Table 1.

Summary of models of large artery stiffness and findings in the brain

	Model	Benefits	Drawbacks	Key Findings
Humans	Human cross-sectional and prospective studies Refs 9–13, 18, 19	Directly applicable to aging and disease populations, including AD	Only correlative evidence	Greater large artery stiffness is correlated with: Lower cerebral perfusion Greater Aβ deposition Onset of MCI Progression from MCI to AD
Rodent models: direct modulation of arterial stiffness	Elastin haploinsufficient: Heterozygote Eln deletion (full knockout of Eln not viable). Refs 35–37	Young Eln+/− mice have aortic stiffness and systolic blood pressure comparable to old mice Stiffness of cerebral arteries not affected	Potential confounding effects of reduced elastin in other tissues (e.g., the heart) Potential confounding influence of elastin haploinsufficiency during development	Greater large artery stiffness leads to: Cerebral artery endothelial dysfunction and greater vasoconstriction response to angiotensin II Cerebral artery oxidative stress Lower cerebral perfusion
	Fibrillin-1 mutation: Heterozygote mutation of fribrillin-1, Fbn1C1039G/+. A model of Marfan Syndrome. Ref 39	Targeted increase in arterial extracellular matrix stiffness	Confounding risk for aortic aneurysm and dissection Potential confounding influence of fibrillin-1 mutation during development	Greater large artery stiffness leads to: Greater cerebral artery oxidative stress Greater cerebral artery wall thickness
	Carotid artery calcification: Mice studied 2–3 wk after application of calcium chloride to the carotid artery. Refs 28, 42, 43	Direct modulation of carotid artery decreases confounding factors Allows for comparison of ipsilateral and contralateral brain to the side of calcification	An acute, dramatic increase in arterial stiffness that does not model the gradual process of arterial stiffening with human aging.	Increased carotid artery stiffness leads to: Increased cerebral artery blood flow pulsatility Decreased cerebral blood flow Increased BBB permeability Increased neuroinflammation, oxidative stress, and neurodegeneration Impaired memory
	Cross-link breakers: ALT-711 (Alagebrium) treatment typically for 4–8 wk. Ref 46	Reduces large artery stiffness (unlike other rodent models of increased stiffness)	Potential confounding effects on nonvascular tissue Unsuccessful in human trials	Reduced large artery stiffness leads to: Improved working memory (in a diabetes model)
Rodent model associated with greater pulse pressure	Transverse aortic constriction (TAC): Constriction resulting from suture tied around the aortic arch, usually between the right and left carotid artery branches. Refs 17, 22, 50	Demonstrates downstream effects of high carotid artery pulse pressure Widely used procedure	An acute, dramatic increase in blood pressure that does not model the gradual process of arterial stiffening with human aging. Confounding effects of heart failure	Increased carotid artery pulse pressure leads to: Cerebral artery endothelial dysfunction Decreased cerebral perfusion Increased BBB permeability and microbleeds Increased Aβ deposition • Impaired memory

Aβ, amyloid-β; AD, Alzheimer’s disease; BBB, blood-brain barrier; MCI, mild cognitive impairment.