Examining Effects of Intensive BP Control on MCI/Dementia and Plasma Biomarker Trajectories by AD Pathology: Elucidating neuroprotective effects in the racially and ethnically diverse SPRINT trial

ABSTRACT: Alzheimer’s disease (AD) and AD-related dementias (AD/ADRD) are leading causes of dependence and disability in older adults, projected to impact ~153 million people worldwide by 2050. Hypertension (HTN) increases the risk of both AD and Vascular Cognitive Impairment and Dementia (VCID). Black and Hispanic adults have higher average blood pressure (BP) and nearly 1.5 to 2 times higher dementia incidence than white adults, despite having less brain β-amyloid (Aβ). The Systolic Blood Pressure Intervention Trial (SPRINT), which included 9,361 US adults, found that intensive vs standard systolic BP (SBP) treatment (<120 vs <140 mm Hg) reduced risk of combined emergent mild cognitive impairment (MCI) or dementia. Epidemiological evidence suggests a synergism between SBP and AD pathology; however, significant gaps remain in our understanding the role AD pathology plays in how intensive SBP control affects MCI/dementia risk overall and if there are differences by sex, race/ethnicity, and APOE ε4 genotype (ε4). Understanding the extent to which intensive SBP treatment affects dementia risk in the presence or absence of AD pathology and by age, race/ethnicity, and sex can refine HTN treatment strategies to lower dementia risk and inform future trial designs. We will assess AD/ADRD plasma biomarkers longitudinally using stored SPRINT plasma samples (4 time points; n=8,797; mean age at baseline 68 years; 40% Black or Hispanic; median 7 years follow-up). We will determine whether baseline AD pathology or ε4 modifies the effects of intensive SBP control on MCI/dementia; whether intensive SBP control reduces longitudinal change in AD biomarkers (ptau217, Aβ 42/40), neurodegeneration (neurofilament light; NfL), measures of vascular remodeling (placental growth factor; PlGF), or neuroinflammation (glial fibrillary acidic protein; GFAP); how this varies by baseline AD pathology, ε4, race/ethnicity, age, and sex; and which plasma biomarker(s), including novel biomarker candidates assessed on the NULISA platform, can predict dementia risk. The aims are: (1) Determine effects of intensive vs standard SBP control on MCI/dementia (primary) by baseline AD pathology (primary effect modifier) and by age, sex, race/ethnicity, and ε4 (secondary effect modifiers); (2) Determine effects of intensive vs standard SBP control on longitudinal AD/ADRD biomarkers, overall and in subgroups; and (3) Provide a shared public repository of AD/ADRD biomarker data to investigate the effect of other biological and non-biological risk modifiers in the diverse and well-characterized SPRINT trial. Exploratory work will use proteomics to identify additional plasma biomarkers that add to established AD/ADRD biomarkers in explaining the emergence of dementia. This project will help inform patient selection for particular therapies, create a shareable research resource, and examine how cross-sectional and longitudinal plasma biomarkers can be applied in a large, representative population of at-risk older adults.