Abstract

Introduction: Hypertension (HTN) is a well-established modifiable risk factor for neurodegeneration and dementia. However, traditional neuroimaging markers, such as white matter hyperintensity volume (WMH), often lack the sensitivity required for early detection and individualized risk stratification of HTN-related brain changes and their cognitive consequences. Understanding individual susceptibility and the underlying mechanisms remains a critical challenge for effective intervention. Methods: To address this gap, we developed SPARE-HTN (Spatial Patterns of Abnormalities for Recognition of Hypertension), a machine learning-based marker from structural magnetic resonance images. This model was trained on a large, diverse set of studies from the iSTAGING dataset, leveraging regional gray matter volumes from T1- weighted images and lobar WMH volumes from T2-weighted FLAIR images to quantify HTN- related neurodegeneration at an individual level. We performed a genome-wide association study (GWAS) on a subset of hypertensive participants from the UK Biobank to identify genetic variants underlying SPARE-HTN. Longitudinal clinical data from multiple studies were analyzed to evaluate SPARE-HTN's predictive capacity for incident HTN and its mediating role in cognitive decline. Results: SPARE-HTN demonstrated superior sensitivity in detecting HTN-related brain changes compared to total WMH, effectively differentiating even subclinical stages of HTN (e.g., Cohen's d=0.2 vs 0.04 for Normal-Stage 1 HTN; d=0.71 vs d=0.38 Normal-Stage 2 HTN). Longitudinal analyses revealed that SPARE-HTN was significantly elevated in participants who were normotensive at baseline but developed HTN within 3-7 years (+0.44, p=0.01). Furthermore, SPARE-HTN mediated up to 26% of the effect of HTN on cognitive measures, significantly more than conventional WMH volumes. GWAS identified significant genomic risk loci on Chromosomes 2 and 17 associated with SPARE-HTN, encompassing genes previously linked to cardiovascular conditions and WM damage. Demographic associations showed higher SPARE-HTN scores in men, Asian and Black individuals, and those with lower education levels. Conclusions: SPARE-HTN promises individualized MRI estimation of subtle HTN-related brain changes, predicting incident hypertension and significantly mediating HTN’s impact on cognition. These findings, supported by genetic and longitudinal data, highlight SPARE-HTN's potential for enhanced individualized risk stratification and for serving as a more sensitive outcome measure in clinical trials targeting dementia prevention through treatment of modifiable vascular risk factors.