Early-onset Alzheimer's Disease
   HOME

TheInfoList



OR:

Early-onset Alzheimer's disease (EOAD), also called younger-onset Alzheimer's disease (YOAD), is
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
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 Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
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. 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.


Familial and nonfamilial Alzheimer's disease

Alzheimer's disease (AD) is a
neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...
and the most common cause of
dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
; it usually occurs in
old age Old age is the range of ages for people nearing and surpassing life expectancy. People who are of old age are also referred to as: old people, elderly, elders, senior citizens, seniors or older adults. Old age is not a definite biological sta ...
. 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.


Signs and symptoms

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 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 In psychology, confusion is the quality or emotional state of being bewildered or unclear. The term "acute mental confusion"
, poor judgement, language disturbance, agitation, withdrawal,
hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...
s,
seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
s, Parkinsonian deficits, decreased
muscle tone In physiology, medicine, and anatomy, muscle tone (residual muscle tension or tonus) is the continuous and passive partial contraction of the muscles, or the muscle's resistance to passive stretch during resting state.O’Sullivan, S. B. (2007) ...
, myoclonus,
urinary incontinence Urinary incontinence (UI), also known as involuntary urination, is any uncontrolled leakage of urine. It is a common and distressing problem, which may have a significant effect on quality of life. Urinary incontinence is common in older women ...
,
fecal incontinence Fecal incontinence (FI), or in some forms, encopresis, is a lack of control over defecation, leading to involuntary loss of bowel contents—including flatus (gas), liquid stool elements and mucus, or solid feces. FI is a sign or a symptom ...
and
mutism In human development, muteness or mutism is defined as an absence of speech, with or without an ability to hear the speech of others. Mutism is typically understood as a person's inability to speak, and commonly observed by their family members, c ...
. 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 In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
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 2, and APP.


PSEN1 – Presenilin 1

The presenilin 1 gene ('' PSEN1'' 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 sequence ...
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, 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'') 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 (biology), cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as Organ (anatomy), organs are to th ...
s as each other, in
mammal A mammal () is a vertebrate animal of the Class (biology), class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three ...
ian
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
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. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ...
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. 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. 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. 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. This type accounts for no more than 10–15% of EOFAD. 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 Carol Jennings by a research team led by John Hardy. Other notable APP mutations include the Swedish and Arctic mutations. 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.


Non-genetic risk factors

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.


Mechanism

Histologically Histology, also known as microscopic anatomy or microanatomy, is the branch of biology that studies the microscopic anatomy of biological tissue (biology), tissues. Histology is the microscopic counterpart to gross anatomy, which looks at large ...
, 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 typically 7–13 nm in diameter, a β-sheet secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the human ...
can be seen in sections of
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
tissue. This amyloid protein forms plaques and
neurofibrillary tangles Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary Biomarker (medicine), biomarker of Alzheimer's disease. Their presence is also found in numerous other disea ...
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 biological tissue, tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of s ...
(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, 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 Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
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. 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 with early-onset Alzheimer's who is unaware of their condition has caused distress. Younger people with Alzheimer's may also lose their ability to take care of their own needs, such as money management. Studies indicate that cognitive rehabilitation can be beneficial in supporting the everyday functioning of those with EOAD. 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, 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, neuropathologist and colleague of Emil Kraepelin. He is credited with identifying the first published case of "presenile dementia", which Kraepelin later ide ...
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'', 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


External links

{{CNS diseases of the nervous system Alzheimer's disease