Apolipoprotein A1 Modifications Related to Cognitive Decline in Type 2 Diabetes and Preclinical Alzheimer s Disease
Abstract
Aging and age-related clinical syndromes, such as Alzheimer’s disease (AD) dementia and mixed dementia, are among the leading cause of disability and are a major public health concern of the 21st century. There is significant interest in understanding clinical and environmental factors that predispose people to the onset of dementia, as they provide a window into intervening early to mitigate dementia onset. Individuals with type 2 diabetes (T2DM) have among the highest risk of developing dementia in their lifetimes in some study cohorts (25%-91% elevated risk). According to the National Diabetes Statistics Report (2020), 34.2 million Americans (approximately 1 in 10) have diabetes mellitus (DM), and more people are developing Type 1 and Type 2 DM (T2DM) during youth. The number of young newly diagnosed diabetics is increasing nationwide. Further, DM affects nearly 1 in 4 Veterans. This large number of younger diabetics among both the general population and among Veterans is therefore vulnerable to a significant future risk of dementia. It is therefore a significant public health imperative to delineate the specific pathophysiology of DM’s role in increasing dementia risk. Currently we do not know with certainty which molecular pathways underlie the increased risk of future AD and dementia among diabetics and if these same molecular pathways are also shared among elderly individuals in the earliest stages of AD. T2DM is associated with systemic metabolic changes including insulin resistance and lipoprotein abnormalities with increased triglycerides, small dense low density lipoprotein cholesterol (LDL), and low concentrations of high density lipoprotein cholesterol (HDL) cholesterol. Beneficial functions of HDL have emerged in recent years with the discovery that HDLs and some of their constituent apolipoproteins have potent antidiabetic properties. Among humans, high plasma HDL levels are also associated with better cognition in the elderly, while low HDL levels are a risk factor for memory decline in middle-aged adults. Previous studies from our group has demonstrated that T2DM individuals had impaired antioxidant properties of HDL and further had increased turnover of HDL’s main lipoprotein constituent Apolipoprotein A1 (ApoA1). Based on our prior results, we have a strong rationale to evaluate the role for the ApoA1, whose important function in HDL transport is disturbed by poorly controlled T2DM, as a key factor predisposing individuals to cognitive decline among diabetics and those at the preclinical stages of AD. This knowledge is likely to be useful for understanding clinical outcomes in both DM and AD and developing novel therapies targeting lipoprotein changes to improve cognitive function. The main goal of the study is to evaluate if poor glycemic control and related changes to peripheral ApoA1 is a significant factor in central nervous system inflammation as well as vascular, neuronal, and synaptic changes related to poor cognition in T2DM and those individuals at the preclinical stages of AD. On completion, this study will confirm whether blood ApoA1 level and its modification (glycation) from poorly controlled T2DM is a marker for the risk of future cognitive decline in both T2DM and preclinical stages of AD and which key factors mediate its cognitive outcomes. Towards this, we will carefully characterize and collect detailed data and model the key players important in cognitive outcomes (cardiovascular disease, inflammation, neuronal, and AD-related brain changes) among 70 adults with T2DM and 120 individuals at high risk of AD. This research will evaluate whether glycated and total plasma ApoA1 levels are a potential biomarker for future cognitive decline among both diabetics and individuals at the earliest stage of AD and if lipoprotein changes are a key factor in mediating cognitive health among both cohorts. These results will provide robust data to help plan for future well-powered longitudinal studie
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210335
Entities
People
- Jagan A Pillai
Organizations
- Cleveland Clinic
- United States Army