The study team will evaluate whether metabolomic signatures of neurocognitive decline trajectories are exacerbated by the presence of type 2 diabetes mellitus (T2D) and whether these signatures contribute in part, to ethnic disparities in cognitive decline between European Americans and African Americans with T2D.

Aim 1. Re-examine the Diabetes Heart Study Memory IN Diabetes (DHS MIND) cohort for progression of neurocognitive decline using an established cognitive battery, literacy testing, and adjudicated physician diagnosis of dementia.Another neurocognitive evaluation will be completed in European-American and African-American DHS MIND participants, providing longitudinal follow-up more than eight years after initial assessment. The cognitive battery will reassess domains of executive function, memory, and global cognition. In addition, a clinical exam will include a literacy evaluation to circumvent the shortcomings of differences in educational attainment among participants. A physician adjudicated assessment of cognitively normal, mild cognitive impairment, or dementia will be obtained. Cognitive evaluations will inform epidemiological analyses regarding cross-sectional and trajectories of cognition decline relative to existing and repeat measures of cardio-metabolic risk factors.

Aim 2. Examine the metabolomic basis of neurocognitive measures in people with T2D. The presence of T2D, cardiovascular disease and reduced kidney function are significant risk factors for development of cognitive impairment. These risk factors are enriched in the DHS and lack early diagnostic tools. Untargeted metabolomic profiling offers the potential to identify relevant biomarkers that could impact the diagnosis, prognosis, and treatment of cognitive decline. This will be accomplished through untargeted metabolomic analysis of European American and African American DHS MIND participants using stored samples from baseline visits acquired more than 10 years prior to the current (repeat) neurocognitive assessment. These data will be used to A) provide information on novel mechanistic insights into cognition and trajectories of cognitive decline, B) develop a risk prediction model using the baseline exam, and C) validate extremes of neurocognitive performance using longitudinal assessments while examining ancestry/ethnic-specific differences.

Aim 3. Comprehensive genetic analysis of DHS participants to examine the genetic architecture of metabolomic signatures associated with the trajectories of neurocognitive decline. Existing genome-wide data will be used to map regions of the human genome that contain loci contributing to measures of neurocognition and metabolomics signatures of change in these variables through longitudinal assessment. Causal effect modeling will validate the association of modifiable exposures, i.e. genetic markers and metabolites on the outcome (i.e. trajectories of neurocognitive decline).

Inclusion Criteria:

• At the baseline visit, European American and African American individuals with T2D must have had diabetes diagnosed after the age of 30, 3 years disease duration and lack historical evidence of diabetic ketoacidosis.

Exclusion Criteria:

• At the baseline visit, participants with pre-existing kidney disease, defined as a serum creatinine concentration >1.5 mg/dl or blood urea nitrogen >35 mg/dl were excluded due to the elevation of serum AGE levels in individuals with kidney disease.

European Americans and African Americans with T2D from the general population.