Evaluating clinical and pathological markers of cognitive decline and Alzheimer's dementia in long-duration type 1 diabetes. - ABSTRACT The burden of diabetes-associated cognitive dysfunction is on the rise as both type 1 (T1D) and type 2 (T2D) diabetes increase worldwide, and people affected are living longer. However, while cognitive dysfunction, Alzheimer’s’ disease and related disorders (AD/ADRD) have been extensively studied in T2D, within T1D this remains understudied and restricted to younger populations. Detailed clinical characterization of cognitive dysfunction in a large cohort with long-duration T1D has been limited given that living longer than 55 years in this population is only a recent phenomenon. This proposal focuses on the necessary need to understand specific pathology and mechanisms underlying cognitive decline in those with long-duration T1D to uncover novel pathways for intervention and prevention in this population. The Joslin 50-year Medalist Study (“Medalists”), a well-characterized cohort of individuals with ≥50 years of T1D, offers a unique opportunity to study potential markers of cognitive decline and AD/ADRD in long-duration T1D. Preliminary studies show that Medalists had worse cognitive function and lower brain volumes compared to non-diabetic controls. Significant associations between cognitive impairment and retinal neural and vasculature changes (assessed by Optical Coherence Tomography [OCT] and OCT-angiography [OCTA]) were also observed. Additionally, post-mortem brain histopathology revealed only mild-moderate AD-related or vascular pathology, unlike those with type 2 diabetes (T2D), supporting the urgent need to better characterize the underlying pathophysiology of cognitive decline in T1D. The overarching goal of this R01 proposal is to elucidate the distinct pathophysiological mechanisms driving cognitive decline in people with long-duration T1D, and identify predictive markers and pathways that can inform improved screening and management strategies in the future. Specific Aim 1. To evaluate functional and pathological markers of Alzheimer’s disease and cognitive decline in long-duration T1D via comprehensive cross-sectional and longitudinal clinical and cognitive assessments, brain imaging, and post-mortem brain gross and histopathological examinations. We aim to recruit an additional 100 Medalists each for the cross-sectional (total n=322), and longitudinal (total n=148) studies, and to procure 25 additional post-mortem brains for histopathology (total n=51). A subset of Medalists (n=20) will undergo amyloid PET scans. Plasma p-tau217 will also be assayed. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Rush Alzheimer's Disease Center (RADC) databases will be leveraged for comparisons with non-diabetic individuals and those with T2D. Specific Aim 2. To evaluate the relationships between retinal neurovasculature and cognitive decline and Alzheimer’s disease in long-duration T1D. The 100 participants will also undergo retinal imaging (OCT/OCTA) (total n=222).
