We thank the author of this letter for the careful reading of our research article and appreciate the thoughtful points raised. We agree that white matter hyperintensity (WMH) is an important consideration in the appearance of amyloid-related imaging abnormalities (ARIA), particularly ARIA-H, as highlighted in this paper.1 We believe that this association may be primarily driven by latent, “silent” cerebral amyloid angiopathy (CAA) that has not yet manifested in magnetic resonance imaging (MRI)-visible microhemorrhages, and which may be exacerbated by the administration of anti-amyloid antibody therapies. We would like to take this opportunity to emphasize the multifactorial nature of WMH, as demonstrated in several studies by our group and others.2-4 In the A4 dataset specifically, we observed that WMH volume and its rate of progression were independently associated with older age, CAA, gray matter atrophy, and systemic vascular risk.2 These findings underscore that WMH is not a singular phenomenon but rather reflects a complex interplay of CAA, neurodegenerative, and vascular processes. In this context, we concur with the author that management of systemic vascular risk—including elevated blood pressure, diabetes, and other modifiable factors—should be prioritized in individuals at risk for Alzheimer's disease (AD). Such interventions may not only help reduce WMH burden but could also potentially slow AD progression.5-8 This perspective aligns with growing evidence that vascular health is a critical component of brain aging and neurodegenerative disease prevention. Finally, we agree that further research is warranted to examine whether aggressive control of systemic vascular risk factors can mitigate the emergence of ARIA in patients receiving amyloid-targeting treatments. Understanding this interaction will be essential for optimizing therapeutic strategies and improving safety profiles for individuals undergoing disease-modifying interventions. The A4 Study is a secondary prevention trial in preclinical Alzheimer's disease, aiming to slow cognitive decline associated with brain amyloid accumulation in clinically normal older individuals. The A4 Study is funded by a public-private-philanthropic partnership, including funding from the National Institutes of Health-National Institute on Aging, Eli Lilly and Company, Alzheimer's Association, Accelerating Medicines Partnership, GHR Foundation, an anonymous foundation and additional private donors, with in-kind support from Avid and Cogstate. The A4 Study is led by Dr. Reisa Sperling at Brigham and Women's Hospital, Harvard Medical School and Dr. Paul Aisen at the Alzheimer's Therapeutic Research Institute (ATRI), University of Southern California. The A4 Study is coordinated by ATRI at the University of Southern California, and the data are made available through the Laboratory for Neuro Imaging at the University of Southern California. The participants screening for the A4 Study provided permission to share their de-identified data in order to advance the quest to find a successful treatment for Alzheimer's disease. We acknowledge the dedication of all the participants, the site personnel, and all of the partnership team members who continue to make the A4 Study possible. The complete A4 Study Team list is available on: a4study.org/a4-study-team. Zahra Shirzadi gratefully acknowledges fellowship awards from the Health Enhancement Scientific Program and the BrightFocus Foundation that supported this work. The authors declare no conflicts of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Shirzadi et al. (Thu,) studied this question.