Alzheimer'S Disease

Biological and Genetic Characteristics

The characteristic histological markers of AD are intercellular neuritic plaques and intracellular neurofibrillary tangles. Plaques occur in the spaces between neurons and comprise a beta-amyloid (β-amyloid) protein core surrounded by a cluster of dead and dying neurons. Neurofibrillary tangles consist of the tau protein fibers that normally organize and give shape to a cell but that have become deformed, possibly as a result of interaction with β-amyloid. The tau protein aggregates into intracellular tangles that block the normal flow of nutrients and information within the neuron. Consequently, the number of synapses the cell can maintain with other cells diminishes, and eventually the cell dies.

Amyloid proteins transport cholesterol throughout the body and brain so that it can be used for cellular repair. β-Amyloid is one of three common variants of the amyloid protein, and unlike other variants, none of the enzymes normally produced by the body can break it down. Moreover, the β-amyloid protein is particularly sticky and has been associated with the deposition of fatty cholesterol deposits in blood vessels as well as with neuritic plaques in AD. Consequently, the individual who has this version of the amyloid protein is at risk for cardiovascular disease in addition to AD. β-Amyloid protein is encoded by a particular gene on chromosome 19, known as the apolipoprotein ε4 (ApoE4) gene. This gene variant cuts the amyloid precursor protein in a different place than normal, yielding the insoluble β-amyloid. Like all genes, individuals have two copies of the ApoE gene. People carrying one copy of ApoE4 (about 25% of the population) have a higher risk for AD than individuals with other variants of the ApoE gene; individuals who carry two copies of the ApoE4 gene (about 2% of the population) have a much higher risk for developing AD at a younger age than those with only one copy of the gene. In fact, the ApoE4 gene variant accounts for about 50% of all cases of late-onset AD, that is, AD diagnosed after age 60. Furthermore, compared with noncarriers, carriers of the ApoE4 gene show metabolic differences in their brain in the same areas that are affected by AD as early as age 30; however, cognitive differences are minimal or absent between noncarriers and carriers of the ApoE4 gene from age 30 to 55. Early-onset AD refers to the 1% of AD cases that are diagnosed in people in their 40s and 50s, caused by mutations to genes other than ApoE. In addition to genetics, other risk factors for AD include increasing age, family history of AD, previous head trauma or stroke, and lower education and verbal ability.

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