Free radical theory of aging: Alzheimer’s disease pathogenesis

Senile dementia of the Alzheimer’s type (SDAT) is the major cause of dementia. SDAT cases can be categorized into two groups: 1) late onset, after about age 60, 90–95 percent of cases; largely nonfamilial, i.e., sporadic, 2) early onset, before about age 60; 5–10 percent of cases, most — if not all — are familial. It is a systemic disorder whose major manifestations are in the brain. The brain lesions in both early and late-onset SDAT are the same as those seen in smaller numbers in normal older individuals.It is hypothesized that SDAT is caused by increased free radical reaction levels in brain neurons that advance in time patterns of neuronal dysfunction and cell loss. Measures to this end include: 1) mutations in mitochondrial (mt) DNA and/or nuclear (nuc) DNA in a somatic cell early in development that adversely effect mitochondrial function, 2) mutations in maternal mtDNA and/or nucDNA that impair mitochondria in offspring, 3) mutations in the amyloid precursor protein (APP), and 4) increased formation of both normal APP and superoxide dismutase (SOD).The incidence of SDAT may be decreased by efforts to minimize free radical reactions involved in initiation. The clinical decline of SDAT patients may be slowed by measures which lower the level of more-or-less random deleterious free radical reactions.