α2-macroglobulin (α 2 M) is an abundant plasma protein similar in structure and function to a group of proteins called α-macroglobulins. α 2 M is also produced in the brain where it binds multiple extracellular ligands and is internalized by neurons and astrocytes. In the brain of Alzheimer's disease (AD) patients, α 2 M has been localized to diffuse amyloid plaques. α 2 M also binds soluble β-amyloid, of which it mediates degradation. However, an excess of α 2 M can also have neurotoxic effects. Based on genetic evidence, is now recognized as one of the two confirmed late onset AD genes. As for the three early onset genes (the amyloid β-protein precursor and the two presenilins) and for the other late onset gene (ApoE), DNA polymorphisms in the A2M gene associated with AD result in significantly increased accumulation of amyloid plaques in AD brains. These data support an important role for A2M in AD etiopathology.