The term “ADDLs” stands for Amyloid beta-Derived Diffusible Ligands. When discovered in 1996, the term “amyloid” meant fibular plaques. So the term “ADDLs” was coined to make three very important distinctions from “amyloid”:

1. ADDLs are highly ordered aggregates of amyloid beta 1-42 peptides, appearing as certain multiples of monomer like trimers, tetramers and 12mers. By contrast, amyloid is amorphous and heterogeneous consisting primarily of a shorter peptide, 1-40.
2. ADDLs are soluble, not insoluble like amyloid.
3. ADDLs are ligands, meaning they bind to a specific subset of postsynaptic proteins.

The illustration above shows that, normally, the secretase enzymes process APP, producing Amyloid Beta peptide (1). This peptide is typically 40 amino acids long (Ab 40). However, a small portion of the peptide generated is 42 amino acids long. This is Amyloid Beta 1-42 (Ab 42). These two extra amino acids fundamentally change the behavior of Ab 42 compared to Ab 40. This discovery was the spark that resulted in patent filings and the creation of Acumen Pharmaceuticals. The Company has focused on anti-ADDL therapeutics since 1996.

A beta 42 is often cleared before doing harm. However, sometimes free A beta 42 monomer self-assembles into oligomers – soluble aggregates of variable number of monomer components. It is believed that these oligomers are in equilibrium with each other, so at any point in time, oligomers of different sizes present (2). The trouble begins when certain oligomers bind to neurons and initiate aberrant signaling [(3) and (4)]. This is the start of Alzheimer’s disease. After years of ADDL assault, the cumulative effects of aberrant signaling are detectable to a physician. From there, patients live an average of ten years having been diagnosed with AD.