SUMMARY Alzheimer’s disease (AD) is a leading cause of death among older adults. Its high prevalence, amounting to one third of all seniors, warrants new research directions on the pathogenesis of AD that can unlock new treatments. Studying AD in the context of emerging allergic diseases presents a key opportunity in this regard. Emerging allergic diseases to food allergens present an important public health problem whose ramifications may extend beyond the gastrointestinal tract to other organ systems, including the brain. This project capitalizes on pioneering work by the study team on “alpha-gal syndrome” (AGS), by exploring how neuroinflammatory profiles relate to tick-induced allergy to mammalian meat in patients sensitized to the carbohydrate allergen, galactose- alpha-1,3-galactose (alpha-gal). The proposed work builds on the idea that tick bites promote systemic inflammatory processes that could adversely impact the brain. This notion is bolstered by recent data, including that of the study team, to support a link between sensitization to alpha-gal and cardiovascular disease. The central hypothesis is that patients with IgE to alpha-gal develop inflammatory profiles that promote neuroinflammation. Given that AGS is an antigen-driven disorder, we further posit that T cells are pivotal to this process. The project leverages an extensive set of existing specimens and data from highly characterized cohorts spanning the spectrum of sensitization to alpha-gal, as well as a unique comparison group of chronically inflamed patients suffering from post-acute sequelae of severe COVID-19 illness. The approach in Aim 1A will define neuroinflammatory states using an unsupervised integrative approach across hundreds of serum samples from patients with alpha-gal sensitivity. This will include assaying canonical and candidate biomarkers of AD using ultrasensitive assays, in conjunction with a broad set of cytokines and chemokines, and then defining discrete inflammatory states using cluster analyses. Longitudinal assessments will be performed in a subsample of 100 patients with IgE to alpha-gal who return for a follow up visit at 3-10 years after their initial visit, in order to monitor the development of neuroinflammatory profiles in relation to change in IgE and decline in neurocognitive function. Profiles will be validated using samples from patients with AD and in COVID-19 patients with neurocognitive sequelae. In Aim 1B, deep T-cell profiling using spectral flow cytometry and machine learning methods will be used to elucidate complex T-cell signatures that constitute “functional networks” governing neuroinflammatory states that are defined in Aim 1A. Establishing a new paradigm for the immunopathogenesis of AD will identify novel avenues for exploring the interaction between AD and allergic disease, and ultimately aid in the design of new therapies for this devastating disease.