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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. Familial Alzheimer's can appear as early as 16 years of age.

Sometimes the term is called "early-onset dementia", although Alzheimer's is a disease that is just one type of dementia.

Clinical features of Alzheimer's disease

Alzheimer disease (AD) is the most common form of dementia 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.

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 generous decision that the disease would bear Alzheimer's name (J. Psychiat. Res., 1997, Vol 31, No. 6, pp. 635–643).

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 16 and 65 years of age) and is inherited in an autosomal dominant fashion. 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 relatives 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. Moreover, the early-onset familial AD gene mutations guide the vast majority of therapeutic discovery and development for AD. The genetic causes 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 form of dementia 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.

Familial Alzheimer disease is an uncommon form of Alzheimer's that comes on earlier in life, before the age of 65 (incidents occurring before 50 years of age are rarer) and is inherited in an autosomal dominant fashion. The familial early-onset AD, is identified by genetics and other characteristics such as the age of onset. As a whole, this form of the disease accounts for only about 5% of all cases of AD.

Histologically, familial AD is practically indistinguishable from other forms of the disease. Deposits of amyloid can be seen in sections 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.

Genetics

Familial Alzheimer disease is inherited in an autosomal dominant fashion.

Familial Alzheimer disease is caused by mutations in at least 3 genes: presenilin 1, amyloid precursor protein and presenilin 2.^[1][2][3] Other gene mutations are in study.

PSEN1 - Presenilin 1

The presenilin 1 gene (PSEN1) 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 exons, 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.

There are over 150 allelic mutations in PSEN1 that cause AD including Met146Leu which has been found in unrelated families in Italy by Sherrington (1995), and in Argentina by Morelli (1998). There are other mutations at this same amino acid position including Met146Val, found by the Alzheimer's Disease Collaborative Group (1995), and Met146Ile identified as two different point mutations, one in a Danish family by Jorgensen (1996), and another in a Swedish family by Gustafson (1998).

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.

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 (Levy-Lahad et al. Nature, 1995). A subsequent study by Kovacs (1996) in Nature Medicine 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) 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.

APP – Amyloid beta (A4) precursor protein

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.^[3]

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.

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.^[2]

Prevention

Environment enrichment

Environment enrichment reduces the disease symptoms in mouse expressing APP and PSEN1 mutations.^[4][5]

Impact of Early-onset Alzheimer's

Early-onset Alzheimer's disease can have devastating effects on the careers and family members of patients^[6][7].

As many patients are in the age range common to those raising children, children of patients 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^[8].

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^[8].

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^[9].

Sufferers may also lose their ability to take care of their own needs, such as money management^[10].

References

Bibliography

• Alzheimer's Disease Collaborative Group (1995), The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nature Genetics, vol. 11, pp. 219–222.
• Amouyel, P., Vidal, O., Launay, J. M., Laplanche, J. L. (1994), The apolipoprotein E alleles as major susceptibility factors for Creutzfeldt-Jakob disease. Lancet, vol. 344, pp. 1315–1318.
• Campion, D., Brice, A., Hannequin, D., Tardieu, S., Dubois, B., Calenda, A., Brun, E., Penet, C., Tayot, J., Martinez, M., et al. (1995), A large pedigree with early-onset Alzheimer's disease: clinical, neuropathologic, and genetic characterization. Neurology, vol. 45, no. 1, pp. 80–85.
• Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., Pericak-Vance, M. A. (1993), Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science, vol. 261, pp. 921–923.
• 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, vol. 229, no. 1-2, pp. 193–201.
• Gureje O., Ogunniyi A., Baiyewu O., Price B., Unverzagt F. W., Evans R. M., Smith-Gamble V., Lane K. A., Gao S, Hall K. S., Hendrie H. C., Murrell J. R. (2006) APOE epsilon4 is not associated with Alzheimer's disease in elderly Nigerians. Annals of Neurology vol. 59, pp. 182–185.
• Gustafson, L., Brun, A., Englund, E., Hagnell, O., Nilsson, K., Stensmyr, M., Ohlin, A. K., Abrahamson, M. (1998), A 50-year perspective of a family with chromosome-14-linked Alzheimer's disease. Human Genetics, vol. 102, pp. 253–257.
• Levy-Lahad E Wasco W, Poorkaj P, Romano DM, Oshima Jm Pettingell WH, Yu C, Jondro PD, Schmidt SD, Wang K, Crowley AC, Fu Y-H, Guenette SY, Galas D, Nemens E, Wijsman EM, Bird TD, Schellenberg GD, Tanzi RE. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science, 1995; 269: 973-977.
• Levy-Lahad, E., Poorkaj, P., Wang, K., Fu, Y. H., Oshima, J., Mulligan, J., Schellenberg, G. D. (1996),Genomic structure and expression of STM2, the chromosome 1 familial Alzheimer disease gene. Genomics, vol. 34, pp. 198–204.
• Liao, A., Nitsch, R. M., Greenberg, S. M., Finckh, U., Blacker, D., Albert, M., Rebeck, G. W., Gomez-Isla, T., Clatworthy, A., Binetti, G., Hock, C., Mueller-Thomsen, T., Mann, U., Zuchowski, K., Beisiegel, U., Staehelin, H., Growdon, J. H., Tanzi, R. E., Hyman, B. T. (1998), Genetic association of an alpha-2-macroglobulin (val1000ile) polymorphism and Alzheimer's disease. Human Molecular Genetics, vol. 7, pp. 1953–1956.
• Lin, F. H., Lin, R., Wisniewski, H. M., Hwang, Y.-W., Grundke-Iqbal, I., Healy-Louie, G., Iqbal, K. (1992), Detection of point mutations in codon 331 of mitochondrial NADH dehydrogenase subunit 2 in Alzheimer's brains. Biochemical & Biophysical Research Communications, vol. 182, pp. 238–246.
• 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, vol. 57, pp. 1926–1928.
• Jorgensen, P., Bus, C., Pallisgaard, N., Bryder, M., Jorgensen, A. L. (1996), Familial Alzheimer's disease co-segregates with a met146ile substitution in presenilin-1. Clinical Genetics, vol. 50, pp. 281–286.
• 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., Felsenstein, K. M., Hyman, B. T., Tanzi, R. E., Wasco, W. (1996), Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nature Medicine, vol. 2, pp. 224–229.
• 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, vol. 1, no. 1, pp. 43–54.
• 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, vol. 128, no. 8, pp. 1391–402.
• Morelli, L., Prat, M. I., Levy, E., Mangone, C. A., Castano, E. M. (1998), Presenilin 1 met146leu variant due to an A-T transversion in an early-onset familial Alzheimer's disease pedigree from Argentina. Genetics, vol. 53, pp. 469–473.
• Olson, J. M., Goddard, K. A. B., Dudek, D. M. (2002), A second locus for very-late-onset Alzheimer disease: a genome scan reveals linkage to 20p and epistasis between 20p and the amyloid precursor protein region. American Journal of Human Genetics, vol. 71, pp. 154–161.
• Rogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., Liang, Y., Chi, H., Lin, C., Holman, K., Tsuda, T., Mar, L., Sorbi, S., Nacmias, B., Placentini, S., Amaducci, L., Chumakov, I., Cohen, D., Lannfelt, L., Fraser, P. E., Rommens, J. M., St George-Hyslop, P. H. (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, vol. 376, pp. 775–778.
• 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-prime sequence, genomic structure, and alternative splicing of the presenilin-1 gene (PSEN1) associated with early onset Alzheimer disease. Genomics, vol. 40, pp. 415–424.
• 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., Roses, A. D., Fraser, P. E., Rommens, J. M., St George P. H. (1995), Cloning of a gene bearing mis-sense mutations in early-onset familial Alzheimer's disease. Nature, vol. 375, pp. 754–760.
• 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, vol. 7, no. 7, pp. 776–781.
• Tanzi, R and Parson A. "Decoding Darkness: The Search for the Genetics Causes of Alzheimer's Disease" Perseus Press, 2000.
• Tomita, T., Maruyama, K., Saido, T. C., Kume, H., Shinozaki, K., Tokuhiro, S., Capell, A., Walter, J., Grunberg, J., Haass, C., Iwatsubo, T., Obata, K. (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 Science, vol. 94, pp. 2025–2030.
• Van Broeckhoven C, Backhovens H, Cruts M, De Winter G, Bruyland M, Cras P, Martin JJ., Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3, Nat Genet. 1992 Dec;2(4):335-9.
• Yoshikai, S., Sasaki, H., Doh-ura, K., Furuya, H., Sakaki, Y. (1990), Genomic organization of the human amyloid beta-protein precursor gene. Gene, vol. 87, pp. 257–263.
• Zubenko, G. S., Hughes, H. B., III, Stiffler, J. S. (2001), D10S1423 identifies a susceptibility locus for Alzheimer's disease in a prospective, longitudinal, double-blind study of asymptomatic individuals. Molecular Psychiatry, vol. 6, pp. 413–419.

Notes

External links

• Laboratory for Alzheimer's and Parkinson's Disease Research - Prof. Dr. Christian Haass
• Early-Onset Familial AD - Alzheimer Research Forum, 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)