Alzheimer’s Disease Pathogenesis: The Role of Aging

Alzheimer’s disease (AD) is characterized by intraneuronal fibrillary tangles, plaques and cell loss. Brain lesions in both sporadic AD (SAD) and familial AD (FAD) are the same, and in the same distribution pattern, as those in individuals with Down’s syndrome (DS) and in smaller numbers in non-demented older individuals. Dementia onset is around 40 years for Down’s syndrome, 40-60 years for FAD, and usually over 60 years for SAD. The different categories of AD may be due to processes which augment to different degrees the innate cellular aging rate, i.e. mitochondrial superoxide radical (SO) formation. Thus, they increase the rate of accumulation of AD lesions. This lowers the age of onset into the dementia ranges associated with Down’s syndrome, FAD, and SAD, and concomitantly, shortens life spans. Faster aging lowers AD onset age by decreasing the onset age for neurofibrillary tangle formation and neuronal loss, and the age when brain intercellular H2O2 can activate microglial cells. The early AD onset in Down’s syndrome is attributed to a defective mitochondrial complex 1. The proteins associated with FAD and their normal counterparts undergo proteolytic processing in the endoplasmic reticulum (ER). The mutated compounds increase the ratio of ßA42 to ßA40 and likely also down-regulate the ER calcium (Ca) buffering activity. Decreases in ER Ca content should increase the mitochondrial Ca pool, thus enhancing SO formation. SAD may be due to increased SO formation caused by mutations in the approximately 1000 genes involved in mitochondrial biogenesis and function. The hypothesis suggests measures to prevent and treat. 1. University of Nebraska Medical Center, , Nebraska 68198­ Introduction Alzheimer’s disease (AD) is the chief cause of dementia. It is a systemic disorder whose major manifestations are in the brain. The majority of cases (90-95 percent) are sporadic (SAD). The remaining 510 percent are familial (FAD). Most FAD cases are caused by mutations in the gene for presenilin 1 (PS1) on chromosome 14, some by mutations in the gene for presenilin 2 (PS2) on chromosome 1, while a few have mutations in the gene for the amyloid precursor protein (APP) on chromosome 21. AD is characterized by intraneuronal fibrillary tangles, plaques, and cell loss; major steps in pathogenesis have been summarized. Plaques contain βA peptides (mainly βA42), formed by proteolysis of APP, that have aggregated into fibrils. Most peptides are in plaques that are not recognized by the usual Congo red and thioflavin methods, i.e., preamyloid plaques–also termed diffuse or amorphous plaques. The minor peptide fraction, formed by the action of free radicals on the fibrillary form of the βA peptide present in preamyloid, is in plaques recognized by Congo red, i.e. amyloid plaques. Amyloid formation is generally associated with the clinical manifestations of AD. The brain lesions in both SAD and FAD are the same, and in the same distribution pattern, as those seen in individuals with Down’s syndrome (DS), and in smaller numbers in non-demented older individuals. Dementia onset is around age 40 for Down’s syndrome, 40-60 years for FAD, and usually 60 years for SAD. Lower dementia onset ages are associated with shorter life spans. Extensive studies of AD have yet to result in a generally accepted hypothesis on pathogenesis. Major emphasis has been placed on the role of amy-