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Alzheimer disease type 1(AD1)

MedGen UID:
354892
•Concept ID:
C1863052
•
Disease or Syndrome
Synonyms: AD1; ALZHEIMER DISEASE, FAMILIAL, 1; ALZHEIMER DISEASE, FAMILIAL, 1, AUTOSOMAL RECESSIVE
 
Genes (locations): APP (21q21.3); MPO (17q22); NOS3 (7q36.1); PLAU (10q22.2)
 
Monarch Initiative: MONDO:0007088
OMIM®: 104300

Definition

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), associated with variation in the ABCA7 gene (605414) on 19p13; AD10 (609636) on 7q36; AD11 (609790) on 9q22; AD12 (611073) on 8p12-q22; AD13 (611152) on 1q21; AD14 (611154) on 1q25; AD15 (604154) 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). [from OMIM]

Clinical features

From HPO
Alzheimer disease
MedGen UID:
1853
•Concept ID:
C0002395
•
Disease or Syndrome
Alzheimer's 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.\n\nMemory loss is the most common sign of Alzheimer's 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's 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.\n\nAs the disorder progresses, some people with Alzheimer's 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 Alzheimer's disease usually require total care during the advanced stages of the disease.\n\nIndividuals with Alzheimer's disease usually survive 8 to 10 years after the appearance of symptoms, but the course of the disease can range from 1 to 25 years. Survival is usually shorter in individuals diagnosed after age 80 than in those diagnosed at a younger age. In Alzheimer's disease, death usually results from pneumonia, malnutrition, or general body wasting (inanition).\n\nAlzheimer's disease can be classified as early-onset or late-onset. The signs and symptoms of the early-onset form appear between a person's thirties and mid-sixties, while the late-onset form appears during or after a person's mid-sixties. The early-onset form of Alzheimer's disease is much less common than the late-onset form, accounting for less than 10 percent of all cases of Alzheimer's disease.
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Neurofibrillary tangles
MedGen UID:
39273
•Concept ID:
C0085400
•
Finding
Pathological protein aggregates formed by hyperphosphorylation of a microtubule-associated protein known as tau, causing it to aggregate in an insoluble form.
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Parkinsonian disorder
MedGen UID:
66079
•Concept ID:
C0242422
•
Disease or Syndrome
Characteristic neurologic anomaly resulting from 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.
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Dementia
MedGen UID:
99229
•Concept ID:
C0497327
•
Mental or Behavioral Dysfunction
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.
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Long-tract signs
MedGen UID:
356397
•Concept ID:
C1865903
•
Finding
Long-tract signs refer to symptoms that are attributable to the involvement of the long fiber tracts in the spinal cord, which connect the spinal cord to the brain and mediate spinal and motor functions.
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Decreased circulating GABA concentration
MedGen UID:
1647139
•Concept ID:
C4703620
•
Finding
A decrease in the level of GABA in the serum.
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Professional guidelines

PubMed

Genetic heterogeneity in Alzheimer disease and implications for treatment strategies.
Ringman JM, Goate A, Masters CL, Cairns NJ, Danek A, Graff-Radford N, Ghetti B, Morris JC; Dominantly Inherited Alzheimer Network
Curr Neurol Neurosci Rep 2014 Nov;14(11):499. doi: 10.1007/s11910-014-0499-8. PMID: 25217249Free PMC Article

Recent clinical studies

Etiology

INFLAMMATION's cognitive impact revealed by a novel "Line of Identity" approach.
Royall DR, Palmer RF
PLoS One 2024;19(3):e0295386. Epub 2024 Mar 22 doi: 10.1371/journal.pone.0295386. PMID: 38517924Free PMC Article
Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage.
Joseph-Mathurin N, Feldman RL, Lu R, Shirzadi Z, Toomer C, Saint Clair JR, Ma Y, McKay NS, Strain JF, Kilgore C, Friedrichsen KA, Chen CD, Gordon BA, Chen G, Hornbeck RC, Massoumzadeh P, McCullough AA, Wang Q, Li Y, Wang G, Keefe SJ, Schultz SA, Cruchaga C, Preboske GM, Jack CR Jr, Llibre-Guerra JJ, Allegri RF, Ances BM, Berman SB, Brooks WS, Cash DM, Day GS, Fox NC, Fulham M, Ghetti B, Johnson KA, Jucker M, Klunk WE, la Fougère C, Levin J, Niimi Y, Oh H, Perrin RJ, Reischl G, Ringman JM, Saykin AJ, Schofield PR, Su Y, Supnet-Bell C, Vöglein J, Yakushev I, Brickman AM, Morris JC, McDade E, Xiong C, Bateman RJ, Chhatwal JP, Benzinger TLS; Dominantly Inherited Alzheimer Network
Alzheimers Dement 2024 Apr;20(4):2680-2697. Epub 2024 Feb 21 doi: 10.1002/alz.13729. PMID: 38380882Free PMC Article
Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional and longitudinal cohort study.
Quiroz YT, Zetterberg H, Reiman EM, Chen Y, Su Y, Fox-Fuller JT, Garcia G, Villegas A, Sepulveda-Falla D, Villada M, Arboleda-Velasquez JF, Guzmán-Vélez E, Vila-Castelar C, Gordon BA, Schultz SA, Protas HD, Ghisays V, Giraldo M, Tirado V, Baena A, Munoz C, Rios-Romenets S, Tariot PN, Blennow K, Lopera F
Lancet Neurol 2020 Jun;19(6):513-521. Epub 2020 May 26 doi: 10.1016/S1474-4422(20)30137-X. PMID: 32470423Free PMC Article
Thyroid hormone receptor and liver X receptor competitively up-regulate human selective Alzheimer's disease indicator-1 gene expression at the transcriptional levels.
Ishida E, Hashimoto K, Okada S, Satoh T, Yamada M, Mori M
Biochem Biophys Res Commun 2013 Mar 15;432(3):513-8. Epub 2013 Feb 14 doi: 10.1016/j.bbrc.2013.02.023. PMID: 23416078
Prevalence of neuropsychiatric symptoms in young-onset compared to late-onset Alzheimer's disease - part 1: findings of the two-year longitudinal NeedYD-study.
van Vliet D, de Vugt ME, Aalten P, Bakker C, Pijnenburg YA, Vernooij-Dassen MJ, Koopmans RT, Verhey FR
Dement Geriatr Cogn Disord 2012;34(5-6):319-27. Epub 2012 Dec 3 doi: 10.1159/000342824. PMID: 23208452

Diagnosis

Concordance of Alzheimer's Disease-Related Biomarkers Between Intraventricular and Lumbar Cerebrospinal Fluid in Idiopathic Normal Pressure Hydrocephalus.
Lukkarinen H, Vanninen A, Tesseur I, Pemberton D, Van Der Ark P, Kokkola T, Herukka SK, Rauramaa T, Hiltunen M, Blennow K, Zetterberg H, Leinonen V
J Alzheimers Dis 2023;91(1):305-319. doi: 10.3233/JAD-220652. PMID: 36404546Free PMC Article
Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional and longitudinal cohort study.
Quiroz YT, Zetterberg H, Reiman EM, Chen Y, Su Y, Fox-Fuller JT, Garcia G, Villegas A, Sepulveda-Falla D, Villada M, Arboleda-Velasquez JF, Guzmán-Vélez E, Vila-Castelar C, Gordon BA, Schultz SA, Protas HD, Ghisays V, Giraldo M, Tirado V, Baena A, Munoz C, Rios-Romenets S, Tariot PN, Blennow K, Lopera F
Lancet Neurol 2020 Jun;19(6):513-521. Epub 2020 May 26 doi: 10.1016/S1474-4422(20)30137-X. PMID: 32470423Free PMC Article
Still alice.
Hepburn K
Gerontologist 2015 Apr;55(2):328-9. Epub 2015 Mar 16 doi: 10.1093/geront/gnv017. PMID: 26035610
Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer disease kindred: a cross-sectional study.
Fleisher AS, Chen K, Quiroz YT, Jakimovich LJ, Gutierrez Gomez M, Langois CM, Langbaum JB, Roontiva A, Thiyyagura P, Lee W, Ayutyanont N, Lopez L, Moreno S, Muñoz C, Tirado V, Acosta-Baena N, Fagan AM, Giraldo M, Garcia G, Huentelman MJ, Tariot PN, Lopera F, Reiman EM
JAMA Neurol 2015 Mar;72(3):316-24. doi: 10.1001/jamaneurol.2014.3314. PMID: 25580592Free PMC Article
Prevalence of neuropsychiatric symptoms in young-onset compared to late-onset Alzheimer's disease - part 1: findings of the two-year longitudinal NeedYD-study.
van Vliet D, de Vugt ME, Aalten P, Bakker C, Pijnenburg YA, Vernooij-Dassen MJ, Koopmans RT, Verhey FR
Dement Geriatr Cogn Disord 2012;34(5-6):319-27. Epub 2012 Dec 3 doi: 10.1159/000342824. PMID: 23208452

Therapy

Genetic heterogeneity in Alzheimer disease and implications for treatment strategies.
Ringman JM, Goate A, Masters CL, Cairns NJ, Danek A, Graff-Radford N, Ghetti B, Morris JC; Dominantly Inherited Alzheimer Network
Curr Neurol Neurosci Rep 2014 Nov;14(11):499. doi: 10.1007/s11910-014-0499-8. PMID: 25217249Free PMC Article
Operationalizing hippocampal volume as an enrichment biomarker for amnestic mild cognitive impairment trials: effect of algorithm, test-retest variability, and cut point on trial cost, duration, and sample size.
Yu P, Sun J, Wolz R, Stephenson D, Brewer J, Fox NC, Cole PE, Jack CR Jr, Hill DL, Schwarz AJ; Coalition Against Major Diseases and the Alzheimer's Disease Neuroimaging Initiative
Neurobiol Aging 2014 Apr;35(4):808-18. Epub 2013 Oct 3 doi: 10.1016/j.neurobiolaging.2013.09.039. PMID: 24211008Free PMC Article

Prognosis

INFLAMMATION's cognitive impact revealed by a novel "Line of Identity" approach.
Royall DR, Palmer RF
PLoS One 2024;19(3):e0295386. Epub 2024 Mar 22 doi: 10.1371/journal.pone.0295386. PMID: 38517924Free PMC Article
Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage.
Joseph-Mathurin N, Feldman RL, Lu R, Shirzadi Z, Toomer C, Saint Clair JR, Ma Y, McKay NS, Strain JF, Kilgore C, Friedrichsen KA, Chen CD, Gordon BA, Chen G, Hornbeck RC, Massoumzadeh P, McCullough AA, Wang Q, Li Y, Wang G, Keefe SJ, Schultz SA, Cruchaga C, Preboske GM, Jack CR Jr, Llibre-Guerra JJ, Allegri RF, Ances BM, Berman SB, Brooks WS, Cash DM, Day GS, Fox NC, Fulham M, Ghetti B, Johnson KA, Jucker M, Klunk WE, la Fougère C, Levin J, Niimi Y, Oh H, Perrin RJ, Reischl G, Ringman JM, Saykin AJ, Schofield PR, Su Y, Supnet-Bell C, Vöglein J, Yakushev I, Brickman AM, Morris JC, McDade E, Xiong C, Bateman RJ, Chhatwal JP, Benzinger TLS; Dominantly Inherited Alzheimer Network
Alzheimers Dement 2024 Apr;20(4):2680-2697. Epub 2024 Feb 21 doi: 10.1002/alz.13729. PMID: 38380882Free PMC Article
Concordance of Alzheimer's Disease-Related Biomarkers Between Intraventricular and Lumbar Cerebrospinal Fluid in Idiopathic Normal Pressure Hydrocephalus.
Lukkarinen H, Vanninen A, Tesseur I, Pemberton D, Van Der Ark P, Kokkola T, Herukka SK, Rauramaa T, Hiltunen M, Blennow K, Zetterberg H, Leinonen V
J Alzheimers Dis 2023;91(1):305-319. doi: 10.3233/JAD-220652. PMID: 36404546Free PMC Article
Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer disease kindred: a cross-sectional study.
Fleisher AS, Chen K, Quiroz YT, Jakimovich LJ, Gutierrez Gomez M, Langois CM, Langbaum JB, Roontiva A, Thiyyagura P, Lee W, Ayutyanont N, Lopez L, Moreno S, Muñoz C, Tirado V, Acosta-Baena N, Fagan AM, Giraldo M, Garcia G, Huentelman MJ, Tariot PN, Lopera F, Reiman EM
JAMA Neurol 2015 Mar;72(3):316-24. doi: 10.1001/jamaneurol.2014.3314. PMID: 25580592Free PMC Article
Prevalence of neuropsychiatric symptoms in young-onset compared to late-onset Alzheimer's disease - part 1: findings of the two-year longitudinal NeedYD-study.
van Vliet D, de Vugt ME, Aalten P, Bakker C, Pijnenburg YA, Vernooij-Dassen MJ, Koopmans RT, Verhey FR
Dement Geriatr Cogn Disord 2012;34(5-6):319-27. Epub 2012 Dec 3 doi: 10.1159/000342824. PMID: 23208452

Clinical prediction guides

INFLAMMATION's cognitive impact revealed by a novel "Line of Identity" approach.
Royall DR, Palmer RF
PLoS One 2024;19(3):e0295386. Epub 2024 Mar 22 doi: 10.1371/journal.pone.0295386. PMID: 38517924Free PMC Article
Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage.
Joseph-Mathurin N, Feldman RL, Lu R, Shirzadi Z, Toomer C, Saint Clair JR, Ma Y, McKay NS, Strain JF, Kilgore C, Friedrichsen KA, Chen CD, Gordon BA, Chen G, Hornbeck RC, Massoumzadeh P, McCullough AA, Wang Q, Li Y, Wang G, Keefe SJ, Schultz SA, Cruchaga C, Preboske GM, Jack CR Jr, Llibre-Guerra JJ, Allegri RF, Ances BM, Berman SB, Brooks WS, Cash DM, Day GS, Fox NC, Fulham M, Ghetti B, Johnson KA, Jucker M, Klunk WE, la Fougère C, Levin J, Niimi Y, Oh H, Perrin RJ, Reischl G, Ringman JM, Saykin AJ, Schofield PR, Su Y, Supnet-Bell C, Vöglein J, Yakushev I, Brickman AM, Morris JC, McDade E, Xiong C, Bateman RJ, Chhatwal JP, Benzinger TLS; Dominantly Inherited Alzheimer Network
Alzheimers Dement 2024 Apr;20(4):2680-2697. Epub 2024 Feb 21 doi: 10.1002/alz.13729. PMID: 38380882Free PMC Article
Pathological manifestation of the induced pluripotent stem cell-derived cortical neurons from an early-onset Alzheimer's disease patient carrying a presenilin-1 mutation (S170F).
Li L, Kim HJ, Roh JH, Kim M, Koh W, Kim Y, Heo H, Chung J, Nakanishi M, Yoon T, Hong CP, Seo SW, Na DL, Song J
Cell Prolif 2020 Apr;53(4):e12798. Epub 2020 Mar 25 doi: 10.1111/cpr.12798. PMID: 32216003Free PMC Article

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