TY - JOUR
T1 - Higher levels of myelin are associated with higher resistance against tau pathology in Alzheimer's disease
AU - Rubinski, Anna
AU - Franzmeier, Nicolai
AU - Dewenter, Anna
AU - Luan, Ying
AU - Smith, Ruben
AU - Strandberg, Olof
AU - Ossenkoppele, Rik
AU - Dichgans, Martin
AU - Alzheimer’s Disease Neuroimaging Initiative (ADNI)
AU - Hansson, Oskar
AU - Ewers, Michael
N1 - Funding Information: ADNI data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12–2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging, and Bioengineering, and through contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). Funding Information: Open Access funding enabled and organized by Projekt DEAL. The study was supported by the German Center for Neurodegenerative Diseases (DZNE), and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) grant for major research instrumentation (INST 409/193–1 FUGG). Publisher Copyright: © 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - BACKGROUND: In Alzheimer's disease (AD), fibrillar tau initially occurs locally and progresses preferentially between closely connected regions. However, the underlying sources of regional vulnerability to tau pathology remain unclear. Previous brain-autopsy findings suggest that the myelin levels-which differ substantially between white matter tracts in the brain-are a key modulating factor of region-specific susceptibility to tau deposition. Here, we investigated whether myelination differences between fiber tracts of the human connectome are predictive of the interregional spreading of tau pathology in AD. METHODS: We included two independently recruited samples consisting of amyloid-PET-positive asymptomatic and symptomatic elderly individuals, in whom tau-PET was obtained at baseline (ADNI: n = 275; BioFINDER-1: n = 102) and longitudinally in a subset (ADNI: n = 123, mean FU = 1.53 [0.69-3.95] years; BioFINDER-1: n = 39, mean FU = 1.87 [1.21-2.78] years). We constructed MRI templates of the myelin water fraction (MWF) in 200 gray matter ROIs and connecting fiber tracts obtained from adult cognitively normal participants. Using the same 200 ROI brain-parcellation atlas, we obtained tau-PET ROI values from each individual in ADNI and BioFINDER-1. In a spatial regression analysis, we first tested the association between cortical myelin and group-average tau-PET signal in the amyloid-positive and control groups. Secondly, employing a previously established approach of modeling tau-PET spreading based on functional connectivity between ROIs, we estimated in a linear regression analysis, whether the level of fiber-tract myelin modulates the association between functional connectivity and longitudinal tau-PET spreading (i.e., covariance) between ROIs. RESULTS: We found that higher myelinated cortical regions show lower tau-PET uptake (ADNI: rho = - 0.267, p < 0.001; BioFINDER-1: rho = - 0.175, p = 0.013). Fiber-tract myelin levels modulated the association between functional connectivity and tau-PET spreading, such that at higher levels of fiber-tract myelin, the association between stronger connectivity and higher covariance of tau-PET between the connected ROIs was attenuated (interaction fiber-tract myelin × functional connectivity: ADNI: β = - 0.185, p < 0.001; BioFINDER-1: β = - 0.166, p < 0.001). CONCLUSION: Higher levels of myelin are associated with lower susceptibility of the connected regions to accumulate fibrillar tau. These results enhance our understanding of brain substrates that explain regional variation in tau accumulation and encourage future studies to investigate potential underlying mechanisms.
AB - BACKGROUND: In Alzheimer's disease (AD), fibrillar tau initially occurs locally and progresses preferentially between closely connected regions. However, the underlying sources of regional vulnerability to tau pathology remain unclear. Previous brain-autopsy findings suggest that the myelin levels-which differ substantially between white matter tracts in the brain-are a key modulating factor of region-specific susceptibility to tau deposition. Here, we investigated whether myelination differences between fiber tracts of the human connectome are predictive of the interregional spreading of tau pathology in AD. METHODS: We included two independently recruited samples consisting of amyloid-PET-positive asymptomatic and symptomatic elderly individuals, in whom tau-PET was obtained at baseline (ADNI: n = 275; BioFINDER-1: n = 102) and longitudinally in a subset (ADNI: n = 123, mean FU = 1.53 [0.69-3.95] years; BioFINDER-1: n = 39, mean FU = 1.87 [1.21-2.78] years). We constructed MRI templates of the myelin water fraction (MWF) in 200 gray matter ROIs and connecting fiber tracts obtained from adult cognitively normal participants. Using the same 200 ROI brain-parcellation atlas, we obtained tau-PET ROI values from each individual in ADNI and BioFINDER-1. In a spatial regression analysis, we first tested the association between cortical myelin and group-average tau-PET signal in the amyloid-positive and control groups. Secondly, employing a previously established approach of modeling tau-PET spreading based on functional connectivity between ROIs, we estimated in a linear regression analysis, whether the level of fiber-tract myelin modulates the association between functional connectivity and longitudinal tau-PET spreading (i.e., covariance) between ROIs. RESULTS: We found that higher myelinated cortical regions show lower tau-PET uptake (ADNI: rho = - 0.267, p < 0.001; BioFINDER-1: rho = - 0.175, p = 0.013). Fiber-tract myelin levels modulated the association between functional connectivity and tau-PET spreading, such that at higher levels of fiber-tract myelin, the association between stronger connectivity and higher covariance of tau-PET between the connected ROIs was attenuated (interaction fiber-tract myelin × functional connectivity: ADNI: β = - 0.185, p < 0.001; BioFINDER-1: β = - 0.166, p < 0.001). CONCLUSION: Higher levels of myelin are associated with lower susceptibility of the connected regions to accumulate fibrillar tau. These results enhance our understanding of brain substrates that explain regional variation in tau accumulation and encourage future studies to investigate potential underlying mechanisms.
KW - Alzheimer’s disease
KW - Amyloid-PET
KW - Myelin
KW - Myelin water fraction
KW - Resistance
KW - Tau spreading
KW - Tau-PET
UR - http://www.scopus.com/inward/record.url?scp=85138458336&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s13195-022-01074-9
DO - https://doi.org/10.1186/s13195-022-01074-9
M3 - Article
C2 - 36153607
SN - 1758-9193
VL - 14
SP - 139
JO - Alzheimer's Research & Therapy
JF - Alzheimer's Research & Therapy
IS - 1
M1 - 139
ER -