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Early-onset Alzheimer's disease

April 29, 2023

Early-onset Alzheimer's disease (EOAD), also called Younger-onset Alzheimer's disease (YOAD),[1] is Alzheimer's disease 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 autosomal dominant 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.

Early-onset Alzheimer's disease
Other names
  • EOAD
  • Younger-onset Alzheimer's disease
  • YOAD
SpecialtyNeurology

Nonfamilial early-onset AD can develop in people who are in their 30s or 40s, but this is extremely rare,[2] and mostly people in their 50s or early 60s are affected.

Familial and nonfamilial Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of dementia; it usually occurs in old age. Familial Alzheimer's disease 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.[medical citation needed] Nonfamilial cases of AD are referred to as "sporadic" AD, where genetic risk factors are minor or unclear.[3] Familial Alzheimer's accounts for 10-15% of all EOAD cases. The rest are sporadic and not based on genetic mutations.

Signs and symptoms

EOAD strikes earlier in life, defined as before the age of 65 (usually between 30 and 60 years of age).[medical citation needed] Early signs of AD include unusual memory loss, particularly in remembering recent events and the names of people and things (logopenic primary progressive aphasia). As the disease progresses, the patient exhibits more serious problems, becoming subject to mood swings and unable to perform complex activities such as driving. Other common findings include confusion, poor judgement, language disturbance, agitation, withdrawal, hallucinations, seizures, Parkinsonian deficits, increased muscle tone, myoclonus, urinary incontinence, fecal incontinence and mutism.[medical citation needed] 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.

Causes

Familial AD is inherited in an autosomal dominant fashion, identified by genetics and other characteristics such as the age of onset.[medical citation needed]

Genetics

 
Familial AD is inherited in an autosomal dominant fashion.

Familial Alzheimer disease is caused by a mutation in one of at least three genes, which code for presenilin 1, presenilin 2, and APP.[4][5][6]

PSEN1 – Presenilin 1

The presenilin 1 gene (PSEN1 located on chromosome 14) was identified by Sherrington (1995)[7] and multiple mutations have been identified. Mutations in this gene cause familial Alzheimer's type 3 with certainty and usually under 50 years old.[medical citation needed] This type accounts for 30–70% of EOFAD. This protein has been identified as part of the enzymatic complex that cleaves amyloid-beta peptide from APP.

The gene contains 14 exons, and the coding portion is estimated at 60 kb, as reported by Rogaev (1997)[8] and Del-Favero (1999).[9] The protein the gene codes for (PS1) is an integral membrane protein. As stated by Ikeuchi (2002)[10] it cleaves the protein Notch1 so is thought by Koizumi (2001)[11] 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.

Some of the mutations in the gene, of which over 90 are known, include: His163Arg, Ala246Glu, Leu286Val and Cys410Tyr. Most display complete penetrance, but a common mutation is Glu318Gly and this predisposes individuals to familial AD, with a study by Taddei (2002)[12] finding an incidence of 8.7% in patients with familial AD.

PSEN2 – Presenilin 2

The presenilin 2 gene (PSEN2) is very similar in structure and function to PSEN1. 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.[medical citation needed] The gene was identified by Rudolph Tanzi and Jerry Schellenberg in 1995.[13] A subsequent study by Kovacs (1996)[14] showed that PS1 and PS2 proteins are expressed in similar amounts, and in the same organelles as each other, in mammalian neuronal cells. Levy-Lahad (1996)[15] determined that PSEN2 contained 12 exons, 10 of which were coding exons, and that the primary transcript encodes a 448-amino-acid polypeptide with 67% homology to PS1. This protein has been identified as part of the enzymatic complex that cleaves amyloid beta peptide from APP (see below).

The mutations have not been studied as much as PSEN1, 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 angiopathy in the affected individuals in a family. This phenotype may be explained by a study by Tomita (1997)[16] suggesting that the Asn141Ile mutation alters APP metabolism causing an increased rate of protein deposition into plaques.

Other allelic variants are Met239Val which was identified in an Italian pedigree by Rogaev (1995)[17] 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)[18] to change the endoproteolytic processing of the PS2.

APP – amyloid beta (A4) precursor protein

Further information: Swedish mutation
 
Processing of the amyloid precursor protein

Mutations to the amyloid beta A4 precursor protein (APP) located on the long arm of chromosome 21 (21q21.3) cause familial Alzheimer disease.[6]

[19] This type accounts for no more than 10–15% of EOFAD.[medical citation needed]

Three of the different APP mutations identified and characterized are the Swedish mutation,[20] the London mutation (APP V717I),[21][22] and the Arctic mutation.[23] Functional analyses of these mutations have significantly increased the understanding of the disease pathogenesis. Whereas the Swedish mutation, located at the cleavage site for β-secretase, results in an overall higher production of Aβ peptides by increasing the β-secretory cleavage,[24] the London 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,[25] while the Arctic mutation leads to a conformation change of the Aβ peptide and increased formation of toxic Aβ protofibrils.[26]

Mechanism

Histologically, familial AD is practically indistinguishable from other forms of the disease. Deposits of amyloid can be seen in sections of brain tissue. This amyloid protein forms plaques and neurofibrillary tangles 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.[citation needed]

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 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.[27]

Beta-amyloid is a small piece of a larger protein called amyloid precursor protein (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.[28]

Following cleavage by β-secretase, APP is cleaved by a membrane-bound protein complex called γ-secretase to generate Aβ.[29] 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.

Genetic testing

Genetic testing is available for symptomatic individuals and asymptomatic relatives.[5] 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.[medical citation needed]

Prognosis

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.[30][31]

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.[32] Those who are forced to retire early may not have access to the full range of benefits available to those who retire at the minimum age set by the government.[32] 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.[33]

Younger people with Alzheimer's may also lose their ability to take care of their own needs, such as money management.[34]

It has been suggested that conceptualizations of Alzheimer's and ageing should resist the notion that there are two distinct conditions.[35] A binary model, which focuses in particular on the needs of younger people, could lead to the challenges experienced by older people being understated.[36]

History

Main article: Alzheimer's disease § History

The symptoms of Alzheimer's disease as a distinct nosologic entity were first identified by Emil Kraepelin, who worked in Alzheimer's laboratory, and the characteristic neuropathology was first observed by Alois Alzheimer 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.[37]

Research directions

While early-onset familial AD is estimated to account for only 1% of total Alzheimer's disease,[2] 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 development for AD.[38]

See also

References

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External links

April 29, 2023
early, onset, alzheimer, disease, this, article, needs, more, medical, references, verification, relies, heavily, primary, sources, please, review, contents, article, appropriate, references, unsourced, poorly, sourced, material, challenged, removed, find, sou. This article needs more medical references for verification or relies too heavily on primary sources Please review the contents of the article and add the appropriate references if you can Unsourced or poorly sourced material may be challenged and removed Find sources Early onset Alzheimer s disease news newspapers books scholar JSTOR December 2021 Early onset Alzheimer s disease EOAD also called Younger onset Alzheimer s disease YOAD 1 is Alzheimer s disease 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 autosomal dominant 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 Early onset Alzheimer s diseaseOther namesEOADYounger onset Alzheimer s diseaseYOADSpecialtyNeurologyNonfamilial early onset AD can develop in people who are in their 30s or 40s but this is extremely rare 2 and mostly people in their 50s or early 60s are affected Contents 1 Familial and nonfamilial Alzheimer s disease 2 Signs and symptoms 3 Causes 3 1 Genetics 3 1 1 PSEN1 Presenilin 1 3 1 2 PSEN2 Presenilin 2 3 1 3 APP amyloid beta A4 precursor protein 3 2 Mechanism 3 3 Genetic testing 4 Prognosis 5 History 6 Research directions 7 See also 8 References 9 External linksFamilial and nonfamilial Alzheimer s disease EditAlzheimer s disease AD is a neurodegenerative disease and the most common cause of dementia it usually occurs in old age Familial Alzheimer s disease 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 medical citation needed Nonfamilial cases of AD are referred to as sporadic AD where genetic risk factors are minor or unclear 3 Familial Alzheimer s accounts for 10 15 of all EOAD cases The rest are sporadic and not based on genetic mutations Signs and symptoms EditEOAD strikes earlier in life defined as before the age of 65 usually between 30 and 60 years of age medical citation needed Early signs of AD include unusual memory loss particularly in remembering recent events and the names of people and things logopenic primary progressive aphasia As the disease progresses the patient exhibits more serious problems becoming subject to mood swings and unable to perform complex activities such as driving Other common findings include confusion poor judgement language disturbance agitation withdrawal hallucinations seizures Parkinsonian deficits increased muscle tone myoclonus urinary incontinence fecal incontinence and mutism medical citation needed 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 Causes EditFamilial AD is inherited in an autosomal dominant fashion identified by genetics and other characteristics such as the age of onset medical citation needed Genetics Edit Familial AD is inherited in an autosomal dominant fashion Familial Alzheimer disease is caused by a mutation in one of at least three genes which code for presenilin 1 presenilin 2 and APP 4 5 6 PSEN1 Presenilin 1 Edit The presenilin 1 gene PSEN1 located on chromosome 14 was identified by Sherrington 1995 7 and multiple mutations have been identified Mutations in this gene cause familial Alzheimer s type 3 with certainty and usually under 50 years old medical citation needed This type accounts for 30 70 of EOFAD This protein has been identified as part of the enzymatic complex that cleaves amyloid beta peptide from APP The gene contains 14 exons and the coding portion is estimated at 60 kb as reported by Rogaev 1997 8 and Del Favero 1999 9 The protein the gene codes for PS1 is an integral membrane protein As stated by Ikeuchi 2002 10 it cleaves the protein Notch1 so is thought by Koizumi 2001 11 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 Some of the mutations in the gene of which over 90 are known include His163Arg Ala246Glu Leu286Val and Cys410Tyr Most display complete penetrance but a common mutation is Glu318Gly and this predisposes individuals to familial AD with a study by Taddei 2002 12 finding an incidence of 8 7 in patients with familial AD PSEN2 Presenilin 2 Edit The presenilin 2 gene PSEN2 is very similar in structure and function to PSEN1 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 medical citation needed The gene was identified by Rudolph Tanzi and Jerry Schellenberg in 1995 13 A subsequent study by Kovacs 1996 14 showed that PS1 and PS2 proteins are expressed in similar amounts and in the same organelles as each other in mammalian neuronal cells Levy Lahad 1996 15 determined that PSEN2contained 12 exons 10 of which were coding exons and that the primary transcript encodes a 448 amino acid polypeptide with 67 homology to PS1 This protein has been identified as part of the enzymatic complex that cleaves amyloid beta peptide from APP see below The mutations have not been studied as much as PSEN1 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 angiopathy in the affected individuals in a family This phenotype may be explained by a study by Tomita 1997 16 suggesting that the Asn141Ile mutation alters APP metabolism causing an increased rate of protein deposition into plaques Other allelic variants are Met239Val which was identified in an Italian pedigree by Rogaev 1995 17 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 18 to change the endoproteolytic processing of the PS2 APP amyloid beta A4 precursor protein Edit Further information Swedish mutation Processing of the amyloid precursor protein Mutations to the amyloid beta A4 precursor protein APP located on the long arm of chromosome 21 21q21 3 cause familial Alzheimer disease 6 19 This type accounts for no more than 10 15 of EOFAD medical citation needed Three of the different APP mutations identified and characterized are the Swedish mutation 20 the London mutation APP V717I 21 22 and the Arctic mutation 23 Functional analyses of these mutations have significantly increased the understanding of the disease pathogenesis Whereas the Swedish mutation located at the cleavage site for b secretase results in an overall higher production of Ab peptides by increasing the b secretory cleavage 24 the London mutation as well as other mutations in the APP at codon 717 shifts the ratio of toxic Ab species to the more aggregate prone 42 amino acid length peptide 25 while the Arctic mutation leads to a conformation change of the Ab peptide and increased formation of toxic Ab protofibrils 26 Mechanism Edit This section does not cite any sources Please help improve this section by adding citations to reliable sources Unsourced material may be challenged and removed October 2009 Learn how and when to remove this template message Histologically familial AD is practically indistinguishable from other forms of the disease Deposits of amyloid can be seen in sections of brain tissue This amyloid protein forms plaques and neurofibrillary tangles 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 citation needed 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 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 27 Beta amyloid is a small piece of a larger protein called amyloid precursor protein APP Once APP is activated it is cut into smaller sections of other proteins One of the fragments produced in this cutting process is b amyloid b 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 b amyloid plaques in the brain causes the body to recruit and activate microglial cells and astrocytes 28 Following cleavage by b secretase APP is cleaved by a membrane bound protein complex called g secretase to generate Ab 29 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 Ab 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 Ab domain Genetic testing Edit Genetic testing is available for symptomatic individuals and asymptomatic relatives 5 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 medical citation needed Prognosis EditThe 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 30 31 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 32 Those who are forced to retire early may not have access to the full range of benefits available to those who retire at the minimum age set by the government 32 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 33 Younger people with Alzheimer s may also lose their ability to take care of their own needs such as money management 34 It has been suggested that conceptualizations of Alzheimer s and ageing should resist the notion that there are two distinct conditions 35 A binary model which focuses in particular on the needs of younger people could lead to the challenges experienced by older people being understated 36 History EditMain article Alzheimer s disease History The symptoms of Alzheimer s disease as a distinct nosologic entity were first identified by Emil Kraepelin who worked in Alzheimer s laboratory and the characteristic neuropathology was first observed by Alois Alzheimer 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 37 Research directions EditWhile early onset familial AD is estimated to account for only 1 of total Alzheimer s disease 2 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 development for AD 38 See also EditStill Alice novel and the movie Still Alice whose main protagonist has EOAD Spirit Unforgettable a documentary film about the farewell tour of musician John Mann and his band Spirit of the West following his diagnosis with early onset Alzheimer s Thanmathra film an award winning Indian film detailing the effects of early onset Alzheimer s disease on a father and his relationship with his son References Edit Younger Early onset Alzheimer s Alzheimer s Association Retrieved 9 July 2020 a b Harvey RJ Skelton Robinson M Rossor MN September 2003 The prevalence and 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1 206 doi 10 1186 s12974 022 02565 0 ISSN 1742 2094 PMC 9382837 PMID 35978311 Chow VW Mattson MP Wong PC Gleichmann M March 2010 An overview of APP processing enzymes and products Neuromolecular Medicine 12 1 1 12 doi 10 1007 s12017 009 8104 z PMC 2889200 PMID 20232515 Mayo Clinic staff Early onset Alzheimer s When symptoms begin before 65 Mayo Clinic Mary Brophy Marcus Family shares journey after early Alzheimer s diagnosis USA Today September 2 2008 a b Living With Early Onset Alzheimer s Disease Archived 2007 10 19 at the Wayback Machine Cleveland Clinic Health System Early Onset Alzheimer s On The Rise CBS News March 8 2008 Archived February 10 2009 at the Wayback Machine Kathleen Fackelmann Who thinks of Alzheimer s in someone so young USA Today June 11 2007 Rahman S 2016 Young Onset Dementia a label too far Dementia Society July 27 2016 Tolhurst E 2016 The Burgeoning Interest in Young Onset Dementia Redressing the balance or reinforcing ageism PDF The International Journal of Ageing and Later Life 10 2 9 29 doi 10 3384 ijal 1652 8670 16302 Weber MM 1997 Aloys Alzheimer a coworker of Emil Kraepelin Journal of Psychiatric Research 31 6 635 643 doi 10 1016 S0022 3956 97 00035 6 PMID 9447568 Elsheikh SS Chimusa ER Mulder NJ Crimi A January 2020 Genome wide association study of brain connectivity changes for Alzheimer s disease Scientific Reports 10 1 1433 Bibcode 2020NatSR 10 1433E doi 10 1038 s41598 020 58291 1 PMC 6989662 PMID 31996736 External links Edit Retrieved from https en wikipedia org w index php title Early onset Alzheimer 27s disease amp oldid 1141576721, wikipedia, wiki, book, books, library,

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