Preclinical advances in antibodies against N‐terminal Aβ4‐x species for Alzheimer's disease and cerebral amyloid angiopathy

Abstract Alzheimer's disease (AD) pathogenesis is characterized by the accumulation of amyloid beta (Aβ) deposits in the cerebral parenchyma and vasculature, a condition referred to as cerebral amyloid angiopathy (CAA). Besides the full‐length form, Aβ deposits showed a highly heterogenous composition due to the action of different proteolytic enzymes. N‐terminal Aβ peptides have shown higher aggregation propensity and toxicity compared to the other truncated forms, with species starting at residue phenylalanine 4 (Aβ4‐x) being more neurotoxic than the others. Thus, Aβ4‐x species have drawn attention in AD pathogenesis, potentially offering novel therapeutic targets to halt or reverse disease progression. Antibodies targeting specifically Aβ4‐x species were designed with the aim of preventing their aggregation and promoting their clearance counterbalancing their neurotoxic effect. This work provides an update on monoclonal and polyclonal antibodies developed to specifically target Aβ4‐x species in AD and CAA preclinical studies (in vitro and in vivo models).