Early neutrophil-associated immune remodeling in the olfactory mucosa detected by FPR1 PET in a mouse model of Alzheimer's disease

Alzheimer’s disease (AD) is the leading cause of dementia, yet pathological changes emerge years before cognitive symptoms, underscoring the need for accessible markers of preclinical disease-associated processes. The olfactory system is affected early in AD, but prior work has focused largely on neuronal pathology or central olfactory structures. Here, we identify the olfactory mucosa (OM) as a peripheral neuroimmune interface that undergoes early, neutrophil-centered remodeling and is amenable to in vivo imaging. Using a two-phase odor-driven exploratory paradigm, we show that 5xFAD transgenic (TG) mice exhibit altered odor-preference behavior at 3–4 and 5 months of age. At 5 months, no significant genotype difference in Y-maze spontaneous alternation was detected. Single-cell RNA sequencing of CD45⁺ OM immune cells reveals a marked shift toward a neutrophil-dominant landscape, with expansion of activated neutrophil subsets and a transcriptional signature associated with myeloid-driven inflammation and oxidative stress responses. Differential analysis of immune receptor genes identified formyl peptide receptor 1 (Fpr1) , a receptor involved in neutrophil chemotaxis, as predominantly expressed in neutrophils, with increased population-level expression in TG mice reflecting neutrophil expansion. Consistent with these changes, FPR1 positron emission tomography (PET) reveals elevated tracer uptake in the OM of TG mice at 5 and 8 months of age. Together, these findings establish the OM as an accessible peripheral neuroimmune interface for monitoring early AD-associated immune remodeling and show that elevated FPR1 PET uptake parallels neutrophil-associated immune remodeling at an early disease stage in this model.