Date of Award
Master of Science
Food Science and Human Nutrition
Hypometabolism of glucose in the brain is associated with the neurodegenerative disorder, Alzheimer’s disease (AD), warranting further study of the relationship between metabolic function and structural integrity of the brain. While demyelination is observed with AD, less is known about the impact of glucose levels in combination with genetic risk factors on myelination. Ketone bodies are the brain’s alternative fuel source during periods of low fuel such as in Alzheimer’s disease (AD). Demyelination of the brain may lead to accumulations of amyloid beta plaques, associated with the disease (Bartzokis et al., 2007). Individuals with a family history (FH) or the APOE4 allele have been seen to have a predisposition for developing AD. Therefore, in efforts to achieve neuroprotection for people at-risk for developing the disease or during the prognosis of the disease, serum ketone bodies and glucose levels were studied in relation to white matter integrity in the brain from the Alzheimer’s Disease Neuroimaging Initiative. Cholecystokinin (CCK) was also examined in the cerebral spinal fluid. CCK is a satiety hormone that is highly expressed in brain regions like the hippocampus. CCK is integral for maintaining or enhancing memory, and thus may be a useful marker of cognitive and neural integrity in participants with normal cognition, mild cognitive impairment (MCI), and Alzheimer’s disease (AD). Interactions were also tested with genetic risk factors for AD, family history (FH) and apolipoprotein E ε4 (APOE4) status. Participants with FH or APOE4 allele showed increased myelin integrity as glucose levels increased when examining DTI fractional anisotropy in the fornix. Additionally, participants diagnosed with AD showed more demyelination compared to those who had mild cognitive impairment or who were cognitively normal as measured by DTI radial diffusivity in the fornix. Overall, the ketone levels predicted improved myelin integrity. The individuals without genetic risk factors showed improved myelin integrity with increases in ketone bodies. Participants with MCI or AD displayed more demyelination with increases in ketones. However, over a period of 2 years, the increases in demyelination for APOE4 carriers, FH positive group, and MCI progressors all show decreased or no association with demyelination. Briefly, higher CCK was related to a decreased likelihood of having MCI or AD, better global and memory scores, and more GM volume primarily spanning parahippocampal gyrus. CSF CCK was also strongly related to higher CSF total tau and p-tau181. Tau levels partially mediated CCK and cognition associations. Participants with FH of AD or the APOE4 allele may show compensatory mechanisms by increasing glucose uptake to protect against degradation caused by the disease. When the disease progresses to full AD diagnosis, the damage may overcome the benefit from hypermetabolism of glucose and thus need to increase the metabolism of ketone bodies. CCK levels also reflect compensatory protection as AD pathology progresses. CCK is released as a response to the ingestion of dietary fats so an increase in ketone body may increase these effects of CCK. The white matter integrity of at-risk groups before symptoms of the disease appear should be studied as these individuals may be predisposed to less myelin integrity and as myelin in being broken down, ketones increase as a product of the demyelination. Over time the brain becomes more efficient at metabolizing ketones and with a greater pool, the demyelination slows.
Plagman, Alexandra, "The role of cholecystokinin, fasting glucose, and ketone bodies on the pathogenesis of Alzheimer’s disease" (2019). Graduate Theses and Dissertations. 17073.