Inflammatory dermatologic disease increases in the elderly due to aging-related dysfunctional cutaneous alterations. Given the aging population of the U.S. and veteran population, it is imperative to improve understanding and optimize treatment choice for elderly skin diseases. In this proposal, we focus on atopic dermatitis (AD) of the elderly, an understudied inflammatory skin disease subgroup with significant disease burden and an estimated prevalence of ~5-11% amongst individuals over 65 years of age. While the distinct molecular features of elderly AD are still undercharacterized, it appears to include lesser Th2 and increased Th17 inflammatory activation relative to classic childhood-onset AD. Increasingly, inflammatory skin disease is being treated with therapies targeting specific inflammatory pathways (e.g. Th2-directed IL-4Rα blockade in atopic dermatitis); however, low precision in defining patient-level disease mechanism contributes to treatment failure. ~30% of patients do not completely respond to a given targeted immunomodulatory drug, likely because of the pervasive genetic heterogeneity underlying these diseases of immunological overactivity. The fundamental unmet need in inflammatory disease is the ability to precisely determine molecular pathology of individual patients. Identification of patient-level biomarkers in chronic inflammatory disease has been hindered by A) a greater role of epigenetics (i.e. RNA levels) compared to easily assayed DNA variants and B) poor molecular resolution resulting from profiling of mixed immune and stromal cells. The goals of this proposal are to 1) define molecular abnormalities underlying atopic dermatitis of the elderly and how they change with IL-4Rα blockade treatment and 2) develop a precision medicine approach for choosing optimal targeted treatment for individual cases of elderly atopic dermatitis, a molecular framework that can eventually be extended to any chronic inflammatory disease. Our genomics-experienced team is qualified to accomplish these goals based on our discovery of single cell RNA-sequencing derived transcriptional signatures in atopic dermatitis and psoriasis vulgaris, as well as successful genetic dissection of other complex skin diseases.