Untangling the effects of anti-amyloid therapy on neurodegeneration and neuroinflammation

In this K23 career development award, Dr. Christopher Brown, a cognitive neurologist and Instructor of Neurology at the University of Pennsylvania, will obtain training in integrating advanced imaging and fluid- based biomarkers in clinical research studies of Alzheimer’s disease (AD) and related dementias (ADRD). This project will support his long-term career goal of an independent career using multimodal biomarkers to understand neuropathology propagation and clearance and its clinical manifestations in ADRD. Dr. Brown will benefit from the strong institutional environment of the University of Pennsylvania, and the expertise of his mentorship team, including his primary mentor, Dr. David Wolk, and co-mentor, Dr. Corey McMillan. The advisory team brings additional specialized expertise that will help Dr. Brown meet his training goals to learn: 1) additional skills in clinical research methods and project management in observational longitudinal studies in ADRD, 2) longitudinal analysis of advanced MRI, and 3) biomarkers of neuroinflammation. To obtain these goals, Dr. Brown will receive a combination of didactic and one-on-one training while carrying out a research project examining neurodegeneration and neuroinflammation in the setting of anti-amyloid therapy. Anti- amyloid therapy is associated with robust clearance of amyloid and slowing of cognitive decline, but a lack of clarity of its benefits on downstream aspects of the AD pathologic cascade as well as neuroinflammatory side effects have limited enthusiasm for its use. This study will evaluate two barriers: 1) accelerated brain volume loss associated with treatment, and 2) frequent occurrence of amyloid related imaging abnormalities (ARIA). Participants will be followed over their first year of treatment with FDA-approved anti-amyloid therapy and have additional advanced MRI sequences added to clinical safety MRIs and plasma draws at infusion visits. This minimal additional burden will allow for increased participation in research while receiving treatment. In Aim 1, advanced MRI will be used to evaluate the microstructural alterations driving brain volume loss in the first year of treatment. Based on prior work, this aim will test the hypothesis that reductions in brain volume are primarily driven by decreases in non-tissue components, including perivascular spaces, that are known to increase with higher levels of AD pathology. Aim 2 will evaluate microstructural and perivascular space changes in the setting of ARIA, as well as evaluate alterations in plasma biomarkers of neuroinflammation during ARIA. Finally, Aim 3 will explore how neuroinflammatory response in early stages of treatment influence changes in downstream measures of AD neuropathology at 1 year. The results of these studies will help identify important markers of treatment response, neuroinflammatory and structural alterations associated with ARIA, and further our understanding of the interplay between neuroinflammation and neurodegeneration. Moreover, this project provides the critical training and resources to support Dr. Brown’s successful transition to independence. Project Number: 1K23AG093167-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Christopher Brown | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $196,020 | Activity Code: K23 | Study Section: Special Emphasis Panel[ZRG1 CN-F (91)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11301462