TABLE 1.

Human and animal model evidence of vascular dysfunction and contact system activation in AD

Symptom/Phenotype		Reference
Patients with AD
Vascular Pathology	Vascular dysfunction is an early pathology.	[16, 30]
	CAA is observed in 80%‐95% of patients.	[3, 32]
	Impaired BBB integrity and extravasation of fibrin(ogen) into the brain parenchyma is observed.	[17, 33, 34, 79]
	Dutch and Iowa APP mutations increase cerebral fibrin deposits.	[55]
	Patient plasma exhibits increased aPTT.	[57]
Contact System Activation	Aβ42 activates FXII to trigger the contact system.	[43, 44, 45, 46]
	FXII is found in Aβ plaques in postmortem brain tissue.	[50]
	FXIIa, cHK, and bradykinin levels are increased in patient plasma.	[13, 64, 65]
	Kallikrein activity is increased in patient plasma.	[13]
	Intact HK levels are decreased in patient plasma.	[13]
	FXI levels are decreased in patient plasma.	[43]
	cHK levels are increased in patient CSF.	[70]
	Memory impairment correlates with vascular deficits and cHK levels.	[64, 65, 71]
Animal models
Vascular Pathology	Anticoagulation treatment delays AD pathogenesis.	[54]
	Fibrin(ogen) is associated with abnormal thrombosis, fibrinolysis, inflammation, neuronal damage, and cognitive impairment in AD.	[15, 33, 52, 79]
	BBB integrity is impaired in AD.	[17, 54]
	Cerebrovascular lesions induce Aβ deposition in AD.	[82, 83]
Contact System Activation	Aβ42 activates FXII to trigger the contact system.	[13]
	Contact system activation is associated with BBB damage.	[62, 63, 66]
	Inhibition of contact system activation ameliorates AD pathology and cognitive decline.	[69]

Abbreviations: Aβ, beta‐amyloid; AD, Alzheimer's disease; APP, amyloid precursor protein; aPTT, activated partial thromboplastin time; BBB, blood‐brain barrier; CAA, cerebral amyloid angiopathy; cHK, cleaved high molecular weight kininogen; CSF, cerebrospinal fluid; FXI, factor XI; FXII, factor XII; FXIIa, activated factor XII; HK, high molecular weight kininogen.