Acumen Pharmaceuticals, Inc. has demonstrated the utility of a human in vitro model of iPSC-derived excitatory neurons for a better understanding of which forms of amyloid beta oligomers contribute to the pathogenesis of AD in the human brain. This research will be presented in a poster at the International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders (AD/PD), held in-person in Gothenburg, Sweden, and virtually March 28 – April 1, 2023. There is considerable scientific evidence that supports the role of toxic forms of soluble aggregates of Aß, such as oligomers and protofibrils, in the pathogenesis of AD.

Soluble AßOs have been found to bind at synapses, which leads to altered neuronal function, and can initiate and perpetuate the process of neurodegeneration. However, soluble AßOs exist in many forms – including globular and linear conformations, a wide range of size distributions, and diverse epitope displays – and it remains unclear which of these species are most relevant to AD pathogenesis. Soluble AßOs have been challenging to model in the laboratory even though they have been identified in the cerebrospinal fluid (CSF) of AD patients; their concentrations are low in CSF, and an understanding of their diversity, especially with regard to molecular weights in the human brain, needs additional refinement.

Utilizing human iPSC-derived excitatory neurons as a model, a panel of Aß detection antibodies, and a panel of globular sAßOs plus monomers, the current study found that sAß size may influence synaptic binding. Regardless of sAß preparation or detection antibody, low-molecular weight sAß species (monomers-trimers) demonstrated the lowest levels of detectable synaptic binding, compared with those of mid- and high-molecular weight (> 150 kDa). This research complements Acumen's ongoing clinical development of ACU193, a humanized monoclonal antibody candidate that selectively targets toxic globular sAßOs.

Acumen recently completed patient enrollment in INTERCEPT-AD, a Phase 1, U.S.-based, multi-center, randomized, double-blind, placebo-controlled clinical trial evaluating the safety and tolerability, and establishing clinical proof of mechanism, of ACU193 in patients with early AD. The Company plans to initiate a Phase 2 trial of ACU193 with the potential to expand into a Phase 3 trial.