Zahra Shirzadi, Aaron P. Schultz, Nazila Loghmani, Hyun‐Sik Yang, Jeremy N. Ford, R. Yaari, Michael Properzi, Wai‐Ying Wendy Yau, Lei Liu, Michael S. Rafii, Michael Donohue, Adam M. Brickman, Clifford R. Jack, Steven M. Greenberg, Paul Aisen, Reisa A. Sperling, Jasmeer P. Chhatwal, the A4 Study Team
INTRODUCTION: Increased white matter hyperintensity (WMH) volume is a common but non-specific finding in AD. This study investigates the effect of baseline WMH volume and APOE ε4 on magnetic resonance imaging (MRI)-visible hemorrhagic lesion emergence. METHODS: We included A4 participants with 0/1 hemorrhagic lesion at baseline and >1 post-baseline MRI. We examined age, sex, amyloid, WMH, APOEε4, and cardiovascular risk as predictors of whether people would accrue ≥2 hemorrhagic lesions by their last MRI. RESULTS: Among 1097 individuals with 0/1 baseline lesion, 120 had at least two hemorrhagic lesions on their last MRI. Elevated baseline WMH (odds ratio [OR] = 2.3, p = 0.002) and APOE ɛ4/ɛ4 (OR = 4.8, p < 0.001) independently predicted membership to this group. Both hetero- and homozygous APOE ɛ4 carriers with low WMH volume had a low risk of accumulating hemorrhagic lesions. DISCUSSION: These results support the independent consideration of WMH and APOE ɛ4 in the natural history of hemorrhagic lesion accumulation and suggest that individuals with low WMH volume have a low short-term risk, irrespective of APOE genotype. TRIAL REGISTRATION: NCT02008357 HIGHLIGHTS: Elevated baseline white matter lesion volume is related to the risk of ARIA-H emergence. The effects of white matter lesion volume and APOE ɛ4 on ARIA-H are independent. APOE ɛ4 carriers with low white matter lesion volume had a low risk of ARIA-H emergence.