ABSTRACT NUMBER: ESOC2026A1654 THRESHOLD EFFECTS OF WHITE MATTER HYPERINTENSITY VOLUME ON COGNITIVE DECLINE: A 13-YEAR LONGITUDINAL STUDY

Abstract Background and aims White matter hyperintensities (WMH) volume changes over time are associated with cognitive decline. We investigated whether changes in WMH volume exhibit threshold effects on declining cognitive performance and whether effects differ between deep WMH (DWMH) and periventricular WMH (PVWMH). Methods We longitudinally followed 339 GeneSTAR cohort participants with brain MRI and neuropsychological testing at baseline and 13-years (62% female, 33% Black, mean baseline age 49.7±9.6 years). WMH were classified as PVWMH (within 2mm of ventricles) or DWMH. Two-segment linear spline regression models using adjusted mixed linear regression were used to identify test-specific thresholds beyond which cognitive decline accelerated. Cognitive scores from both timepoints were treated as repeated measures, with WMH included as time-varying predictor. Models were adjusted for age, sex, race, education, blood pressure, and family clustering. Results Motor function decline accelerated beyond thresholds of changing PVWMH and DWMH volumes. For Grooved Pegboard, changes in volume were associated with minimal effects below thresholds (log-transformed PVWMH: -9.42 to -9.29; DWMH: -11.8 to -11.7). Substantial declines in motor performance were observed above thresholds (slope differences: PVWMH 14.5-15.1 seconds per log-unit, p<0.001; DWMH 9.54-10.9, p<0.001). Mini-Mental State Examination demonstrated threshold effects for DWMH (threshold=-10.1, slope difference=-0.124, p=0.03) and total WMH (slope difference=-0.212, p=0.03), but not PVWMH (p=0.18). Conclusions Changes in WMH volume exhibit nonlinear threshold effects on cognitive performance over time, differing by anatomic region. Minimal cognitive impact occurred below thresholds, with accelerated declines above. PVWMH demonstrate larger effects on motor function than DWMH, particularly for manual dexterity. Conflict of interest Sarvin Sasannia: nothing to disclose; Shimeng Wang: nothing to disclose; Keenan A. Walker: has given unpaid presentations and seminars on behalf of SomaLogic; Jerry L. Prince : nothing to disclose; Lewis C. Becker: nothing to disclose; Lisa R. Yanek: nothing to disclose; Peter van Zijl: nothing to disclose; Dhananjay Vaidya: nothing to disclose; Linda Knutsson: nothing to disclose; Paul A. Nyquist : nothing to disclose