KEGG DISEASE: Alzheimer disease

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 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-based classification of diseases [BR:br08402]
Cellular processes
  nt06546  IgSF CAM signaling
   H00056  Alzheimer disease
  nt06534  Unfolded protein response
   H00056  Alzheimer disease
  nt06535  Efferocytosis
   H00056  Alzheimer disease

Disease
pathway

hsa05010

Alzheimer disease

Pathway

hsa04517 IGSF CAM signaling

Network

nt06460 Alzheimer disease
nt06466 Pathways of neurodegeneration
nt06534 Unfolded protein response
nt06535 Efferocytosis
nt06546 IgSF CAM signaling

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]
(AD17) TREM2 [HSA:54209] [KO:K14378]
(AD18) ADAM10 [HSA:102] [KO:K06704]

Drug

Donepezil hydrochloride [DR:D00670]
Rivastigmine [DR:D03822]
Rivastigmine tartrate [DR:D02558]
Galantamine hydrobromide [DR:D02173]
Benzgalantamine gluconate [DR:D12931]
Memantine hydrochloride [DR:D04905]
Aducanumab [DR:D10541]
Lecanemab [DR:D11678]
Donanemab [DR:D11500]
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

MeSH:

D000544

OMIM:

104300 104310 607822 606889 608907 615080 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

PMID:19524503

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

PMID:18802446

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

PMID:18414205

Authors

Bird TD

Title

Genetic aspects of Alzheimer disease.

Journal

Genet Med 10:231-9 (2008)
DOI:10.1097/GIM.0b013e31816b64dc

Reference

PMID:17158517

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

PMID:17082447

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

PMID:12788204

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:23150908 (AD17)

Authors

Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K

Title

Variant of TREM2 associated with the risk of Alzheimer's disease.

Journal

N Engl J Med 368:107-16 (2013)
DOI:10.1056/NEJMoa1211103

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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