318:
542:(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.
310:
549:, 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.
378:, 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.
217:. 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.
535:
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.
25:
455:
117:
403:. 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
574:
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.
1688:
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,
445:
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
366:
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
616:
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
534:
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
433:, 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
580:
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.
530:
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.
1884:
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".
466:
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.
560:
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.
506:
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.
1022:
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".
1467:
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".
569:
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.
1264:
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".
437:
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.
705:
441:
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.
473:
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
189:
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
2489:
2470:
1058:
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".
607:
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.
1791:
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".
225:
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
1740:
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).
1308:
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".
971:
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".
1519:
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".
194:
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.
3005:
1345:"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"
1094:
Ikeuchi T, Sisodia SS (2002). "Cell-free generation of the notch1 intracellular domain (NICD) and APP-CTfgamma: evidence for distinct intramembranous "gamma-secretase" activities".
1689:
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".
385:, 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.
3391:
3386:
1213:
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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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
1742:"Prominent amyloid plaque pathology and cerebral amyloid angiopathy in APP V717I (London) carrier – phenotypic variability in autosomal dominant Alzheimer's disease"
197:
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.
2554:
2010:
Hendriks, Stevie; Ranson, Janice M.; Peetoom, Kirsten; Lourida, Ilianna; Tai, Xin You; de Vugt, Marjolein; Llewellyn, David J.; Köhler, Sebastian (2023-12-26).
490:
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
35:
2283:
2750:
96:
2745:
1137:
Koizumi K, Nakajima M, Yuasa S, Saga Y, Sakai T, Kuriyama T, et al. (April 2001). "The role of presenilin 1 during somite segmentation".
381:
Some of the mutations in the gene, of which over 90 are known, include: His163Arg, Ala246Glu, Leu286Val and Cys410Tyr. Most display complete
68:
1930:"Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability"
289:. 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.
2547:
1564:"miR-212-3p attenuates neuroinflammation of rats with Alzheimer's disease via regulating the SP1/BACE1/NLRP3/Caspase-1 signaling pathway"
1412:"miR-212-3p attenuates neuroinflammation of rats with Alzheimer's disease via regulating the SP1/BACE1/NLRP3/Caspase-1 signaling pathway"
75:
662:, an award-winning Indian film detailing the effects of early-onset Alzheimer's disease on a father and his relationship with his son.
3373:
82:
824:
Bertram L, Tanzi RE (October 2008). "Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses".
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328:. iPSCs from a patient with familial Alzheimer's disease, a mutation in the PSEN1 gene. TUJ-1-positive cells express a marker (
317:
64:
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3000:
426:. This protein has been identified as part of the enzymatic complex that cleaves amyloid beta peptide from APP (see below).
246:
3206:
3194:
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1628:
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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.
3128:
2931:
54:
1174:"Association between presenilin-1 Glu318Gly mutation and familial Alzheimer's disease in the Australian population"
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3247:
1971:"Physiochemical characterization of the Alzheimer's disease-related peptides A beta 1-42Arctic and A beta 1-42wt"
680:
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2738:
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Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, et al. (September 2001).
349:
89:
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230:
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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
3410:
2784:
50:
2232:
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2293:
2211:
3398:
2948:
2620:
2061:
590:
1836:"The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation"
1835:
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2696:
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43:
603:, who worked in Alzheimer's laboratory, and the characteristic neuropathology was first observed by
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Familial Alzheimer disease is caused by a mutation in one of at least three genes, which code for
3420:
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2779:
2769:
2613:
2324:
527:
479:
39:
2532:
2325:"The Burgeoning Interest in Young Onset Dementia: Redressing the balance or reinforcing ageism?"
3285:
3277:
3232:
2908:
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2728:
2087:"Astrocytic and microglial cells as the modulators of neuroinflammation in Alzheimer's disease"
186:
1969:
Johansson AS, Berglind-Dehlin F, Karlsson G, Edwards K, Gellerfors P, Lannfelt L (June 2006).
1563:
1411:
329:
233:). As the disease progresses, the patient exhibits more serious problems, becoming subject to
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2808:
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266:
518:, familial AD is practically indistinguishable from other forms of the disease. Deposits of
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2407:
1698:
1477:
1356:
1343:
Tomita T, Maruyama K, Saido TC, Kume H, Shinozaki K, Tokuhiro S, et al. (March 1997).
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980:
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8:
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and unable to perform complex activities such as driving. Other common findings include
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2396:"Genome-wide association study of brain connectivity changes for Alzheimer's disease"
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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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2011:
1349:
Proceedings of the National Academy of Sciences of the United States of America
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802:
723:
333:
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2723:
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1996:
1955:
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1199:
1158:
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957:
905:
845:
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743:
728:"The prevalence and causes of dementia in people under the age of 65 years"
345:
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1968:
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53:
if you can. Unsourced or poorly sourced material may be challenged and
2903:
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1378:
992:
515:
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321:
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Spinal muscular atrophy with lower extremity predominance (SMALED)
3083:
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1621:
Molecular Neuropharmacology: A Foundation for Clinical Neuroscience
1562:
Nong, Wei; Bao, Chuanhong; Chen, Yixin; Wei, Zhiquan (2022-07-29).
1410:
Nong, Wei; Bao, Chuanhong; Chen, Yixin; Wei, Zhiquan (2022-07-29).
596:
254:
210:
2359:
Weber MM (1997). "Aloys Alzheimer, a coworker of Emil Kraepelin".
2562:
793:
776:
519:
454:
262:
214:
2509:
2394:
Elsheikh, SS; Chimusa, ER; Mulder, NJ; Crimi, A (January 2020).
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341:
2009:
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1739:
1212:
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1021:
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375:
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Familial AD is inherited in an autosomal dominant fashion.
2144:
Chow VW, Mattson MP, Wong PC, Gleichmann M (March 2010).
2143:
2012:"Risk Factors for Young-Onset Dementia in the UK Biobank"
646:, a documentary film about the farewell tour of musician
538:
Beta-amyloid is a small piece of a larger protein called
1518:
1136:
2212:
Family shares journey after early Alzheimer's diagnosis
1342:
1307:
1171:
869:
777:"Genetics of familial and sporadic Alzheimer s disease"
324:
neuronal culture after 40 days of differentiation from
2194:
Early-onset Alzheimer's: When symptoms begin before 65
924:"Genetics of Alzheimer's disease: a centennial review"
860:
470:
This type accounts for no more than 10–15% of EOFAD.
2452:
2146:"An overview of APP processing enzymes and products"
1263:
865:
863:
654:
following his diagnosis with early-onset Alzheimer's
2062:"What Happens to the Brain in Alzheimer's Disease?"
1618:
2332:The International Journal of Ageing and Later Life
732:Journal of Neurology, Neurosurgery, and Psychiatry
595:The symptoms of Alzheimer's disease as a distinct
336:(green). Cell nuclei are stained with DAPI (blue).
16:Alzheimer's disease developed before the age of 65
2275:
2204:
870:Williamson J, Goldman J, Marder KS (March 2009).
3464:
2284:"Who thinks of Alzheimer's in someone so young?"
1623:(2nd ed.). New York: McGraw-Hill Medical.
526:tissue. This amyloid protein forms plaques and
429:The mutations have not been studied as much as
399:) is very similar in structure and function to
1561:
1409:
1093:
49:Please review the contents of the article and
2548:
921:
2250:
917:
915:
823:
717:
715:
706:"What Are the Signs of Alzheimer's Disease?"
201:Familial and nonfamilial Alzheimer's disease
3267:
2352:
2233:Living With Early-Onset Alzheimer's Disease
501:
458:Processing of the amyloid precursor protein
2555:
2541:
2322:
2281:
482:. Other notable APP mutations include the
2427:
2343:
2169:
2120:
2102:
1986:
1945:
1927:
1767:
1757:
1619:Malenka EJ, Nestler SE, Hyman RC (2009).
1595:
1568:Bosnian Journal of Basic Medical Sciences
1443:
1416:Bosnian Journal of Basic Medical Sciences
1386:
1368:
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792:
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450:APP – amyloid beta (A4) precursor protein
414:cells. Levy-Lahad (1996) determined that
453:
316:
308:
2228:
2226:
774:
464:amyloid beta A4 precursor protein (APP)
388:
355:
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3344:Distal hereditary motor neuronopathies
3017:Template:Demyelinating diseases of CNS
2308:Young Onset Dementia: a label too far?
2282:Fackelmann, Kathleen (June 11, 2007).
872:"Genetic aspects of Alzheimer disease"
611:
2536:
2358:
2084:
231:logopenic primary progressive aphasia
220:
3195:Idiopathic intracranial hypertension
2584:
2223:
2186:
1746:Acta Neuropathologica Communications
326:induced human pluripotent stem cells
229:and the names of people and things (
18:
2257:Early Onset Alzheimer's On The Rise
13:
3426:Infantile progressive bulbar palsy
681:"Younger/ Early-onset Alzheimer's"
591:Alzheimer's disease § History
552:
14:
3484:
3129:Template:Cerebrovascular diseases
2932:Frontotemporal lobar degeneration
2448:
638:, whose main protagonist has EOAD
179:younger-onset Alzheimer's disease
146:Younger-onset Alzheimer's disease
65:"Early-onset Alzheimer's disease"
3149:For more detailed coverage, see
3127:For more detailed coverage, see
3098:For more detailed coverage, see
3064:For more detailed coverage, see
3015:For more detailed coverage, see
1988:10.1111/j.1742-4658.2006.05263.x
599:entity were first identified by
115:
23:
2387:
2361:Journal of Psychiatric Research
2316:
2312:Dementia Society, July 27, 2016
2300:
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2003:
1962:
1928:De Jonghe, C. (1 August 2001).
1921:
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1512:
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1403:
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1301:
1257:
1206:
1165:
1130:
1087:
1051:
922:Ertekin-Taner N (August 2007).
722:Harvey RJ, Skelton-Robinson M,
367:enzymatic complex that cleaves
297:Familial AD is inherited in an
171:Early-onset Alzheimer's disease
132:Early-onset Alzheimer's disease
2245:Cleveland Clinic Health System
1015:
964:
817:
768:
698:
673:
205:Alzheimer's disease (AD) is a
51:add the appropriate references
1:
3442:Amyotrophic lateral sclerosis
3327:Hereditary spastic paraplegia
3185:Normal pressure hydrocephalus
2373:10.1016/S0022-3956(97)00035-6
2085:Singh, Deepali (2022-08-17).
1073:10.1016/S0378-1119(99)00023-2
666:
209:and the most common cause of
3411:Progressive muscular atrophy
2345:10.3384/ijal.1652-8670.16302
2091:Journal of Neuroinflammation
2028:10.1001/jamaneurol.2023.4929
1899:10.1016/0014-5793(94)01137-0
888:10.1097/NRL.0b013e318187e76b
826:Nature Reviews. Neuroscience
564:
510:
7:
2921:Primary progressive aphasia
2066:National Institute on Aging
620:
522:can be seen in sections of
332:) of mature neurons (red).
304:
36:reliable medical references
10:
3489:
3243:Hashimoto's encephalopathy
2949:Posterior cortical atrophy
2770:Striatonigral degeneration
2621:Cavernous sinus thrombosis
2420:10.1038/s41598-020-58291-1
2269:February 10, 2009, at the
2104:10.1186/s12974-022-02565-0
1669:. Alzheimer Research Forum
1647:. Alzheimer Research Forum
588:
584:
478:by a research team led by
3349:Spinal muscular atrophies
3317:Primary lateral sclerosis
3299:
3276:
3260:
3215:
3175:Intracranial hypertension
3165:
3137:
3108:
3074:
3036:
3025:
2991:
2969:
2955:Creutzfeldt–Jakob disease
2894:
2704:
2695:
2681:
2641:
2575:
2456:
2162:10.1007/s12017-009-8104-z
1759:10.1186/s40478-020-0891-3
940:10.1016/j.ncl.2007.03.009
540:amyloid precursor protein
292:
227:remembering recent events
207:neurodegenerative disease
156:
136:
131:
42:or relies too heavily on
3416:Progressive bulbar palsy
3207:Intracranial hypotension
3190:Choroid plexus papilloma
2604:Herpesviral encephalitis
1934:Human Molecular Genetics
1580:10.17305/bjbms.2021.6723
1428:10.17305/bjbms.2021.6723
502:Non-genetic risk factors
2928:Frontotemporal dementia
2614:Encephalitis lethargica
2150:Neuromolecular Medicine
1235:10.1126/science.7638622
1096:Neuromolecular Medicine
781:Frontiers in Bioscience
775:Piaceri, Irene (2013).
685:Alzheimer's Association
528:neurofibrillary tangles
393:The presenilin 2 gene (
360:The presenilin 1 gene (
213:; it usually occurs in
3233:Hepatic encephalopathy
1947:10.1093/hmg/10.16.1665
1533:10.1212/WNL.57.10.1926
1370:10.1073/pnas.94.5.2025
1322:10.1006/geno.1996.0266
1151:10.1242/dev.128.8.1391
1037:10.1006/geno.1996.4523
744:10.1136/jnnp.74.9.1206
545:Following cleavage by
459:
337:
314:
3291:Ataxia–telangiectasia
3248:Static encephalopathy
2971:Mitochondrial disease
2809:Spasmodic torticollis
2719:Basal ganglia disease
1191:10.1038/sj.mp.4001072
457:
422:with 67% homology to
374:The gene contains 14
320:
312:
267:Parkinsonian deficits
3238:Toxic encephalopathy
2944:Lewy bodies dementia
2220:(September 2, 2008).
2210:Mary Brophy Marcus,
1667:"APP V717I (London)"
1178:Molecular Psychiatry
643:Spirit Unforgettable
617:development for AD.
389:PSEN2 – Presenilin 2
369:amyloid-beta peptide
356:PSEN1 – Presenilin 1
279:urinary incontinence
247:language disturbance
3473:Alzheimer's disease
3286:Friedreich's ataxia
2669:Meningoencephalitis
2609:Limbic encephalitis
2412:2020NatSR..10.1433E
2323:Tolhurst E (2016).
2306:Rahman, S. (2016).
2296:on August 19, 2009.
2192:Mayo Clinic staff,
1843:Nature Neuroscience
1703:1991Natur.349..704G
1482:1995Natur.376..775R
1361:1997PNAS...94.2025T
1227:1995Sci...269..973L
985:1995Natur.375..754S
612:Research directions
334:GABA-positive cells
187:Alzheimer's disease
3322:Pseudobulbar palsy
3060:Status epilepticus
3011:Multiple sclerosis
2848:Myoclonic epilepsy
2711:movement disorders
2657:Acute disseminated
2599:Viral encephalitis
2400:Scientific Reports
2238:2007-10-19 at the
1855:10.1038/nn0901-887
1805:10.1038/ng0892-345
1279:10.1038/nm0296-224
1108:10.1385/NMM:1:1:43
928:Neurologic Clinics
726:(September 2003).
652:Spirit of the West
460:
407:as each other, in
338:
315:
299:autosomal dominant
283:fecal incontinence
221:Signs and symptoms
192:autosomal dominant
3460:
3459:
3456:
3455:
3452:
3451:
3256:
3255:
3161:
3160:
3100:Template:Headache
3066:Template:Epilepsy
2987:
2986:
2961:Vascular dementia
2804:Status dystonicus
2677:
2676:
2652:Encephalomyelitis
2530:
2529:
2265:(March 8, 2008).
1981:(12): 2618–2630.
1940:(16): 1665–1671.
1697:(6311): 704–706.
1527:(10): 1926–1928.
1476:(6543): 775–778.
1221:(5226): 973–977.
979:(6534): 754–760.
934:(3): 611–667, v.
659:Thanmathra (film)
462:Mutations to the
168:
167:
126:Medical condition
124:
123:
100:
3480:
3274:
3273:
3265:
3264:
3223:Brain herniation
3034:
3033:
2874:Intention tremor
2869:Essential tremor
2734:Postencephalitic
2702:
2701:
2693:
2692:
2582:
2581:
2563:Diseases of the
2557:
2550:
2543:
2534:
2533:
2454:
2453:
2442:
2441:
2431:
2391:
2385:
2384:
2356:
2350:
2349:
2347:
2329:
2320:
2314:
2304:
2298:
2297:
2292:. Archived from
2279:
2273:
2254:
2248:
2230:
2221:
2208:
2202:
2190:
2184:
2183:
2173:
2141:
2135:
2134:
2124:
2106:
2082:
2076:
2075:
2073:
2072:
2058:
2052:
2051:
2042: 10751655.
2007:
2001:
2000:
1990:
1975:The FEBS Journal
1966:
1960:
1959:
1949:
1925:
1919:
1918:
1881:
1875:
1874:
1840:
1831:
1825:
1824:
1788:
1782:
1781:
1771:
1761:
1737:
1731:
1730:
1711:10.1038/349704a0
1685:
1679:
1678:
1676:
1674:
1663:
1657:
1656:
1654:
1652:
1641:
1635:
1634:
1616:
1610:
1609:
1599:
1559:
1553:
1552:
1516:
1510:
1509:
1490:10.1038/376775a0
1464:
1458:
1457:
1447:
1407:
1401:
1400:
1390:
1372:
1355:(5): 2025–2030.
1340:
1334:
1333:
1305:
1299:
1298:
1261:
1255:
1254:
1210:
1204:
1203:
1193:
1169:
1163:
1162:
1145:(8): 1391–1402.
1134:
1128:
1127:
1091:
1085:
1084:
1067:(1–2): 193–201.
1055:
1049:
1048:
1019:
1013:
1012:
993:10.1038/375754a0
968:
962:
961:
951:
919:
910:
909:
899:
867:
858:
857:
821:
815:
814:
796:
772:
766:
765:
755:
738:(9): 1206–1209.
719:
710:
709:
702:
696:
695:
693:
691:
677:
129:
128:
119:
118:
110:
107:
101:
99:
58:
27:
26:
19:
3488:
3487:
3483:
3482:
3481:
3479:
3478:
3477:
3463:
3462:
3461:
3448:
3374:Congenital DSMA
3295:
3252:
3211:
3157:
3145:Sleep disorders
3133:
3110:Cerebrovascular
3104:
3070:
3027:
3021:
2983:
2965:
2890:
2836:Choreoathetosis
2709:
2686:
2673:
2637:
2571:
2561:
2531:
2526:
2525:
2465:
2451:
2446:
2445:
2392:
2388:
2357:
2353:
2327:
2321:
2317:
2305:
2301:
2280:
2276:
2271:Wayback Machine
2255:
2251:
2240:Wayback Machine
2231:
2224:
2209:
2205:
2191:
2187:
2142:
2138:
2083:
2079:
2070:
2068:
2060:
2059:
2055:
2008:
2004:
1967:
1963:
1926:
1922:
1882:
1878:
1838:
1832:
1828:
1793:Nature Genetics
1789:
1785:
1738:
1734:
1686:
1682:
1672:
1670:
1665:
1664:
1660:
1650:
1648:
1643:
1642:
1638:
1631:
1617:
1613:
1560:
1556:
1517:
1513:
1465:
1461:
1408:
1404:
1341:
1337:
1306:
1302:
1267:Nature Medicine
1262:
1258:
1211:
1207:
1170:
1166:
1135:
1131:
1092:
1088:
1056:
1052:
1020:
1016:
969:
965:
920:
913:
876:The Neurologist
868:
861:
838:10.1038/nrn2494
832:(10): 768–778.
822:
818:
773:
769:
720:
713:
704:
703:
699:
689:
687:
679:
678:
674:
669:
623:
614:
605:Alois Alzheimer
593:
587:
567:
558:Genetic testing
555:
553:Genetic testing
513:
504:
452:
391:
358:
307:
295:
223:
203:
177:), also called
152:
127:
120:
116:
111:
105:
102:
59:
48:
44:primary sources
28:
24:
17:
12:
11:
5:
3486:
3476:
3475:
3458:
3457:
3454:
3453:
3450:
3449:
3447:
3446:
3445:
3444:
3433:
3432:
3431:
3430:
3429:
3428:
3423:
3413:
3408:
3407:
3406:
3401:
3396:
3395:
3394:
3389:
3384:
3376:
3371:
3366:
3361:
3356:
3346:
3332:
3331:
3330:
3329:
3324:
3319:
3305:
3303:
3297:
3296:
3294:
3293:
3288:
3282:
3280:
3271:
3262:
3258:
3257:
3254:
3253:
3251:
3250:
3245:
3240:
3235:
3230:
3225:
3219:
3217:
3213:
3212:
3210:
3209:
3204:
3202:Cerebral edema
3199:
3198:
3197:
3192:
3187:
3182:
3171:
3169:
3163:
3162:
3159:
3158:
3156:
3155:
3154:
3153:
3151:Template:Sleep
3141:
3139:
3135:
3134:
3132:
3131:
3125:
3120:
3114:
3112:
3106:
3105:
3103:
3102:
3096:
3091:
3086:
3080:
3078:
3072:
3071:
3069:
3068:
3062:
3057:
3052:
3046:
3044:
3031:
3023:
3022:
3020:
3019:
3013:
3008:
3003:
2997:
2995:
2989:
2988:
2985:
2984:
2982:
2981:
2979:Leigh syndrome
2975:
2973:
2967:
2966:
2964:
2963:
2952:
2951:
2946:
2941:
2940:
2939:
2925:
2924:
2923:
2918:
2917:
2916:
2900:
2898:
2892:
2891:
2889:
2888:
2883:
2878:
2877:
2876:
2871:
2860:
2859:
2858:
2857:
2852:
2851:
2850:
2840:
2839:
2838:
2828:
2823:
2822:
2821:
2816:
2811:
2806:
2790:
2789:
2788:
2787:
2782:
2777:
2772:
2767:
2766:
2765:
2755:
2754:
2753:
2743:
2742:
2741:
2736:
2731:
2715:
2713:
2706:Extrapyramidal
2699:
2690:
2688:encephalopathy
2679:
2678:
2675:
2674:
2672:
2671:
2666:
2661:
2660:
2659:
2648:
2646:
2639:
2638:
2636:
2635:
2634:
2633:
2623:
2618:
2617:
2616:
2611:
2606:
2601:
2590:
2588:
2579:
2573:
2572:
2565:nervous system
2560:
2559:
2552:
2545:
2537:
2528:
2527:
2524:
2523:
2512:
2501:
2486:
2466:
2461:
2460:
2458:
2457:Classification
2450:
2449:External links
2447:
2444:
2443:
2386:
2367:(6): 635–643.
2351:
2315:
2299:
2274:
2249:
2222:
2203:
2185:
2136:
2077:
2053:
2022:(2): 134–142.
2016:JAMA Neurology
2002:
1961:
1920:
1893:(3): 274–278.
1876:
1849:(9): 887–893.
1826:
1799:(5): 345–347.
1783:
1732:
1680:
1658:
1636:
1630:978-0071481274
1629:
1611:
1574:(4): 540–552.
1554:
1511:
1459:
1422:(4): 540–552.
1402:
1335:
1316:(2): 198–204.
1300:
1273:(2): 224–229.
1256:
1205:
1184:(7): 776–781.
1164:
1129:
1086:
1050:
1031:(3): 415–424.
1014:
963:
911:
859:
816:
787:(1): 167–177.
767:
711:
697:
671:
670:
668:
665:
664:
663:
655:
639:
632:and the movie
622:
619:
613:
610:
601:Emil Kraepelin
589:Main article:
586:
583:
566:
563:
554:
551:
516:Histologically
512:
509:
503:
500:
476:Carol Jennings
451:
448:
390:
387:
357:
354:
306:
303:
294:
291:
259:hallucinations
222:
219:
202:
199:
166:
165:
160:
154:
153:
151:
150:
147:
144:
140:
138:
134:
133:
125:
122:
121:
114:
112:
31:
29:
22:
15:
9:
6:
4:
3:
2:
3485:
3474:
3471:
3470:
3468:
3443:
3440:
3439:
3438:
3435:
3434:
3427:
3424:
3422:
3419:
3418:
3417:
3414:
3412:
3409:
3405:
3402:
3400:
3397:
3393:
3390:
3388:
3385:
3383:
3380:
3379:
3377:
3375:
3372:
3370:
3367:
3365:
3362:
3360:
3357:
3355:
3352:
3351:
3350:
3347:
3345:
3342:
3341:
3340:
3338:
3334:
3333:
3328:
3325:
3323:
3320:
3318:
3315:
3314:
3313:
3311:
3307:
3306:
3304:
3302:
3298:
3292:
3289:
3287:
3284:
3283:
3281:
3279:
3275:
3272:
3270:
3266:
3263:
3259:
3249:
3246:
3244:
3241:
3239:
3236:
3234:
3231:
3229:
3228:Reye syndrome
3226:
3224:
3221:
3220:
3218:
3214:
3208:
3205:
3203:
3200:
3196:
3193:
3191:
3188:
3186:
3183:
3181:
3180:Hydrocephalus
3178:
3177:
3176:
3173:
3172:
3170:
3168:
3164:
3152:
3148:
3147:
3146:
3143:
3142:
3140:
3136:
3130:
3126:
3124:
3121:
3119:
3116:
3115:
3113:
3111:
3107:
3101:
3097:
3095:
3092:
3090:
3087:
3085:
3082:
3081:
3079:
3077:
3073:
3067:
3063:
3061:
3058:
3056:
3053:
3051:
3048:
3047:
3045:
3043:
3039:
3035:
3032:
3030:
3024:
3018:
3014:
3012:
3009:
3007:
3004:
3002:
2999:
2998:
2996:
2994:
2993:Demyelinating
2990:
2980:
2977:
2976:
2974:
2972:
2968:
2962:
2959:
2958:
2957:
2956:
2950:
2947:
2945:
2942:
2938:
2935:
2934:
2933:
2929:
2926:
2922:
2919:
2915:
2912:
2911:
2910:
2907:
2906:
2905:
2902:
2901:
2899:
2897:
2893:
2887:
2884:
2882:
2881:Restless legs
2879:
2875:
2872:
2870:
2867:
2866:
2865:
2862:
2861:
2856:
2853:
2849:
2846:
2845:
2844:
2841:
2837:
2834:
2833:
2832:
2829:
2827:
2824:
2820:
2819:Blepharospasm
2817:
2815:
2812:
2810:
2807:
2805:
2802:
2801:
2800:
2797:
2796:
2795:
2792:
2791:
2786:
2783:
2781:
2778:
2776:
2775:Hemiballismus
2773:
2771:
2768:
2764:
2761:
2760:
2759:
2756:
2752:
2749:
2748:
2747:
2744:
2740:
2737:
2735:
2732:
2730:
2727:
2726:
2725:
2722:
2721:
2720:
2717:
2716:
2714:
2712:
2707:
2703:
2700:
2698:
2694:
2691:
2689:
2684:
2680:
2670:
2667:
2665:
2662:
2658:
2655:
2654:
2653:
2650:
2649:
2647:
2645:
2640:
2632:
2629:
2628:
2627:
2626:Brain abscess
2624:
2622:
2619:
2615:
2612:
2610:
2607:
2605:
2602:
2600:
2597:
2596:
2595:
2592:
2591:
2589:
2587:
2583:
2580:
2578:
2574:
2570:
2566:
2558:
2553:
2551:
2546:
2544:
2539:
2538:
2535:
2522:
2518:
2517:
2513:
2511:
2507:
2506:
2502:
2500:
2496:
2495:
2491:
2487:
2485:
2481:
2477:
2476:
2472:
2468:
2467:
2464:
2459:
2455:
2439:
2435:
2430:
2425:
2421:
2417:
2413:
2409:
2405:
2401:
2397:
2390:
2382:
2378:
2374:
2370:
2366:
2362:
2355:
2346:
2341:
2337:
2333:
2326:
2319:
2313:
2309:
2303:
2295:
2291:
2290:
2285:
2278:
2272:
2268:
2264:
2263:
2258:
2253:
2247:
2246:
2241:
2237:
2234:
2229:
2227:
2219:
2218:
2213:
2207:
2201:
2200:
2195:
2189:
2181:
2177:
2172:
2167:
2163:
2159:
2155:
2151:
2147:
2140:
2132:
2128:
2123:
2118:
2114:
2110:
2105:
2100:
2096:
2092:
2088:
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106:December 2021
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67: –
66:
62:
61:Find sources:
56:
52:
46:
45:
41:
37:
32:This article
30:
21:
20:
3436:
3335:
3308:
3269:Degenerative
3006:Inflammatory
2953:
2913:
2886:Stiff-person
2724:Parkinsonism
2697:Degenerative
2594:Encephalitis
2577:Inflammation
2567:, primarily
2514:
2503:
2488:
2469:
2403:
2399:
2389:
2364:
2360:
2354:
2335:
2331:
2318:
2311:
2302:
2294:the original
2287:
2277:
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2252:
2243:
2215:
2206:
2197:
2188:
2153:
2149:
2139:
2094:
2090:
2080:
2069:. Retrieved
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2056:
2019:
2015:
2005:
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1890:
1887:FEBS Letters
1886:
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1842:
1829:
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1673:13 September
1671:. Retrieved
1661:
1651:13 September
1649:. Retrieved
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1102:(1): 43–54.
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972:
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931:
927:
882:(2): 80–86.
879:
875:
829:
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819:
794:10.2741/E605
784:
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735:
731:
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688:. Retrieved
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394:
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380:
373:
361:
359:
346:presenilin 2
342:presenilin 1
339:
296:
269:, decreased
224:
204:
196:
182:
178:
174:
170:
169:
103:
93:
86:
79:
72:
60:
40:verification
33:
3421:Fazio–Londe
3261:Both/either
3055:Generalised
2914:Early-onset
2909:Alzheimer's
2644:spinal cord
2406:(1): 1433.
2338:(2): 9–29.
2199:Mayo Clinic
2156:(1): 1–12.
1139:Development
635:Still Alice
628:Still Alice
547:β-secretase
420:polypeptide
271:muscle tone
235:mood swings
137:Other names
34:needs more
3029:paroxysmal
3001:Autoimmune
2794:Dyskinesia
2664:Meningitis
2642:Brain and
2097:(1): 206.
2071:2020-05-07
667:References
480:John Hardy
435:angiopathy
405:organelles
383:penetrance
371:from APP.
330:β3-tubulin
255:withdrawal
76:newspapers
3026:Episodic/
2904:Tauopathy
2855:Akathisia
2843:Myoclonus
2826:Athetosis
2758:Tauopathy
2289:USA Today
2217:USA Today
2113:1742-2094
2036:2168-6149
1752:(1): 31.
1588:2831-090X
1521:Neurology
1436:2831-090X
803:1945-0494
724:Rossor MN
648:John Mann
597:nosologic
565:Prognosis
511:Mechanism
409:mammalian
322:Forebrain
275:myoclonus
251:agitation
243:judgement
239:confusion
163:Neurology
158:Specialty
3467:Category
3392:SMALED2B
3387:SMALED2A
3084:Migraine
3076:Headache
3042:epilepsy
3038:Seizures
2896:Dementia
2799:Dystonia
2438:31996736
2267:Archived
2262:CBS News
2236:Archived
2180:20232515
2131:35978311
2048:38147328
1997:16817891
1956:11487570
1915:43080346
1871:13516479
1863:11528419
1821:20046036
1778:32164763
1606:35150479
1549:19309825
1541:11723295
1454:35150479
1310:Genomics
1295:25596140
1251:27296868
1200:12192622
1159:11262239
1124:21552663
1116:12025815
1081:10095119
1025:Genomics
958:17659183
906:19276785
846:18802446
811:23276979
762:12933919
621:See also
412:neuronal
305:Genetics
263:seizures
211:dementia
3404:SMA-PME
3399:SMA-PCH
3382:SMALED1
3094:Tension
3089:Cluster
2814:Meige's
2631:Amoebic
2521:D000544
2429:6989662
2408:Bibcode
2381:9447568
2171:2889200
2122:9382837
1907:7957938
1813:1302033
1769:7068954
1727:4336069
1719:1671712
1699:Bibcode
1597:9392983
1506:4259326
1498:7651536
1478:Bibcode
1445:9392983
1397:9050898
1357:Bibcode
1330:8661049
1287:8574969
1243:7638622
1223:Bibcode
1215:Science
1045:9073509
1009:4308372
1001:7596406
981:Bibcode
949:2735049
897:3052768
854:5946769
753:1738690
630:(novel)
585:History
520:amyloid
488:Swedish
484:Swedish
241:, poor
215:old age
90:scholar
55:removed
3123:Stroke
2937:Pick's
2864:Tremor
2831:Chorea
2510:104300
2436:
2426:
2379:
2178:
2168:
2129:
2119:
2111:
2046:
2034:
1995:
1954:
1913:
1905:
1869:
1861:
1819:
1811:
1776:
1766:
1725:
1717:
1691:Nature
1627:
1604:
1594:
1586:
1547:
1539:
1504:
1496:
1470:Nature
1452:
1442:
1434:
1395:
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1241:
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1157:
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1007:
999:
973:Nature
956:
946:
904:
894:
852:
844:
809:
801:
760:
750:
690:9 July
496:Arctic
492:London
416:PSEN2
348:, and
293:Causes
287:mutism
185:), is
92:
85:
78:
71:
63:
3437:both:
3369:DSMA1
3364:SMAX2
3359:SMAX1
3339:only:
3312:only:
3216:Other
3138:Other
3050:Focal
2683:Brain
2586:Brain
2499:331.0
2484:F00.0
2480:G30.0
2328:(PDF)
1911:S2CID
1867:S2CID
1839:(PDF)
1817:S2CID
1723:S2CID
1645:"APP"
1545:S2CID
1502:S2CID
1388:20036
1379:41579
1375:JSTOR
1291:S2CID
1247:S2CID
1120:S2CID
1005:S2CID
850:S2CID
524:brain
431:PSEN1
401:PSEN1
396:PSEN2
376:exons
363:PSEN1
97:JSTOR
83:books
3040:and
2751:PKAN
2746:NBIA
2516:MeSH
2505:OMIM
2494:9-CM
2434:PMID
2377:PMID
2176:PMID
2127:PMID
2109:ISSN
2044:PMID
2032:ISSN
1993:PMID
1952:PMID
1903:PMID
1859:PMID
1809:PMID
1774:PMID
1715:PMID
1675:2023
1653:2023
1625:ISBN
1602:PMID
1584:ISSN
1537:PMID
1494:PMID
1450:PMID
1432:ISSN
1393:PMID
1326:PMID
1283:PMID
1239:PMID
1196:PMID
1155:PMID
1112:PMID
1077:PMID
1061:Gene
1041:PMID
997:PMID
954:PMID
902:PMID
842:PMID
807:PMID
799:ISSN
758:PMID
692:2020
285:and
183:YOAD
175:EOAD
149:YOAD
143:EOAD
69:news
38:for
3354:SMA
3337:LMN
3310:UMN
3301:MND
3167:CSF
3118:TIA
2763:PSP
2739:NMS
2708:and
2569:CNS
2490:ICD
2471:ICD
2424:PMC
2416:doi
2369:doi
2340:doi
2166:PMC
2158:doi
2117:PMC
2099:doi
2040:PMC
2024:doi
1983:doi
1979:273
1942:doi
1895:doi
1891:354
1851:doi
1801:doi
1764:PMC
1754:doi
1707:doi
1695:349
1592:PMC
1576:doi
1529:doi
1486:doi
1474:376
1440:PMC
1424:doi
1383:PMC
1365:doi
1318:doi
1275:doi
1231:doi
1219:269
1186:doi
1147:doi
1143:128
1104:doi
1069:doi
1065:229
1033:doi
989:doi
977:375
944:PMC
936:doi
892:PMC
884:doi
834:doi
789:doi
748:PMC
740:doi
424:PS1
350:APP
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3278:SA
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2780:HD
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