PROJECT SUMMARY Alzheimer’s disease and related dementias (ADRD) are the leading cause of dependence and disability in the elderly population worldwide, costing the US healthcare system over $200 billion annually. Because ADRD represents a continuous irreversible physical and cognitive decline, identifying effective approaches for its prevention is imperative. Hypertension, particularly in midlife, is associated with an increased risk of cognitive decline and ADRD. Recent data from the randomized Systolic Blood Pressure (SBP) Intervention Trial (SPRINT) Memory and cognition IN Decreased hypertension (SPRINT MIND) demonstrated that intensive SBP control (<120 mmHg) reduced the combined incidence of adjudicated mild cognitive impairment (MCI) and probable dementia, as well as abnormal white matter lesion (WML) volume compared to standard BP control (<140 mmHg) over five years follow up. To maximize public health impact, it is critical to identify which patients derive the greatest cognitive and net (overall) benefit from intensive SBP treatment and if cognitive benefits were due to direct effects of specific antihypertensive medications on cognition independent of, or in addition to, their BP-lowering effect. Prior animal and human studies, as well as our preliminary data, suggest that angiotensin II receptor blockers (ARB) have greater effects on cognition than angiotensin-converting- enzyme inhibitors (ACEI). If verified, this finding would be significant since ARBs and ACEIs are currently among the medications most commonly prescribed to older adults and are thought to be equivalent in benefit and safety. Our objective is to answer remaining questions of how to safely implement SPRINT in older patients most likely to derive cognitive benefits from intensive SBP treatment. With its large sample size, 5 years follow-up, and high-quality repeated measures of rigorously adjudicated cognitive outcomes, brain imaging, and antihypertensive medication use, SPRINT MIND provides a unique, cost-efficient, and ideal setting to answer these questions. We aim to: (1) develop and validate a prediction tool that quantifies patients’ expected cognitive benefits and net (overall) benefit incorporating cognitive and cardiovascular benefit and risk of SAEs under intensive SBP treatment, and (2) determine comparative effects, including dose-response, of ARB- vs. ACEI-based antihypertensive medication regimens on cognitive and brain structure outcomes independent of SBP-lowering effects. Though SPRINT MIND is among the first randomized trials to demonstrate a beneficial preventive effect on cognition, it is uncertain how SPRINT-MIND should be implemented and in which patients. Successful completion of this project will guide next steps for implementation by determining: (1) which patients derive the greatest cognitive and net (overall) benefit from intensive SBP treatment and (2) if ARBs have greater beneficial effects on cognitive outcomes and WML volume than ACEIs, independent of their similar SBP lowering effects.

PROJECT NARRATIVE Because Alzheimer’s disease and related dementias (ADRD) are the leading cause of dependence and disability in the elderly population worldwide and they represent a continuous irreversible physical and cognitive decline, identifying effective approaches for prevention is imperative. Hypertension, particularly in midlife, is associated with an increased risk of cognitive decline and ADRD and recent data from the randomized Systolic Blood Pressure Intervention Trial (SPRINT) Memory and cognition IN Decreased hypertension (SPRINT-MIND) demonstrated that intensive systolic blood pressure control (<120 mm Hg) reduced the combined incidence of adjudicated mild cognitive impairment and probable dementia, as well as abnormal white matter lesion (WML) volume compared to standard blood pressure control (<140 mm Hg) over five years follow up. In this study, we will use machine learning and predicting modeling and modern causal inference methods to determine which patients derive the greatest cognitive and net (overall) benefit from intensive systolic blood pressure treatment and if angiotensin II receptor blocker (ARB)- vs. angiotensin-converting enzyme inhibitor (ACEI)-based antihypertensive medication regimens have greater beneficial effects on cognitive and brain structure outcomes, independent of their similar BP lowering effects.