Biomarker Based ARIA Stress Test: A Proposed Conceptual Framework for Dynamic Biomarker-Guided ARIA Risk...

While anti-amyloid immunotherapy has shown clinical benefit, amyloid-related imaging abnormalities (ARIA), comprising vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H), represent the principal safety limitation. This paper presents a theoretical construct not yet based on empirical data. As a theoretical construct, we systematically synthesize current published findings on ARIA pathophysiology, plasma biomarker biology (glial fibrillary acidic protein [GFAP], amyloid-beta [Aβ] 42/40 ratio, neurofilament light chain [NfL], and phosphorylated tau [p-tau217]), and clinical trial outcomes. We propose that ARIA is fundamentally a kinetic-not static-pathological event, driven by the velocity of immune-mediated amyloid clearance. The Neuro-Pharmacological Kinetic Stress Test (NPKST) measures plasma biomarker velocity (rate of change per unit time) at Days 3-4 and 7 following the first therapeutic dose. A rapid spike in plasma GFAP velocity (ΔpGFAP/Δt), a precipitous decline in Aβ42/40 ratio velocity, and early NfL elevation constitute early biochemical signatures of individuals at high risk for clinically significant ARIA before macroscopic MRI changes are detectable. The Biomarker Velocity Composite Index (BVCI) stratifies patients into Low, Intermediate, and High Velocity tiers, each linked to specific dosing modification protocols. The cardiac stress test analogy provides the conceptual scaffold: the first therapeutic dose serves as the 'pharmacological stress,' and the BVCI captures the individual's dynamic neuro-immune-vascular response phenotype. This proposed theoretical framework, if validated through future pilot studies and the KINETIC-ARIA trial, would shift ARIA prevention from reactive MRI surveillance to proactive biomarker-guided risk management. Long-term monitoring of potential ARIA effects is warranted.