Studies have shown that Aβ aggregates enhance FXII activation both in vitro and in vivo (Shibayama Y et al., 1999; Joseph K et al., 1999; Bergamaschini L et al., 2001; Zamolodchikov D et al., 2015, 2016; Chen ZL et al., 2019; reviewed by Kaplan AP et al., 2024). Therapeutic antibodies, such as lecanemab, target Aβ plaques blocking this activation (Chen ZL et al., 2023; Johannesson M et al., 2024). Elevated kallikrein activity and increased levels of cleaved HMWK in the cerebrospinal fluid, along with higher plasma concentrations of FXIIa, cleaved HMWK, and bradykinin, have been observed in AD patients and correlated with AD pathology and cognitive impairment (Bergamaschini L et al., 1998; Yamamoto-Imoto H et al., 2018; Singh PK et al., 2020). In post-mortem studies, Aβ plaques from the brain tissue of AD patients were found to contain both FXII and bradykinin (Yasuhara O et al., 1994; Singh PK et al., 2020). A similar activation of the FXII-induced kallikrein–kinin system has been observed in Alzheimer’s mouse models and in wild-type mice injected with Aβ aggregates (Zamolodchikov D et al., 2015; Chen ZL et al., 2017; reviewed by Kaplan AP et al., 2024). Additionally, Alzheimer’s patients exhibit increased plasma levels of FXI, which contribute to FXII-induced thrombin formation (Zamolodchikov D et al., 2016; Begic E et al., 2020; Schmaier AH, 2016a,b). These findings suggest that interactions between Aβ aggregates and FXII may contribute to vascular dysfunction, prothrombotic state, and neuroinflammation associated with Alzheimer’s disease pathology.