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Alzheimer's disease(AD)

MedGen UID:
1853
Concept ID:
C0002395
Disease or Syndrome
Synonyms: AD; Alzheimer dementia (AD); ALZHEIMER DISEASE, FAMILIAL, 1, AUTOSOMAL RECESSIVE; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer''s disease; Alzheimer-type dementia (ATD); dementia; Dementia; Early-Onset Familial Alzheimer Disease; familial Alzheimer disease (FAD); Presenile and senile dementia; Primary Senile Degenerative Dementia
Modes of inheritance:
Heterogeneous
MedGen UID:
5539
Concept ID:
C0019409
Qualitative Concept
Made up of elements or ingredients that are not alike.
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
SNOMED CT: AD - Alzheimer's disease (26929004); Alzheimer disease (26929004); Alzheimers disease (26929004); Alzheimer's disease (26929004)
 
Genes: PAXIP1; SORL1; PLAU; NOS3; MPO; HFE; ACE; BLMH; APP; APBB2; A2M
Cytogenetic locations: 10q22.2; 11q24.1; 12p13.31; 17q11.2; 17q22; 17q23.3; 21q21.3; 4p14-13; 6p22.2; 7q36.1; 7q36.2
OMIM: 104300

Disease characteristics

Excerpted from the GeneReview: Alzheimer Disease Overview
Alzheimer disease (AD) is characterized by dementia that typically begins with subtle and poorly recognized failure of memory and slowly becomes more severe and, eventually, incapacitating. Other common findings include confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations. Occasionally, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism occur. Death usually results from general inanition, malnutrition, and pneumonia. The typical clinical duration of the disease is eight to ten years, with a range from one to 25 years. Approximately 25% of all AD is familial (i.e., ≥2 persons in a family have AD) of which approximately 95% is late onset (age >60-65 years) and 5% is early onset (age <65 years). [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  Definition  |  Causes  |  Evaluation Strategy  |  Genetic Counseling  |  Resources  |  Management  |  References  |  Chapter Notes
Authors:
Thomas D Bird   view full author information

Additional descriptions

From OMIM
Alzheimer disease is the most common form of progressive dementia in the elderly. It is a neurodegenerative disorder characterized by the neuropathologic findings of intracellular neurofibrillary tangles (NFT) and extracellular amyloid plaques that accumulate in vulnerable brain regions (Sennvik et al., 2000). Terry and Davies (1980) pointed out that the 'presenile' form, with onset before age 65, is identical to the most common form of late-onset or 'senile' dementia, and suggested the term 'senile dementia of the Alzheimer type' (SDAT). Haines (1991) reviewed the genetics of AD. Selkoe (1996) reviewed the pathophysiology, chromosomal loci, and pathogenetic mechanisms of Alzheimer disease. Theuns and Van Broeckhoven (2000) reviewed the transcriptional regulation of the genes involved in Alzheimer disease. Genetic Heterogeneity of Alzheimer Disease Alzheimer disease is a genetically heterogeneous disorder. See also AD2 (104310), associated with the APOE*4 allele (107741) on chromosome 19; AD3 (607822), caused by mutation in the presenilin-1 gene (PSEN1; 104311) on 14q; and AD4 (606889), caused by mutation in the PSEN2 gene (600759) on 1q31. There is evidence for additional AD loci on other chromosomes; see AD5 (602096) on 12p11, AD6 (605526) on 10q24, AD7 (606187) on 10p13, AD8 (607116) on 20p, AD9 (608907) on 19p13, AD10 (609636) on 7q36, AD11 (609790) on 9q22, AD12 (611073) on 8p12-q22, AD13 (611152) on 1q21, AD14 (611154) on 1q25, AD15 (611155) on 3q22-q24, AD16 (300756) on Xq21.3, AD17 (615080) on 6p21.2, and AD18 (615590), associated with variation in the ADAM10 gene (602192) on 15q21. Evidence also suggests that mitochondrial DNA polymorphisms may be risk factors in Alzheimer disease (502500). Finally, there have been associations between AD and various polymorphisms in other genes, including alpha-2-macroglobulin (A2M; 103950.0005), low density lipoprotein-related protein-1 (LRP1; 107770), the transferrin gene (TF; 190000), the hemochromatosis gene (HFE; 613609), the NOS3 gene (163729), the vascular endothelial growth factor gene (VEGF; 192240), the ABCA2 gene (600047), and the TNF gene (191160) (see MOLECULAR GENETICS).  http://www.omim.org/entry/104300
From GHR
Alzheimer disease is a degenerative disease of the brain that causes dementia, which is a gradual loss of memory, judgment, and ability to function. This disorder usually appears in people older than age 65, but less common forms of the disease appear earlier in adulthood. Memory loss is the most common sign of Alzheimer disease. Forgetfulness may be subtle at first, but the loss of memory worsens over time until it interferes with most aspects of daily living. Even in familiar settings, a person with Alzheimer disease may get lost or become confused. Routine tasks such as preparing meals, doing laundry, and performing other household chores can be challenging. Additionally, it may become difficult to recognize people and name objects. Affected people increasingly require help with dressing, eating, and personal care. As the disorder progresses, some people with Alzheimer disease experience personality and behavioral changes and have trouble interacting in a socially appropriate manner. Other common symptoms include agitation, restlessness, withdrawal, and loss of language skills. People with this disease usually require total care during the advanced stages of the disease. Affected individuals usually survive 8 to 10 years after the appearance of symptoms, but the course of the disease can range from 1 to 25 years. Death usually results from pneumonia, malnutrition, or general body wasting (inanition). Alzheimer disease can be classified as early-onset or late-onset. The signs and symptoms of the early-onset form appear before age 65, while the late-onset form appears after age 65. The early-onset form is much less common than the late-onset form, accounting for less than 5 percent of all cases of Alzheimer disease.  http://ghr.nlm.nih.gov/condition/alzheimer-disease

Clinical features

Dementia
MedGen UID:
504574
Concept ID:
CN000683
Finding
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
Parkinsonism
MedGen UID:
504793
Concept ID:
CN001191
Finding
Characteristic neurologic anomaly resulting form degeneration of dopamine-generating cells in the substantia nigra, a region of the midbrain, characterized clinically by shaking, rigidity, slowness of movement and difficulty with walking and gait.
Neurofibrillary tangles
MedGen UID:
505147
Concept ID:
CN001981
Finding
Pathological protein aggregates formed by hyperphosphorylation of a microtubule-associated protein known as tau, causing it to aggregate in an insoluble form.
Alzheimer disease
MedGen UID:
505259
Concept ID:
CN002282
Finding
A degenerative disease of the brain characterized by the insidious onset of dementia. Impairment of memory, judgment, attention span, and problem solving skills are followed by severe apraxia and a global loss of cognitive abilities. The condition primarily occurs after age 60, and is marked pathologically by severe cortical atrophy and the triad of senile plaques, neurofibrillary tangles, and neuropil threads.

Professional guidelines

PubMed

Goldman JS, Hahn SE, Catania JW, LaRusse-Eckert S, Butson MB, Rumbaugh M, Strecker MN, Roberts JS, Burke W, Mayeux R, Bird T; American College of Medical Genetics and the National Society of Genetic Counselors
Genet Med 2011 Jun;13(6):597-605. doi: 10.1097/GIM.0b013e31821d69b8. PMID: 21577118Free PMC Article
Williams JW, Plassman BL, Burke J, Benjamin S
Evid Rep Technol Assess (Full Rep) 2010 Apr;(193):1-727. PMID: 21500874
Hort J, O'Brien JT, Gainotti G, Pirttila T, Popescu BO, Rektorova I, Sorbi S, Scheltens P; EFNS Scientist Panel on Dementia
Eur J Neurol 2010 Oct;17(10):1236-48. doi: 10.1111/j.1468-1331.2010.03040.x. PMID: 20831773

Recent clinical studies

Etiology

Ayutyanont N, Langbaum JB, Hendrix SB, Chen K, Fleisher AS, Friesenhahn M, Ward M, Aguirre C, Acosta-Baena N, Madrigal L, Muñoz C, Tirado V, Moreno S, Tariot PN, Lopera F, Reiman EM
J Clin Psychiatry 2014 Jun;75(6):652-60. doi: 10.4088/JCP.13m08927. PMID: 24816373
Mattsson N, Tosun D, Insel PS, Simonson A, Jack CR Jr, Beckett LA, Donohue M, Jagust W, Schuff N, Weiner MW; Alzheimer's Disease Neuroimaging Initiative
Brain 2014 May;137(Pt 5):1550-61. Epub 2014 Mar 12 doi: 10.1093/brain/awu043. [Epub ahead of print] PMID: 24625697Free PMC Article
Dohler F, Sepulveda-Falla D, Krasemann S, Altmeppen H, Schlüter H, Hildebrand D, Zerr I, Matschke J, Glatzel M
Brain 2014 Mar;137(Pt 3):873-86. Epub 2014 Feb 10 doi: 10.1093/brain/awt375. [Epub ahead of print] PMID: 24519981
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R; Alzheimer's Disease Cooperative Study Steering Committee; Solanezumab Study Group
N Engl J Med 2014 Jan 23;370(4):311-21. doi: 10.1056/NEJMoa1312889. PMID: 24450890
Ahmed S, Haigh AM, de Jager CA, Garrard P
Brain 2013 Dec;136(Pt 12):3727-37. Epub 2013 Oct 18 doi: 10.1093/brain/awt269. [Epub ahead of print] PMID: 24142144Free PMC Article

Diagnosis

Ayutyanont N, Langbaum JB, Hendrix SB, Chen K, Fleisher AS, Friesenhahn M, Ward M, Aguirre C, Acosta-Baena N, Madrigal L, Muñoz C, Tirado V, Moreno S, Tariot PN, Lopera F, Reiman EM
J Clin Psychiatry 2014 Jun;75(6):652-60. doi: 10.4088/JCP.13m08927. PMID: 24816373
Lai SW, Lin CL, Liao KF
Eur J Epidemiol 2014 Jun;29(6):405-9. Epub 2014 Apr 22 doi: 10.1007/s10654-014-9903-6. [Epub ahead of print] PMID: 24752464
Okamura N, Furumoto S, Fodero-Tavoletti MT, Mulligan RS, Harada R, Yates P, Pejoska S, Kudo Y, Masters CL, Yanai K, Rowe CC, Villemagne VL
Brain 2014 Jun;137(Pt 6):1762-71. Epub 2014 Mar 27 doi: 10.1093/brain/awu064. [Epub ahead of print] PMID: 24681664
Mattsson N, Tosun D, Insel PS, Simonson A, Jack CR Jr, Beckett LA, Donohue M, Jagust W, Schuff N, Weiner MW; Alzheimer's Disease Neuroimaging Initiative
Brain 2014 May;137(Pt 5):1550-61. Epub 2014 Mar 12 doi: 10.1093/brain/awu043. [Epub ahead of print] PMID: 24625697Free PMC Article
Ahmed S, Haigh AM, de Jager CA, Garrard P
Brain 2013 Dec;136(Pt 12):3727-37. Epub 2013 Oct 18 doi: 10.1093/brain/awt269. [Epub ahead of print] PMID: 24142144Free PMC Article

Therapy

Ayutyanont N, Langbaum JB, Hendrix SB, Chen K, Fleisher AS, Friesenhahn M, Ward M, Aguirre C, Acosta-Baena N, Madrigal L, Muñoz C, Tirado V, Moreno S, Tariot PN, Lopera F, Reiman EM
J Clin Psychiatry 2014 Jun;75(6):652-60. doi: 10.4088/JCP.13m08927. PMID: 24816373
Lai SW, Lin CL, Liao KF
Eur J Epidemiol 2014 Jun;29(6):405-9. Epub 2014 Apr 22 doi: 10.1007/s10654-014-9903-6. [Epub ahead of print] PMID: 24752464
Mattsson N, Tosun D, Insel PS, Simonson A, Jack CR Jr, Beckett LA, Donohue M, Jagust W, Schuff N, Weiner MW; Alzheimer's Disease Neuroimaging Initiative
Brain 2014 May;137(Pt 5):1550-61. Epub 2014 Mar 12 doi: 10.1093/brain/awu043. [Epub ahead of print] PMID: 24625697Free PMC Article
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R; Alzheimer's Disease Cooperative Study Steering Committee; Solanezumab Study Group
N Engl J Med 2014 Jan 23;370(4):311-21. doi: 10.1056/NEJMoa1312889. PMID: 24450890
Zotova E, Bharambe V, Cheaveau M, Morgan W, Holmes C, Harris S, Neal JW, Love S, Nicoll JA, Boche D
Brain 2013 Sep;136(Pt 9):2677-96. Epub 2013 Aug 13 doi: 10.1093/brain/awt210. [Epub ahead of print] PMID: 23943781

Prognosis

Lai SW, Lin CL, Liao KF
Eur J Epidemiol 2014 Jun;29(6):405-9. Epub 2014 Apr 22 doi: 10.1007/s10654-014-9903-6. [Epub ahead of print] PMID: 24752464
Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, Mantua V, Mecocci P, Pani L, Winblad B, Kivipelto M
J Intern Med 2014 Mar;275(3):251-83. doi: 10.1111/joim.12191. PMID: 24605808Free PMC Article
Sherva R, Tripodis Y, Bennett DA, Chibnik LB, Crane PK, de Jager PL, Farrer LA, Saykin AJ, Shulman JM, Naj A, Green RC; GENAROAD Consortium; Alzheimer's Disease Neuroimaging Initiative; Alzheimer's Disease Genetics Consortium
Alzheimers Dement 2014 Jan;10(1):45-52. Epub 2013 Mar 25 doi: 10.1016/j.jalz.2013.01.008. [Epub ahead of print] PMID: 23535033Free PMC Article
Zotova E, Bharambe V, Cheaveau M, Morgan W, Holmes C, Harris S, Neal JW, Love S, Nicoll JA, Boche D
Brain 2013 Sep;136(Pt 9):2677-96. Epub 2013 Aug 13 doi: 10.1093/brain/awt210. [Epub ahead of print] PMID: 23943781
Pluta R, Jabłoński M, Ułamek-Kozioł M, Kocki J, Brzozowska J, Januszewski S, Furmaga-Jabłońska W, Bogucka-Kocka A, Maciejewski R, Czuczwar SJ
Mol Neurobiol 2013 Dec;48(3):500-15. Epub 2013 Mar 22 doi: 10.1007/s12035-013-8439-1. [Epub ahead of print] PMID: 23519520Free PMC Article

Clinical prediction guides

Ayutyanont N, Langbaum JB, Hendrix SB, Chen K, Fleisher AS, Friesenhahn M, Ward M, Aguirre C, Acosta-Baena N, Madrigal L, Muñoz C, Tirado V, Moreno S, Tariot PN, Lopera F, Reiman EM
J Clin Psychiatry 2014 Jun;75(6):652-60. doi: 10.4088/JCP.13m08927. PMID: 24816373
Okamura N, Furumoto S, Fodero-Tavoletti MT, Mulligan RS, Harada R, Yates P, Pejoska S, Kudo Y, Masters CL, Yanai K, Rowe CC, Villemagne VL
Brain 2014 Jun;137(Pt 6):1762-71. Epub 2014 Mar 27 doi: 10.1093/brain/awu064. [Epub ahead of print] PMID: 24681664
Shinohara M, Fujioka S, Murray ME, Wojtas A, Baker M, Rovelet-Lecrux A, Rademakers R, Das P, Parisi JE, Graff-Radford NR, Petersen RC, Dickson DW, Bu G
Brain 2014 May;137(Pt 5):1533-49. Epub 2014 Mar 12 doi: 10.1093/brain/awu046. [Epub ahead of print] PMID: 24625695Free PMC Article
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R; Alzheimer's Disease Cooperative Study Steering Committee; Solanezumab Study Group
N Engl J Med 2014 Jan 23;370(4):311-21. doi: 10.1056/NEJMoa1312889. PMID: 24450890
Pluta R, Jabłoński M, Ułamek-Kozioł M, Kocki J, Brzozowska J, Januszewski S, Furmaga-Jabłońska W, Bogucka-Kocka A, Maciejewski R, Czuczwar SJ
Mol Neurobiol 2013 Dec;48(3):500-15. Epub 2013 Mar 22 doi: 10.1007/s12035-013-8439-1. [Epub ahead of print] PMID: 23519520Free PMC Article

Recent systematic reviews

Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C
Lancet Neurol 2014 Aug;13(8):788-94. doi: 10.1016/S1474-4422(14)70136-X. PMID: 25030513
Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, Mantua V, Mecocci P, Pani L, Winblad B, Kivipelto M
J Intern Med 2014 Mar;275(3):251-83. doi: 10.1111/joim.12191. PMID: 24605808Free PMC Article
Henderson VW
J Steroid Biochem Mol Biol 2014 Jul;142:99-106. Epub 2013 May 28 doi: 10.1016/j.jsbmb.2013.05.010. [Epub ahead of print] PMID: 23727128Free PMC Article
Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thorton-Wells TA, Jones N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, Kamatani Y, Lin CF, Gerrish A, Schmidt H, Kunkle B, Dunstan ML, Ruiz A, Bihoreau MT, Choi SH, Reitz C, Pasquier F, Cruchaga C, Craig D, Amin N, Berr C, Lopez OL, De Jager PL, Deramecourt V, Johnston JA, Evans D, Lovestone S, Letenneur L, Morón FJ, Rubinsztein DC, Eiriksdottir G, Sleegers K, Goate AM, Fiévet N, Huentelman MW, Gill M, Brown K, Kamboh MI, Keller L, Barberger-Gateau P, McGuiness B, Larson EB, Green R, Myers AJ, Dufouil C, Todd S, Wallon D, Love S, Rogaeva E, Gallacher J, St George-Hyslop P, Clarimon J, Lleo A, Bayer A, Tsuang DW, Yu L, Tsolaki M, Bossù P, Spalletta G, Proitsi P, Collinge J, Sorbi S, Sanchez-Garcia F, Fox NC, Hardy J, Deniz Naranjo MC, Bosco P, Clarke R, Brayne C, Galimberti D, Mancuso M, Matthews F; European Alzheimer's Disease Initiative (EADI); Genetic and Environmental Risk in Alzheimer's Disease; Alzheimer's Disease Genetic Consortium; Cohorts for Heart and Aging Research in Genomic Epidemiology, Moebus S, Mecocci P, Del Zompo M, Maier W, Hampel H, Pilotto A, Bullido M, Panza F, Caffarra P, Nacmias B, Gilbert JR, Mayhaus M, Lannefelt L, Hakonarson H, Pichler S, Carrasquillo MM, Ingelsson M, Beekly D, Alvarez V, Zou F, Valladares O, Younkin SG, Coto E, Hamilton-Nelson KL, Gu W, Razquin C, Pastor P, Mateo I, Owen MJ, Faber KM, Jonsson PV, Combarros O, O'Donovan MC, Cantwell LB, Soininen H, Blacker D, Mead S, Mosley TH Jr, Bennett DA, Harris TB, Fratiglioni L, Holmes C, de Bruijn RF, Passmore P, Montine TJ, Bettens K, Rotter JI, Brice A, Morgan K, Foroud TM, Kukull WA, Hannequin D, Powell JF, Nalls MA, Ritchie K, Lunetta KL, Kauwe JS, Boerwinkle E, Riemenschneider M, Boada M, Hiltuenen M, Martin ER, Schmidt R, Rujescu D, Wang LS, Dartigues JF, Mayeux R, Tzourio C, Hofman A, Nöthen MM, Graff C, Psaty BM, Jones L, Haines JL, Holmans PA, Lathrop M, Pericak-Vance MA, Launer LJ, Farrer LA, van Duijn CM, Van Broeckhoven C, Moskvina V, Seshadri S, Williams J, Schellenberg GD, Amouyel P
Nat Genet 2013 Dec;45(12):1452-8. Epub 2013 Oct 27 doi: 10.1038/ng.2802. [Epub ahead of print] PMID: 24162737Free PMC Article
Diniz BS, Butters MA, Albert SM, Dew MA, Reynolds CF 3rd
Br J Psychiatry 2013 May;202(5):329-35. doi: 10.1192/bjp.bp.112.118307. PMID: 23637108Free PMC Article

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