Blood will out: vascular contributions to Alzheimer's disease

Abstract

The fundamental pathology in Alzheimer's disease (AD) is neuronal dysfunction leading to cognitive impairment. The amyloid-β peptide (Aβ), derived from amyloid precursor protein, is one driver of AD, but how it leads to neuronal dysfunction is not established. In this Review, I discuss the complexity of AD and possible cause-and-effect relationships between Aβ and the vascular and hemostatic systems. AD can be considered a multifactorial syndrome with various contributing pathological mechanisms. Therefore, as is routinely done with cancer, it will be important to classify patients with respect to their disease signature so that specific pathologies, including vascular pathways, can be therapeutically targeted.

Figure 1. Multiple pathogenic pathways contribute to and provide therapeutic targets for AD.

While neuronal dysfunction is the defining pathology underlying cognitive decline in AD, this disease is likely the product of multiple pathogenic mechanisms and might benefit from combination therapy (–130). Increasing evidence implicates vascular dysfunction in AD pathogenesis. Aβ plaques and tau tangles drive neuronal dysfunction and neuroinflammation through mechanisms that are not fully established. Aβ is also implicated in vascular pathology, having been shown to interact with fibrin(ogen) and the contact system. The prevalence of vascular dysfunction in patients exhibiting cognitive decline suggests that combining existing treatment strategies targeting neuronal dysfunction (e.g., cholinesterase inhibitors) and vascular dysfunction (e.g., antiinflammatory, antihypertensive, or anticoagulant medications) may advance AD treatment efficacy.

Figure 2. Possible influence of Aβ on fibrin deposition and AD pathology.

The interaction of Aβ with fibrinogen leads to increased formation of structurally abnormal fibrin clots that are resistant to degradation. This persistent fibrin and resulting predisposition towards blood vessel occlusion and inflammation could contribute to the neurodegeneration observed in AD. Images reproduced with permission from Cortes-Canteli et al. (53).

Figure 3. The contact activation system.

Aβ-mediated dysregulation or overactivation of the contact system could contribute to the coagulopathy and inflammation observed in AD. Aβ can trigger activation of factor XII (FXII) into FXIIa. FXIIa’s activation of FXI initiates the intrinsic coagulation system and fibrin formation, whereas its activation of plasma prekallikrein leads to inflammation. PPK, plasma prekallikrein; PK, plasma kallikrein; HK, high molecular weight kininogen; HKc, cleaved HK. a = activated form.