Early-onset Alzheimer's disease

Early-onset Alzheimer's disease
Classification and external resources
ICD-10 G30.0, F00.0
ICD-9-CM 331.0
OMIM 104300
MeSH D000544

Early-onset Alzheimer's disease, also called early-onset Alzheimer's, or early-onset AD, 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. Approximately 13% of the cases of early-onset Alzheimer's are familial Alzheimer's disease,[1] 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 of 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 thirties or forties, but that is extremely rare.[2] The majority of people with early-onset Alzheimer's are in their fifties or early sixties.

History of Alzheimer's disease

The symptoms of the disease as a distinct nosologic entity were first identified by Emil Kraepelin, 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 decision that the disease would bear Alzheimer's name.[3]

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 3.5% 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.

Clinical features

Alzheimer's disease (AD) is the most common cause of dementia and usually occurs in old age. It is invariably fatal, generally within ten years of the first signs. 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. 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. 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 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.

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 Alzheimer's disease. The major molecules involved in these pathways include: glial cells (specifically astrocytes and microglia), beta-amyloid, and pro-inflammatory compounds.

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 fragments produced in this cutting process is β-amyloid. β-amyloid is “stickier” than any other fragment produced from cut-up APP and due to this property it starts an accumulation process in the brain. The accumulation 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. This is typically a beneficial response; however not with Alzheimer's because β-amyloid plaques stimulate the glial cells to release oxygen free radicals (this pathway is not yet clear). Free radicals are typically effective against abnormal cells, but there is no way for the free radicals to differentiate between normal and abnormal cells. The free radicals destroy β-amyloid plaques but also destroy the surrounding healthy tissue. As more tissue dies, the glial cells release chemokines and cytokines (pro-inflammatory compounds). These compounds recruit more glial cells, which means more free radicals. This uncontrolled glial response and inflammatory storm directly contributes to the neurodegenerative progression of Alzheimer's.

Genetics

Familial Alzheimer disease is inherited in an autosomal dominant fashion.

Familial Alzheimer disease is caused by a mutation in one of at least 3 genes: presenilin 1, presenilin 2 and amyloid precursor protein (APP).[4][5][6] Other gene mutations are in study.

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. This protein has been identified as part of the enzymatic complex that cleaves amyloid beta peptide from APP (see below).

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 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)[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. 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 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)[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 suggest by Lleo (2001)[18] to change the endoproteolytic processing of the PS2.

APP – Amyloid beta (A4) precursor protein

Main article: 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) causes familial Alzheimer disease.[6]

[19]

Pathophysiology

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 is available for symptomatic individuals and asymptomatic relatives.[5]

Impact of early-onset Alzheimer's

Early-onset Alzheimer's disease can have devastating effects on the careers, caretakers and family members of patients.[20][21] Many patients are within an 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.[22] 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.[22] 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.[23]

People with Alzheimer's may also lose their ability to take care of their own needs, such as money management.[24]

See also

References

  1. ↑ Campion, Dominque (1999). "Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum.". American Journal of Human Genetics. 65 (3): 664–670. doi:10.1086/302553. PMID 10441572.
  2. 1 2 R J Harvey; M Skelton-Robinson; M N Rossor (2003). "The prevalence and causes of dementia in people under the age of 65 years". J Neurol Neurosurg Psychiatry. 74 (9): 1206–1209. doi:10.1136/jnnp.74.9.1206. PMC 1738690Freely accessible. PMID 12933919.
  3. ↑ Weber MM (1997). "Aloys Alzheimer, a coworker of Emil Kraepelin". J Psychiatr Res. 31 (6): 635–43. doi:10.1016/S0022-3956(97)00035-6. PMID 9447568.
  4. ↑ Bertram, L.; Tanzi, R. E. (2008). "Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses". Nature reviews. Neuroscience. 9 (10): 768–778. doi:10.1038/nrn2494. PMID 18802446.
  5. 1 2 Williamson; Goldman, J.; Marder, K. (2009). "Genetic aspects of Alzheimer disease". The neurologist. 15 (2): 80–86. doi:10.1097/NRL.0b013e318187e76b. PMC 3052768Freely accessible. PMID 19276785.
  6. 1 2 Ertekin-taner (2007). "Genetics of Alzheimer's disease: a centennial review". Neurologic Clinics. 25 (3): 611–667, v. doi:10.1016/j.ncl.2007.03.009. PMC 2735049Freely accessible. PMID 17659183.
  7. ↑ Sherrington R.; Rogaev E. I.; Liang Y.; Rogaeva E. A.; Levesque G.; Ikeda M.; Chi H.; Lin C.; Li G.; et al. (1995). "Cloning of a gene bearing mis-sense mutations in early-onset familial Alzheimer's disease". Nature. 375 (6534): 754–760. Bibcode:1995Natur.375..754S. doi:10.1038/375754a0. PMID 7596406.
  8. ↑ Rogaev E. I.; Sherrington R.; Wu C.; Levesque G.; Liang Y.; Rogaeva E. A.; Ikeda M.; Holman K.; Lin C.; et al. (1997). "Analysis of the 5-prime sequence, genomic structure, and alternative splicing of the presenilin-1 gene (PSEN1) associated with early onset Alzheimer disease". Genomics. 40 (3): 415–424. doi:10.1006/geno.1996.4523. PMID 9073509.
  9. ↑ Del-Favero J., Goossens D., Van , den Bossche D., Van Broeckhoven C. (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.
  10. ↑ Ikeuchi T.; Sisodia S. S. (2002). "Cell-free generation of the notch1 intracellular domain (NICD) and APP-CTfgamma: evidence for distinct intramembranous "gamma-secretase" activities". Neuromolecular Medicine. 1 (1): 43–54. doi:10.1385/NMM:1:1:43. PMID 12025815.
  11. ↑ 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.
  12. ↑ Taddei K.; Fisher C.; Laws S. M.; Martins G.; Paton A.; Clarnette R. M.; Chung C.; Brooks W. S.; Hallmayer J.; et al. (2002). "Association between presenilin-1 Glu318Gly mutation and familial Alzheimer's disease in the Australian population". Molecular Psychiatry. 7 (7): 776–781. doi:10.1038/sj.mp.4001072. PMID 12192622.
  13. ↑ Levy-Lahad E, Wasco W, Poorkaj P, et al. (August 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.
  14. ↑ Kovacs D. M.; Fausett H. J.; Page K. J.; Kim T.-W.; Moir R. D.; Merriam D. E.; Hollister R. D.; Hallmark O. G.; Mancini R.; et al. (1996). "Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells". Nature Medicine. 2 (2): 224–229. doi:10.1038/nm0296-224. PMID 8574969.
  15. ↑ Levy-Lahad E, Poorkaj P, Wang K, et al. (June 1996). "Genomic structure and expression of STM2, the chromosome 1 familial Alzheimer disease gene". Genomics. 34 (2): 198–204. doi:10.1006/geno.1996.0266. PMID 8661049.
  16. ↑ Tomita T.; Maruyama K.; Saido T. C.; Kume H.; Shinozaki K.; Tokuhiro S.; Capell A.; Walter J.; Grunberg J.; et al. (1997). "The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue". Proceedings of the National Academy of Sciences. 94 (5): 2025–2030. Bibcode:1997PNAS...94.2025T. doi:10.1073/pnas.94.5.2025. PMC 20036Freely accessible. PMID 9050898.
  17. ↑ Rogaev E. I.; Sherrington R.; Rogaeva E. A.; Levesque G.; Ikeda M.; Liang Y.; Chi H.; Lin C.; Holman K.; et al. (1995). "Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene". Nature. 376 (6543): 775–778. Bibcode:1995Natur.376..775R. doi:10.1038/376775a0. PMID 7651536.
  18. ↑ Lleo A.; Blesa R.; Gendre J.; Castellvi M.; Pastor P.; Queralt R.; Oliva R. (2001). "A novel presenilin 2 gene mutation (D439A) in a patient with early-onset Alzheimer's disease". Neurology. 57 (10): 1926–1928. doi:10.1212/WNL.57.10.1926. PMID 11723295.
  19. ↑ Malenka, Eric J. Nestler, Steven E. Hyman, Robert C. (2009). Molecular neuropharmacology : a foundation for clinical neuroscience (2nd ed.). New York: McGraw-Hill Medical. ISBN 9780071481274.
  20. ↑ Mayo Clinic staff, Early-onset Alzheimer's: When symptoms begin before 65, Mayo Clinic
  21. ↑ Mary Brophy Marcus, Family shares journey after early Alzheimer's diagnosis, USA Today (September 2, 2008).
  22. 1 2 Living With Early-Onset Alzheimer's Disease, Cleveland Clinic Health System
  23. ↑ Early Onset Alzheimer's On The Rise, CBS News (March 8, 2008).
  24. ↑ Kathleen Fackelmann, Who thinks of Alzheimer's in someone so young?, USA Today (June 11, 2007).
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