Spread of pathological tau proteins through communicating neurons in human Alzheimer’s disease
Jacob W. Vogel, Yasser Iturria‐Medina, Olof Strandberg, Ruben Smith, Elizabeth Levitis, Alan C. Evans, Oskar Hansson, Alzheimer’s Disease Neuroimaging Initiative, Michael W. Weiner, Paul Aisen, Ronald Petersen, Clifford R. Jack, William J. Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John R. Morris, Leslie M. Shaw, Enchi Liu, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Danielle Harvey, Michael Donohue, Matt A. Bernstein, Nick C. Fox, Paul M. Thompson, Norbert Schuff, Charles DeCarli, Bret Borowski, Jeff Gunter, Matthew L. Senjem, Prashanthi Vemuri, David T. Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, Nigel J. Cairns, Erin Householder, Lisa Taylor Reinwald, Virginia M.‐Y. Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana Foroud, Steven G. Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Zaven Kachaturian, Richard Frank, Peter J. Snyder, Susan Molchan, Jeffrey Kaye, Joseph F. Quinn, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Beccera, Liberty Teodoro, Bryan M. Spann, James M. Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne Lord, Ronald Petersen, Sara S. Mason, Colleen S. Albers, David S. Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva Meyer, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau M. Ances, John C. Morris, Maria Carroll, Sue Leon, Erin Householder, Mark A. Mintun
Abstract
Tau is a hallmark pathology of Alzheimer's disease, and animal models have suggested that tau spreads from cell to cell through neuronal connections, facilitated by β-amyloid (Aβ). We test this hypothesis in humans using an epidemic spreading model (ESM) to simulate tau spread, and compare these simulations to observed patterns measured using tau-PET in 312 individuals along Alzheimer's disease continuum. Up to 70% of the variance in the overall spatial pattern of tau can be explained by our model. Surprisingly, the ESM predicts the spatial patterns of tau irrespective of whether brain Aβ is present, but regions with greater Aβ burden show greater tau than predicted by connectivity patterns, suggesting a role of Aβ in accelerating tau spread. Altogether, our results provide evidence in humans that tau spreads through neuronal communication pathways even in normal aging, and that this process is accelerated by the presence of brain Aβ.