Etiology and pathogenesis of Alzheimer's disease.

The diagnosis, genetics, risk factors, neuropathology, and pathogenesis of Alzheimer's disease (AD) are discussed. AD is a degenerative brain disorder and is the leading cause of dementia. Clinical manifestations of AD are primarily the progressive loss of memory and language. Other signs and symptoms of the disease include psychiatric and behavioral disturbances and impairments in the performance of activities of daily living (ADL). To diagnose AD, other causes of dementia-- some of which may be reversible--must be ruled out by laboratory testing and neuroimaging. The pathogenic process that causes AD has not been fully delineated; however, it clearly leads to neuropathology characterized by neuritic plaques, neurofibrillary tangles, and loss of cholinergic neurons in the nucleus basalis of Meynert. Genetic factors, including mutations in the amyloid precursor protein and the two presenilin genes, appear important in the development of early-onset familial AD, whereas the apolipoprotein E genotype influences the timing of disease onset after age 65. Genetic factors may promote or accelerate deposition of beta-amyloid protein to form plaques, as well as abnormal phosphorylation of tau protein to form neurofibrillary tangles. Several biochemical factors, such as inflammation, oxidative stress, and hormonal deficiency (estrogen), and other unmodifiable risk factors, notably aging, also play a role in the pathogenic process. The loss of neurons and synaptic connections is selective and causes deficiencies in cholinergic and other neurotransmitter systems, leading to cognitive dysfunction, psychiatric and behavioral disturbances, and eventual loss of ability to perform ADL. The etiology and pathogenesis of AD are highly complex; more effective therapeutic approaches than those currently available will be needed to address these underlying factors more specifically.