Alzheimer's Disease (AD) and Vascular Brain Injury- related changes in longitudinal Magnetic Resonance Imaging associated with Intraindividual Cognitive Variability in Aging American Indians.

Project Summary/ Abstract American Indians are at higher risk for Alzheimer’s disease and Alzheimer’s disease related dementia (AD/ADRD) compared to the general population, yet dementia onset and frequency in this population are understudied. American Indians have a disproportionate burden of diabetes and vascular brain injury along with

evidence of health disparities. Diabetes increases the risk of vascular disease, which accelerate Alzheimer’s disease-related processes coexisting in mixed forms of dementia. Intraindividual cognitive variability (IICV), a measure of variability in neuropsychological test performance within a person at a single timepoint, may be a

novel, low-cost, noninvasive biomarker of neurodegeneration and early dementia. We aim to characterize associations between IICV, longitudinal changes in magnetic resonance imaging (MRI) measures related to AD/ADRD, and diabetes among older American Indians. For this we will use data from the Strong Heart Study

(SHS) and Cerebrovascular Disease and its Consequences in American Indians (CDCAI) Study, calculating IICV measures for memory, executive function and processing speed, and multidomain cognition for 403 American Indians (age 70-95) who had diabetes assessments at three different timepoints over the course of ~27-years

(SHS Time 0, CDCAI time 1 and CDCAI time 2); neuropsychological and neuroimaging data at two time points, with an interval of ~7-years (CDCAI time 1 and CDCAI time 2), and dementia adjudication at time 2. We will accomplish this work through the following Specific Aims: (1) Examine (a) whether IICV at time 1 is associated

with neurodegenerative-related changes in MRI in critical brain regions (entorhinal, hippocampal, whole brain atrophy), in American Indians, and (b) whether diabetes moderates this relationship. We expect (a) that IICV will be positively associated with neurogenerative-related MRI changes, and (b) a stronger association

between IICV and MRI findings in those with diabetes at midlife (time 0) or later life (time 1 and 2); (2) Examine (a) whether IICV at time 1 is associated with vascular brain injury in American Indians (WMH volume progression), and (b) whether diabetes moderates this relationship. We expect (a) that IICV will be

positively associated with WMH progression, and (b) a stronger association between IICV and MRI findings in those with diabetes; and (3) Examine whether (a) IICV at time 1 is associated with cognitive decline and dementia adjudication at time 2, and (b) whether diabetes moderates these associations. We expect (a)

that increased IICV will be associated with an increased likelihood of cognitive decline, MCI, and dementia and (b) a stronger association in those with diabetes. The validation of IICV as a marker of future AD/ADRD risk will allow for earlier noninvasive identification and mitigation of risk in American Indians. Results from this study are

expected to advance the understanding of how IICV relates to neuropathology, dementia, and type 2 diabetes among aging American Indians, and is expected to serve as preliminary data to optimize the design of a future R01 dedicated to investigating the utility of IICV as early marker of AD in minority populations.