Alzheimer's disease pathogenesis: role of aging

Alzheimer's disease (AD) is the chief cause of dementia, and age is its major risk factor. The majority of cases (90-95%) are sporadic (SAD), and the remainder are familial (FAD). AD is characterized by two brain lesions, intraneuronal fibrillary tangles and extracellular plaques. The lesions are identical in SAD and FAD as well as to those in persons with Down's syndrome (DS). The same lesions are also observed frequently in elderly non-demented individuals (E-ND). Both AD lesions may stem from the normal progressive increases in oxidative stress (OxS) throughout the body with age. Onset of dementia due to the accumulating lesions is around 40 years for DS, 40-60 years for FAD, over about 65 years for SAD, while that for E-ND is unknown. The lesions are made clinically manifest with time by the normal increase with age of OxS, "the dementia of old age," or by a process specific for each AD category, which enhances the normal OxS so as to lower the unknown onset age of dementia for E-ND individuals to that associated with the AD category. A plausible process can be advanced for each AD category. The hypothesis suggests convenient, effective measures to prevent and treat, for example, by decreasing brain OxS levels with oral antioxidants such as lipoic or dehydroascorbic acids that are capable of passing the blood-brain barrier.