Chapter 4 - The genetics of Alzheimer's disease and mutations in the amyloid β-protein precursor gene

Abstract

This chapter discusses the genetics of Alzheimer's disease (AD) and mutations in the amyloid β-protein precursor (APP) gene. The most convincing evidence supporting the importance of a genetic component comes from the existence of a number of large, multiply affected families in which the disease segregates in a manner consistent with fully penetrant autosomal dominant inheritance. In familial Alzheimer's disease (FAD) pedigrees the age of onset is fairly consistent between affected members of the same pedigree but differs markedly between pedigrees. AD neuropathology is characterized by the presence of large numbers of senile plaques and neurofibrillary tangles, with extensive neuronal cell loss, primarily in the temporal cortex and hippocampus. Senile plaques are extracellular deposits consisting of a central core of amyloid fibrils, surrounded by a rim of dystrophic neurites together with reactive microglia and astrocytes. The APP gene appeared to be excluded as the chromosome 21 FAD locus, when several studies reported recombination between FAD and the APP locus. It is found that APP and AD were genetically distinct unless these crossovers occurred within the APP gene.