SUMMARY Hypertension (HTN), affects over 60% of US population above 60. It increases the risk of Alzheimer's disease (AD) through compromised regulation of cerebral blood flow (CBF). Multiple studies failed to establish that lowering blood pressure (BP) entails consistent benefits for cognition and brain measures. This is probably due to a preexisting compromise of the vascular system, which does not compensate properly for relative perfusion pressure decrease caused by BP lowering. In a previous cycle, we showed that, in HTN, there is an optimal BP level that maximizes CBF. We also show 1) an optimal BP that decreases white matter lesion risk, 2) perfusion correlates with tau pathology, and 3) all these findings occur in older HTN subjects. Despite these new discoveries, there is a large variance in CBF and cognition due factors other than age and BP, suggesting the need for further fine-tuning of the model for optimal BP. In this competitive renewal of our NIH/NHLBI R01 HL111724 we propose to focus on variants of the circle of Willis (CoW). They adversely influence CBF and outcome in chronic and acute conditions. However, very little is known about how they affect perfusion, cognition and AD markers in HTN. Our data indicate that incomplete variants play a role in circumstances when there is already a pre-existing impairment of the vascular system (HTN). We offer that these variants in the setting of HTN necessitate higher perfusion pressure to maintain adequate blood flow, thus increasing the risk for hypoperfusion and AD-related pathology. Over a 2-year we will enroll 140 hypertensive, cognitively healthy subjects, 70-85 years old, with (n=70) and without (n=70) typical anatomy of the CoW. At baseline and 24-month follow-up, we will perform BP and cognition assessments, magnetic resonance imaging (including perfusion and vessel anatomy). 50% of the group will receive both tau (PI-2620) and amyloid (Neuraceq) positron emission tomography at baseline and follow-up. We will test whether: AIM1. H1. For the same BP, CBF is lower in subjects with an incomplete CoW than in subjects with a complete circle. H2. Longitudinally, in subjects with an incomplete CoW, for the same baseline BP, an equal reduction in BP entails greater reduction in CBF than in subjects with a complete circle. AIM2. H1. For the same BP, baseline amyloid and tau accumulation is higher in subjects with an incomplete CoW than in subjects with a complete circle. H2. AD biomarkers correlate with CBF. H3. Longitudinally, in subjects with an incomplete CoW, for the same baseline BP, an equal reduction in BP entails greater accumulation of amyloid and tau than in subjects who have a complete circle. Secondary AIM. H1. Variants of the posterior circulation (incomplete posterior circle, vertebral artery hypoplasia) are selectively related to lower hippocampal CBF, and to H2. higher hippocampal tau accumulation. We hope our research will contribute to fine-tuning of HTN management and ...