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Early-onset Alzheimer's disease, also called younger-onset Alzheimer's, is
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...
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 In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
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. Non-familial 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.


Familial Alzheimer's disease

Alzheimer's disease (AD) is a
neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophi ...
and the most common cause of
dementia Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
; it usually occurs in
old age Old age refers to ages nearing or surpassing the life expectancy of human beings, and is thus the end of the human life cycle. Terms and euphemisms for people at this age include old people, the elderly (worldwide usage), OAPs (British usa ...
. Familial Alzheimer's disease is an inherited and uncommon form of AD. Familiar 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 Alzheimers accounts for 10-15% of all EOAD cases. The rest is 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). 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 features, increased muscle tone, myoclonus, incontinence, and mutism. In the latter 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 In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
fashion, identified by genetics and other characteristics such as the age of onset.


Genetics

Familial Alzheimer disease is caused by a mutation in one of at least three genes, which code for
presenilin 1 Presenilin-1 (PS-1) is a presenilin protein that in humans is encoded by the ''PSEN1'' gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta ...
,
presenilin 2 Presenilin-2 is a protein that (in humans) is encoded by the ''PSEN2'' gene. Function Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or the amyloid precursor ...
, and APP.


PSEN1 – Presenilin 1

The presenilin 1 gene (''
PSEN1 Presenilin-1 (PS-1) is a presenilin protein that in humans is encoded by the ''PSEN1'' gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta ...
'' 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 enzymatic complex that cleaves amyloid beta peptide from APP. The gene contains 14
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
s, 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. Some of the mutations in the gene, of which over 90 are known, include: His163Arg, Ala246Glu, Leu286Val and Cys410Tyr. Most display complete
penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is t ...
, 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.


PSEN2 – Presenilin 2

The presenilin 2 gene (''
PSEN2 Presenilin-2 is a protein that (in humans) is encoded by the ''PSEN2'' gene. Function Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or the amyloid precursor p ...
'') 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. 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
organelle In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' th ...
s as each other, in
mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur ...
ian
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
al cells. Levy-Lahad (1996) determined that ''PSEN2 ''contained 12 exons, 10 of which were coding exons, and that the primary transcript encodes a 448-amino-acid
polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...
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) 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) 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.


APP – amyloid beta (A4) 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. This type accounts for no more than 10–15% of EOFAD. Three of the different APP mutations identified and characterized are the ''Swedish'' mutation, the ''London'' mutation (APP V717I), and the ''Arctic'' mutation. 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, 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, while the ''Arctic'' mutation leads to a conformation change of the Aβ peptide and increased formation of toxic Aβ protofibrils.


Mechanism

Histologically Histology, also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vis ...
, familial AD is practically indistinguishable from other forms of the disease. Deposits of
amyloid Amyloids are aggregates of proteins characterised by a fibrillar morphology of 7–13 nm in diameter, a beta sheet (β-sheet) secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the huma ...
can be seen in sections of
brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...
tissue. This amyloid protein forms plaques and
neurofibrillary tangles Neurofibrillary tangles (NFTs) are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. Their presence is also found in numerous other diseases known as tauopathies. Little is ...
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. 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. Beta-amyloid is a small piece of a larger protein called
amyloid precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse forma ...
(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. Following cleavage by
β-secretase Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is enc ...
, 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.


Genetic testing

Genetic testing 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.


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.Mayo Clinic staff
Early-onset Alzheimer's: When symptoms begin before 65
''
Mayo Clinic The Mayo Clinic () is a nonprofit American academic medical center focused on integrated health care, education, and research. It employs over 4,500 physicians and scientists, along with another 58,400 administrative and allied health staf ...
''
Mary Brophy Marcus
Family shares journey after early Alzheimer's diagnosis
''
USA Today ''USA Today'' (stylized in all uppercase) is an American daily middle-market newspaper and news broadcasting company. Founded by Al Neuharth on September 15, 1982, the newspaper operates from Gannett's corporate headquarters in Tysons, Virgini ...
'' (September 2, 2008).
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.Living With Early-Onset Alzheimer's Disease
, ''
Cleveland Clinic Health System Cleveland Clinic is a nonprofit American academic medical center based in Cleveland, Ohio. Owned and operated by the Cleveland Clinic Foundation, an Ohio nonprofit corporation established in 1921, it runs a 170-acre (69 ha) campus in Cleveland, ...
''
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. 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.Early Onset Alzheimer's On The Rise
''
CBS News CBS News is the news division of the American television and radio service CBS. CBS News television programs include the '' CBS Evening News'', '' CBS Mornings'', news magazine programs '' CBS News Sunday Morning'', '' 60 Minutes'', and '' 4 ...
'' (March 8, 2008).
Younger people with Alzheimer's may also lose their ability to take care of their own needs, such as money management.Kathleen Fackelmann
Who thinks of Alzheimer's in someone so young?
''
USA Today ''USA Today'' (stylized in all uppercase) is an American daily middle-market newspaper and news broadcasting company. Founded by Al Neuharth on September 15, 1982, the newspaper operates from Gannett's corporate headquarters in Tysons, Virgini ...
'' (June 11, 2007).
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.


History

The symptoms of Alzheimer's disease as a distinct nosologic entity were first identified by
Emil Kraepelin Emil Wilhelm Georg Magnus Kraepelin (; ; 15 February 1856 – 7 October 1926) was a German psychiatrist. H. J. Eysenck's ''Encyclopedia of Psychology'' identifies him as the founder of modern scientific psychiatry, psychopharmacology and psych ...
, who worked in Alzheimer's laboratory, and the characteristic neuropathology was first observed by
Alois Alzheimer Alois Alzheimer ( , , ; 14 June 1864 – 19 December 1915) was a German psychiatrist and neuropathologist and a colleague of Emil Kraepelin. Alzheimer is credited with identifying the first published case of "presenile dementia", which Kraep ...
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.


Research directions

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 development for AD.


See also

* ''Still Alice'' (novel) and the movie '' Still Alice'', whose main protagonist has EOAD * ''
Spirit Unforgettable ''Spirit Unforgettable'' is a Canadian documentary film, which premiered at the Hot Docs Canadian International Documentary Festival in 2016.Norman Wilner"Spirit Unforgettable" ''NOW'', April 26, 2016. Directed by Pete McCormack,
'', a documentary film about the farewell tour of musician John Mann and his band
Spirit of the West Spirit of the West were a Canadian folk rock band from North Vancouver, active from 1983 to 2016. They were popular on the Canadian folk music scene in the 1980s before evolving a blend of hard rock, Britpop, and Celtic folk influences which ...
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


External links

{{DEFAULTSORT:Early-Onset Alzheimer's Disease Alzheimer's disease