Blood-brain barrier and microstructural brain biomarkers of ARIA and treatment outcomes with anti-amyloid immunotherapy for Alzheimer's disease

University Of California, San Diego, La Jolla CA

Investigators

Abstract

PROJECT SUMMARY The advent of anti-A immunotherapies is transforming the treatment of Alzheimer's disease (AD), demanding novel precision medicine approaches to inform prescribing guidelines and risk-benefit assessment. Critically, this emerging class of AD therapeutics carries significant risks, including amyloid-related imaging abnormalities (ARIA) associated with brain edema and microhemorrhages, and brain atrophy, for which the mechanisms and long-term consequences remain undetermined. Risk for ARIA increases dose-dependently with APOE4, the strongest single genetic risk factor for AD that is also associated with elevated blood-brain barrier (BBB) permeability and cerebral amyloid angiopathy. Evidence implicating cerebrovascular fragility in ARIA development, attributed to immunotherapy-triggered A clearance from blood vessels, suggests that BBB dysfunction may be a critical mechanism underlying ARIA, and perhaps serve as a valuable biomarker for predicting and monitoring ARIA. Consistent reports of brain atrophy following anti-A immunotherapies raise concern for drug-induced acceleration of neurodegeneration, yet the cellular changes contributing to volume loss on structural MRI have not been investigated. Distinguishing benign alterations in fluid dynamics or inflammation from neuronal loss will be essential for ensuring safe and effective widespread roll-out of these novel agents. The proposed investigation will address these pressing outstanding issues by integrating advanced MRI techniques into real-world clinical settings to evaluate BBB permeability and brain microstructure as biomarkers for ARIA risk and treatment response. A-positive individuals prescribed anti-A immunotherapy will undergo cognitive assessment, amyloid PET, and plasma AD biomarker measurement at screening and 12-months, as well as routine MRIs to screen for ARIA. Participants will complete research MRIs, including restriction spectrum imaging to measure brain microstructure and dynamic contrast-enhanced MRI to quantify BBB permeability, prior to treatment, upon detection of ARIA, and at 12-months. This project will test the hypotheses that pre-treatment BBB permeability and abnormal microstructure predict ARIA incidence and colocalize with regions of ARIA, and will characterize trajectories of dynamics in BBB permeability and brain microstructure over the treatment course (Aim 1). BBB leakage and microstructure are expected to predict and correlate with treatment response, as quantified by change in cognition and AD biomarkers (Aim 2). Associations of BBB permeability and microstructure with ARIA and treatment outcomes are expected to differ by factors previously suggested to modify anti-A immunotherapy response, including sex, age, APOE4, and race/ethnicity (Aim 3). As the first study to directly evaluate BBB breakdown and brain microstructure along the time-course of anti-A immunotherapy, this project is anticipated to inform the development of critically-needed screening and monitoring biomarkers and guide clinical recommendations that enhance safety, efficacy, and patient access.