Plasma Biomarkers of Brain Injury and Their Association with Brain MRI and Cognition in Type 1 Diabetes

Objective: To evaluate associations between plasma biomarkers of brain injury and MRI and cognitive measures in participants with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Research Design and Methods: Plasma amyloidß-40, amyloidß-42, neurofilament light chain (NfL), phosphorylated Tau-181 (pTau-181), and glial fibrillary acidic protein (GFAP) were measured in 373 DCCT/EDIC adults. MRI assessments included total brain and white matter hyperintensity volumes, white matter mean fractional anisotropy, and indices of Alzheimer’s Disease (AD)-like atrophy and predicted brain age. Cognitive measures included memory and psychomotor and mental efficiency tests and assessments of cognitive impairment. Results: Participants were 60 (range 44-74) years old with 38 (30-51) years T1D duration. Higher NfL was associated with an increase in predicted brain age (0.51 years per 20% increase in NfL, p<0.001) and a 19.5% increase in the odds of impaired cognition (p<0.01). Higher NfL and pTau-181 were associated with lower psychomotor and mental efficiency (p<0.001), but not poorer memory. Amyloid-ß measures were not associated with study measures. A 1-percentage increase in mean HbA1c was associated with a 14.6% higher NfL and 12.8% higher pTau-181 (p<0.0001). Conclusions: In this aging T1D cohort, biomarkers of brain injury did not demonstrate an AD-like profile. NfL emerged as a biomarker of interest in T1D due to its association with higher HbA1c, accelerated brain aging on MRI, and cognitive dysfunction. Our study suggests that early neurodegeneration in adults with T1D is likely due to non-AD/non-amyloid mechanisms.