Early-onset Alzheimer's disease
Encyclopedia
Early-onset Alzheimer's disease, also called early-onset Alzheimer's, or early-onset AD, is the term used for cases of 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 sufferers. Approximately half the cases of early-onset Alzheimer's are Familial Alzheimer's disease, where a genetic predisposition leads to the disease. The other incidences of early onset Alzheimer's, however, share the same traits as the 'late onset' form commonly referred to as "Alzheimer's disease", and little is understood about how it starts.
Non-Familial early onset Alzheimer's can develop in people who are in their 30's or 40's, but that is extremely rare. The majority of sufferers are in their 50's, or early 60's.
Sometimes the term "early-onset dementia" is used, although Alzheimer's is a disease that is just one cause of dementia
.
, and the characteristic neuropathology was first observed by Alois Alzheimer
in 1906. In this sense, the disease was co-discovered by Kraepelin and Alzheimer, who worked in Kraepelin's laboratory. Because of the overwhelming importance Kraepelin attached to finding the neuropathological basis of psychiatric disorders, Kraepelin made the generous decision that the disease would bear Alzheimer's name.
While early-onset familial AD is estimated to account for only 4-5% 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. The genetic causes of this minority form of AD are summarized in "Decoding Darkness: The Search for the Genetics Causes of Alzheimer's Disease" by Rudolph Tanzi and Ann Parson, Perseus Press, 2000.
and usually occurs in old age
. It is invariably fatal, generally within ten years of the first signs. Normal aging involves forgetfulness but the early signs of AD include unusual memory loss, particularly in remembering recent events and the names of people and things. As the disease progresses the patient exhibits more serious problems, becoming subject to mood swings and unable to perform complex activities such as driving. In the latter stages they forget how to do simple things such as brushing their hair and then require full-time care.
Histologically
, familial AD is practically indistinguishable from other forms of the disease. Deposits of amyloid
can be seen in sections of brain
tissue (visible as an apple-green yellow birefringence under polarised light). This amyloid protein forms plaques and neurofibrillary tangles that progress through the memory centres of the brain. Very rarely the plaque may be unique, or uncharacteristic of AD; this can happen when there is a mutation in one of the genes that creates a functional, but malformed, protein instead of the ineffective gene products that usually result from mutations.
Familial Alzheimer disease is caused by a mutation in one of at least 3 genes: presenilin 1
, presenilin 2 and amyloid precursor protein
(APP). Other gene mutations are in study.
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 protein has been identified as part of the enzymatic complex that cleaves amyloid beta peptide from APP (see below).
The gene contains 14 exon
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 there are over 90, include: His163Arg, Ala246Glu, Leu286Val and Cys410Tyr. Most display complete penetrance
, but a common mutation is Glu318Gly and this predisposes individuals to familial Alzheimer disease, with a study by Taddei (2002) finding an incidence of 8.7% in patients with familial AD.
) 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. 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
s as each other, in mammal
ian neuron
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 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 has been identified by 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 amyloid precursor protein (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 a Asp439Ala mutation in exon 12 of the gene which is suggest by Lleo (2001) to change the endoproteolytic processing of the PS2.
Mutations to the amyloid beta A4 precursor protein (APP)
located on the long arm of chromosome 21 (21q21.3) causes familial Alzheimer disease.
, 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.
reduces the disease symptoms in mice expressing APP and PSEN1 mutations.
As many patients are in the age range common to those raising children, patients' children who are not full grown suffer physically and emotionally as their parents are no longer able to care for them.
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 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 suffering from Early-onset Alzheimer's but unaware of it at the time has unleashed a disaster.
Sufferers may also lose their ability to take care of their own needs, such as money management.
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5-10% of all Alzheimer's sufferers. Approximately half the cases of early-onset Alzheimer's are Familial Alzheimer's disease, where a genetic predisposition leads to the disease. The other incidences of early onset Alzheimer's, however, share the same traits as the 'late onset' form commonly referred to as "Alzheimer's disease", and little is understood about how it starts.
Non-Familial early onset Alzheimer's can develop in people who are in their 30's or 40's, but that is extremely rare. The majority of sufferers are in their 50's, or early 60's.
Sometimes the term "early-onset dementia" is used, although Alzheimer's is a disease that is just one cause of dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
.
History of Alzheimer's disease
The symptoms of the disease as a distinct nosologic entity were first identified by Emil KraepelinEmil Kraepelin
Emil Kraepelin was a German psychiatrist. H.J. Eysenck's Encyclopedia of Psychology identifies him as the founder of modern scientific psychiatry, as well as of psychopharmacology and psychiatric genetics. Kraepelin believed the chief origin of psychiatric disease to be biological and genetic...
, and the characteristic neuropathology was first observed by Alois Alzheimer
Alois Alzheimer
Aloysius "Alois" Alzheimer, 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 Kraepelin would later identify as Alzheimer's disease....
in 1906. In this sense, the disease was co-discovered by Kraepelin and Alzheimer, who worked in Kraepelin's laboratory. Because of the overwhelming importance Kraepelin attached to finding the neuropathological basis of psychiatric disorders, Kraepelin made the generous decision that the disease would bear Alzheimer's name.
Familial Alzheimer's disease
Familial Alzheimer's disease (FAD) or Early onset Familial Alzheimer's disease (EOFAD) is an uncommon form of Alzheimer's disease that usually strikes earlier in life, defined as before the age of 65 (usually between 50 and 65 years of age, but can be as early as 15) and is inherited in an autosomal dominant fashion, identified by genetics and other characteristics such as the age of onset. It accounts for approximately half the cases of early-onset Alzheimer's disease. Familial AD requires the patient to have at least one first degree relative with a history of AD. Non-familial cases of AD are referred to as "sporadic" AD, where genetic risk factors are minor or unclear.While early-onset familial AD is estimated to account for only 4-5% 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. The genetic causes of this minority form of AD are summarized in "Decoding Darkness: The Search for the Genetics Causes of Alzheimer's Disease" by Rudolph Tanzi and Ann Parson, Perseus Press, 2000.
Clinical features
Alzheimer disease (AD) is the most common cause of dementiaDementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
and usually occurs in old age
Old age
Old age consists of ages nearing or surpassing the average life span of human beings, and thus the end of the human life cycle...
. It is invariably fatal, generally within ten years of the first signs. Normal aging involves forgetfulness but the early signs of AD include unusual memory loss, particularly in remembering recent events and the names of people and things. As the disease progresses the patient exhibits more serious problems, becoming subject to mood swings and unable to perform complex activities such as driving. In the latter stages they forget how to do simple things such as brushing their hair and then require full-time care.
Histologically
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
, familial AD is practically indistinguishable from other forms of the disease. Deposits of amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
can be seen in sections of brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
tissue (visible as an apple-green yellow birefringence under polarised light). This amyloid protein forms plaques and neurofibrillary tangles that progress through the memory centres of the brain. Very rarely the plaque may be unique, or uncharacteristic of AD; this can happen when there is a mutation in one of the genes that creates a functional, but malformed, protein instead of the ineffective gene products that usually result from mutations.
Genetics
PSEN1
Presenilin-1 is a protein that in humans is encoded by the PSEN1 gene.- Function :Alzheimer's disease patients with an inherited form of the disease carry mutations in the presenilin proteins or the amyloid precursor protein...
, presenilin 2 and amyloid precursor protein
Amyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...
(APP). Other gene mutations are in study.
PSEN1 - Presenilin 1
The presenilin 1 gene (PSEN1PSEN1
Presenilin-1 is a protein that in humans is encoded by the PSEN1 gene.- Function :Alzheimer's disease patients with an inherited form of the disease carry mutations in the presenilin proteins or the amyloid precursor protein...
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 protein has been identified as part of the enzymatic complex that cleaves amyloid beta peptide from APP (see below).
The gene contains 14 exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
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 there are over 90, include: His163Arg, Ala246Glu, Leu286Val and Cys410Tyr. Most display complete penetrance
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
, but a common mutation is Glu318Gly and this predisposes individuals to familial Alzheimer disease, with a study by Taddei (2002) finding an incidence of 8.7% in patients with familial AD.
PSEN2 - Presenilin 2
The presenilin 2 gene (PSEN2PSEN2
Presenilin-2 is a protein that in humans is encoded by the PSEN2 gene.- Function :Alzheimer's disease patients with an inherited form of the disease carry mutations in the presenilin proteins or the amyloid precursor protein...
) 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. 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
Organelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
s as each other, in mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
ian neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
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 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 has been identified by 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
Angiopathy
Angiopathy is the generic term for a disease of the blood vessels . The best known and most prevalent angiopathy is diabetic angiopathy, a common complication of chronic diabetes.-By caliber:...
in the affected individuals in a family. This phenotype may be explained by a study by Tomita (1997) suggesting that the Asn141Ile mutation alters amyloid precursor protein (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 a Asp439Ala mutation in exon 12 of the gene which is suggest by Lleo (2001) to change the endoproteolytic processing of the PS2.
APP – Amyloid beta (A4) precursor protein
Amyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...
located on the long arm of chromosome 21 (21q21.3) causes familial Alzheimer disease.
Pathophysiology
Following cleavage by β-secretaseBace
Bace is a village in the municipality of Prokuplje, Serbia. According to the 2002 census, the village has a population of 284 people.-References:...
, 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.
Diagnosis
The familial early-onset AD, is identified by genetics and other characteristics such as the age of onset.Genetic testing
Genetic testing is available for symptomatic individuals and asymptomatic relatives.Environment enrichment
Environment enrichmentEnvironmental enrichment (neural)
Environmental enrichment concerns how the brain is affected by the stimulation of its information processing provided by its surroundings . Brains in richer, more stimulating environments, have increased numbers of synapses, and the dendrite arbors upon which they reside are more complex...
reduces the disease symptoms in mice expressing APP and PSEN1 mutations.
Impact of Early-onset Alzheimer's
Early-onset Alzheimer's disease can have devastating effects on the careers, carers and family members of patients.As many patients are in the age range common to those raising children, patients' children who are not full grown suffer physically and emotionally as their parents are no longer able to care for them.
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 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 suffering from Early-onset Alzheimer's but unaware of it at the time has unleashed a disaster.
Sufferers may also lose their ability to take care of their own needs, such as money management.
See also
- Aging
- Aging movement controlAging movement controlNormal aging movement control in human is about the changes on the muscles, motor neurons, nerves, sensory functions, gait, fatigue, visual and manual responses, in men and women as they get older but who do not have neurological, muscular or neuromuscular disorder...
- Alzheimer's diseaseAlzheimer's diseaseAlzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
- DementiaDementiaDementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
- Aging BrainAging brainAge is a major risk factor for most common neurodegenerative diseases, including Alzheimer's disease, cerebrovascular disease, Parkinson's disease and Lou Gehrig's disease. Other risk factors, including genetic mutations, low educational attainments and head injury contribute much less to the risk...
External links
- Laboratory for Alzheimer's and Parkinson's Disease Research - Prof. Dr. Christian Haass
- Early-Onset Familial AD - Alzheimer Research ForumAlzheimer Research ForumAlzheimer Research Forum , or Alzforum as it is known among Alzheimer’s researchers, is a website which exploits to the fullest the potential of web technology to accelerate research into Alzheimer's disease...
, Updated 10 April 2008. - Wall Street Journal - Brian Kammerer: Alzheimer's at 40
- Early-Onset Familial Alzheimer Disease - by Thomas D Bird, MD at GeneRevies (NIH.gov)