Many noncovalent ligands of α2M including the Alzheimer's disease-associated Aβ peptide [21], neurotrophins [14], and tumour necrosis factor-alpha (TNF-α) preferentially bind to transformed α2M which is generated following the reaction of native α2M with a protease or with small nucleophilic compounds that also target the α2M thioester bond [6]. This evidence concerns the gene A2M and early-onset autosomal dominant Alzheimer disease.