Blood Glucose Levels and Genetic Factors as Predictors of Neurocognitive Outcomes

Alzheimer"s disease;dementia;glucose;genetic factors;not listed

Wennberg, AlexandraAlbert, Marilyn S. ;

Johns Hopkins University

关键词: Alzheimer";    s disease;    dementia;    glucose;    genetic factors;    not listed;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/39386/WENNBERG-DISSERTATION-2015.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Alzheimer’s disease (AD), a neurodegenerative disease characterized by progressive cognitive decline, is becoming increasingly prevalent as the population ages. There is no effective treatment for AD, so manipulating modifiable risk factors before clinical symptoms of dementia develop may be the most effective course to prevent, delay, or modify the course of AD. Type II diabetes mellitus (DM), characterized by hyperglycemia and insulin resistance, affects over a quarter of older adults and has been linked with AD, cognitive decline, and brain atrophy. Because DM is preventable and treatable, it represents an intervention target for AD. This dissertation investigated the association between glucose levels and three outcomes – performance on a battery of cognitive tests over time, time to symptom onset of mild cognitive impairment (MCI) or dementia, and cortical thickness in AD-signature regions (i.e., entorhinal cortex, inferior temporal gyrus, parahippocampal gyrus pars triangularis, precuneus, superior frontal and parietal gyri, supramarginal gyrus, and temporal pole). Additionally, it investigated how two genes – apolipoprotein E (APOE) and translocase of the outer mitochondrial membrane (TOMM) 40 – may modify the relationship between glucose and these outcomes. Both the APOE ε4 allele and the TOMM40 very long/very long (VL/VL) genotype (versus the short/short (S/S) genotype) have been associated with increased risk of dementia, cognitive decline, and brain atrophy, and some evidence suggests that these genetic factors may further increase the risk in individuals with DM. This research was conducted using data from the BIOCARD Study (n=349), which enrolled primarily middle-aged individuals, three-quarters of whom had a first-degree relative with dementia. The goal of the study was to examine the early signs and symptoms of AD in a high-risk cohort. For this dissertation, baseline blood glucose level, which was ascertained from a blood draw in a clinical exam, was the primary predictor and was available for 333 participants. APOE and TOMM40 genotypes were also determined from blood samples. Age of MCI or dementia symptom onset was determined through consensus diagnosis. At annual visits, participants completed a neuropsychological test battery, and at baseline and bi-annually, participants completed magnetic resonance imaging (MRI) scans. The first paper in this study used linear mixed effects models (LMMs) and generalized estimating equation (GEE) models to investigate the association between glucose and cognitive performance over time. We used confirmatory factor analysis (CFA) to create one factor based on performance on tests of executive function (the executive function factor) and one factor based on performance on tests of memory (the memory factor). We found that higher baseline glucose was associated with greater decline on the executive function factor score in both LMMs (B=-0.005; 95% CI -0.008, -0.001) and GEE models (B=-0.004; 95% CI -0.007, -0.001) that controlled for age, sex, race, education, depression, and medical conditions (i.e., cardiovascular conditions, hypertension, hypercholesterolemia, traumatic brain injury (TBI)). Interaction analyses using LMMs found that higher glucose was associated with significant decline in executive function score in ε4 carriers (B=-0.013; 95% CI -0.020, -0.006), but not in non-carriers (B=-0.002, 95% CI -0.006, 0.002). In LMMs, higher glucose was also associated with poorer memory factor score over time in subjects with the S/S genotype (B=-0.013; 95% CI -0.024, -0.002), versus the VL/VL genotype (B=0.004; 95% CI -0.003, 0.010). The second paper in this study used Cox proportional hazard models to investigate the association between baseline blood glucose level and time to MCI or dementia symptom onset, as well as the association between the interaction of APOE and glucose and TOMM40 and glucose and time to symptom onset. We did not find an association between glucose level and time to symptom onset; additionally, we did not find that APOE or TOMM40 modified this relationship. In the final paper, linear regression analyses showed that glucose level was associated with reduced cortical thickness in the parahippocampal gyrus (B=-0.002; 95% CI -0.003, -0.0001) and temporal pole (B=-0.002; 95% CI -0.003, -0.0002) in a fully-adjusted model. Additionally, higher glucose levels were associated with thinner measures of the superior parietal gyri (B=-0.001; 95% CI -0.002, 0.0005 vs. B=0.0007; 95% CI 3.05e-6, 0.001) and temporal pole (B=-0.004; 95% CI -0.008, -0.0009 vs. B=-0.0003; 95% CI -0.002, 0.001) in ε4 allele carriers versus non-carriers. This evidence suggests that even in middle-aged, cognitively healthy samples, higher levels of glucose, even in those without DM, can negatively impact cognitive performance and cortical thickness. Maintaining normal blood glucose levels may be important in middle age for reducing risk of cognitive decline, AD, and brain atrophy.