Molecular genetics of Alzheimer's disease

Application of genetic paradigms to Alzheimer's disease (AD) has led to con firmation that genetic factors play a role in this disease. Additionally, r esearchers now understand that AD is genetically heterogeneous and that som e generic isoforms appear to have similar or related biochemical consequenc es. Generic epidemiologic studies indicate that first-degree relatives of A D probands have an age-dependent risk for AD congruent to 38% by age 90 yea rs (range 10% to 50%). This incidence strongly suggests that transmission m ay be more complicated than a simple autosomal dominant trait. Nevertheless , a small proportion of AD cases with unequivocal autosomal dominant transm ission 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 presenil in 1 (PS1) gene (on chromosome 14), and the presenilin 2 (PS2) gene (on chr omosome 1) gene are all associated with early-onset AD. Missense mutations in these genes cause abnormal beta APP processing with resultant overproduc tion of A beta(42) peptides. In addition, the epsilon 4 allele of apolipopr otein E (APOE) is associated with a increased risk for late-onset AD, Altho ugh attempts to develop symptomatic treatments based on neurotransmitter re placement continue, some laboratories are attempting to design treatments t hat will modulate production or disposition of A beta peptides. Biol Psychi atry 2000;47: 183-199 (C) 2000 Society of Biological Psychiatry.