To the Editor: The incidence and severity of amyloid-related imaging abnormalities (ARIA) are consistently higher in apoelipoprotein E4 (APOE4) carriers enrolled in anti-amyloid antibody trials, with the greatest risk observed in those with APOE4 homozygosity. Mechanistically, apoE4 inherently undermines cerebrovascular integrity through direct injury to the neurovascular unit and the promotion of cerebral amyloid angiopathy. We previously showed that apoE4 drove the excessive production of cerebrovascular reactive oxygen species (ROS) and the resultant neurovascular dysfunction, including endothelial dysfunction and neurovascular uncoupling.1 At the cellular level, border-associated macrophages (BAMs), i.e., myeloid cells closely opposed to neocortical microvessels, act as apoE4-dependent sources and effectors of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase-derived ROS, which impair neurovascular function.2 In parallel, apoE4 activates the cyclophilin A–matrix metallopeptidase 9 pathway, amplifying inflammation and blood–brain barrier (BBB) disruption.3 Chronic ROS and inflammation exposure converge on BBB breakdown through reduced tight junction integrity, diminished transendothelial electrical resistance, and basement membrane thinning.3-5 Within the cerebral amyloid angiopathy axis, apoE4 increases the amyloid beta (Aβ)40/Aβ42 ratio, favors vascular over parenchymal deposition, and slows the clearance of Aβ–apoE4 complexes across the BBB.6, 7 Collectively, these pathways plausibly increase the risk of ARIA in APOE4 carriers. We read with great interest the article entitled “Independent effects of white matter lesion volume and APOE ɛ4 on ARIA-H in A4 Study” by Shirzadi et al.8 This elegant study demonstrates that the risk of spontaneous hemorrhagic lesions is low in both homozygous and heterozygous APOE4 carriers with low volume of white matter lesion, suggesting that ARIA is, at least in part, modifiable in APOE4 carriers and that the risk of ARIA may be attenuated if white matter lesion burden is minimized before and during anti-amyloid therapy. Consistent with this view, in a secondary data analysis of the TRAILBLAZER-ALZ and ALZ-2 trials, mean arterial pressure < 93 mmHg with antihypertensive therapy independently predicted lower ARIA risk, whereas antidiabetic medications were associated with reduced risk in univariate analysis.9 Hypertension and diabetes are leading drivers of white matter lesions; therefore, these data support the utility of strategies preserving cerebrovascular integrity in preventing ARIA. Additional common contributors to white matter lesions include smoking, atrial fibrillation, chronic kidney disease, obesity/metabolic syndrome, physical inactivity, sleep apnea, and excessive alcohol intake. Thus, a focused, multidomain lifestyle/vascular intervention through tight blood pressure and glycemic control, smoking cessation, exercise, sleep optimization, weight management, moderation of alcohol intake, and treatment of atrial fibrillation and sleep apnea may be particularly valuable for APOE4 carriers initiating anti-amyloid antibodies. Translationally, apoE4-directed vascular protection can complement an optimization for risk factors. First, reduced sirtuin 1 (SIRT1) activity driven by APOE4 contributes to microvascular endothelial barrier dysfunction; therefore, SIRT1-enhancing strategies, including lifestyle adjustments and resveratrol, can aid in BBB stabilization4 as a potential strategy to counteract apoE4-induced microvascular endothelial cell dysfunction, which contributes to ARIA. Second, targeted inhibition of NADPH oxidase, i.e., gp91ds-tat peptide treatment, in BAMs lowers ROS and normalizes neurovascular uncoupling and endothelial dysfunction in the APOE4 context.2 Third, experimental depletion of BAMs via intraventricular/intraspinal clodronate liposome injection reduces cerebrovascular ROS and improves neurovascular function in vivo.2, 10 Although they are not yet ready for clinical deployment, the latter two approaches illuminate tractable upstream nodes, i.e., BAM-derived ROS and endothelial resilience, which can be addressed through safer pharmacologic approaches. We propose the following three practical steps for ongoing and future anti-amyloid trials and clinical programs involving APOE4 carriers: baseline stratification and monitoring of participants according to the white matter lesion burden by incorporating standardized quantification of white matter hyperintensities/lesions to identify high-risk individuals and track treatment-emergent changes; protocolized multidomain vascular care by embedding aggressive management of blood pressure (target mean artery pressure < 93 mmHg when appropriate), diabetes, and other white matter lesion risk factors throughout anti-amyloid therapy, with adherence support; and adjunct vasculoprotective strategies utilizing candidate agents and lifestyle/vascular interventions that enhance endothelial health, such as those targeting SIRT1-associated pathways, and dampen cerebrovascular oxidative stress. In summary, Shirzadi et al. extend our understanding of APOE4-related ARIA, pointing to preventability through the minimization of white matter lesion burden. Together with trial-level signals indicating the control of vascular risk factors to mitigate ARIA, these data argue for randomized controlled trials testing multidomain lifestyle/vascular interventions and, eventually, vasculoprotective adjuncts as cotherapies with anti-amyloid antibodies in APOE4 carriers. Such strategies directly target the vascular pathology underlying ARIA while preserving access to disease-modifying treatment for those at greatest genetic risk. The author has nothing to report. The author declares no conflicts of interest. Author disclosures are available in the Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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Yorito Hattori (Thu,) studied this question.