Welcome to the complex disease world. Alpha2-macroglobulin and Alzheimer's disease.

The recent explosion in our understanding of Alzheimer’s disease (AD) at both the molecular and biochemical levels is due, in large part, to the successful utilization of genetic and genomic analyses over the past two decades. Initial positional cloning efforts of the 80s and 90s led to the identification of three genes, amyloid precursor protein (APP) and presenilins 1 and 2 (PSEN1 and PSEN2), that can harbor mutations leading to the rare, early-onset ( 60 years) familial form of AD. Phenotypically, the majority of these early-onset mutations ( 150 in total; a complete list of early-onset AD mutations can be found at the Alzheimer’s disease mutation database (http://molgenwww.uia.ac.be/ADMutations) lead to increased generation of the highly amyloid plaque-prone A 42 peptide from APP (Haass and De Strooper, 1999; Hardy, 1997; Price et al., 1998; Tanzi, 1999; Tanzi and Bertram, 2001). Similarly, genetic analysis of the more common, lateonset form of AD holds great promise for expanding our understanding of AD pathogenesis, accelerating means for early prediction of AD, and developing novel therapeutic modalities for the prevention and treatment of this devastating neurodegenerative disorder. Despite intensive efforts, only one gene to date, apolipoprotein E (APOE), has been universally established as a susceptibility gene for late-onset AD. In this case, the 4 variant of APOE only increases age-related risk for AD, but does not guarantee onset (Blacker et al., 1997; Meyer et al., 1998; Saunders et al., 1993). Recent segregation analyses suggest that an additional four to seven AD susceptibility genes, of at least moderate effect, remain to be discovered (Daw et al., 2000). Intensive searches for the additional risk-conferring genes is under way in laboratories worldwide and has already resulted in reports of over 100 different genes tested for genetic association with AD. However, with the exception of APOE, none of these putative AD genetic risk factors have been universally replicated in independent samples. The reason for the dearth of confirmed susceptibility genes is the highly complex genetic nature of AD itself. Unlike Mendelian diseases, risk-conferring genes in complex diseases usually impart modestly increased risk with low penetrance and unknown inheritance patterns. These complexities make unequivocal identification of susceptibility genes extremely challenging. While these challenges are formidable, they are not prohibitive. In fact, the future for analyses of complex genetic disorders can be considered as quite bright due to the ongoing deciphering of the human genome, the accelerating discovery of DNA variants (primarily, single nucleotide polymorphisms; SNPs), and technological advances that continue to make high-throughput genotyping and sequencing increasingly fast and relatively inexpensive. In the search for late-onset AD susceptibility genes, no gene besides APOE has been as widely investigated as that encoding 2-macroglobulin (protein: 2M; gene: A2M). A2M is an ideal positional candidate gene for late-onset AD. Biologically, 2M mediates A toxicity, clearance, and degradation. 2M binds the A peptide specifically and tightly (Du et al., 1998; Hughes et al., 1998) and consequently there are three biological manifestations of A / 2M interactions that are directly relevant to the etiology and pathogenesis of AD. First, the interaction between 2M and A prevents A fibril formation and fibril-associated neurotoxicity (Du et al., 1998; Hughes et al., 1998). Second, 2M is a protease inhibitor; protease activation of 2M/A complexes or protease activation of 2M followed by A binding can promote the protease-mediated degradation of * Corresponding author. Fax: 1-617-724-1949. E-mail address: tanzi@helix.mgh.harvard.edu (R.E. Tanzi). R Available online at www.sciencedirect.com