HAI Book 2025 - Flipbook - Page 469
Shirzadi, Zahra
Independent effects of baseline white matter hyperintensity and APOE ɛ4
on future ARIA-H emergence in A4 trial
Zahra Shirzadi1, Aaron Schultz1, Nazila Loghmani1, Michael Properzi1, Michael Rafii2, Michael
Donohue2, Shunran Wang2, Clifford Jack Jr3, Steven Greenberg1, Rema Raman2, Paul Aisen2,
Reisa Sperling1, Jasmeer Chhatwal1
Department of Neurology, Massachusetts General Hospital, Brigham and Women’s Hospital, Harvard Medical School,
Boston, MA, US
2
Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, US
3
Mayo Clinic, Radiology, Rochester, MN, US
1
Background: Increased white matter hyperintensity volume (WMH) visible on MRI is a common but non-specific
finding in Alzheimer9s disease (AD). Recent evidence shows that elevated WMH correlates with cerebral amyloid
angiopathy (CAA), and may precede ARIA-H manifestations, including microhemorrhages (MCH) and superficial
siderosis (SS). We hypothesized that people with preclinical AD who had increased WMH would have a greater
likelihood of developing ARIA-H lesions during longitudinal follow-up. We examined this hypothesis using
longitudinal data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer9s study (A4).
Methods: ARIA-H lesions (MCH and SS) were identified by experienced radiologists at Mayo Clinic. People were
categorized as having 0, 1, or 2+ lesions based on Boston criteria for CAA, and WMH volume was categorized using
tertiles. Focusing on people with 0 or 1 lesion at baseline (i.e., those without probable CAA), we examined age, sex,
amyloid, WMH, APOE ɛ4, cardiovascular risk, and treatment group as predictors of whether people would develop
2+ ARIA-H lesions (emergence of probable CAA) by the time of their last MRI (4.5y post-baseline).
Results: Among 1097 individuals with 0 or 1 ARIA-H lesions at baseline, 120 had 2+ ARIA-H lesions observed on
their last MRI. Elevated baseline WMH (OR= 2.16, p=.004) and APOE ɛ4 carriage (OR=1.72, p=.01) independently
predicted membership in this group (Figure 1). 7% of individuals developed 1+ new ARIA-H lesion every two years,
and elevated baseline WMH volume (OR= 2.99, p=.001) and APOE ɛ4 carriage (OR=2.5, p=.001) independently
predicted membership in this group (Figure 2).
Conclusion: These results suggest that both elevated WMH and APOE ɛ4 carriage are associated with a greater
likelihood and rate of ARIA-H emergence in people with preclinical AD. More broadly, these results support the
hypothesis that increased WMH volume may be an early marker for CAA pathophysiologic changes.
HAI2025 - 469
