease". American Journal of Geriatric Psychiatry 13 (6): 460–468. doi:10.1176/appi.ajgp.13.6.460. PMID 15956265. Tatsch MF, Bottino CM, Azevedo D, Hototian SR, Moscoso MA, Folquitto JC, Scalco AZ, Louzã MR (2006). "Neuropsychiatric symptoms in Alzheimer disease and cognitively impaired, nondemented elderly from a community-based sample in Brazil: prevalence and relationship with dementia severity". American Journal of Geriatric Psychiatry 14 (5): 438–45. doi:10.1097/01.JGP.0000218218.47279.db. PMID 16670248. Often urinary incontinence develops.Honig LS, Mayeux R (2001). "Natural history of Alzheimer\'s disease". Aging (Milano) 13 (3): 171–82. PMID 11442300. Because of delusions and communication deficit, patients often resist when caregiver attempt to provide care.Volicer L, Bass EA, Luther SL (2007). "Agitation and resistiveness to care are two separate behavioral syndromes of dementia". J Am Med Dir Assoc. 2007 Oct;8(8):527-32 8 (8): 527-32. PMID 17931577. It is important to prevent escalation of resistiveness to care into combativeness when patient might strike out. All these symptoms create stress for relatives and caretakers, increasing the likelihood of moving the patient from home care to other long-term care facilities.Förstl H, Kurz A (1999). "Clinical features of Alzheimer\'s disease". European Archives of Psychiatry and Clinical Neuroscience 249 (6): 288–290. PMID 10653284. Gold DP, Reis MF, Markiewicz D, Andres D (1995). "When home caregiving ends: a longitudinal study of outcomes for caregivers of relatives with dementia". Journal of the American Geriatric Society 43 (1): 10–16. PMID 7806732.
In the last stage of Alzheimer\'s disease all human behavior is likely to become entirely automatic. Language is reduced to simple phrases or even single words before being lost altogether.Frank EM (1994). "Effect of Alzheimer\'s disease on communication function". J S C Med Assoc 90 (9): 417–423. PMID 7967534. Nevertheless many patients can receive and return emotional signals long after the loss of verbal language.Bär M, Kruse A, Re S (2003). "Situations of emotional significance in residents suffering from dementia" (in (German)). Z Gerontol Geriatr 36 (6): 454–462. doi:10.1007/s00391-003-0191-0. PMID 14685735. Although aggressiveness can still present, extreme apathy and exhaustion are much more common. Förstl H, Kurz A (1999). "Clinical features of Alzheimer\'s disease". European Archives of Psychiatry and Clinical Neuroscience 249 (6): 288–290. PMID 10653284. Patients will ultimately not be able to perform even the most simple tasks independently. Finally, deterioration of muscle and mobility will develop, leading the patient to become bedriddenSouren LE, Franssen EH, Reisberg B (1995). "Contractures and loss of function in patients with Alzheimer\'s disease". Journal of the American Geriatric Society 43 (6): 650–655. PMID 7775724. and to lose the ability to feed oneselfBerkhout AM, Cools HJ, van Houwelingen HC (1998). "The relationship between difficulties in feeding oneself and loss of weight in nursing-home patients with dementia". Age Ageing 27 (5): 637–641. PMID 12675103. if death from some external cause, such as infection due to pressure ulcers or pneumonia, does not occur first.Wada H, Nakajoh K, Satoh-Nakagawa T, Suzuki T, Ohrui T, Arai H, Sasaki H (2001). "Risk factors of aspiration pneumonia in Alzheimer\'s disease patients". Gerontology 47 (5): 271–276. PMID 11490146. Gambassi G, Landi F, Lapane KL, Sgadari A, Mor V, Bernabei R (1999). "Predictors of mortality in patients with Alzheimer\'s disease living in nursing homes". J Neurol Neurosurg Psychiatr 67 (1): 59–65. PMID 10369823.
Most cases of Alzheimer\'s disease are sporadic, i.e., do not exhibit familial inheritance. Nonetheless, at least 80% of sporadic AD cases most likely involve genetic risk factors. Inheritance of the ε4 allele of the apolipoprotein E (ApoE) gene is regarded as a risk factor for development of up to 50% of late-onset sporadic Alzheimer\'s. Genetic experts agree that there are other risk and protective factor genes that influence the development of late onset Alzheimer\'s disease. Over 400 genes have been tested for association with late-onset sporadic AD. Alzheimer\'s Disease Genetics Fact Sheet. National Institute of Health (2007-10-27). Retrieved on 2008-02-22.
On the other hand, five to ten percent of AD cases involve a clear familial pattern of inheritance in which the patient has at least two first-degree relatives with a history of AD. These cases often have an early age of onset (usually younger than sixty years). Nearly 200 different mutations in the presenilin-1 or presenilin-2 genes have been documented in over 500 families. Mutations of presenilin 1 (PS1) lead to the most aggressive form of familial Alzheimer\'s disease. Over twenty different mutations in the amyloid precursor protein (APP) gene on chromosome 21 can also cause early onset of the disease. The presenilins have been identified as essential components of the proteolytic processing machinery that produces beta amyloid peptides through cleavage of APP. Most mutations in the APP and presenilin genes increase the production of a small protein (peptide) called Abeta42, the main component of senile plaques in brains of AD patients.
MRI images of a normal aged brain (right) and an Alzheimer\'s patient\'s brain (left). In the Alzheimer brain, atrophy is clearly seen.
At a macroscopic level, AD is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.Wenk GL (2003). "Neuropathologic changes in Alzheimer\'s disease". Journal of Clinical Psychiatry 64 Suppl 9: 7–10. PMID 12934968.
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains.Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J (2004). "The importance of neuritic plaques and tangles to the development and evolution of AD". Neurology 62 (11): 1984–1989. PMID 15184601. Plaques are dense, mostly insoluble deposits of amyloid-beta protein and cellular material outside and around neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. Though many older people develop some plaques and tangles, the brains of AD patients have them to a much greater extent and in different brain locations.Bouras C, Hof PR, Giannakopoulos P, Michel JP, Morrison JH (1994). "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): 138–150. PMID 8038565.
Alzheimer\'s disease has been identified as a protein misfolding disease, or proteopathy, due to the accumulation of abnormally folded A-beta and tau proteins in the brains of AD patients.Hashimoto M, Rockenstein E, Crews L, Masliah E (2003). "Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer\'s and Parkinson\'s diseases". Neuromolecular Medicine 4 (1–2): 21–36. doi:10.1385/NMM:4:1-2:21. PMID 14528050. Plaques are made of a peptide called beta-amyloid (also A-beta or Aβ), a protein fragment snipped from a larger protein called amyloid precursor protein (APP). APP is a transmembrane protein; which means that it sticks through the neuron\'s membrane; and is believed to help neurons grow, survive and repair themselves after injury.Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J (2006). "Synapse formation and function is modulated by the amyloid precursor protein". Journal of Neuroscience 26 (27): 7212–7221. doi:10.1523/JNEUROSCI.1450-06.2006. PMID 16822978. Turner PR, O\'Connor K, Tate WP, Abraham WC (2003). "Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory". Prog. Neurobiology 70 (1): 1–32. PMID 12927332. In AD, something causes APP to be divided by enzymes through a mechanism called proteolysis.Hooper NM (2005). "Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein". Biochemical Society Transactions 33 (Pt 2): 335–338. doi:10.1042/BST0330335. PMID 15787600. One of these fragments is beta-amyloid. Beta-amyloid fragments (amyloid fibrils) outside the cell come together into clumps that deposit outside neurons in dense formations known as senile plaques.Ohnishi S, Takano K (2004). "Amyloid fibrils from the viewpoint of protein folding". Cellular Molecular Life Sciences 61 (5): 511–524. doi:10.1007/s00018-003-3264-8. PMID 15004691. Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J (2004). "The importance of neuritic plaques and tangles to the development and evolution of AD". Neurology 62 (11): 1984–1989. PMID 15184601.
AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Healthy neurons have an internal support structure, or cytoskeleton, partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell down to the ends of the axon and back. A special kind of protein, tau, makes the microtubules stable through a process named phosphorylation and is therefore called a microtubule-associated protein.Hernández F, Avila J (2007). "Tauopathies". Cellular Molecular Life Sciences 64 (17): 2219–2233. doi:10.1007/s00018-007-7220-x. PMID 17604998. In AD, tau is changed chemically, becoming hyperphosphorylated. Hyperphosphorylated tau begins to pair with other threads of tau and they become tangled up together inside nerve cell bodies in masses known as neurofibrillary tangles.Goedert M, Spillantini MG, Crowther RA (1991). "Tau proteins and neurofibrillary degeneration". Brain Pathology 1 (4): 279–286. PMID 1669718. When this happens, the microtubules disintegrate, collapsing the neuron\'s transport system. This may result first in malfunctions in communication between neurons and later in the death of the cells.Chun W, Johnson GV (2007). "The role of tau phosphorylation and cleavage in neuronal cell death". Frontiers of Bioscience 12: 733–756. PMID 17127334.
Three major competing hypotheses exist to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is known as the cholinergic hypothesis and suggests that AD is due to reduced biosynthesis of the neurotransmitter acetylcholine. However, the medications that treat acetylcholine deficiency only affect symptoms of the disease and neither halt nor reverse it.Walker LC, Rosen RF (2006). "Alzheimer therapeutics-what after the cholinesterase inhibitors?". Age Ageing 35 (4): 332–335. doi:10.1093/ageing/afl009. PMID 16644763. The cholinergic hypothesis has not maintained widespread support in the face of this evidence, although cholinergic effects have been proposed to initiate large-scale aggregation,Shen ZX (2004). "Brain cholinesterases: II. The molecular and cellular basis of Alzheimer\'s disease". Medical Hypotheses 63 (2): 308–321. doi:10.1016/j.mehy.2004.02.031. PMID 15236795. leading to generalized neuroinflammation.Wenk GL (2003). "Neuropathologic changes in Alzheimer\'s disease". Journal of Clinical Psychiatry 64 Suppl 9: 7–10. PMID 12934968.
In 1991 the amyloid hypothesis was proposed, Hardy J, Allsop D (1991). "Amyloid deposition as the central event in the aetiology of Alzheimer\'s disease". Trends Pharmacol. Sci. 12 (10): 383–8. PMID 1763432. while research after 2000 is also centered on tau proteins. The two positions differ with one stating that the tau protein abnormalities initiate the disease cascade, while the other states that amyloid beta (Aβ) deposits are the causative factor in the disease.Mudher A, Lovestone S (2002). "Alzheimer\'s disease-do tauists and baptists finally shake hands?". Trends in Neuroscience 25 (1): 22–26. PMID 11801334. The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques does not correlate well with neuron loss,Schmitz C, Rutten BP, Pielen A, Schäfer S, Wirths O, Tremp G, Czech C, Blanchard V, Multhaup G, Rezaie P, Korr H, Steinbusch HW, Pradier L, Bayer TA (2004). "Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer\'s disease". Am. J. Pathol. 164 (4): 1495–502. PMID 15039236. but a majority of researchers support the alternative hypothesis that Aβ is the primary causative agent.Mudher A, Lovestone S (2002). "Alzheimer\'s disease-do tauists and baptists finally shake hands?". Trends in Neuroscience 25 (1): 22–26. PMID 11801334. The amyloid hypothesis is compelling because the gene for the amyloid beta precursor (APP) is located on chromosome 21, and patients with trisomy 21 (Down Syndrome) who thus have an extra gene copy almost universally exhibit AD-like disorders by 40 years of age.Nistor M, Don M, Parekh M, Sarsoza F, Goodus M, Lopez GE, Kawas C, Leverenz J, Doran E, Lott IT, Hill M, Head E (2007). "Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain". Neurobiol. Aging 28 (10): 1493–506. doi:10.1016/j.neurobiolaging.2006.06.023. PMID 16904243. Lott IT, Head E (2005). "Alzheimer disease and Down syndrome: factors in pathogenesis". Neurobiology of Aging 26 (3): 383–389. doi:10.1016/j.neurobiolaging.2004.08.005. PMID 15639317. The traditional formulation of the amyloid hypothesis points to the cytotoxicity of mature aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell\'s calcium ion homeostasis and thus inducing apoptosis.Yankner BA, Duffy LK, Kirschner DA (1990). "Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides". Science 250 (4978): 279–282. PMID 2218531. It should be noted further that ApoE4, the major genetic risk factor for AD, leads to excess amyloid build-up in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD.Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, Niinistö L, Halonen P, Kontula K (1995). "Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein". New England Journal of Medicine 333 (19): 1242–1247. PMID 7566000. Another strong support for the amyloid hypothesis, which looks at Aβ as the common initiating factor for Alzheimer\'s disease, is that transgenic mice solely expressing a mutant human APP gene develop fibrillar amyloid plaques.Beta-amyloid precursor protein
Dementia is by definition a clinical condition but not an exact diagnosis. Alzheimer\'s disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions.Mendez MF (2006). "The accurate diagnosis of early-onset dementia". International Journal of Psychiatry Medicine 36 (4): 401–412. PMID 17407994. Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J (2006). "Therapeutic approaches to Alzheimer\'s disease". Brain 129 (Pt 11): 2840–2855. doi:10.1093/brain/awl280. PMID 17018549. Advanced medical imaging with CT or MRI are generally used to help to diagnose the subtype of dementia and exclude other cerebral pathology. Dementia: Quick reference guide (PDF). National Institute for Health and Clinical Excellence (November 2006). Retrieved on 2008-02-22. Neuropsychological evaluation including memory testing and assessment of intellectual functioning can further characterize the dementia. Waldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, Scheltens P, Tariska P, Winblad B (2007). "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. doi:10.1111/j.1468-1331.2006.01605.x. PMID 17222085. Medical organizations have created diagnostic criteria to ease and standardize the process for practicing physicians. Sometimes the diagnoses can be confirmed or made at postmortem when brain material is available and can be examined histologically and histochemically. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984). "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. PMID 6610841.
The diagnostic criteria for Alzheimer of the NINCDS-ADRDA (NINCDS and the ADRDA) are among the most used.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 (2007). "Research criteria for the diagnosis of Alzheimer\'s disease: revising the NINCDS-ADRDA criteria". Lancet Neurology 6 (8): 734–746. doi:10.1016/S1474-4422(07)70178-3. PMID 17616482. 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 while they need histopathologic confirmation (microscopic examination of brain tissue) for the definitive diagnosis. They have shown good reliability and validity. Blacker D, Albert MS, Bassett SS, Go RC, Harrell LE, Folstein MF (1994). "Reliability and validity of NINCDS-ADRDA criteria for Alzheimer\'s disease. The National Institute of Mental Health Genetics Initiative". Archives of Neurology 51 (12): 1198–1204. PMID 7986174. They specify as well eight cognitive domains that may be impaired in AD (i.e., memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional abilities). Similar to the NINCDS-ADRDA Alzheimer\'s Criteria are the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria published by the American Psychiatric Association. American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental disorders, 4th Edition Text Revision. Ito N (1996). "Clinical aspects of dementia" (in Japanese). Hokkaido Igaku Zasshi 71 (3): 315–320. PMID 8752526.
Neuropsychological screening tests as the Mini mental state examination (MMSE) are widely used to evaluate the cognitive impairments needed for diagnosis, but more comprehensive batteries are necessary for high reliability by this method; especially in the earliest stages of the disease. Tombaugh TN, McIntyre NJ (1992). "The mini-mental state examination: a comprehensive review". J Am Geriatr Soc 40 (9): 922–935. PMID 1512391.
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