Peripheral insulin resistance and creatinine levels are associated with plasma phosphorylated tau

Abstract

AbstractBackgroundType 2 diabetes (T2D) and insulin resistance (IR) are associated with increased dementia risk, but their association with plasma AD biomarkers e.g., plasma phosphorylated tau (pTau) is unknown. Here, we tested the relationship between diabetes, IR, and pTau, as well as considering the influence of comorbid conditions (obesity and kidney disease) on plasma biomarker measurements.Method425 participants from the Wisconsin Registry for Alzheimer’s Prevention were included based on availability of plasma assays. Plasma pTau181 and pTau231 were measured using a single molecule array (Simoa) assay on Quanterix. Diabetes status at baseline visit was determined using fasting blood glucose and medication usage. IR was measured using the homeostatic model assessment of IR (HOMA2‐IR) and z‐scored. Obesity was indicated through body mass index (BMI) and kidney function was determined by blood creatinine levels. We used Welch’s t‐test to examine differences in pTau levels based on diabetes status. Pearson correlations tested the linear relationships between longitudinal pTau181 and pTau231 with baseline HOMA2‐IR, BMI, and creatinine. Two linear mixed effects models were fitted; one for each of the pTau markers. Each model included random intercepts and age‐related slopes with fixed effects of baseline z‐scored HOMA2‐IR, BMI, and creatinine. Results were considered significant at p<.05unadjusted.ResultSample characteristics are in the Table. Baseline HOMA2‐IR correlated with pTau181 (r = 0.066, p = 0.021), but not pTau 231. Baseline creatinine associated with both pTau181 and pTau231 (Figure 1). Creatinine was also longitudinally associated with pTau231 (β = 4.82, p = 0.004; Figure 2). When accounting for BMI and creatinine, HOMA2‐IR was no longer associated with longitudinal pTau181 or pTau231. Age was robustly associated with pTau181 (β = 0.04, p = 6.06×10−7) and pTau231 (β = 0.15, p = 5.21×10−7) change. Plasma pTau did not differ based on diabetes status.ConclusionIR associated with pTau181 but this relationship did not hold when adjusting for obesity and kidney function. Creatinine levels were associated with longitudinal changes in pTau231 levels. Age was strongly associated with pTau181 and pTau231 change, such that older age was associated with increasing pTau181 and pTau231 levels. Though this study was completed in a largely healthy cohort, the results suggest comorbid conditions are important considerations when utilizing plasma pTau biomarkers as primary outcomes.