Association of Increase in White Matter Hyperintensity Volume With Rate of Hippocampal Atrophy in a Population-Based...

Higher white matter hyperintensity volume (WMHV) is associated with hippocampal atrophy, cognitive decline, and dementia; however, it is unknown whether continually increasing WMHV is related to hippocampal atrophy. The aim of this study was to determine whether higher WMHV change rate (WMHVR) is related to higher hippocampal atrophy rate (HAR); this relationship is dependent on cardiovascular risk factors (CVRFs), Alzheimer disease (AD) pathology, and genetic risk; and this relationship is mediated by neuroaxonal degradation.

Participants from Insight46, a substudy of the 1946 British Birth Cohort, underwent combined [¹⁸F]florbetapir PET/MRI scans at University College London approximately 2.5 years apart. WMHVR was quantified from T2/fluid-attenuated inversion recovery and HAR from T1 sequences. Life-course blood pressure and CVRF data were measured at 6 and 3 time points, respectively. APOE genotype and neurofilament light chain (NfL) quantification were derived from blood samples. Participants with neurologic conditions were excluded from primary analyses. Linear regression was used to test the relationships between WMHVR and HAR, adjusting for sex, age, and total intracranial volume (TIV) and CVRF, APOE-ε4 status, and β-amyloid (Aβ) in separate models. Semipartial R² was calculated from these models. In a post hoc analysis, structural equation modeling aimed to determine whether NfL mediated the relationship between WMHVR and HAR.

A total of 317 individuals without neurologic conditions (48% female, 100% White British, mean baseline age [SD] = 70.5 [0.6] years) were included. The mean HAR was 0.04 [0.04] mL/y. Each 1 mL/y increase in WMHVR was associated with a 0.014 mL/y (95% CI 0.005-0.022) increase in HAR, adjusted for TIV, age, and sex (p = 0.002). Adjustment for additional variables did not meaningfully attenuate this association (≥0.012 mL/y, p ≤ 0.005, all models), and there was no indirect effect through NfL (0.0004 mL/y [95% CI -0.0006 to 0.0012], p < 0.1).

Higher WMHVR was associated with HAR between approximately 70 and 73 years, independent of CVRF levels, APOE-ε4 status, and Aβ load, and not mediated by markers of neuroaxonal degradation. Although AD-specific pathology is typically considered the main cause of accelerated HAR, we demonstrated that HAR is also linked to deteriorating WM health. These results will need to be replicated in more diverse cohorts with longer follow-up periods to confirm the findings.