Educational and Early Life Predictors of Mild Cognitive Impairment: New Evidence about Mediators and Moderators from High School & Beyond

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PROJECT SUMMARY/ABSTRACT We propose a supplement to the award that supports the 2021 High School and Beyond (HSB) fieldwork that would add additional blood-based biomarkers. We are already funded to construct measures in the A/T/N framework—that is, amyloid (A) and tau (T) specific to ADRD pathophysiology as well as neurodegenerative (N) changes captured by NfL. This is a great first step since measures from the A/T/N framework are now considered central to the characterization of ADRD pathophysiology. In this supplement, we request additional support for biomarkers outside of this framework that have been the focus of increasing interest as relevant to cognition, especially in samples outside of clinical settings. There is growing evidence that these biomarkers may be relevant even within the context of the A/T/N framework; for example, inflammatory markers not specific to the brain may interact with brain-specific markers in the A/T/N framework to shape ADRD outcomes. We propose to add (a) newer biomarkers that may be specific to ADRD pathophysiology but that were developed only recently and (b) biomarkers that have been the focus of increasing interest as relevant to cognition, especially in community settings. In doing so, we will integrate established and novel biomarkers reflecting (a) vascular, inflammatory, and immunological injury and (b) biological aging in order to probe their independent impacts on cognitive outcomes and the degree to which they interact with A/T/N biomarkers. Specifically, we propose to add additional blood-based biomarkers including the Olink Neurology panel, hemoglobin A1c, inflammatory markers potentially related to vascular disease and progression of the amyloid- tau cascade, markers of endothelial function, markers of blood-brain barrier problems, blood lead levels, and measures of biological aging [Aim 1]; document the new measures [Aim 2]; construct blood-based biomarker- specific sampling weights [Aim 3]; and disseminate the new measures, weights, and documentation [Aim 4]. All proposed supplemental activities would be completed by the end of the original five-year R01 budget period. The proposed supplemental activities will increase and preserve the overall impact of the project consistent with its originally approved Aims and purposes.