Impact of Intensive Treatment of Systolic Blood Pressure on Brain Perfusion, Amyloid and Tau in Older Adults (IPAT-study) Project Summary Recently, the NIA-AA research framework has defined AD as a biological construct of abnormal accumulation of Aβ and tau proteins in the brain. Similarly, the importance of cerebrovascular contributions to AD pathogenesis is now well recognized. Hypertension is the leading cause of cerebrovascular disease; >70% of adults aged 65 or older have hypertension. The SPRINT trial showed that intensive treatment of hypertension reduced risk of cognitive impairment or dementia. However, the underlying mechanisms are unclear. Hypertension and the associated arterial stiffening compromise regional cerebral blood flow (CBF), reduce brain white matter integrity, and impact brain amyloid and tau clearance via the brain glymphatic system. Our studies also showed that high blood pressure and central arterial stiffness are associated positively with brain Aβ burden measured with PET and that the amplitude of low frequency fluctuations of blood-oxygen-level- dependent signal measured with rs-fMRI (BOLD ALFF) is correlated negatively brain amyloid burden in older adults, suggesting its role in brain Aβ regulation. The overarching goal of this project is to determine whether intensive lowering of systolic blood pressure (SBP) to a target of <120 mmHg, compared with <140 mmHg, reduces brain amyloid and tau in older adults who are at high risk of dementia. Furthermore, we will determine the impact of BP lowering on CBF, arterial stiffness, BOLD ALFF, white matter hyperintensity (WMH), brain network connectivity, and neurocognitive function, as well as the relationships of these changes with brain amyloid and tau. We will enroll 180 older adults age 60 to 80 years who have hypertension (SBP≥130 mmHg), FH of dementia, and/or subjective memory complaints. Participants will be randomized into the intensive treatment (SBP<120 mmHg) or usual care (SBP<140 mmHg) arms and followed for 2 years to accomplish the following specific aims: 1) To determine the effects of intensive SBP lowering on brain amyloid, tau, and neurocognitive function. Hypotheses: Intensive SBP lowering, when compared with usual care, reduces the progression of brain Aβ and tau deposition; changes in tau are correlated with neurocognitive function. 2) To determine the effects of intensive SBP lowering on CBF, central arterial stiffness, and BOLD ALFF. Hypotheses: Intensive SBP lowering reduces central arterial stiffness and increases regional CBF and BOLD ALFF; changes in CBF, arterial stiffness, and BOLD ALFF are correlated with brain Aβ and tau. 3) To determine the effects of intensive SBP lowering on brain WMH, white matter microstructural integrity, and neural network connectivity. Hypotheses: Intensive SBP lowering reduces the progression of brain WMH, improves white matter microstructural integrity and brain network connectivity which are correlated with changes in ...