As the population ages, Alzheimer's disease and dementia are becoming a public health crisis. In our initial cycle, the Vanderbilt Memory & Aging Project was established to examine cardiovascular function in relation to structural neuroimaging changes and cognition. We also tested whether associations were more prominent in clinically symptomatic individuals. We successfully enrolled several hundred participants age 60 and older, our data successfully supported multiple training grant opportunities (e.g., National Research Service Awards, Career Development Awards), and we published numerous papers. Our results suggest subclinical cardiovascular changes relate to worse cognition, white matter changes, and cerebral atrophy, especially in the hippocampus and other cortical regions primarily affected in Alzheimer's disease. Evidence to date supports our central hypothesis that well-established homeostatic mechanisms designed to protect cerebral blood supply become less effective with age, altering the integrity of cerebral hemodynamics, and lowering the threshold for neurodegenerative and cognitive changes. Interestingly, our preliminary associations between subclinical cardiovascular integrity and cerebral hemodynamics are stronger among carriers of the apolipoprotein E ?4 (APOE-?4) allele, an Alzheimer's disease genetic risk factor. Furthermore, findings are more prominent in cognitively unimpaired participants, suggesting subtle cardiac hemodynamic changes may act as an underrecognized precipitating contributor of neurodegeneration and corresponding cognitive decline, distinct from the exacerbating effects of overt cerebrovascular disease. In the next cycle, we propose to better characterize underlying mechanisms linking early cardiac hemodynamic changes to abnormal brain aging in cognitively unimpaired participants, and test whether APOE-?4 moderates the effect of vascular damage on brain health. We will follow the existing cohort and supplement it with enrollment of several hundred cognitively unimpaired participants to increase statistical power for more comprehensive analyses. The new participants will complete serial longitudinal assessments with identical procedures plus lumbar puncture for cerebrospinal fluid acquisition. Innovative translational efforts leveraging sophisticated neuroimaging and molecular biomarkers are critical to better detect early, asymptomatic cardiac hemodynamic changes, which may be more influential in initiating downstream cerebrovascular and neurodegenerative processes than previously recognized.

Public Health Relevance

The incidence of dementia is dramatically increasing, and there is an urgent need to identify risk factors and prevention strategies for cognitive impairment and dementia, including Alzheimer?s disease. There is growing recognition that cardiovascular integrity is associated with abnormal brain changes and cognitive impairment. The proposed project will generate evidence to support the development of novel strategies for delaying dementia onset and progression.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Study Section
Behavioral Medicine, Interventions and Outcomes Study Section (BMIO)
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Silverberg, Nina B
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Vanderbilt University Medical Center
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Jefferson, Angela L; Cambronero, Francis E; Liu, Dandan et al. (2018) Higher Aortic Stiffness Is Related to Lower Cerebral Blood Flow and Preserved Cerebrovascular Reactivity in Older Adults. Circulation 138:1951-1962
Gifford, Katherine A; Liu, Dandan; Neal, Jacquelyn E et al. (2018) Validity and Normative Data for the Biber Figure Learning Test: A Visual Supraspan Memory Measure. Assessment :1073191118773870
Deming, Yuetiva; Dumitrescu, Logan; Barnes, Lisa L et al. (2018) Sex-specific genetic predictors of Alzheimer's disease biomarkers. Acta Neuropathol 136:857-872
Cambronero, Francis E; Liu, Dandan; Neal, Jacquelyn E et al. (2018) APOE genotype modifies the association between central arterial stiffening and cognition in older adults. Neurobiol Aging 67:120-127
Moore, Elizabeth E; Hohman, Timothy J; Badami, Faizan S et al. (2018) Neurofilament relates to white matter microstructure in older adults. Neurobiol Aging 70:233-241
Osborn, Katie E; Liu, Dandan; Samuels, Lauren R et al. (2018) Cerebrospinal fluid ?-amyloid42 and neurofilament light relate to white matter hyperintensities. Neurobiol Aging 68:18-25
Hohman, Timothy J; Dumitrescu, Logan; Cox, Nancy J et al. (2017) Genetic resilience to amyloid related cognitive decline. Brain Imaging Behav 11:401-409
Lane, Elizabeth M; Hohman, Timothy J; Jefferson, Angela L et al. (2017) Insulin-like growth factor binding protein-2 interactions with Alzheimer's disease biomarkers. Brain Imaging Behav 11:1779-1786
Bell, S P; Liu, D; Samuels, L R et al. (2017) Late-Life Body Mass Index, Rapid Weight Loss, Apolipoprotein E ?4 and the Risk of Cognitive Decline and Incident Dementia. J Nutr Health Aging 21:1259-1267
Jefferson, Angela L; Gifford, Katherine A; Acosta, Lealani Mae Y et al. (2016) The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview. J Alzheimers Dis 52:539-59

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