These include: (1) distinct spatiotemporal expression patterns of these IGFBP genes, (2) differences in their ligand-binding affinity and selectivity, (3) different roles in the circulation including formation of the ternary complex with ALS, (4) different abilities to interact with cell surface proteins, extracellular proteins, and other growth factors, (5) different subcellular localization, and (6) various IGF-independent activities (Figure 4). Here, IGF1 is linked to amyotrophic lateral sclerosis.