Aging of the Brain and Alzheimer's Disease

Alzheimer's disease (AD) is the most common progressive dementia syndrome of the elderly. Because of prevalence, lack of mechanism-based treatments, care costs, and impact on individuals and families, AD is an extraordinarily challenging disease. It is characterized by dysfunction and death of specific populations of neurons, particularly those in neural systems involved in memory and cognition, and by intracellular and extracellular protein aggregates (tau and A. Α peptides) in neurofibrillary tangles (NFTs) and amyloid plaques, respectively. Genetic evidence indicates that the inheritance of mutations in several genes causes autosomal dominant familial AD (fAD) and the majority of mutations increase the levels of toxic A. Α amyloid peptide species in the brain. In this review, we describe the clinical features, diagnostic studies, the neuropathology, and the biochemistry of the disease with a particular focus on the amyloid precursor protein and Α- and Α-secretase enzyme activities which generate the A. Α peptide. Taking advantage of this new information, and the ability to manipulate genes, it is has been possible to produce transgenic models of the disease and to target genes encoding proteins critical in the disease pathways. In turn, this information has been used to develop experimental therapeutics, including strategies to reduce secretase activities and to clear the amyloid peptide from the brain. These discoveries offer genuine hope for the development of mechanism-based therapeutics for this illness.