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Breaking News: New Mutations That May be Responsible for The Alzheimer’s Disease

DeCODE has reported discovery of a variant of the amyloid precursor protein (APP) gene that may provide protection against both Alzheimer’s disease (AD) and cognitive decline in the elderly.

Common variants in ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease reported by deCODE on Nature Genetics. The implication of these data is that general cognitive fuction decline and late-onset Alzheimer‘s disease share biological pathways.

Alzheimer’s disease (AD) is the most common form of dementia, with both environmental and genetic factors contributing to risk. AD is genetically complex and shows heritability up to 79%. Rare variants in three genes (APP, PSEN1 & PSEN2) cause disease in a minority of cases, but until recently the Apolipoprotein E gene (APOE), was the only gene known to increase disease risk for the common form of AD with late-onset. There is limited evidence supporting a role for mutations in the gene in the more common late-onset form of the disease.

Figure above shows the basic principle of the cleavage of APP

APP can be cleaved in two pathways: the more common, non-pathogenic, non-amyloidogenic pathway, or the pathogenic, amyloidogenic pathway (bottom). In normal conditions, the majority of APP is cleaved within the Aβ domain (small red rectangle) by α-secretase to produce sAPPα and membrane-bound C83. C83 can be further cleaved by γ-secretase, producing extracellular fragment p3 and intracellular AICD. In the pathogenic pathway, APP is first cleaved by β-secretase at the start of the Aβ domain, producing sAPPβ and membrane-bound CTFβ (C89/C99). Cleavage of CTFβ by γ-secretase yields pathogenic Aβ fragments, and intracellular AICD. (Ma, et al., 2007)

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