KEGG   DISEASE: Alzheimer disease
Entry
H00056                      Disease                                
Name
Alzheimer disease;
Dementia due to Alzheimer disease
Description
Alzheimer disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-beta (Abeta), a major component of senile plaques, has various pathological effects on cell and organelle function. To date genetic studies have revealed four genes that may be linked to autosomal dominant or familial early onset AD (FAD). These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2), and apolipoprotein E (ApoE). All mutations associated with APP and PS proteins can lead to an increase in the production of Abeta peptides, specifically the more amyloidogenic form, Abeta42. It was proposed that Abeta forms Ca2+ permeable pores and binds to and modulates multiple synaptic proteins, including NMDAR, mGluR5, and VGCC, leading to the overfilling of neurons with calcium ions. Consequently, cellular Ca2+ disruptions will lead to neuronal apoptosis, autophagy deficits, mitochondrial abnormality, defective neurotransmission, impaired synaptic plasticity, and neurodegeneration in AD. FAD-linked PS1 mutation downregulates the unfolded protein response and leads to vulnerability to ER stress.
Category
Neurodegenerative disease
Brite
Human diseases [BR:br08402]
 Nervous system diseases
  Neurodegenerative diseases
   H00056  Alzheimer disease
Human diseases in ICD-11 classification [BR:br08403]
 08 Diseases of the nervous system
  Disorders with neurocognitive impairment as a major feature
   8A20  Alzheimer disease
    H00056  Alzheimer disease
Pathway
hsa05010  Alzheimer disease
Related
pathway
hsa05022  Pathways of neurodegeneration - multiple diseases
Network
nt06410  Calcium signaling
nt06412  Unfolded protein response (UPR) signaling
nt06414  Apoptosis
nt06417  AGE-RAGE signaling
nt06418  Oxidative phosphorylation
nt06419  Microtubule-based transport
nt06420  Ubiquitin-proteasome system
nt06460  Alzheimer disease
Gene
(AD1) APP [HSA:351] [KO:K04520]
(AD2) APOE [HSA:348] [KO:K04524]
(AD3) PSEN1 [HSA:5663] [KO:K04505]
(AD4) PSEN2 [HSA:5664] [KO:K04522]
(AD9) ABCA7 [HSA:10347] [KO:K05645]
(AD18) ADAM10 [HSA:102] [KO:K06704]
Drug
Donepezil hydrochloride [DR:D00670]
Rivastigmine [DR:D03822]
Rivastigmine tartrate [DR:D02558]
Galantamine hydrobromide [DR:D02173]
Memantine hydrochloride [DR:D04905]
Aducanumab [DR:D10541]
Memantine and donepezil [DR:D11387]
Comment
Disease class: tauopathy
Affected region: hippocampus, cerebral cortex
Microscopic lesion: amyloid plaques, neurofibrillary tangles, Lewy bodies (seen in Lewy body variant)
Other DBs
ICD-11: 8A20
ICD-10: G30
MeSH: D000544
OMIM: 104300 104310 607822 606889 608907 615590
Reference
PMID:19679070 (AD2)
  Authors
Kim J, Basak JM, Holtzman DM
  Title
The role of apolipoprotein E in Alzheimer's disease.
  Journal
Neuron 63:287-303 (2009)
DOI:10.1016/j.neuron.2009.06.026
Reference
  Authors
Kim D, Tsai LH
  Title
Bridging physiology and pathology in AD.
  Journal
Cell 137:997-1000 (2009)
DOI:10.1016/j.cell.2009.05.042
Reference
  Authors
Bertram L, Tanzi RE
  Title
Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses.
  Journal
Nat Rev Neurosci 9:768-78 (2008)
DOI:10.1038/nrn2494
Reference
  Authors
Bird TD
  Title
Genetic aspects of Alzheimer disease.
  Journal
Genet Med 10:231-9 (2008)
DOI:10.1097/GIM.0b013e31816b64dc
Reference
  Authors
Thomas P, Fenech M
  Title
A review of genome mutation and Alzheimer's disease.
  Journal
Mutagenesis 22:15-33 (2007)
DOI:10.1093/mutage/gel055
Reference
  Authors
Goedert M, Spillantini MG
  Title
A century of Alzheimer's disease.
  Journal
Science 314:777-81 (2006)
DOI:10.1126/science.1132814
Reference
PMID:16631796 (AD2)
  Authors
Fazekas F, Enzinger C, Ropele S, Schmidt H, Schmidt R, Strasser-Fuchs S
  Title
The impact of our genes: consequences of the apolipoprotein E polymorphism in Alzheimer disease and multiple sclerosis.
  Journal
J Neurol Sci 245:35-9 (2006)
DOI:10.1016/j.jns.2005.08.018
Reference
  Authors
Rocchi A, Pellegrini S, Siciliano G, Murri L.
  Title
Causative and susceptibility genes for Alzheimer's disease: a review.
  Journal
Brain Res Bull 61:1-24 (2003)
DOI:10.1016/S0361-9230(03)00067-4
Reference
PMID:1303291 (AD3)
  Authors
Mullan M, Houlden H, Windelspecht M, Fidani L, Lombardi C, Diaz P, Rossor M, Crook R, Hardy J, Duff K, et al.
  Title
A locus for familial early-onset Alzheimer's disease on the long arm of chromosome 14, proximal to the alpha 1-antichymotrypsin gene.
  Journal
Nat Genet 2:340-2 (1992)
DOI:10.1038/ng1292-340
Reference
PMID:7651536 (AD4)
  Authors
Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, et al.
  Title
Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.
  Journal
Nature 376:775-8 (1995)
DOI:10.1038/376775a0
Reference
PMID:26141617 (AD9)
  Authors
Cuyvers E, De Roeck A, Van den Bossche T, Van Cauwenberghe C, Bettens K, Vermeulen S, Mattheijssens M, Peeters K, Engelborghs S, Vandenbulcke M, Vandenberghe R, De Deyn PP, Van Broeckhoven C, Sleegers K
  Title
Mutations in ABCA7 in a Belgian cohort of Alzheimer's disease patients: a targeted resequencing study.
  Journal
Lancet Neurol 14:814-822 (2015)
DOI:10.1016/S1474-4422(15)00133-7
Reference
PMID:19608551 (AD18)
  Authors
Kim M, Suh J, Romano D, Truong MH, Mullin K, Hooli B, Norton D, Tesco G, Elliott K, Wagner SL, Moir RD, Becker KD, Tanzi RE
  Title
Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate {alpha}-secretase activity.
  Journal
Hum Mol Genet 18:3987-96 (2009)
DOI:10.1093/hmg/ddp323
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