ABSTRACT As the population ages, the prevalence of Alzheimer’s disease and related dementias (ADRD) will increase markedly. Prior studies have shown that excessive aortic stiffness represents a potentially modifiable risk factor for ADRD. Higher aortic stiffness is associated with evidence of brain small vessel disease, which is thought to mediate the relation between stiffness and ADRD. However, specific hemodynamic mechanisms that mediate the harmful effects of aortic stiffness on small vessels in the brain are only partially understood. Stiffening of the aorta is associated with increased transmission of pulsatile energy into the carotid circulation. When the aorta is compliant, it buffers the pressure and flow swings associated with each heartbeat. As the aorta stiffens, pressure and flow pulsatility increase markedly in the carotid arteries. If these highly pulsatile pressure and flow waveforms reach the brain microcirculation, associated excessive pulsatile energy can damage fragile small vessels in the brain. Another potential mechanism involves adverse effects of aortic stiffening on mechanical coupling between heart and aorta. When the heart contracts, it stretches the proximal aorta like a spring. When the heart relaxes, energy stored in the “aortic spring” elevates the base of the heart and facilitates ventricular filling in preparation for the next heartbeat. Excessive aortic spring stiffness increases load on the heart and impairs systolic and diastolic function of the heart. Thus, aortic stiffening may represent a mechanistic link between known associations between heart health and brain health. With the following 3 specific aims, we will examine the foregoing mechanisms during examination 4 of the deeply phenotyped Framingham Heart Study (FHS) Third Generation (G3), New Offspring Spouse (NOS), and minority Omni-2 (O2) cohorts. Aim 1: Examine relations of aortic stiffness, the carotid “pulsatility filter,” measures of global wave reflection, total arterial compliance, and aortic Windkessel pressure with intracranial flow pulsatility in the middle cerebral artery (MCA) assessed with transcranial Doppler ultrasound. Aim 2: Examine relations of aortic stiffness measures and carotid and intracranial MCA flow pulsatility with a) measures of brain microvascular damage assessed by magnetic resonance imaging using a novel state-of-the- art pattern analysis and machine learning (PAML) method and b) cognitive function assessed by quantitative neuropsychiatric testing. Aim 3: Assess relations of aortic spring stiffness and peak aortic strain force and work with a) left ventricular structure and systolic and diastolic function, and b) common carotid mean flow and MCA flow pulsatility index. We will leverage the already funded basic and laboratory core FHS examinations, brain imaging, and neurocognitive testing to evaluate this critical conundrum. Our application will inform the development of intervention strategies that limit damage to the brain microcirculation and prevent the severe consequential effects of arterial stiffness on brain structure, cognitive function, and incident ADRD.

PROJECT NARRATIVE The aorta stiffens markedly with age, particularly during midlife, resulting in high blood pressure, reduced pumping efficiency of the heart, and damage to the small blood vessels in the brain. The high prevalence of aortic stiffening as we grow older, particularly in women and in those affected by obesity and diabetes, contributes to accelerated brain aging, memory loss, and development of Alzheimer’s disease and related dementias. We propose to study mechanisms that link aortic stiffness to damage in small vessels in the brain.