The utility of cyclooxygenase-1 PET imaging as a novel neuroinflammatory biomarker for Alzheimer's disease

Epidemiological evidence has suggested that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) can protect against Alzheimer’s disease (AD); however, results from large-scale trials investigating the ability of NSAIDs to prevent AD have been disappointing, in part because of a lack of specific biomarkers that could optimize study conditions such as drug dose and temporal window for drug intervention. Thus, a critical need exists to develop neuroinflammation-specific biomarkers in AD for future application in drug trials. A promising development in this regard derives from our recent studies developing a novel positron emission tomography (PET) radioligand targeting cyclooxygenase (COX)-1. COX-1 is primarily localized in microglia surrounding amyloid plaques in the human brains with AD, potentially contributing to proinflammatory actions in AD pathology. What remains unknown, however, is the ability of this radioligand to identify neuroinflammatory activity in the brains of patients with AD. Our long-term goal is to develop this COX-1 PET radioligand as a novel neuroinflammatory biomarker for AD to be used in inflammation-modifying drug trials. Our overall objective in this proposal is to determine the ability of the novel COX-1 radioligand to detect different levels of neuroinflammation in individuals at various stages of the AD spectrum—from preclinical AD to AD dementia— and to investigate the associations with other biomarkers for AD. Our central hypothesis is that the level of COX- 1 binding in the brain will be significantly associated with the disease stage of AD, the severity of cognitive impairment, and the burden of AD pathology measured by other imaging and plasma biomarkers. The central hypothesis will be tested by pursuing three Specific Aims: 1) Evaluate the association of COX-1 brain binding with the disease stage and severity of AD; 2) Evaluate the association of COX-1 brain binding with the AD pathology burden measured by other imaging and plasma biomarkers; 3) Improve the feasibility of COX-1 brain PET scan methods to be more applicable in larger populations for clinical trials. This research is significant because neuroinflammation is a major component of AD pathology and COX-1 is a promising diagnostic and therapeutic target in AD. This proposal is innovative because the first PET radioligand that acts directly at COX- 1 is applied for the first time in patients with AD. The rationale for this work is that its completion is expected to establish the utility of COX-1 PET radioligand as a novel imaging biomarker for neuroinflammation, to be applied in future trials of inflammation-modifying drugs (e.g., repurposed NSAIDs) for AD. Upon completion of the proposed program, we anticipate having established the efficacy and feasibility of COX-1 PET imaging to pave the way for future clinical trials specifically targeting neuroinflammation in AD. Project Number: 1R01AG093678-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Min-Jeong Kim | Institution: STATE UNIVERSITY NEW YORK STONY BROOK, STONY BROOK, NY | Award Amount: $921,020 | Activity Code: R01 | Study Section: Clinical Neurodegeneration Translational Neuroscience Study Section[CNTN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11132117