Genetic predisposition and age are the key factors that contribute to the onset of Alzheimer's disease. Specific genes can increase the likelihood of early-onset and late onset, and sporadic AD, These AD-associated genes and risk factors effect the generation, processing and clearance of the amyloidogenic beta amyloid protein. Abeta is a 42 amino acid peptide that is the major component of senile plaques, the neuropathological hallmark of AD. Recently, we have identified a new gene associated with late onset AD, alpha-2- macroglobulin. A pentanucleotide deletion in this gene increases the risk of late onset AD. The effect of the A2M-2 deletion on Abeta generation, processing and clearance is unknown. Intact a2M is a serum pan-protease inhibitor that binds Abeta, attenuates Abeta fibrillogenesis and neurotoxicity, and localizes to senile plaques. Importantly, a2M can mediate Abeta endocytosis and lysosomal degradation by utilizing the low density lipoprotein receptor related protein. The A2M-2 genotype could potentially disrupt any of these a2M functions. This application is aimed at testing whether the increased risk for late onset AD associated with A2M2 results from impairment or abolition of the a2M mediated clearance and degradation of Abeta.
