KEGG   DISEASE: Alzheimer disease
H00056                      Disease                                

Alzheimer disease;
Dementia due to Alzheimer disease
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, specfically the more amyloidogenic form, Abeta42. It was proposed that Abeta form Ca2+ permeable pores and bind to and modulate 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.
Neurodegenerative disease
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
hsa05010  Alzheimer disease
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
N00996  Mutation-caused aberrant Abeta to AGE-RAGE signaling pathway
N00997  Mutation-caused aberrant Abeta to electron transfer in Complex I
N00999  Mutation-caused aberrant Abeta to electron transfer in Complex IV
N01001  Mutation-caused aberrant Abeta to mAchR-Ca2+ -apoptotic pathway
N01002  Mutation-caused aberrant Abeta to mGluR5-Ca2+ -apoptotic pathway
N01003  Mutation-caused aberrant Abeta to transport of calcium
N01004  Mutation-caused aberrant Abeta to VGCC-Ca2+ -apoptotic pathway
N01005  Mutation-caused aberrant Abeta to crosstalk between extrinsic and intrinsic apoptotic pathways
N01006  Mutation-caused aberrant Abeta to VGCC-Ca2+ -apoptotic pathway
N01007  Mutation-caused aberrant PSEN to mGluR5-Ca2+ -apoptotic pathway
N01008  Mutation-caused aberrant PSEN1 to mGluR5-Ca2+ -apoptotic pathway
N01010  Mutation-caused aberrant PSEN1 to PERK-ATF4 signaling pathway
N01012  Mutation-caused aberrant PSEN1 to IRE1a-XBP1 signaling pathway
N01014  Mutation-caused aberrant Abeta to IRE1a-JNK signaling pathway
N01016  Mutation-caused aberrant PSEN1 to ATF6-mediated transcription
N01017  Mutation-caused aberrant PSEN1 to anterograde axonal transport
N01018  Mutation-caused aberrant Abeta to anterograde axonal transport
N01060  Mutation-caused aberrant Abeta to 26S proteasome-mediated protein degradation
(AD1) APP; amyloid beta (A4) protein (mutation) [HSA:351] [KO:K04520]
(AD2) APOE; apolipoprotein E (mutation) [HSA:348] [KO:K04524]
(AD3) PSEN1; presenilin 1 (mutation) [HSA:5663] [KO:K04505]
(AD4) PSEN2; presenilin 2 (mutation) [HSA:5664] [KO:K04522]
Donepezil hydrochloride [DR:D00670]
Rivastigmine [DR:D03822]
Rivastigmine tartrate [DR:D02558]
Galantamine hydrobromide [DR:D02173]
Memantine hydrochloride [DR:D04905]
Memantine and donepezil [DR:D11387]
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
PMID:19679070 (AD2)
Kim J, Basak JM, Holtzman DM
The role of apolipoprotein E in Alzheimer's disease.
Neuron 63:287-303 (2009)
Kim D, Tsai LH
Bridging physiology and pathology in AD.
Cell 137:997-1000 (2009)
Bertram L, Tanzi RE
Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses.
Nat Rev Neurosci 9:768-78 (2008)
Bird TD
Genetic aspects of Alzheimer disease.
Genet Med 10:231-9 (2008)
PMID:18370236 (drug)
Cacabelos R
Pharmacogenomics in Alzheimer's disease.
Methods Mol Biol 448:213-357 (2008)
Thomas P, Fenech M
A review of genome mutation and Alzheimer's disease.
Mutagenesis 22:15-33 (2007)
Goedert M, Spillantini MG
A century of Alzheimer's disease.
Science 314:777-81 (2006)
PMID:16631796 (AD2)
Fazekas F, Enzinger C, Ropele S, Schmidt H, Schmidt R, Strasser-Fuchs S
The impact of our genes: consequences of the apolipoprotein E polymorphism in Alzheimer disease and multiple sclerosis.
J Neurol Sci 245:35-9 (2006)
Rocchi A, Pellegrini S, Siciliano G, Murri L.
Causative and susceptibility genes for Alzheimer's disease: a review.
Brain Res Bull 61:1-24 (2003)
PMID:1303291 (AD3)
Mullan M, Houlden H, Windelspecht M, Fidani L, Lombardi C, Diaz P, Rossor M, Crook R, Hardy J, Duff K, et al.
A locus for familial early-onset Alzheimer's disease on the long arm of chromosome 14, proximal to the alpha 1-antichymotrypsin gene.
Nat Genet 2:340-2 (1992)
PMID:7651536 (AD4)
Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, et al.
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 376:775-8 (1995)

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