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The concentrations of neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and plasma have become key biomarkers of many neurodegenerative diseases, including Huntington's Disease (HD). However, the relationship between the dynamics of NfL concentrations in CSF and the time-course of neurodegeneration (whole brain atrophy) has not yet been described in a quantitative and mechanistic manner. Here, we present a novel semi-mechanistic model, which postulates that the amount of NfL entering the CSF corresponds to the amount of NfL released from damaged neurons, whose degeneration results in a decrease in brain volume. In mathematical terms, the model expresses the NfL concentration in CSF in terms of the NfL concentration in brain tissue, the rate of change of whole brain volume and the CSF flow rate. To test our model, we used a non-linear mixed effects approach to analyze NfL and brain volume data from the HD-CSF study, a 24-month prospective study of individuals with premanifest HD, manifest HD and healthy controls. The time-course of whole brain volume, obtained from MRI, was represented empirically by a 2nd order polynomial, from which its rate of change was computed. CSF flow rates in healthy and HD populations were taken from recent literature data. By estimating the NfL concentration in brain tissue, the model successfully described the time-course of the NfL concentration in CSF in both HD subjects and healthy controls. Furthermore, the model-derived estimate of NfL concentration in brain agreed well with recent direct experimental measurements. The consistency of our model with the NfL and brain volume data suggests that the NfL concentration in CSF reflects the rate, rather than the extent, of neurodegeneration and that the increase in NfL concentration over time is a measure of the accelerating rate of neurodegeneration associated with aging and HD. For HD subjects, the degree of acceleration was found to increase markedly with the number of CAG repeats on their HTT gene. The application of our semi-mechanistic NfL model to other neurodegenerative diseases is discussed., Competing Interests: MM and EG-M are employees of LYO-X AG. PM and PS-D are employees of F. Hoffmann—La Roche Ltd. NM was a former employee of F. Hoffmann—La Roche Ltd and is presently contracted as a consultant. NM is an employee of NAM Consulting. PM is an employee of Roche Products Limited. The authors declare that this study received funding from F. Hoffmann - La-Roche Ltd, Basel, Switzerland. The funder had the following involvement in the study: study design, collection, analysis, interpretation of data, the writing of this article, and the decision to submit it for publication., (Copyright © 2024 Machacek, Garcia-Montoya, McColgan, Sanwald-Ducray and Mazer.)

Introduction: A quantitative model of Alzheimer's disease (AD) based on the amyloid/tau/neurodegeneration biomarker framework (Q-ATN model) was developed to sequentially link amyloid positron emission tomography (PET), tau PET, medial temporal cortical thickness, and clinical outcome (Clinical Dementia Rating - Sum of Boxes; CDR-SB)., Methods: Published data and biologically plausible mechanisms were used to construct, calibrate, and validate the model. Clinical trial simulations were performed for different anti-amyloid antibodies, including a 5-year simulation of subcutaneous gantenerumab treatment., Results: The simulated time-course of biomarkers and CDR-SB was consistent with natural history studies and described the effects of several anti-amyloid antibodies observed in trials with positive and negative (or non-significant) outcomes. The 5-year simulation predicts that the beneficial effects of continued anti-amyloid treatment should increase markedly over time., Discussion: The Q-ATN model offers a novel approach for linking amyloid PET to CDR-SB, and provides theoretical support for the potential clinical benefit of anti-amyloid therapy., Highlights: A semi-mechanistic model was developed to link amyloid/tau/neurodegeneration biomarkers to clinical outcome (Q-ATN model). The Q-ATN model describes the disease progression seen in natural history studies. Model simulations agree well with mean data from the aducanumab EMERGE study. A 5-year simulation of gantenerumab predicts greater benefit with longer treatment., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Amyloid-related imaging abnormalities with edema/effusion (ARIA-E) are commonly observed with anti-amyloid therapies in Alzheimer's disease. We developed a semi-mechanistic, in silico model to understand the time course of ARIA-E and its dose dependency., Methods: Dynamic and statistical analyses of data from 112 individuals that experienced ARIA-E in the open-label extension of SCarlet RoAD (a study of gantenerumab in participants with prodromal Alzheimer's disease) and Marguerite RoAD (as study of Gantenerumab in participants with mild Alzheimer's disease) studies were used for model building. Gantenerumab pharmacokinetics, local amyloid removal, disturbance and repair of the vascular wall, and ARIA-E magnitude were represented in the novel vascular wall disturbance (VWD) model of ARIA-E., Results: The modeled individual-level profiles provided a good representation of the observed pharmacokinetics and time course of ARIA-E magnitude. ARIA-E dynamics were shown to depend on the interplay between drug-mediated amyloid removal and intrinsic vascular repair processes., Discussion: Upon further refinement and validation, the VWD model could inform strategies for dosing and ARIA monitoring in individuals with an ARIA-E history., Competing Interests: RA, HPG, CH, DL, SB, PD, GK, ML, and NAM are full‐time employees of F. Hoffmann‐La Roche. RG is a former employee of F. Hoffmann‐La Roche, currently acting as consultant for F. Hoffmann‐La Roche. HPG, RG, CH, DL, SB, PD, GK, ML, and NAM are shareholders of F. Hoffmann‐La Roche. FP and ROC are consultants for F. Hoffmann‐La Roche. FP is the Funding Member and Coordinator of the iCAβ international Network and the CAA study Group of the Italian Society of Neurology‐dementia (SINdem) and is a member of the European Alzheimer's Disease Consortium (EADC) General Assembly. He is the inventor (without ownership) of a patent for a method and kit for anti‐Aβ autoantibody ultrasensitive detection of ARIA and CAA‐ri. He served as a consultant and he has been involved in Global Advisory Boards on Alzheimer's disease immunotherapy and biomarkers done by Roche. He is the Principal Investigator of the ModelCAA Research Grant AARG‐18‐561699 funded by the Alzheimer's Association. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)