Molecular genetics of familial Alzheimer disease

Alzheimer disease (AD) is a genetically heterogeneous and progressive degenerative disorder of the brain. It affects approximately 4 million Americans and causes more than 100,000 deaths each year, and there is no cure. It is estimated that by the year 2020, 14 million Americans will be affected by the disease. Although the major pathology is confined to regions of the brain, some patients show an impaired sense of smell and selective loss of retinal ganglion cells. The biochemical processes that lead to AD are largely unknown. Genetic studies on inherited AD have identified three genes that when mutated can cause an early-onset form of the disease. Mutation of these genes has been shown to increase the production of a unique protein called beta-amyloid, which is the predominant component of neuritic plaques found in the brain of AD patients. Also, one susceptibility gene has been shown to be associated with the risk of late-onset AD in both familial and sporadic forms. The available data support to a large extent the amyloid cascade hypothesis as a mechanism of the disease pathology. The newly identified "AMY plaques" and the future identification of other susceptibility genes may give further clues to the neurodegenerative mechanisms of AD.