187-LB: Preclinical Biomarkers of Alzheimer's Disease Neuropathology in Young Adults with Youth-Onset Diabetes (YDM)—A Proof-of-Concept Study

Adult-onset diabetes increases one's risk for Alzheimer's disease and its related dementias (AD/ADRD). However, little is known about the risk for AD/ADRD in young adults with YDM. The current study quantified preclinical plasma and imaging biomarkers of AD/ADRD in a subset of young adults with YDM from the SEARCH for Diabetes in Youth study cohort (type 1 diabetes [T1D], n=20; type 2 diabetes [T2D], n=21; mean [SD], age=27.4 years [2.2], diabetes duration=13.6 years [2.4], 59% female). Plasma biomarkers were assayed from stored samples at two timepoints: within 1-year of YDM diagnosis (baseline) and in young adulthood via the Quanterix Simoa platform including glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), phosphorylated tau-181 (pTau181), amyloid beta (Aβ)40, and Aβ42. Seven participants from the SEARCH subset (T1D=6, T2D=1; age=30.7 years [2.4], 87% female) and four age-similar controls (age=26.5 years [4.4], 50% female) underwent [18F]PI-2620 tau positron emission tomography (PET) to quantify brain tau density. Tau standardized uptake value ratios (SUVRs) with partial volume correction were derived in AD/ADRD sensitive brain regions. From baseline to young adulthood, plasma pTau181 significantly increased in both YDM-T1D and YDM-T2D (mean change=9.5 pg/mL [3.8] and 12.4 pg/mL [6.3], respectively; p<0.001). Average tau SUVRs in the middle temporal poles (SUVR=1.26 [0.14] vs 1.17 [0.04]) and parahippocampal gyri (SUVR=1.01 [0.33] vs 0.92 [0.05]) were greater in YDM vs. controls. However, these differences were not statistically significant. Our preliminary results suggest that YDM may increase the risk of AD/ADRD via accelerated accumulation of soluble phosphorylated tau. Additional measurement of AD/ADRD neuropathology, including amyloid PET scans, is currently underway to further understand the trajectory of preclinical AD/ADRD pathology in YDM.