Biomarker Velocity Composite Index (BVCI) framework proposes dynamic ARIA risk stratification for anti-amyloid immunotherapies

Anti-amyloid immunotherapies offer clinical benefits for Alzheimer's disease (AD), but amyloid-related imaging abnormalities (ARIA), including vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H), pose a significant safety concern. Current ARIA management relies on reactive MRI surveillance, often detecting macroscopic changes after they occur. This theoretical framework addresses the critical gap in proactive, dynamic risk stratification, aiming to prevent ARIA by identifying high-risk individuals earlier through biochemical signatures, before MRI changes are evident.

This paper presents a theoretical construct, systematically synthesizing 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. The authors propose the Neuro-Pharmacological Kinetic Stress Test (NPKST) concept, where the first therapeutic dose of an anti-amyloid immunotherapy serves as a 'pharmacological stressor.' They detail how plasma biomarker velocity (rate of change per unit time) would be measured at Days 3-4 and 7 post-dose to capture the individual's dynamic neuro-immune-vascular response phenotype.

The proposed framework identifies early biochemical signatures for high ARIA risk. A rapid spike in plasma GFAP velocity (ΔpGFAP/Δt), a precipitous decline in Aβ42/40 ratio velocity, and early NfL elevation are posited as indicators of individuals at high risk for clinically significant ARIA before macroscopic MRI changes are detectable. The Biomarker Velocity Composite Index (BVCI) would integrate these dynamic biomarker changes to stratify patients into Low, Intermediate, and High Velocity tiers. Each tier is conceptually linked to specific dosing modification protocols, allowing for personalized therapeutic adjustments. The framework emphasizes that ARIA is a kinetic, not static, pathological event, driven by the velocity of immune-mediated amyloid clearance. This dynamic assessment aims to provide a more nuanced understanding of individual patient responses.

The proposed Biomarker Velocity Composite Index (BVCI) would stratify patients into Low, Intermediate, and High Velocity tiers, each linked to specific dosing modification protocols.