Dissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease
Michael Tran Duong, Sandhitsu R. Das, Xueying Lyu, Long Xie, Hayley Richardson, Sharon X. Xie, Paul A. Yushkevich, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Michael W. Weiner, Paul Aisen, Ronald C. Petersen, Clifford R. Jack, William J. Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John C. Morris, Leslie M. Shaw, Enchi Liu, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gustavo Jimenez‐Maggiora, Danielle Harvey, 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 M. Foroud, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Zaven S. Khachaturian, 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 Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne Lord, 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, Maria Carroll, Sue Leon, Mark A. Mintun, Stacy Schneider, Angela Oliver, Randall Griffith, David Clark, David Geldmacher
Abstract
Abstract Alzheimer’s disease (AD) is defined by amyloid (A) and tau (T) pathologies, with T better correlated to neurodegeneration (N). However, T and N have complex regional relationships in part related to non-AD factors that influence N. With machine learning, we assessed heterogeneity in 18 F-flortaucipir vs. 18 F-fluorodeoxyglucose positron emission tomography as markers of T and neuronal hypometabolism (N M ) in 289 symptomatic patients from the Alzheimer’s Disease Neuroimaging Initiative. We identified six T/N M clusters with differing limbic and cortical patterns. The canonical group was defined as the T/N M pattern with lowest regression residuals. Groups resilient to T had less hypometabolism than expected relative to T and displayed better cognition than the canonical group. Groups susceptible to T had more hypometabolism than expected given T and exhibited worse cognitive decline, with imaging and clinical measures concordant with non-AD copathologies. Together, T/N M mismatch reveals distinct imaging signatures with pathobiological and prognostic implications for AD.