Loss of myelinated axons is a feature of symptomatic Alzheimer's disease (AD). Our research group has also detected degeneration of myelinated axons in the preclinical phase. A major theme of our ongoing work has been to leverage the information derived from measures of myelin and axonal degeneration to improve the understanding of AD. This is a renewal application for ?White matter degeneration: biomarkers in preclinical Alzheimer's Disease?. Participants comprise cognitively unimpaired adults from the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Prevention who have been followed longitudinally with neuroimaging and CSF collection. In this renewal application, we propose to continue to follow enrolled participants as well as recruit additional participants to enrich for AD, including cognitively unimpaired biomarker positive participants, individuals with mild cognitive impairment (MCI), and participants with dementia due to AD. Participants will undergo comprehensive neuroimaging every two years. The hypothesis is that that degeneration of myelinated axons is a critical facet of the AD process, and that measures of white matter degeneration (myelin and axonal) can serve as sensitive markers of neurodegeneration in the context of plaque and tangle accumulation. We will examine measures of axons, including the primary measures neurofilament light protein in CSF and blood, and neurite density derived from multi-shell diffusion MRI. We will also evaluate myelin via CSF biomarkers and quantitative myelin imaging with mcDESPOT MRI. Our three aims are to 1) Define norms for white matter maturation/degeneration and determine the temporal ordering of AD pathology and neurodegeneration, using quantile regression and pattern mixture modeling approaches, 2) Determine the extent to which degeneration of myelinated axons predicts cognitive decline in the context of AD, and 3) Determine the cause(s) of myelin and axonal degeneration. This program of research is expected to inform upon the temporal course of AD development, disease severity, and the development of new treatment strategies.

Public Health Relevance

Without intervention, Alzheimer's disease will exert a devastating human toll. This project seeks to determine how Alzheimer's disease develops in the brain and how the loss of myelinated axons contributes to cognitive decline. The proposed work is expected to provide new information that can inform the development of new therapeutic strategies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Hsiao, John
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Wisconsin Madison
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Bettcher, Brianne M; Johnson, Sterling C; Fitch, Ryan et al. (2018) Cerebrospinal Fluid and Plasma Levels of Inflammation Differentially Relate to CNS Markers of Alzheimer's Disease Pathology and Neuronal Damage. J Alzheimers Dis 62:385-397
Merluzzi, Andrew P; Carlsson, Cynthia M; Johnson, Sterling C et al. (2018) Neurodegeneration, synaptic dysfunction, and gliosis are phenotypic of Alzheimer dementia. Neurology 91:e436-e443
Clark, Lindsay R; Berman, Sara E; Norton, Derek et al. (2018) Age-accelerated cognitive decline in asymptomatic adults with CSF ?-amyloid. Neurology 90:e1306-e1315
Clark, Lindsay R; Koscik, Rebecca L; Allison, Samantha L et al. (2018) Hypertension and obesity moderate the relationship between ?-amyloid and cognitive decline in midlife. Alzheimers Dement :
Johnson, Sterling C; Koscik, Rebecca L; Jonaitis, Erin M et al. (2018) The Wisconsin Registry for Alzheimer's Prevention: A review of findings and current directions. Alzheimers Dement (Amst) 10:130-142
Deming, Yuetiva; Dumitrescu, Logan; Barnes, Lisa L et al. (2018) Sex-specific genetic predictors of Alzheimer's disease biomarkers. Acta Neuropathol 136:857-872
Law, Lena L; Rol, Rachael N; Schultz, Stephanie A et al. (2018) Moderate intensity physical activity associates with CSF biomarkers in a cohort at risk for Alzheimer's disease. Alzheimers Dement (Amst) 10:188-195
Vesperman, Clayton J; Pozorski, Vincent; Dougherty, Ryan J et al. (2018) Cardiorespiratory fitness attenuates age-associated aggregation of white matter hyperintensities in an at-risk cohort. Alzheimers Res Ther 10:97
Hoy, Andrew R; Ly, Martina; Carlsson, Cynthia M et al. (2017) Microstructural white matter alterations in preclinical Alzheimer's disease detected using free water elimination diffusion tensor imaging. PLoS One 12:e0173982
Dean 3rd, Douglas C; Hurley, Samuel A; Kecskemeti, Steven R et al. (2017) Association of Amyloid Pathology With Myelin Alteration in Preclinical Alzheimer Disease. JAMA Neurol 74:41-49

Showing the most recent 10 out of 55 publications