PROJECT SUMMARY Alzheimer's disease (AD) is a complex neurodegenerative disorder with multiple pathologies, such as proteinaceous brain inclusions and neuroinflammation. The vascular system is also recognized as a factor in AD, yet there are few models to study the mechanism. We and others have found that the Aβ peptide, a known driver of AD, can activate the plasma contact system, which can lead to blood clot formation and inflammation via generation of bradykinin upon cleavage of high molecular weight kininogen (HK). There are three main lines of evidence that the contact system is involved in AD pathology: 1) Aβ activates factor XII (F12), which initiates the contact system; 2) AD patient plasma has increased contact system activation compared to that of age-matched, non-demented individuals; and 3) Knockdown of the contact system using an anti-F12 antisense oligonucleotide ameliorates AD pathology in a mouse model. HK circulates in blood as a complex with other coagulation factors, and it serves as a non-enzymatic co-factor for the activation of these proteins. Compared to other components of the contact system, depletion of HK offers more robust protection from blood clotting and inflammation due to its central role in both pathways. We have generated antibodies that are specific for cleaved HK that could help identify AD patients with contact system involvement. We also have developed antibodies that block HK cleavage, which might be beneficial to patients as they might ameliorate some of the pathologies of AD. It is important to note that people who lack a contact system are not prone to bleeding, and therefore, blocking this system in AD patients would not risk intracerebral hemorrhage. Despite decades of research, there are no effective treatments that slow or prevent AD. Progress in treating AD requires a multidisciplinary approach. We hypothesize that blocking the contact system could reduce vascular and inflammatory pathologies in AD patients. We propose to further develop our anti-HK antibodies for AD patient diagnostic and therapeutic use.