Alzheimer's disease is a devastating neuro-degenerative disorder characterized by the death of nerve cells within the brain. Progressive cell death leads to memory loss, changes in personality and behavior, loss of motor functioning and ultimately to death. Most cases of Alzheimer's appear late in life, but a subset of patients suffer from early-onset Alzheimer's disease, which is thought to have a genetic basis. Patients with early-onset Alzheimer's typically have a family history of the disease and begin showing symptoms before age 65. A number of genes have been implicated in the development of familial Alzheimer's disease.
Amyloid Precursor Protein
A hallmark of Alzheimer's disease is the formation of toxic plaques made up of a protein called amyloid beta, which is formed as a result of improper processing of amyloid precursor protein, or APP. In normal brain cells, APP is processed by a series of proteins called proteases, which cut the protein into active forms that can be used by the cell. In Alzheimer's, APP is cut incorrectly to generate amyloid beta, which forms toxic plaques and drives progression of the disease.
Mutations to the APP gene lead to protein abnormalities that facilitate the formation of amyloid beta. The University of Pennsylvania reports that mutations to key parts of the APP gene lead to improper APP processing, and individuals who inherit these mutations have a very high chance of developing Alzheimer's.
Presenilin 1
Presenilin 1, also called PS1, is a gene that is linked to familiar Alzheimer's disease, and individuals carrying a mutation to PS1 usually develop early onset Alzheimer's. PS1 is thought to be involved in signalling on the surface of cells, and it forms protein complexes that affect cellular behavior. PS1 is directly involved with the processing of APP at the surface of the cell.
Molecular Brain indicates that mutations to PS1 are involved with the improper cleavage at APP, leading to increased formation of amyloid beta. Under normal conditions, PS1 functions to ensure that APP is cleaved properly to form bi-products that are useful to the cell. Mutations to PS1 alter this function and APP is cleaved incorrectly, forming amyloid beta. Genetic testing for mutations to PS1 is available to screen patients with a family history of early-onset Alzheimer's disease.
Presenilin 2
Presenilin 2, or PS2 is a protein that is closely related to PS1. Presenilin 2 mutations have also been linked to the development of familial Alzheimer's disease. Like PS1, PS2 also plays a role in the processing of APP. According to Molecular Brain, PS2 forms a complex with the proteins that cleave APP, so mutations to PS2 allow for dysregulation of APP processing and promote the formation of amyloid beta.
Mutations in the PS2 gene are rarer than those in PS1. The University of California reports that mutations to PS2 account for only 1% of familial Alzheimer's disease cases, although PS2 mutation rates are higher in Alzheimer's patients from certain populations.
