User:Ourtcloud/sandbox

Early-onset Alzheimer's disease

Early-onset Alzheimer's disease, also called early-onset Alzheimer's, or early-onset AD, also FAD (see below), 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 13% of the cases of early-onset Alzheimer's are cases where the patient has at least one person in their immediate family who already has Alzheimer’s (familial).[1] This is because there are genes shared by members of the family that lead to the disease. The other incidences of early-onset Alzheimer's, however, share the same traits as the "late-onset" form of Alzheimer's disease, and little is understood about how it starts.

Early-onset AD can develop in people who are in their 30s or 40s with no close relatives diagnosed with Alzheimer’s, but this is extremely rare.[2] Most people with early-onset Alzheimer's are in their 50s or early 60s.

History of Alzheimer's disease

Emil Kraepelin first classified the symptoms of this disease as a distinct type of disease, and Alois Alzheimer first observed the characteristics of the disease in brain tissue in 1906. In this sense, the disease was co-discovered by Kraepelin and Alzheimer, who worked in Kraepelin's laboratory. Because Kraepelin attached so much importance to finding the basis of psychiatric disorders is the study of the brain tissue itself, Kraepelin made the 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). It is inherited from a parent with Alzhiemer’s and is identified by genetics and other characteristics such as the age of onset. Familial AD requires the patient to have at least one first-degree relative with a history of AD. Nonfamilial cases of AD are referred to as "sporadic" AD - they are uncommon and are cases where genetic risk factors are minor or unclear.[citation needed]

While early-onset familial AD may only be 3.5% of total Alzheimer's disease cases,[2] it has proven to be useful for studying various aspects Alzheimer’s Disease.

Clinical features

Alzheimer's disease (AD) is the most common cause of dementia and usually occurs in old age. It is always fatal, generally within 10 years of the first signs. Early signs of AD include unusual memory loss, especially 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.

At a microscopic level, FAD is almost the same as other forms of the disease. Deposits of amyloid - unusual folded proteins - can be seen in sections of brain tissue. This amyloid protein forms hardened substances (plaques) and neurofibrillary tangles - these are clumps of proteins in the brain tissue that spread through the brain as the disease worsens.

Very rarely, the plaques may be non-typical of AD; this can happen when a mutation occurs in a gene. The mutation creates a protein that functions in the brain (usually genetic mutations create non-functional proteins), but these proteins are abnormal.[citation needed]

The ways this disease shows up and works within brain tissue is just recently starting to be understood. Researchers have been working on better understanding the ways early-onset Alzheimer’s can be understood on a cellular level in brain tissue - how it develops, grows, and the negative effects it has on brain functions. The technical names of the molecules they have discovered to be related to the spread of the disease through the brain are: glial cells (specifically astrocytes and microglia), proinflammatory compounds, and beta-amyloid.

A beta-amyloid is a small piece of a larger protein called the amyloid precursor protein (APP). Once APP is activated, it is cut into smaller sections of other proteins. One of the sections produced in this cutting process is a β-amyloid, or beta-amyloid. The β-amyloid is “stickier” than any other piece produced from cut-up APP, so it starts an accumulation process in the brain. Eventually the beta-amyloids stick together to form oligomers, which then join together to form fibrils. Finally, the fibrils stick together with other kinds of brain tissue to form plaques.

These plaques in the brain, made from beta-amyloids, cause the body to activate cells called microglial cells and astrocytes.

Genetics

Familial Alzheimer’s disease is caused by a mutation in one of at least three genes: presenilin 1, presenilin 2, and amyloid precursor protein (APP).[4][5][6]

PSEN1 – Presenilin 1

The presenilin 1 gene 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 in people under 50 years old. This protein - which in exists in humans as a gene - has been identified as part of the molecular process in brain cells where the beta-amyloid section is cut from APP (see above and below).

Presenilin 1 acts on APP, and it is probably part of the process in the development of Familial Alzheimer’s. Genes of a related type to presenilin 1 have been found in both plants and animals.

Over 90 mutations of this gene are known. Most of these mutations will mean the person with the mutated presenilin 1 gene with definitely develop FAD but one mutation only results in an 8.7% chance of developing the disease.

PSEN2 – Presenilin 2

The presenilin 2 gene (PSEN2) is very similar in structure and function to PSEN1. Mutations in this gene cause type 4 FAD. The gene was identified by Rudolph Tanzi and Jerry Schellenberg in 1995.[13] A study by Kovacs (1996)[14] showed the close similarity of presenilin 1 and presenilin 2 in the neurons of mammals. Presenilin 2 has also been identified as part of the molecular process in brain cells where the beta-amyloid section is cut from APP (see above and below).

The mutations in PSEN 2 have not been studied as much as those in PSEN1, but chromosome variations have been found. These include Asn141Ile, which was identified first by Rudolph Tanzi and Jerry Schellenberg in German families with familial Alzheimer disease (Levy-Lahad et al. Nature, 1995). In one study by Nochlin (1998) they found severe blood vessel disease in members of the family who had FAD. This may be because this Asn141Ile mutation causes APP to deposit more plaques.[16]

APP – amyloid beta (A4) precursor protein

Mutations to the APP, located on the long arm of chromosome 21 - the smallest of 23 chromosome pairs in humans - cause familial Alzheimer disease.[6][19]

Two of the different APP mutations identified and characterized are the Swedish mutation[20] and the Arctic mutation[21]. Studies of these have increased the understanding of how FAD develops in the brain.

Genetic testing

Genetic testing is available for people who have the symptoms of FAD and for their relatives who do not have symptoms.[5]

Impact of early-onset Alzheimer’s

Because early-onset Alzheimer's happens in people relatively early in their lives it means that the disease presents it’s own particular effects on them. For example, the disease can have devastating effects on the careers, caretakers and family members of patients.[24][25]

Those who are working loose 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.[26] Those who are forced to retire early because of FAD may not have access to the full range of benefits available to those who retire at the minimum age set by their government.[26] 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.[27]

Younger people with Alzheimer's may also lose their ability to take care of their own needs, such as money management.[28]

It has also been pointed out, however, that people’s ideas of Alzheimer's and ageing should resist the notion that there are two separate conditions - Alzheimer’s and early-onset Alzheimer's.[29] This idea of FAD as a separate disease which focuses in particular on the needs of younger people, could lead to the challenges experienced by older people with Alzheimer’s being under appreciated.[30]

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

References

Campion, Dominique; Dumanchin, Cécile; Hannequin, Didier; Dubois, Bruno; Belliard, Serge; Puel, Michèle; Thomas-Anterion, Catherine; Michon, Agnès; Martin, Cosette; Charbonnier, Françoise; Raux, Grégory; Camuzat, Agnès; Penet, Christiane; Mesnage, Valérie; Martinez, Maria; Clerget-Darpoux, Françoise; Brice, Alexis; Frebourg, Thierry (1999). "Early-Onset Autosomal Dominant Alzheimer Disease: Prevalence, Genetic Heterogeneity, and Mutation Spectrum". The American Journal of Human Genetics. 65 (3): 664–70. doi:10.1086/302553. PMC 1377972. PMID 10441572.

Harvey, R J (2003). "The prevalence and causes of dementia in people under the age of 65 years". Journal of Neurology, Neurosurgery & Psychiatry. 74 (9): 1206–9. doi:10.1136/jnnp.74.9.1206. PMC 1738690. PMID 12933919.

Weber, Matthias M. (1997). "Aloys Alzheimer, a coworker of Emil Kraepelin". Journal of Psychiatric Research. 31 (6): 635–43. doi:10.1016/S0022-3956(97)00035-6. PMID 9447568.

Bertram, Lars; Tanzi, Rudolph E. (2008). "Thirty years of Alzheimer's disease genetics: The implications of systematic meta-analyses". Nature Reviews Neuroscience. 9 (10): 768–78. doi:10.1038/nrn2494. PMID 18802446.

Williamson, Jennifer; Goldman, Jill; Marder, Karen S. (2009). "Genetic Aspects of Alzheimer Disease". The Neurologist. 15 (2): 80–6. doi:10.1097/NRL.0b013e318187e76b. PMC 3052768. PMID 19276785.

Ertekin-Taner, Nilüfer (2007). "Genetics of Alzheimer's Disease: A Centennial Review". Neurologic Clinics. 25 (3): 611–67, v. doi:10.1016/j.ncl.2007.03.009. PMC 2735049. PMID 17659183.

Sherrington, R.; Rogaev, E. I.; Liang, Y.; Rogaeva, E. A.; Levesque, G.; Ikeda, M.; Chi, H.; Lin, C.; Li, G.; Holman, K.; Tsuda, T.; Mar, L.; Foncin, J.-F.; Bruni, A. C.; Montesi, M. P.; Sorbi, S.; Rainero, I.; Pinessi, L.; Nee, L.; Chumakov, I.; Pollen, D.; Brookes, A.; Sanseau, P.; Polinsky, R. J.; Wasco, W.; Da Silva, H. A. R.; Haines, J. L.; Pericak-Vance, M. A.; Tanzi, R. E.; et al. (1995). "Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease". Nature. 375 (6534): 754–60. Bibcode:1995Natur.375..754S. doi:10.1038/375754a0. PMID 7596406.

Rogaev, E.I.; Sherrington, R.; Wu, C.; Levesque, G.; Liang, Y.; Rogaeva, E.A.; Ikeda, M.; Holman, K.; Lin, C.; Lukiw, W.J.; De Jong, P.J.; Fraser, P.E.; Rommens, J.M.; St George-Hyslop, P. (1997). "Analysis of the 5′ Sequence, Genomic Structure, and Alternative Splicing of thepresenilin-1Gene (PSEN1) Associated with Early Onset Alzheimer Disease". Genomics. 40 (3): 415–24. doi:10.1006/geno.1996.4523. PMID 9073509.

Del-Favero, Jurgen; Goossens, Dirk; Van Den Bossche, Dirk; Van Broeckhoven, Christine (1999). "YAC fragmentation with repetitive and single-copy sequences: Detailed physical mapping of the presenilin 1 gene on chromosome 14". Gene. 229 (1–2): 193–201. doi:10.1016/S0378-1119(99)00023-2. PMID 10095119.

Ikeuchi, Takeshi; Sisodia, Sangram S. (2002). "Cell-Free Generation of the Notch1 Intracellular Domain (NICD) and APP-CTFγ". NeuroMolecular Medicine. 1 (1): 43–54. doi:10.1385/NMM:1:1:43. PMID 12025815.

Koizumi, K; Nakajima, M; Yuasa, S; Saga, Y; Sakai, T; Kuriyama, T; Shirasawa, T; Koseki, H (2001). "The role of presenilin 1 during somite segmentation". Development. 128 (8): 1391–402. PMID 11262239.

Taddei, K; Fisher, C; Laws, S M; Martins, G; Paton, A; Clarnette, R M; Chung, C; Brooks, W S; Hallmayer, J; Miklossy, J; Relkin, N; St George-Hyslop, P H; Gandy, S E; Martins, R N (2002). "Association between presenilin-1 Glu318Gly mutation and familial Alzheimer's disease in the Australian population". Molecular Psychiatry. 7 (7): 776–81. doi:10.1038/sj.mp.4001072. PMID 12192622.

Levy-Lahad, E.; Wasco, W.; Poorkaj, P.; Romano, D.; Oshima, J.; Pettingell, W.; Yu, C.; Jondro, P.; Schmidt, S.; Wang, K.; Al., e. (1995). "Candidate gene for the chromosome 1 familial Alzheimer's disease locus". Science. 269 (5226): 973–7. Bibcode:1995Sci...269..973L. doi:10.1126/science.7638622. PMID 7638622.

Kovacs, Dora M.; Fausett, Hillary J.; Page, Keith J.; Kim, Tae-Wan; Moir, Robert D.; Merriam, David E.; Hollister, Richard D.; Hallmark, Olivia G.; Mancini, Ronald; Felsenstein, Kevin M.; Hyman, Bradley T.; Tanzi, Rudolph E.; Wasco, Wilma (1996). "Alzheimer–associated presenilins 1 and 2 : Neuronal expression in brain and localization to intracellular membranes in mammalian cells". Nature Medicine. 2 (2): 224–9. doi:10.1038/nm0296-224. PMID 8574969.