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    Probing contributions of Apolipoprotein E4 to cerebrovascular dysfunction and Alzheimer's disease

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    Available after: 2022-05-31 (2.526Mb)
    Issue Date
    2021-05-31
    Author
    Kaufman, Carolyn Stark
    Publisher
    University of Kansas
    Format
    166 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Molecular & Integrative Physiology
    Rights
    Copyright held by the author.
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    Abstract
    Evidence increasingly points to an early and primary role for vascular dysfunction in the pathogenesis of late-onset Alzheimer’s disease (AD). This early vascular dysfunction may be particularly impactful for people at the highest known genetic risk of AD, Apolipoprotein E4 allele (APOE4) carriers. Though relatively minimal investigation has been conducted into the potential vascular mechanisms of AD pathogenesis for APOE4 carriers, existing literature suggests APOE4 may cause both peripheral and cerebral vascular dysfunction. Furthermore, evidence suggests the APOE4 allele may act synergistically with this vascular dysfunction to promote dementia development. This highlights the need for interventions such as aerobic exercise that improve vascular health and may preferentially benefit APOE4 carriers to delay AD onset.In these collected works, we first examined the impact of APOE4 carrier status on markers of cerebrovascular health. We measured cerebrovascular conductance and pulsatility at rest and found no differences for APOE4 carriers compared to non-carriers with and without AD (Chapter 2, N = 32). Likewise, we report no significant impairment in dynamic cerebrovascular autoregulation for APOE4 carriers with and without AD (Chapter 2, N = 29). In a separate cohort, we found no difference in the cerebrovascular response to an acute bout of exercise for cognitively-normal APOE4 carriers (n =16) compared to non-carriers (n = 36; Chapter 3). Next, we investigated the potential synergistic relationship between vascular dysfunction and the APOE4 allele. We found resting cerebrovascular conductance, or the amount of blood flowing to the brain per a given perfusion pressure, was inversely related to brain β-amyloid load for the APOE4 carriers but not non-carriers (Chapter 3, N = 54). This suggests poor cerebrovascular conductance (i.e. poor brain blood flow delivery) may promote β-amyloid deposition in APOE4 iii carriers only, consistent with previous studies that have found a synergistic relationship between poor cerebrovascular health and the APOE4 allele on increasing dementia risk. Additionally, we report APOE4 carrier status moderates the association between pro-atherogenic cholesterol levels and the cerebrovascular response to an acute bout of exercise (Chapter 3, N = 52). Specifically, APOE4 carriers with higher levels of pro-atherogenic cholesterol had a blunted cerebrovascular response from rest to exercise, while non-carriers exhibited the opposite relationship. These data further support the hypothesis that peripheral vascular risk factors may have a greater impact for APOE4 carriers than non-carriers. In our final study of a randomized clinical trial (Chapter 4, N = 109), we report a year-long aerobic exercise intervention significantly improved hippocampal blood flow for APOE4 carriers with hypertension, while there was no effect for non-carriers. Notably, we found a significant positive association between change in hippocampal blood flow and change in verbal memory performance for the intervention group, suggesting these improvements in hippocampal blood flow delivery may be clinically meaningful. Additionally, we found reductions in systolic blood pressure over one year were associated with increased hippocampal blood flow for APOE4 carriers but not non-carriers. That is, for hypertensive APOE4 carriers, lowering blood pressure improved blood flow delivery to the hippocampus, while this was not apparent for non-carriers, again suggesting peripheral vascular health may have a larger influence on brain health for APOE4 carriers than non-carriers. Taken together, the work in this dissertation supports an important role for systemic vascular health maintenance to preserve brain function in APOE4 carriers. Interventions to improve vascular health, such as aerobic exercise, cholesterol management, and tight blood pressure control, may preferentially prevent or delay cognitive decline for people at the highest known genetic risk of late-onset AD.
    URI
    http://hdl.handle.net/1808/31773
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    • Dissertations [4473]

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    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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