Alzheimer's disease: A hypothesis on pathogenesis.

Alzheimer's disease (AD) is the major cause of dementia. It is a systemic disorder whose major manifestations are in the brain. AD cases can be categorized into two groups on the basis of the age of onset-before or after about age 60. The majority of cases, 90-95 percent, are in the late onset category. Early onset cases are largely, if not all, familial (FAD). These are caused by mutations in the genes for the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2). In contrast late onset cases are mainly sporadic. The disorder is characterized by intraneuronal fibrillary tangles, plaques, and cell loss. The brain lesions in both early and late-onset AD are the same, and in the same distribution pattern, as those seen in individuals with Down's syndrome (DS) and in smaller numbers in normal older individuals. Extensive studies of AD have yet to result in a generally accepted hypothesis on the pathogenesis of the disorder. Major emphasis has been placed on the role of amyloid, the neurotoxin formed by the action of free radicals on preamyloid. The observation that AD lesions are frequently present in normal older individuals prompted the hypothesis that AD is the result of faster than normal aging of the neurons associated with it. This hypothesis provides plausible explanations for FAD and AD. FAD is associated with mutations in APP, PS1, and PS2. These substances, along with their normal counterparts, undergo proteolytic processing in the endoplasmic reticulum (ER). The mutated compounds, aside from increasing the ratio of βA42 to βA40, may down-regulate the calcium buffering activity of the ER in a manner akin to one or more of the many compounds known to do so. Decreases in the ER calcium pool would cause compensatory increases in other calcium pools, particularly in mitochondria. Increases in mitochondrial calcium levels are associated with enhanced formation of superoxide radical formation, and hence of the rate of aging. SAD may be caused by nuclear and/or mitochondrial DNA mutations beginning early in life that enhance mitochondrial superoxide radical formation in the neurons associated with the disorder. The above explanations for FAD and AD are suggestive of measures to prevent and for treatment.