Background: Cerebral amyloid angiopathy (CAA) is a heterogeneous small vessel disease that can occur independently or alongside Alzheimer disease (AD). CAA is diagnosed using the Boston Criteria 2.0, integrating clinical and neuroimaging features, whereas the Cerebrospinal Fluid (CSF) role in clinical practice remains under investigation. This study explores whether CSF biomarkers can identify distinct disease phenotypes, supporting hemorrhagic risk stratification. Methods: We enrolled probable patients with CAA retrospectively (Boston Criteria 2.0) from 2 institutions, collecting clinical, neuroimaging, and follow‐up data alongside core CSF biomarkers (Aβ40 [amyloid β 1–40], Aβ42 [amyloid β 1–42], p‐Tau181 [phosphorylated Tau], total‐Tau). Patients with CAA were stratified applying the Amyloid Tau Neurodegeneration (ATN) research framework, according to the presence of CSF amyloidosis (A ⁺ CAA versus A ⁻ CAA) and tauopathy (A ⁺ T ⁺ CAA versus A ⁺ T ⁻ CAA), and using unsupervised clustering, which defined CAA subgroups based on CSF biomarker levels only. Kaplan‐Meier and Cox regression analyses assessed the predictive value of CSF‐based subgroups for symptomatic hemorrhages during follow‐up. Results: Seventy‐one probable CAA patients (aged 71.77±8.45 years, 66% men, median follow‐up 1.15 years [0.50–2.44]) were enrolled. A ⁺ CAA showed a higher prevalence of cortical superficial siderosis than A ⁻ CAA (67% versus 25%, P =0.016). A ⁺ T ⁻ CAA had a greater hemorrhagic risk than A ⁺ T ⁺ CAA during follow‐up (29 versus 7 events per 100 patient‐years, P =0.010; log‐rank test: P =0.013). Unsupervised clustering identified 2 subgroups, which we defined as pure CAA and CAA‐ADA, with pure CAA presenting more symptomatic hemorrhages during follow‐up (22 versus 0 events per 100 patient‐years, P =0.017; log‐rank test, P =0.011). Conclusions: CSF‐based profiling effectively stratifies CAA phenotypes, offering a promising prognostic tool alongside neuroimaging markers. Further validation is needed to confirm its role in identifying patients with CAA with different natural histories.

Background: Iatrogenic cerebral amyloid angiopathy (iCAA) is a rare form of CAA occurring decades after neurosurgical procedures involving cadaveric dural grafts. While typically associated with recurrent lobar intracerebral hemorrhages, recent reports suggest a possible overlap with CAA-related inflammation (CAAri). We report a case of iCAA with features indicative of active neuroinflammation that demonstrated a positive response to immunosuppressive therapy. Methods: Over a 12-year natural history, the patient underwent a comprehensive work-up, including serial clinical assessments, brain MRIs, core CSF biomarker analysis, amyloid PET imaging, and next-generation sequencing panel testing. Results: Previous clinical charts confirmed the use of cadaveric graft (Lyodura) in a neurosurgical intervention thirty years before. During hospitalization for seizures, brain MRI revealed, along with a severe form of CAA, an area of vasogenic edema. Given the suspicion of an active inflammatory process, corticosteroid and subsequent methotrexate maintenance therapy were introduced, leading to clinical and radiological improvement. Over 30 months of follow-up, the patient has remained clinically and radiologically stable, with no new hemorrhagic or inflammatory events. Conclusions: This case highlights the potential interplay between iCAA and neuroinflammation. The absence of new hemorrhages following immunosuppression suggests a possible disease-modifying effect, warranting further investigation into the role of neuroinflammation in iCAA and its therapeutic implications.