The Oral Microbiome and Cognitive Function - Modified Project Summary/Abstract Section This project investigates the association between oral microbiota and i) biomarkers of ADRD pathophysiology and ii) mid-life cognitive function. Substantial evidence links periodontal disease—a clinical condition characterized by an imbalanced or “dysbiotic” oral microbial ecology—with cognitive functioning and Alzheimer’s Disease and Related Dementias (ADRD). It is biologically plausible that alterations in the oral microbiota itself—which underlies periodontal disease—could contribute to ADRD pathology through both indirect and direct mechanisms. Indirect mechanisms include inflammation, hemodynamic alterations, and/or impaired glucose regulation, all of which are hypothesized to be impacted by the oral microbiome and to predict poor cognitive outcomes. There is also evidence that oral pathogens can directly impact the risk for ADRD by infecting the brain and inducing β-amyloid production and neurotoxic effects on tau proteins. This project addresses limitations of prior research by studying a large, diverse, representative cohort with direct measures of the oral microbiota and by studying biomarkers of ADRD pathology and objectively assessed cognitive functioning in the clinically normal range prior to ADRD onset. The proposed project efficiently leverages new data from the High School & Beyond (HS&B:80) cohort study. HS&B:80 has followed a nationally representative sample of ~25,500 Americans from high school in 1980 through age ~60 in 2021. Participants have been recontacted several times, with high rates of participation. In 2021, HS&B:80 gathered cognitive functioning, anthropometric, and biomarker measures including i) saliva-based microbiota assessments (n=~6,220) and ii) blood-based markers of ADRD pathophysiology (n=~4,220 who also have oral microbiota assessments). Markers of pathophysiological features of ADRD include Aβ42 and Aβ40, phosphorylated tau at threonine 181, neurofilament light chain, and glial fibrillary acidic protein. The project has two primary aims: (1) Investigate the association between the salivary microbiota composition and midlife cognitive functioning. (2) Investigate the association between the salivary microbiota composition and biomarkers of ADRD pathophysiology. Hypotheses: Oral microbiota signatures will be associated with cognitive functioning and biomarkers of ADRD pathology. Specifically, we posit a priori that elevated ratios of Treponema-to-Corynebacterium genera will be associated with i) reduced cognitive functioning and ii) ADRD biomarker concentrations that reflect amyloid and tau pathophysiology, axonal damage/neurodegeneration, and/or inflammation/astrocytosis. We will also consider whether early life education and family socioeconomic background account for observed associations in Aims 1 and 2. Hypothesis: Associations seen in Aims 1 and 2 will be partially attenuated after adjusting for early life education and family socioeconomic background.
