Abstract A111: Driving as a Window to Brain Health: White Matter Hyperintensities, Functional Decline, and Hypertension Treatment

Background: Vascular contributions to cognitive impairment and dementia (VCID) are the most common and preventable cause of late-life cognitive decline, often overlapping with Alzheimer’s disease (AD). Cerebral small vessel disease (CSVD), reflected by white matter hyperintensities (WMH), is a key driver of VCID. Yet the impact of WMH on everyday function remains unclear. Driving, a complex task integrating executive, visuospatial, and motor skills, may serve as a sensitive marker of brain health. We related WMH burden to longitudinal real-world driving behavior, and assessed whether blood pressure control and antihypertensive therapy, key CSVD modifiers, affect these associations. Methods: We studied 220 community-dwelling adults ≥65 years without dementia at baseline. Driving metrics were recorded continuously with in-vehicle dataloggers over 14,781 weeks (mean follow-up 5.6 years). WMH burden was quantified globally and regionally using deep learning-based MRI segmentation. Longitudinal associations with driving outcomes were tested using linear mixed-effects models controlling for demographics, socioeconomic status, and vascular risk. Models included blood pressure control, antihypertensive use, and AD biomarkers (amyloid and tau PET). Results: Greater WMH burden was linked to reduced driving frequency, trip diversity, and adaptability at baseline and with faster decline in these outcomes over time (all P<0.002) (Fig 1). Over follow-up, 17% developed cognitive impairment; in this subgroup, WMH burden predicted more crashes and hard-braking (Fig 2), with posterior WMH growth conferring the highest crash risk (β=0.59, P=2e-6). Antihypertensive use, especially ACE inhibitors, attenuated WMH-related risky driving (β=-0.18, P=0.06). Findings were independent of AD biomarkers, supporting an additive role of CSVD independent of AD pathology. Conclusions: In this population-based cohort, WMH burden predicted functional decline in real-world driving, with posterior WMH most strongly linked to cognitive impairment and unsafe driving. Hypertension control, particularly with ACE inhibitors, may mitigate WMH-related risks. WMH may serve as a functional biomarker of VCID, linking CSVD to real-world outcomes. Vascular risk management, especially hypertension, may slow dementia progression while preserving safe mobility and independence.