Alzheimer?s disease and related dementias (AD/ADRD) are a growing concern in light of the expanding Type 1 diabetes (T1D) prevalence and ageing populations. With marked differences in trajectories of cognitive decline, T1D associated AD/ADRD may have different underlying mechanisms, including vascular abnormalities, and aberrations in glucose, insulin and amyloid metabolism. This is concerning as a patient?s cognitive abilities are critical in ensuring optimal T1D self-management and avoiding fatal mistakes. While T1D studies have shown that poor glycemic control is associated with dementia, the role of the other mechanisms remains unclear. Additionally, T1D brain imaging studies have been limited to younger adults, making it challenging to extrapolate these findings to those with longstanding T1D. For the last 30 years, the Joslin Diabetes Research Center (DRC) has catalyzed the diabetes research effort at Joslin, Harvard and Boston research institutions. The product has been groundbreaking research that has generated many new ideas regarding the pathogenesis of diabetes and its complications. A preliminary review within the Joslin DRC-supported 50-year Medalist Study, a cohort of people with ?50 years of T1D, reported impaired cognitive function, similar to those with type 2 diabetes. Post-mortem brain histopathology collected from deceased Medalists revealed advanced AD pathology as well. As Medalists do not exhibit clinical signs of insulin resistance, and have relatively good glycemic control, they are an ideal cohort to examine the vascular and amyloid etiology of AD/ADRD in T1D. Furthermore, cognitive decline has been associated with structural changes in retinal neural layers and microvasculature as quantified by advanced non-invasive retinal imaging techniques such as optical coherence tomography (OCT) and OCT angiography (OCTA), but these relationships have not been examined in T1D. We hypothesize that AD/ADRD in aging T1D patients has a significant underlying vascular etiopathogenesis, and the Medalist Study is an ideal cohort to examine this hypothesis given they have detailed diabetes profiling and characterization of vascular complications.
Specific Aim 1. To characterize functional and pathological markers of Alzheimer?s and cognitive decline in long-duration T1D via comprehensive cognitive assessments, brain imaging, and post-mortem brain gross and histopathology in Medalists.
Specific Aim 2. To evaluate the relationships between retinal neurovasculature and cognitive decline and Alzheimer?s disease in long-duration T1D. Future plans: This exploratory P&F will allow us to apply for future funding to conduct PET/tau imaging, as well as longitudinal follow-up and examine the roles of other T1D vascular complications.

Public Health Relevance

Alzheimer?s disease and related dementias (AD/ADRD) are a growing concern in the context of an expanding diabetes epidemic and ageing populations, and as yet under-studied in type 1 diabetes. We aim to characterize these complications among aging individuals with long duration type 1 diabetes via comprehensive cognitive clinical assessments, brain imaging and histopathology, and study the relationships between cognitive function and retinal neural vasculature structure and function via retinal imaging. These studies will provide preliminary insights into the vascular etiology of AD/ADRD in long duration type 1 diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Center Core Grants (P30)
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Special Emphasis Panel (ZDK1)
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Hyde, James F
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Joslin Diabetes Center
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