Independent effects of white matter lesion volume and APOE ɛ4 on ARIA-H in A4 Study

Abstract

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.

Keywords: amyloid‐related imaging abnormalities–hemorrhagic (ARIA‐H); cerebral amyloid angiopathy; cerebral microhemorrhages; white matter hyperintensity.