Alzheimer's disease: A hypothesis on pathogenesis

Alzheimer's disease (AD) is the major cause of dementia. It is a systemic d isorder whose major manifestations are in the brain. AD cases can be catego rized into two groups on the basis of the age of onset - before or after ab out age 60. The majority of cases, 90-95 percent, are in the late onset cat egory, 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 ar e 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 s ame, and in the same distribution pattern, as those seen in individuals wit h Down's syndrome (DS) and in smaller numbers in normal older individuals. Extensive studies of AD have yet to result in a generally accepted hypothes is on the pathogenesis of the disorder. Major emphasis has been placed on t he 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 indi viduals prompted the hypothesis that AD is the result of faster than normal aging of the neurons associated with it. This hypothesis provides plausibl e explanations for FAD and AD. FAD is associated with mutations in APP, PS1, and PS2. These substances, al ong with their normal counterparts, undergo proteolytic processing in the e ndoplasmic reticulum (ER). The mutated compounds, aside from increasing the ratio of betaA(42) to betaA(40), may down-regulate the calcium buffering a ctivity of the ER in a manner akin to one or more of the many compounds kno wn to do so. Decreases in the ER calcium pool would cause compensatory incr eases in other calcium pools, particularly in mitochondria, Increases in mi tochondrial calcium levels are associated with enhanced formation of supero xide radical formation, and hence of the rate of aging. SAD may be caused by nuclear and/or mitochondrial DNA mutations beginning e arly 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.