Molecular genetics of Alzheimer's disease

Application of genetic paradigms to Alzheimer's disease (AD) has led to confirmation that genetic factors play a role in this disease. Additionally, researchers now understand that AD is genetically heterogeneous and that some generic isoforms appear to have similar or related biochemical consequences. Generic epidemiologic studies indicate that first-degree relatives of AD probands have an age-dependent risk for AD congruent to 38% by age 90 years (range 10% to 50%). This incidence strongly suggests that transmission may be more complicated than a simple autosomal dominant trait. Nevertheless, a small proportion of AD cases with unequivocal autosomal dominant transmission have been identified Studies of these autosomal dominant familial AD (FAD) pedigrees have thus far identified four distinct FAD genes. The beta-amyloid precursor protein (beta APP) gene (on chromosome 21), the presenilin 1 (PS1) gene (on chromosome 14), and the presenilin 2 (PS2) gene (on chromosome 1) gene are all associated with early-onset AD. Missense mutations in these genes cause abnormal beta APP processing with resultant overproduction of A beta(42) peptides. In addition, the epsilon 4 allele of apolipoprotein E (APOE) is associated with a increased risk for late-onset AD, Although attempts to develop symptomatic treatments based on neurotransmitter replacement continue, some laboratories are attempting to design treatments that will modulate production or disposition of A beta peptides. Biol Psychiatry 2000;47: 183-199 (C) 2000 Society of Biological Psychiatry.