329:
553:(APP). Once APP is activated, it is cut into smaller sections of other proteins. One of the fragments produced in this cutting process is β-amyloid. β-amyloid is "stickier" than any other fragment produced from cut-up APP, so it starts an accumulation process in the brain, which is due to various genetic and biochemical abnormalities. Eventually, the fragments form oligomers, then fibrils, beta-sheets, and finally plaques. The presence of β-amyloid plaques in the brain causes the body to recruit and activate microglial cells and astrocytes.
321:
560:, APP is cleaved by a membrane-bound protein complex called γ-secretase to generate Aβ. Presenilins 1 and 2 are the enzymatic centers of this complex along with nicastrin, Aph1, and PEN-2. Alpha-secretase cleavage of APP, which precludes the production of Aβ, is the most common processing event for APP. 21 allelic mutations have been discovered in the APP gene. These guarantee onset of early-onset familial Alzheimer disease and all occur in the region of the APP gene that encodes the Aβ domain.
389:, and the coding portion is estimated at 60 kb, as reported by Rogaev (1997) and Del-Favero (1999). The protein the gene codes for (PS1) is an integral membrane protein. As stated by Ikeuchi (2002) it cleaves the protein Notch1 so is thought by Koizumi (2001) to have a role in somitogenesis in the embryo. It also has an action on an amyloid precursor protein, which gives its probable role in the pathogenesis of FAD. Homologs of PS1 have been found in plants, invertebrates and other vertebrates.
228:. Familial Alzheimer's disease (FAD or EOFAD for early onset) is an inherited and uncommon form of AD. Familial AD usually strikes earlier in life, defined as before the age of 65. FAD usually implies multiple persons affected in one or more generation. Nonfamilial cases of AD are referred to as "sporadic" AD, where genetic risk factors are minor or unclear. Familial Alzheimer's accounts for 10-15% of all EOAD cases. The rest are sporadic and not based on genetic mutations.
546:
cells (specifically astrocytes and microglia), beta-amyloid, and proinflammatory compounds. As neurons are injured and die throughout the brain, connections between networks of neurons may break down, and many brain regions begin to shrink. By the final stages of
Alzheimer's, this process – called brain atrophy – is widespread, causing significant loss of brain volume. This loss of brain volume affects ones ability to live and function properly, ultimately being fatal.
36:
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128:
414:. It is located on chromosome 1 (1q31-q42), and mutations in this gene cause type 4 FAD. This type accounts for less than 5% of all EOFAD cases. The gene was identified by Rudolph Tanzi and Jerry Schellenberg in 1995. A subsequent study by Kovacs (1996) showed that PS1 and PS2 proteins are expressed in similar amounts, and in the same
585:
to the full range of benefits available to those who retire at the minimum age set by the government. With some jobs, a mistake may have devastating consequences on a large number of people, and cases have been reported in which a person with early-onset
Alzheimer's who is unaware of their condition has caused distress.
1699:
Goate, Alison; Chartier-Harlin, Marie-Christine; Mullan, Mike; Brown, Jeremy; Crawford, Fiona; Fidani, Liana; Giuffra, Luis; Haynes, Andrew; Irving, Nick; James, Louise; Mant, Rebecca; Newton, Phillippa; Rooke, Karen; Roques, Penelope; Talbot, Chris; Pericak-Vance, Margaret; Roses, Alien; Williamson,
456:
Other allelic variants are Met239Val which was identified in an
Italian pedigree by Rogaev (1995) who also suggested early on that the gene may be similar to PSEN1, and an Asp439Ala mutation in exon 12 of the gene which is suggested by Lleo (2001) to change the endoproteolytic processing of the PS2.
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Those who are working lose their ability to perform their jobs competently, and are forced into early retirement. When this can be predicted, employees must discuss their future with their employers and the loss of skills they expect to face. Those who are forced to retire early may not have access
377:
located on chromosome 14) was identified by
Sherrington (1995) and multiple mutations have been identified. Mutations in this gene cause familial Alzheimer's type 3 with certainty and usually under 50 years old. This type accounts for 30–70% of EOFAD. This protein has been identified as part of the
627:
While early-onset familial AD is estimated to account for only 1% of total
Alzheimer's disease, it has presented a useful model in studying various aspects of the disorder. Currently, the early-onset familial AD gene mutations guide the vast majority of animal model-based therapeutic discovery and
545:
The underlying neurobiology of this disease is just recently starting to be understood. Researchers have been working on mapping the inflammation pathways associated with the development, progression, and degenerative properties of AD. The major molecules involved in these pathways include glial
444:, but distinct allelic variants have been identified. These include Asn141Ile, which was identified first by Rudolph Tanzi and Jerry Schellenberg in Volga German families with familial Alzheimer disease (Levy-Lahad et al. Nature, 1995). One of these studies by Nochlin (1998) found severe amyloid
591:
It has been suggested that conceptualizations of
Alzheimer's and ageing should resist the notion that there are two distinct conditions. A binary model, which focuses in particular on the needs of younger people, could lead to the challenges experienced by older people being understated.
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that progress through the brain. Very rarely, the plaque may be unique, or uncharacteristic of AD; this can happen when a mutation occurs in one of the genes that creates a functional, but malformed, protein instead of the ineffective gene products that usually result from mutations.
1895:
Johnston JA, Cowburn RF, Norgren S, Wiehager B, Venizelos N, Winblad B, et al. (November 1994). "Increased beta-amyloid release and levels of amyloid precursor protein (APP) in fibroblast cell lines from family members with the
Swedish Alzheimer's disease APP670/671 mutation".
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located on the long arm of chromosome 21 (21q21.3) cause familial
Alzheimer disease. Further research into molecules like miR-212-3p might shed new light on potential therapeutic approaches for Alzheimer's disease, possibly alongside interventions targeted at APP.
571:
is available for symptomatic individuals and asymptomatic relatives. Among families with EOFAD, 40–80% will have a detectable mutation in the APP, PSEN1, or PSEN2 gene. Therefore, some families with EOFAD will not have an identifiable mutation by testing.
517:
Non-genetic risk factors for early onset sporadic
Alzheimer's disease and other forms of early onset dementia are understudied. However, recent research suggests that there are multiple modifiable and nonmodifiable risk factors for young onset dementia.
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Rogaev EI, Sherrington R, Wu C, Levesque G, Liang Y, Rogaeva EA, et al. (March 1997). "Analysis of the 5' sequence, genomic structure, and alternative splicing of the presenilin-1 gene (PSEN1) associated with early onset
Alzheimer disease".
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Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, et al. (August 1995). "Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene".
580:
The atypical lifecourse timing of early-onset Alzheimer's means that it presents distinctive impacts upon experience. For example, the disease can have devastating effects on the careers, caretakers and family members of patients.
1275:
Kovacs DM, Fausett HJ, Page KJ, Kim TW, Moir RD, Merriam DE, et al. (February 1996). "Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells".
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in the affected individuals in a family. This phenotype may be explained by a study by Tomita (1997) suggesting that the Asn141Ile mutation alters APP metabolism causing an increased rate of protein deposition into plaques.
716:
452:
Similarly, miR-212-3p, another molecule implicated in Alzheimer's disease, has recently been shown to control inflammation in the brain, which could potentially influence plaque formation and Alzheimer's progression.
484:
As of 2023, the count of known pathogenic APP mutations stands at just over 20. The most prevalent among these mutations - APP V717I, known as the London Mutation - was first identified in 1991 within the family of
200:
diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive family history of Alzheimer's and 13% of them are inherited in an
1069:
Del-Favero J, Goossens D, Van den Bossche D, Van Broeckhoven C (March 1999). "YAC fragmentation with repetitive and single-copy sequences: detailed physical mapping of the presenilin 1 gene on chromosome 14".
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618:
in 1906. Because of the overwhelming importance Kraepelin attached to finding the neuropathological basis of psychiatric disorders, Kraepelin made the decision that the disease would bear Alzheimer's name.
1802:
Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, Lannfelt L (August 1992). "A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid".
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Early-onset Alzheimer's disease strikes earlier in life, defined as before the age of 65 (usually between 30 and 60 years of age). Early signs of AD include unusual memory loss, particularly in
3414:
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1751:
Lloyd, Grace M.; Trejo-Lopez, Jorge A.; Xia, Yuxing; McFarland, Karen N.; Lincoln, Sarah J.; Ertekin-Taner, Nilüfer; Giasson, Benoit I.; Yachnis, Anthony T.; Prokop, Stefan (December 2020).
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1319:
Levy-Lahad E, Poorkaj P, Wang K, Fu YH, Oshima J, Mulligan J, Schellenberg GD (June 1996). "Genomic structure and expression of STM2, the chromosome 1 familial Alzheimer disease gene".
982:
Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. (June 1995). "Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease".
1530:
Lleó A, Blesa R, Gendre J, Castellví M, Pastor P, Queralt R, Oliva R (November 2001). "A novel presenilin 2 gene mutation (D439A) in a patient with early-onset Alzheimer's disease".
205:
manner. Most cases of early-onset Alzheimer's share the same traits as the "late-onset" form and are not caused by known genetic mutations. Little is understood about how it starts.
1356:"The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue"
1105:
Ikeuchi T, Sisodia SS (2002). "Cell-free generation of the notch1 intracellular domain (NICD) and APP-CTfgamma: evidence for distinct intramembranous "gamma-secretase" activities".
1700:
Robert; Rossor, Martin; Owen, Mike; Hardy, John (February 1991). "Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease".
396:, but a common mutation is Glu318Gly and this predisposes individuals to familial AD, with a study by Taddei (2002) finding an incidence of 8.7% in patients with familial AD.
46:
1224:
Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, et al. (August 1995). "Candidate gene for the chromosome 1 familial Alzheimer's disease locus".
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505:
mutation, as well as other mutations in the APP at codon 717, shifts the ratio of toxic Aβ species to the more aggregate-prone 42 amino-acid length peptide, while the
1753:"Prominent amyloid plaque pathology and cerebral amyloid angiopathy in APP V717I (London) carrier – phenotypic variability in autosomal dominant Alzheimer's disease"
208:
Nonfamilial early-onset AD can develop in people who are in their 30s or 40s, but this is extremely rare, and mostly people in their 50s or early 60s are affected.
2756:
2021:
Hendriks, Stevie; Ranson, Janice M.; Peetoom, Kirsten; Lourida, Ilianna; Tai, Xin You; de Vugt, Marjolein; Llewellyn, David J.; Köhler, Sebastian (2023-12-26).
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mutation, located at the cleavage site for β-secretase, results in an overall higher production of Aβ peptides by increasing the β-secretory cleavage, the
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and Arctic mutations. Functional analyses of these mutations have significantly increased the understanding of the disease pathogenesis. Whereas the
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107:
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Koizumi K, Nakajima M, Yuasa S, Saga Y, Sakai T, Kuriyama T, et al. (April 2001). "The role of presenilin 1 during somite segmentation".
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Some of the mutations in the gene, of which over 90 are known, include: His163Arg, Ala246Glu, Leu286Val and Cys410Tyr. Most display complete
79:
3379:
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1941:"Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability"
300:. In the later stages of EOAD, persons with EOAD forget how to perform simple tasks such as brushing their hair and require full-time care.
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3205:
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1575:"miR-212-3p attenuates neuroinflammation of rats with Alzheimer's disease via regulating the SP1/BACE1/NLRP3/Caspase-1 signaling pathway"
1423:"miR-212-3p attenuates neuroinflammation of rats with Alzheimer's disease via regulating the SP1/BACE1/NLRP3/Caspase-1 signaling pathway"
86:
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673:, an award-winning Indian film detailing the effects of early-onset Alzheimer's disease on a father and his relationship with his son.
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93:
835:
Bertram L, Tanzi RE (October 2008). "Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses".
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339:. iPSCs from a patient with familial Alzheimer's disease, a mutation in the PSEN1 gene. TUJ-1-positive cells express a marker (
75:
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437:. This protein has been identified as part of the enzymatic complex that cleaves amyloid beta peptide from APP (see below).
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Younger people with Alzheimer's may also lose their ability to take care of their own needs, such as money management.
54:
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1185:"Association between presenilin-1 Glu318Gly mutation and familial Alzheimer's disease in the Australian population"
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65:
50:
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1982:"Physiochemical characterization of the Alzheimer's disease-related peptides A beta 1-42Arctic and A beta 1-42wt"
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Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, et al. (September 2001).
100:
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mutation leads to a conformation change of the Aβ peptide and increased formation of toxic Aβ protofibrils.
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contained 12 exons, 10 of which were coding exons, and that the primary transcript encodes a 448-amino-acid
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1847:"The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation"
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614:, who worked in Alzheimer's laboratory, and the characteristic neuropathology was first observed by
17:
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Familial Alzheimer disease is caused by a mutation in one of at least three genes, which code for
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2336:"The Burgeoning Interest in Young Onset Dementia: Redressing the balance or reinforcing ageism?"
2098:"Astrocytic and microglial cells as the modulators of neuroinflammation in Alzheimer's disease"
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2137:
2119:
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2003:
1980:
Johansson AS, Berglind-Dehlin F, Karlsson G, Edwards K, Gellerfors P, Lannfelt L (June 2006).
1962:
1913:
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244:). As the disease progresses, the patient exhibits more serious problems, becoming subject to
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529:, familial AD is practically indistinguishable from other forms of the disease. Deposits of
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Tomita T, Maruyama K, Saido TC, Kume H, Shinozaki K, Tokuhiro S, et al. (March 1997).
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and unable to perform complex activities such as driving. Other common findings include
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2407:"Genome-wide association study of brain connectivity changes for Alzheimer's disease"
1998:
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fashion, identified by genetics and other characteristics such as the age of onset.
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Taddei K, Fisher C, Laws SM, Martins G, Paton A, Clarnette RM, et al. (2002).
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Proceedings of the National Academy of Sciences of the United States of America
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739:"The prevalence and causes of dementia in people under the age of 65 years"
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if you can. Unsourced or poorly sourced material may be challenged and
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Spinal muscular atrophy with lower extremity predominance (SMALED)
1632:
Molecular Neuropharmacology: A Foundation for Clinical Neuroscience
1573:
Nong, Wei; Bao, Chuanhong; Chen, Yixin; Wei, Zhiquan (2022-07-29).
1421:
Nong, Wei; Bao, Chuanhong; Chen, Yixin; Wei, Zhiquan (2022-07-29).
2370:
Weber MM (1997). "Aloys Alzheimer, a coworker of Emil Kraepelin".
534:
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406:
373:
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Elsheikh, SS; Chimusa, ER; Mulder, NJ; Crimi, A (January 2020).
557:
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29:
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Familial AD is inherited in an autosomal dominant fashion.
2155:
Chow VW, Mattson MP, Wong PC, Gleichmann M (March 2010).
2023:"Risk Factors for Young-Onset Dementia in the UK Biobank"
657:, a documentary film about the farewell tour of musician
549:
Beta-amyloid is a small piece of a larger protein called
2223:
Family shares journey after early Alzheimer's diagnosis
788:"Genetics of familial and sporadic Alzheimer s disease"
335:
neuronal culture after 40 days of differentiation from
61:
2205:
Early-onset Alzheimer's: When symptoms begin before 65
935:"Genetics of Alzheimer's disease: a centennial review"
481:
This type accounts for no more than 10–15% of EOFAD.
2463:
2157:"An overview of APP processing enzymes and products"
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following his diagnosis with early-onset Alzheimer's
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2073:"What Happens to the Brain in Alzheimer's Disease?"
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2343:The International Journal of Ageing and Later Life
743:Journal of Neurology, Neurosurgery, and Psychiatry
606:The symptoms of Alzheimer's disease as a distinct
347:(green). Cell nuclei are stained with DAPI (blue).
27:Alzheimer's disease developed before the age of 65
881:Williamson J, Goldman J, Marder KS (March 2009).
2295:"Who thinks of Alzheimer's in someone so young?"
1634:(2nd ed.). New York: McGraw-Hill Medical.
537:tissue. This amyloid protein forms plaques and
440:The mutations have not been studied as much as
410:) is very similar in structure and function to
60:Please review the contents of the article and
2559:
8:
928:
926:
728:
726:
717:"What Are the Signs of Alzheimer's Disease?"
212:Familial and nonfamilial Alzheimer's disease
2244:Living With Early-Onset Alzheimer's Disease
469:Processing of the amyloid precursor protein
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493:. Other notable APP mutations include the
139:
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2131:
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1997:
1956:
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1630:Malenka EJ, Nestler SE, Hyman RC (2009).
1606:
1579:Bosnian Journal of Basic Medical Sciences
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1427:Bosnian Journal of Basic Medical Sciences
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1379:
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461:APP – amyloid beta (A4) precursor protein
425:cells. Levy-Lahad (1996) determined that
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683:
475:amyloid beta A4 precursor protein (APP)
3355:Distal hereditary motor neuronopathies
3028:Template:Demyelinating diseases of CNS
2319:Young Onset Dementia: a label too far?
2293:Fackelmann, Kathleen (June 11, 2007).
883:"Genetic aspects of Alzheimer disease"
242:logopenic primary progressive aphasia
7:
3206:Idiopathic intracranial hypertension
1757:Acta Neuropathologica Communications
337:induced human pluripotent stem cells
240:and the names of people and things (
18:Early onset Alzheimer's disease
2268:Early Onset Alzheimer's On The Rise
3437:Infantile progressive bulbar palsy
692:"Younger/ Early-onset Alzheimer's"
602:Alzheimer's disease § History
25:
3140:Template:Cerebrovascular diseases
2943:Frontotemporal lobar degeneration
649:, whose main protagonist has EOAD
190:younger-onset Alzheimer's disease
157:Younger-onset Alzheimer's disease
76:"Early-onset Alzheimer's disease"
3160:For more detailed coverage, see
3138:For more detailed coverage, see
3109:For more detailed coverage, see
3075:For more detailed coverage, see
3026:For more detailed coverage, see
1999:10.1111/j.1742-4658.2006.05263.x
610:entity were first identified by
126:
34:
2372:Journal of Psychiatric Research
2323:Dementia Society, July 27, 2016
1939:De Jonghe, C. (1 August 2001).
933:Ertekin-Taner N (August 2007).
733:Harvey RJ, Skelton-Robinson M,
378:enzymatic complex that cleaves
308:Familial AD is inherited in an
182:Early-onset Alzheimer's disease
143:Early-onset Alzheimer's disease
2256:Cleveland Clinic Health System
216:Alzheimer's disease (AD) is a
62:add the appropriate references
1:
3453:Amyotrophic lateral sclerosis
3338:Hereditary spastic paraplegia
3196:Normal pressure hydrocephalus
2384:10.1016/S0022-3956(97)00035-6
2096:Singh, Deepali (2022-08-17).
1084:10.1016/S0378-1119(99)00023-2
220:and the most common cause of
3422:Progressive muscular atrophy
2356:10.3384/ijal.1652-8670.16302
2102:Journal of Neuroinflammation
2039:10.1001/jamaneurol.2023.4929
1910:10.1016/0014-5793(94)01137-0
899:10.1097/NRL.0b013e318187e76b
837:Nature Reviews. Neuroscience
2932:Primary progressive aphasia
2077:National Institute on Aging
533:can be seen in sections of
343:) of mature neurons (red).
47:reliable medical references
3500:
3254:Hashimoto's encephalopathy
2960:Posterior cortical atrophy
2781:Striatonigral degeneration
2632:Cavernous sinus thrombosis
2431:10.1038/s41598-020-58291-1
2280:February 10, 2009, at the
2115:10.1186/s12974-022-02565-0
1680:. Alzheimer Research Forum
1658:. Alzheimer Research Forum
599:
489:by a research team led by
3360:Spinal muscular atrophies
3328:Primary lateral sclerosis
3186:Intracranial hypertension
2966:Creutzfeldt–Jakob disease
2173:10.1007/s12017-009-8104-z
1770:10.1186/s40478-020-0891-3
951:10.1016/j.ncl.2007.03.009
551:amyloid precursor protein
238:remembering recent events
218:neurodegenerative disease
53:or relies too heavily on
3427:Progressive bulbar palsy
3218:Intracranial hypotension
3201:Choroid plexus papilloma
2615:Herpesviral encephalitis
1945:Human Molecular Genetics
1591:10.17305/bjbms.2021.6723
1439:10.17305/bjbms.2021.6723
513:Non-genetic risk factors
2939:Frontotemporal dementia
2625:Encephalitis lethargica
2161:Neuromolecular Medicine
1246:10.1126/science.7638622
1107:Neuromolecular Medicine
792:Frontiers in Bioscience
786:Piaceri, Irene (2013).
696:Alzheimer's Association
539:neurofibrillary tangles
404:The presenilin 2 gene (
371:The presenilin 1 gene (
224:; it usually occurs in
211:
3244:Hepatic encephalopathy
1958:10.1093/hmg/10.16.1665
1544:10.1212/WNL.57.10.1926
1381:10.1073/pnas.94.5.2025
1333:10.1006/geno.1996.0266
1162:10.1242/dev.128.8.1391
1048:10.1006/geno.1996.4523
755:10.1136/jnnp.74.9.1206
556:Following cleavage by
470:
348:
325:
3302:Ataxia–telangiectasia
3259:Static encephalopathy
2982:Mitochondrial disease
2820:Spasmodic torticollis
2730:Basal ganglia disease
1202:10.1038/sj.mp.4001072
468:
433:with 67% homology to
385:The gene contains 14
331:
323:
278:Parkinsonian deficits
3249:Toxic encephalopathy
2955:Lewy bodies dementia
2231:(September 2, 2008).
2221:Mary Brophy Marcus,
1678:"APP V717I (London)"
1189:Molecular Psychiatry
654:Spirit Unforgettable
628:development for AD.
400:PSEN2 – Presenilin 2
380:amyloid-beta peptide
367:PSEN1 – Presenilin 1
290:urinary incontinence
258:language disturbance
3484:Alzheimer's disease
3297:Friedreich's ataxia
2680:Meningoencephalitis
2620:Limbic encephalitis
2423:2020NatSR..10.1433E
2334:Tolhurst E (2016).
2317:Rahman, S. (2016).
2307:on August 19, 2009.
2203:Mayo Clinic staff,
1854:Nature Neuroscience
1714:1991Natur.349..704G
1493:1995Natur.376..775R
1372:1997PNAS...94.2025T
1238:1995Sci...269..973L
996:1995Natur.375..754S
623:Research directions
345:GABA-positive cells
198:Alzheimer's disease
3333:Pseudobulbar palsy
3071:Status epilepticus
3022:Multiple sclerosis
2859:Myoclonic epilepsy
2722:movement disorders
2668:Acute disseminated
2610:Viral encephalitis
2411:Scientific Reports
2249:2007-10-19 at the
1866:10.1038/nn0901-887
1816:10.1038/ng0892-345
1290:10.1038/nm0296-224
1119:10.1385/NMM:1:1:43
939:Neurologic Clinics
737:(September 2003).
663:Spirit of the West
471:
418:as each other, in
349:
326:
310:autosomal dominant
294:fecal incontinence
232:Signs and symptoms
203:autosomal dominant
3471:
3470:
3467:
3466:
3463:
3462:
3267:
3266:
3172:
3171:
3111:Template:Headache
3077:Template:Epilepsy
2998:
2997:
2972:Vascular dementia
2815:Status dystonicus
2688:
2687:
2663:Encephalomyelitis
2541:
2540:
2276:(March 8, 2008).
1992:(12): 2618–2630.
1951:(16): 1665–1671.
1708:(6311): 704–706.
1538:(10): 1926–1928.
1487:(6543): 775–778.
1232:(5226): 973–977.
990:(6534): 754–760.
945:(3): 611–667, v.
670:Thanmathra (film)
473:Mutations to the
179:
178:
137:Medical condition
135:
134:
111:
16:(Redirected from
3491:
3285:
3276:
3234:Brain herniation
3045:
2885:Intention tremor
2880:Essential tremor
2745:Postencephalitic
2713:
2704:
2593:
2574:Diseases of the
2568:
2561:
2554:
2545:
2465:
2453:
2452:
2442:
2402:
2396:
2395:
2367:
2361:
2360:
2358:
2340:
2331:
2325:
2315:
2309:
2308:
2303:. Archived from
2290:
2284:
2265:
2259:
2241:
2232:
2219:
2213:
2201:
2195:
2194:
2184:
2152:
2146:
2145:
2135:
2117:
2093:
2087:
2086:
2084:
2083:
2069:
2063:
2062:
2053: 10751655.
2018:
2012:
2011:
2001:
1986:The FEBS Journal
1977:
1971:
1970:
1960:
1936:
1930:
1929:
1892:
1886:
1885:
1851:
1842:
1836:
1835:
1799:
1793:
1792:
1782:
1772:
1748:
1742:
1741:
1722:10.1038/349704a0
1696:
1690:
1689:
1687:
1685:
1674:
1668:
1667:
1665:
1663:
1652:
1646:
1645:
1627:
1621:
1620:
1610:
1570:
1564:
1563:
1527:
1521:
1520:
1501:10.1038/376775a0
1475:
1469:
1468:
1458:
1418:
1412:
1411:
1401:
1383:
1366:(5): 2025–2030.
1351:
1345:
1344:
1316:
1310:
1309:
1272:
1266:
1265:
1221:
1215:
1214:
1204:
1180:
1174:
1173:
1156:(8): 1391–1402.
1145:
1139:
1138:
1102:
1096:
1095:
1078:(1–2): 193–201.
1066:
1060:
1059:
1030:
1024:
1023:
1004:10.1038/375754a0
979:
973:
972:
962:
930:
921:
920:
910:
878:
869:
868:
832:
826:
825:
807:
783:
777:
776:
766:
749:(9): 1206–1209.
730:
721:
720:
713:
707:
706:
704:
702:
688:
140:
130:
129:
121:
118:
112:
110:
69:
38:
37:
30:
21:
3499:
3498:
3494:
3493:
3492:
3490:
3489:
3488:
3474:
3473:
3472:
3459:
3385:Congenital DSMA
3306:
3263:
3222:
3168:
3156:Sleep disorders
3144:
3121:Cerebrovascular
3115:
3081:
3038:
3032:
2994:
2976:
2901:
2847:Choreoathetosis
2720:
2697:
2684:
2648:
2582:
2572:
2542:
2537:
2536:
2476:
2462:
2457:
2456:
2404:
2403:
2399:
2369:
2368:
2364:
2338:
2333:
2332:
2328:
2316:
2312:
2292:
2291:
2287:
2282:Wayback Machine
2266:
2262:
2251:Wayback Machine
2242:
2235:
2220:
2216:
2202:
2198:
2154:
2153:
2149:
2095:
2094:
2090:
2081:
2079:
2071:
2070:
2066:
2020:
2019:
2015:
1979:
1978:
1974:
1938:
1937:
1933:
1894:
1893:
1889:
1849:
1844:
1843:
1839:
1804:Nature Genetics
1801:
1800:
1796:
1750:
1749:
1745:
1698:
1697:
1693:
1683:
1681:
1676:
1675:
1671:
1661:
1659:
1654:
1653:
1649:
1642:
1629:
1628:
1624:
1572:
1571:
1567:
1529:
1528:
1524:
1477:
1476:
1472:
1420:
1419:
1415:
1353:
1352:
1348:
1318:
1317:
1313:
1278:Nature Medicine
1274:
1273:
1269:
1223:
1222:
1218:
1182:
1181:
1177:
1147:
1146:
1142:
1104:
1103:
1099:
1068:
1067:
1063:
1032:
1031:
1027:
981:
980:
976:
932:
931:
924:
887:The Neurologist
880:
879:
872:
849:10.1038/nrn2494
843:(10): 768–778.
834:
833:
829:
785:
784:
780:
732:
731:
724:
715:
714:
710:
700:
698:
690:
689:
685:
680:
634:
625:
616:Alois Alzheimer
604:
598:
578:
569:Genetic testing
566:
564:Genetic testing
524:
515:
463:
402:
369:
318:
306:
234:
214:
188:), also called
163:
138:
131:
127:
122:
116:
113:
70:
59:
55:primary sources
39:
35:
28:
23:
22:
15:
12:
11:
5:
3497:
3495:
3487:
3486:
3476:
3475:
3469:
3468:
3465:
3464:
3461:
3460:
3458:
3457:
3456:
3455:
3444:
3443:
3442:
3441:
3440:
3439:
3434:
3424:
3419:
3418:
3417:
3412:
3407:
3406:
3405:
3400:
3395:
3387:
3382:
3377:
3372:
3367:
3357:
3343:
3342:
3341:
3340:
3335:
3330:
3316:
3314:
3308:
3307:
3305:
3304:
3299:
3293:
3291:
3282:
3273:
3269:
3268:
3265:
3264:
3262:
3261:
3256:
3251:
3246:
3241:
3236:
3230:
3228:
3224:
3223:
3221:
3220:
3215:
3213:Cerebral edema
3210:
3209:
3208:
3203:
3198:
3193:
3182:
3180:
3174:
3173:
3170:
3169:
3167:
3166:
3165:
3164:
3162:Template:Sleep
3152:
3150:
3146:
3145:
3143:
3142:
3136:
3131:
3125:
3123:
3117:
3116:
3114:
3113:
3107:
3102:
3097:
3091:
3089:
3083:
3082:
3080:
3079:
3073:
3068:
3063:
3057:
3055:
3042:
3034:
3033:
3031:
3030:
3024:
3019:
3014:
3008:
3006:
3000:
2999:
2996:
2995:
2993:
2992:
2990:Leigh syndrome
2986:
2984:
2978:
2977:
2975:
2974:
2963:
2962:
2957:
2952:
2951:
2950:
2936:
2935:
2934:
2929:
2928:
2927:
2911:
2909:
2903:
2902:
2900:
2899:
2894:
2889:
2888:
2887:
2882:
2871:
2870:
2869:
2868:
2863:
2862:
2861:
2851:
2850:
2849:
2839:
2834:
2833:
2832:
2827:
2822:
2817:
2801:
2800:
2799:
2798:
2793:
2788:
2783:
2778:
2777:
2776:
2766:
2765:
2764:
2754:
2753:
2752:
2747:
2742:
2726:
2724:
2717:Extrapyramidal
2710:
2701:
2699:encephalopathy
2690:
2689:
2686:
2685:
2683:
2682:
2677:
2672:
2671:
2670:
2659:
2657:
2650:
2649:
2647:
2646:
2645:
2644:
2634:
2629:
2628:
2627:
2622:
2617:
2612:
2601:
2599:
2590:
2584:
2583:
2576:nervous system
2573:
2571:
2570:
2563:
2556:
2548:
2539:
2538:
2535:
2534:
2523:
2512:
2497:
2477:
2472:
2471:
2469:
2468:Classification
2461:
2460:External links
2458:
2455:
2454:
2397:
2378:(6): 635–643.
2362:
2326:
2310:
2285:
2260:
2233:
2214:
2196:
2147:
2088:
2064:
2033:(2): 134–142.
2027:JAMA Neurology
2013:
1972:
1931:
1904:(3): 274–278.
1887:
1860:(9): 887–893.
1837:
1810:(5): 345–347.
1794:
1743:
1691:
1669:
1647:
1641:978-0071481274
1640:
1622:
1585:(4): 540–552.
1565:
1522:
1470:
1433:(4): 540–552.
1413:
1346:
1327:(2): 198–204.
1311:
1284:(2): 224–229.
1267:
1216:
1195:(7): 776–781.
1175:
1140:
1097:
1061:
1042:(3): 415–424.
1025:
974:
922:
870:
827:
798:(1): 167–177.
778:
722:
708:
682:
681:
679:
676:
675:
674:
666:
650:
643:and the movie
633:
630:
624:
621:
612:Emil Kraepelin
600:Main article:
597:
594:
577:
574:
565:
562:
527:Histologically
523:
520:
514:
511:
487:Carol Jennings
462:
459:
401:
398:
368:
365:
317:
314:
305:
302:
270:hallucinations
233:
230:
213:
210:
177:
176:
171:
165:
164:
162:
161:
158:
155:
151:
149:
145:
144:
136:
133:
132:
125:
123:
42:
40:
33:
26:
24:
14:
13:
10:
9:
6:
4:
3:
2:
3496:
3485:
3482:
3481:
3479:
3454:
3451:
3450:
3449:
3446:
3445:
3438:
3435:
3433:
3430:
3429:
3428:
3425:
3423:
3420:
3416:
3413:
3411:
3408:
3404:
3401:
3399:
3396:
3394:
3391:
3390:
3388:
3386:
3383:
3381:
3378:
3376:
3373:
3371:
3368:
3366:
3363:
3362:
3361:
3358:
3356:
3353:
3352:
3351:
3349:
3345:
3344:
3339:
3336:
3334:
3331:
3329:
3326:
3325:
3324:
3322:
3318:
3317:
3315:
3313:
3309:
3303:
3300:
3298:
3295:
3294:
3292:
3290:
3286:
3283:
3281:
3277:
3274:
3270:
3260:
3257:
3255:
3252:
3250:
3247:
3245:
3242:
3240:
3239:Reye syndrome
3237:
3235:
3232:
3231:
3229:
3225:
3219:
3216:
3214:
3211:
3207:
3204:
3202:
3199:
3197:
3194:
3192:
3191:Hydrocephalus
3189:
3188:
3187:
3184:
3183:
3181:
3179:
3175:
3163:
3159:
3158:
3157:
3154:
3153:
3151:
3147:
3141:
3137:
3135:
3132:
3130:
3127:
3126:
3124:
3122:
3118:
3112:
3108:
3106:
3103:
3101:
3098:
3096:
3093:
3092:
3090:
3088:
3084:
3078:
3074:
3072:
3069:
3067:
3064:
3062:
3059:
3058:
3056:
3054:
3050:
3046:
3043:
3041:
3035:
3029:
3025:
3023:
3020:
3018:
3015:
3013:
3010:
3009:
3007:
3005:
3004:Demyelinating
3001:
2991:
2988:
2987:
2985:
2983:
2979:
2973:
2970:
2969:
2968:
2967:
2961:
2958:
2956:
2953:
2949:
2946:
2945:
2944:
2940:
2937:
2933:
2930:
2926:
2923:
2922:
2921:
2918:
2917:
2916:
2913:
2912:
2910:
2908:
2904:
2898:
2895:
2893:
2892:Restless legs
2890:
2886:
2883:
2881:
2878:
2877:
2876:
2873:
2872:
2867:
2864:
2860:
2857:
2856:
2855:
2852:
2848:
2845:
2844:
2843:
2840:
2838:
2835:
2831:
2830:Blepharospasm
2828:
2826:
2823:
2821:
2818:
2816:
2813:
2812:
2811:
2808:
2807:
2806:
2803:
2802:
2797:
2794:
2792:
2789:
2787:
2786:Hemiballismus
2784:
2782:
2779:
2775:
2772:
2771:
2770:
2767:
2763:
2760:
2759:
2758:
2755:
2751:
2748:
2746:
2743:
2741:
2738:
2737:
2736:
2733:
2732:
2731:
2728:
2727:
2725:
2723:
2718:
2714:
2711:
2709:
2705:
2702:
2700:
2695:
2691:
2681:
2678:
2676:
2673:
2669:
2666:
2665:
2664:
2661:
2660:
2658:
2656:
2651:
2643:
2640:
2639:
2638:
2637:Brain abscess
2635:
2633:
2630:
2626:
2623:
2621:
2618:
2616:
2613:
2611:
2608:
2607:
2606:
2603:
2602:
2600:
2598:
2594:
2591:
2589:
2585:
2581:
2577:
2569:
2564:
2562:
2557:
2555:
2550:
2549:
2546:
2533:
2529:
2528:
2524:
2522:
2518:
2517:
2513:
2511:
2507:
2506:
2502:
2498:
2496:
2492:
2488:
2487:
2483:
2479:
2478:
2475:
2470:
2466:
2459:
2450:
2446:
2441:
2436:
2432:
2428:
2424:
2420:
2416:
2412:
2408:
2401:
2398:
2393:
2389:
2385:
2381:
2377:
2373:
2366:
2363:
2357:
2352:
2348:
2344:
2337:
2330:
2327:
2324:
2320:
2314:
2311:
2306:
2302:
2301:
2296:
2289:
2286:
2283:
2279:
2275:
2274:
2269:
2264:
2261:
2258:
2257:
2252:
2248:
2245:
2240:
2238:
2234:
2230:
2229:
2224:
2218:
2215:
2212:
2211:
2206:
2200:
2197:
2192:
2188:
2183:
2178:
2174:
2170:
2166:
2162:
2158:
2151:
2148:
2143:
2139:
2134:
2129:
2125:
2121:
2116:
2111:
2107:
2103:
2099:
2092:
2089:
2078:
2074:
2068:
2065:
2060:
2056:
2052:
2048:
2044:
2040:
2036:
2032:
2028:
2024:
2017:
2014:
2009:
2005:
2000:
1995:
1991:
1987:
1983:
1976:
1973:
1968:
1964:
1959:
1954:
1950:
1946:
1942:
1935:
1932:
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117:December 2021
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78: –
77:
73:
72:Find sources:
67:
63:
57:
56:
52:
48:
43:This article
41:
32:
31:
19:
3447:
3346:
3319:
3280:Degenerative
3017:Inflammatory
2964:
2924:
2897:Stiff-person
2735:Parkinsonism
2708:Degenerative
2605:Encephalitis
2588:Inflammation
2578:, primarily
2525:
2514:
2499:
2480:
2414:
2410:
2400:
2375:
2371:
2365:
2346:
2342:
2329:
2322:
2313:
2305:the original
2298:
2288:
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2263:
2254:
2226:
2217:
2208:
2199:
2164:
2160:
2150:
2105:
2101:
2091:
2080:. Retrieved
2076:
2067:
2030:
2026:
2016:
1989:
1985:
1975:
1948:
1944:
1934:
1901:
1898:FEBS Letters
1897:
1890:
1857:
1853:
1840:
1807:
1803:
1797:
1760:
1756:
1746:
1705:
1701:
1694:
1684:13 September
1682:. Retrieved
1672:
1662:13 September
1660:. Retrieved
1650:
1631:
1625:
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1143:
1113:(1): 43–54.
1110:
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1071:
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1039:
1035:
1028:
987:
983:
977:
942:
938:
893:(2): 80–86.
890:
886:
840:
836:
830:
805:10.2741/E605
795:
791:
781:
746:
742:
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699:. Retrieved
695:
686:
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626:
605:
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472:
455:
451:
441:
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434:
426:
411:
405:
403:
391:
384:
372:
370:
357:presenilin 2
353:presenilin 1
350:
307:
280:, decreased
235:
215:
207:
193:
189:
185:
181:
180:
114:
104:
97:
90:
83:
71:
51:verification
44:
3432:Fazio–Londe
3272:Both/either
3066:Generalised
2925:Early-onset
2920:Alzheimer's
2655:spinal cord
2417:(1): 1433.
2349:(2): 9–29.
2210:Mayo Clinic
2167:(1): 1–12.
1150:Development
646:Still Alice
639:Still Alice
558:β-secretase
431:polypeptide
282:muscle tone
246:mood swings
148:Other names
45:needs more
3040:paroxysmal
3012:Autoimmune
2805:Dyskinesia
2675:Meningitis
2653:Brain and
2108:(1): 206.
2082:2020-05-07
678:References
491:John Hardy
446:angiopathy
416:organelles
394:penetrance
382:from APP.
341:β3-tubulin
266:withdrawal
87:newspapers
3037:Episodic/
2915:Tauopathy
2866:Akathisia
2854:Myoclonus
2837:Athetosis
2769:Tauopathy
2300:USA Today
2228:USA Today
2124:1742-2094
2047:2168-6149
1763:(1): 31.
1599:2831-090X
1532:Neurology
1447:2831-090X
814:1945-0494
735:Rossor MN
659:John Mann
608:nosologic
576:Prognosis
522:Mechanism
420:mammalian
333:Forebrain
286:myoclonus
262:agitation
254:judgement
250:confusion
174:Neurology
169:Specialty
3478:Category
3403:SMALED2B
3398:SMALED2A
3095:Migraine
3087:Headache
3053:epilepsy
3049:Seizures
2907:Dementia
2810:Dystonia
2449:31996736
2278:Archived
2273:CBS News
2247:Archived
2191:20232515
2142:35978311
2059:38147328
2008:16817891
1967:11487570
1926:43080346
1882:13516479
1874:11528419
1832:20046036
1789:32164763
1617:35150479
1560:19309825
1552:11723295
1465:35150479
1321:Genomics
1306:25596140
1262:27296868
1211:12192622
1170:11262239
1135:21552663
1127:12025815
1092:10095119
1036:Genomics
969:17659183
917:19276785
857:18802446
822:23276979
773:12933919
632:See also
423:neuronal
316:Genetics
274:seizures
222:dementia
3415:SMA-PME
3410:SMA-PCH
3393:SMALED1
3105:Tension
3100:Cluster
2825:Meige's
2642:Amoebic
2532:D000544
2440:6989662
2419:Bibcode
2392:9447568
2182:2889200
2133:9382837
1918:7957938
1824:1302033
1780:7068954
1738:4336069
1730:1671712
1710:Bibcode
1608:9392983
1517:4259326
1509:7651536
1489:Bibcode
1456:9392983
1408:9050898
1368:Bibcode
1341:8661049
1298:8574969
1254:7638622
1234:Bibcode
1226:Science
1056:9073509
1020:4308372
1012:7596406
992:Bibcode
960:2735049
908:3052768
865:5946769
764:1738690
641:(novel)
596:History
531:amyloid
499:Swedish
495:Swedish
252:, poor
226:old age
101:scholar
66:removed
3134:Stroke
2948:Pick's
2875:Tremor
2842:Chorea
2521:104300
2447:
2437:
2390:
2189:
2179:
2140:
2130:
2122:
2057:
2045:
2006:
1965:
1924:
1916:
1880:
1872:
1830:
1822:
1787:
1777:
1736:
1728:
1702:Nature
1638:
1615:
1605:
1597:
1558:
1550:
1515:
1507:
1481:Nature
1463:
1453:
1445:
1406:
1396:
1388:
1339:
1304:
1296:
1260:
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1209:
1168:
1133:
1125:
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1054:
1018:
1010:
984:Nature
967:
957:
915:
905:
863:
855:
820:
812:
771:
761:
701:9 July
507:Arctic
503:London
427:PSEN2
359:, and
304:Causes
298:mutism
196:), is
103:
96:
89:
82:
74:
3448:both:
3380:DSMA1
3375:SMAX2
3370:SMAX1
3350:only:
3323:only:
3227:Other
3149:Other
3061:Focal
2694:Brain
2597:Brain
2510:331.0
2495:F00.0
2491:G30.0
2339:(PDF)
1922:S2CID
1878:S2CID
1850:(PDF)
1828:S2CID
1734:S2CID
1656:"APP"
1556:S2CID
1513:S2CID
1399:20036
1390:41579
1386:JSTOR
1302:S2CID
1258:S2CID
1131:S2CID
1016:S2CID
861:S2CID
535:brain
442:PSEN1
412:PSEN1
407:PSEN2
387:exons
374:PSEN1
108:JSTOR
94:books
3051:and
2762:PKAN
2757:NBIA
2527:MeSH
2516:OMIM
2505:9-CM
2445:PMID
2388:PMID
2187:PMID
2138:PMID
2120:ISSN
2055:PMID
2043:ISSN
2004:PMID
1963:PMID
1914:PMID
1870:PMID
1820:PMID
1785:PMID
1726:PMID
1686:2023
1664:2023
1636:ISBN
1613:PMID
1595:ISSN
1548:PMID
1505:PMID
1461:PMID
1443:ISSN
1404:PMID
1337:PMID
1294:PMID
1250:PMID
1207:PMID
1166:PMID
1123:PMID
1088:PMID
1072:Gene
1052:PMID
1008:PMID
965:PMID
913:PMID
853:PMID
818:PMID
810:ISSN
769:PMID
703:2020
296:and
194:YOAD
186:EOAD
160:YOAD
154:EOAD
80:news
49:for
3365:SMA
3348:LMN
3321:UMN
3312:MND
3178:CSF
3129:TIA
2774:PSP
2750:NMS
2719:and
2580:CNS
2501:ICD
2482:ICD
2435:PMC
2427:doi
2380:doi
2351:doi
2177:PMC
2169:doi
2128:PMC
2110:doi
2051:PMC
2035:doi
1994:doi
1990:273
1953:doi
1906:doi
1902:354
1862:doi
1812:doi
1775:PMC
1765:doi
1718:doi
1706:349
1603:PMC
1587:doi
1540:doi
1497:doi
1485:376
1451:PMC
1435:doi
1394:PMC
1376:doi
1329:doi
1286:doi
1242:doi
1230:269
1197:doi
1158:doi
1154:128
1115:doi
1080:doi
1076:229
1044:doi
1000:doi
988:375
955:PMC
947:doi
903:PMC
895:doi
845:doi
800:doi
759:PMC
751:doi
435:PS1
361:APP
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3289:SA
2796:OA
2791:HD
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