The pathophysiological brain changes associated with Alzheimer's disease [AD] begin decades before clinical symptoms. Although recent advances have led to a preclinical biomarker model of AD pathogenesis (first amyloid-beta [A] pathology, second neurodegeneration, and lastly cognitive symptoms), the mechanisms that underlie these pathological changes remain unknown, impeding the identification of potential biomarkers and treatment targets. Previous studies of blood or CSF biomarkers have mostly employed clinical outcomes (i.e., cognitively normal [CN], mild cognitive impairment [MCI] and AD. However, clinical phenotypes are heterogeneous. Thus, categorizing individuals by their clinical phenotype alone will include a mixture of individuals with varying types and severities of brain pathologies (e.g., A pathology, neurodegeneration, vascular disease). The overarching goal of this project is to determine the temporal relationship between plasma and CSF sphingolipids (e.g., ceramides, sphingomyelins), in vivo measures of A pathology (A imaging, CSF A) and neurodegeneration (FDG-PET hypometabolism, hippocampal atrophy, CSF tau), and clinical endpoints. As inflammation is associated with AD, and is intimately interrelated with sphingolipids, we will also determine whether inflammatory processes (e.g., TNF-? and IL-6) modify the associations between sphingolipids and in vivo AD pathology. While previous studies have examined many plasma and CSF biomarkers with limited success, the study of sphingolipids is uniquely promising and highly innovative. First, cellular and animal studies demonstrate direct links between sphingolipids and measures of A pathology and neurodegeneration. Reducing A-associated increases in ceramide levels prevents neurodegeneration. Second, we consistently demonstrate that high levels of plasma sphingolipids predict cognitive decline among individuals who are CN, MCI, and AD. The next logical step is to determine the cross-sectional and longitudinal associations between the sphingolipids and in vivo evidence of AD pathology. For example, we will determine whether individuals with both abnormal A and elevated ceramides develop more neurodegeneration and cognitive decline compared to individuals with abnormal A and low ceramides. To accomplish our goals we will utilize a longitudinal collection of cognitive endpoints and in vivo measures of A pathology and neurodegeneration from individuals enrolled in the population-based Mayo Clinic Study of Aging [MCSA] and the Mayo Clinic Alzheimer's Disease Research Center. Together these longitudinal studies have accumulated over 2,375 visits with A imaging, FDG-PET, and MRI scans on 1,617 unique individuals, and more than 1,085 CSF samples from 870 unique individuals, providing an ideal resource to test our hypotheses. The proposed research will further our understanding of the interrelationship between plasma and CSF sphingolipids, the development and progression of AD pathology, and the emergence and progression of clinical symptoms. This work will contribute to the identification of new treatment strategies for delaying, or possibly preventing, AD.

Public Health Relevance

The brain changes associated with Alzheimer's disease begin several years before cognitive changes; there is currently no cure for the disease. This study will use resources from the Mayo Clinic Study on Aging and the Mayo Clinic Alzheimer's Disease Research Center to examine sphingolipids and inflammatory markers in relation to the development and progression of the brain changes and memory loss associated with Alzheimer's disease. Our results are important for developing biomarkers to predict who will develop Alzheimer's disease and for identifying new treatment targets.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG049704-01
Application #
8853439
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Anderson, Dallas
Project Start
2015-09-01
Project End
2019-04-30
Budget Start
2015-09-01
Budget End
2016-04-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Wennberg, Alexandra M V; Hagen, Clinton E; Machulda, Mary M et al. (2018) The association between peripheral total IGF-1, IGFBP-3, and IGF-1/IGFBP-3 and functional and cognitive outcomes in the Mayo Clinic Study of Aging. Neurobiol Aging 66:68-74
Chan, Parco; Saleem, Mahwesh; Herrmann, Nathan et al. (2018) Ceramide Accumulation Is Associated with Declining Verbal Memory in Coronary Artery Disease Patients: An Observational Study. J Alzheimers Dis 64:1235-1246
Wennberg, Alexandra M V; Hagen, Clinton E; Petersen, Ronald C et al. (2018) Trajectories of plasma IGF-1, IGFBP-3, and their ratio in the Mayo Clinic Study of Aging. Exp Gerontol 106:67-73
Wennberg, Alexandra M V; Lesnick, Timothy G; Schwarz, Christopher G et al. (2018) Longitudinal Association Between Brain Amyloid-Beta and Gait in the Mayo Clinic Study of Aging. J Gerontol A Biol Sci Med Sci 73:1244-1250
Wennberg, Alexandra M V; Schafer, Marissa J; LeBrasseur, Nathan K et al. (2018) Plasma Sphingolipids are Associated With Gait Parameters in the Mayo Clinic Study of Aging. J Gerontol A Biol Sci Med Sci 73:960-965
Ramanan, Vijay K; Przybelski, Scott A; Graff-Radford, Jonathan et al. (2018) Statins and Brain Health: Alzheimer's Disease and Cerebrovascular Disease Biomarkers in Older Adults. J Alzheimers Dis 65:1345-1352
Rocca, Walter A; Gazzuola Rocca, Liliana; Smith, Carin Y et al. (2018) Personal, reproductive, and familial characteristics associated with bilateral oophorectomy in premenopausal women: A population-based case-control study. Maturitas 117:64-77
Mielke, Michelle M; Hagen, Clinton E; Xu, Jing et al. (2018) Plasma phospho-tau181 increases with Alzheimer's disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Alzheimers Dement 14:989-997
Wennberg, Alexandra M V; Hagen, Clinton E; Edwards, Kelly et al. (2018) Association of antidiabetic medication use, cognitive decline, and risk of cognitive impairment in older people with type 2 diabetes: Results from the population-based Mayo Clinic Study of Aging. Int J Geriatr Psychiatry 33:1114-1120
Knopman, David S; Lundt, Emily S; Therneau, Terry M et al. (2018) Joint associations of ?-amyloidosis and cortical thickness with cognition. Neurobiol Aging 65:121-131

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