Abstract Alzheimer’s disease (AD) affects 6.5 million Americans inflicting tremendous burden on our society both economically and in terms of human suffering, yet the etiology of AD is not fully understood. Risk factors for AD are numerous and include demographic, genetic, lifestyle, medical, environmental, psychiatric, and infectious factors. Among the infectious factors known to be associated with AD is periodontal disease (PerioD). PerioD is a polymicrobial infection of the gingival tissue and one of the most common conditions of the oral cavity. There is a growing interest in the connection between PerioD and AD, yet the mechanism between underlying this association is unknown, and most studies have focused their investigation on a limited number of PerioD- associated organisms, for example Porphyromonas gingivalis, Tanerella forsythia, and Treponema denticola. Currently, a major and fundamental obstacle in the field is the lack of a cross-kingdom (bacterial, viral, fungal), comprehensive characterization of the oral microbiome of PerioD as it relates to AD risk. The overall purpose of the proposed project is to investigate the clinical relevance of the oral microbiome in individuals most at risk for AD. 150 middle aged individuals will be enrolled in this longitudinal cohort study. The main objective is to characterize the taxonomy and function of oral bacteria, viruses and fungi among cognitively normal individuals at risk for AD, and over a two-year period, investigate relationships among PerioD-associated microbiome features, inflammation, social determinants of oral health, and AD CSF biomarkers (Aβ42, total-Tau, and phospho-Tau). We will leverage existing NIH funded, well-characterized cohorts that include racially diverse individuals at high risk for AD (through family history or APOE4 allele). Participants will complete 3 study visits annually. Cerebral spinal fluid for AD and inflammatory markers will be collected at baseline and Yr2. Annual assessments and specimen collection will include: a clinical oral examination; subgingival plaque for microbiome assessment; saliva for inflammatory markers; blood for systemic inflammatory markers; neuropsychological testing; and surveys (medication/health history; oral symptoms, hygiene behavior, and quality of life; social determinants of health). Finally, we will conduct semi-structured in-depth interviews to explore the social determinant factors related to oral health and AD. Generated data will inform larger NIH funded studies and, to our knowledge, provide the largest and most comprehensive characterization of the oral microbiome in a racially diverse sample of individuals at risk for AD.