KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease
Julia Neitzel, Nicolai Franzmeier, Anna Rubinski, Martin Dichgans, Matthias Brendel, Alzheimer’s Disease Neuroimaging Initiative (ADNI), 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 C. Morris, Leslie M. Shaw, Enchi Liu, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, 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 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 Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven 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 B. 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, John C. Morris, Maria Carroll, Sue Leon, Mark A. Mintun, Stacy Schneider, Angela OliverNG, Randall Griffith, David Clark, David Geldmacher
Abstract
Abstract Klotho-VS heterozygosity (KL-VS het ) is associated with reduced risk of Alzheimer’s disease (AD). However, whether KL-VS het is associated with lower levels of pathologic tau, i.e., the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VS het and levels of beta-amyloid, a key driver of tau pathology, on the levels of PET-assessed neurofibrillary tau in 551 controls and patients across the AD continuum. KL-VS het showed lower cross-sectional and longitudinal increase in tau-PET per unit increase in amyloid-PET when compared to that of non-carriers. This association of KL-VS het on tau-PET was stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VS het was related to better memory functions in amyloid-positive participants and this association was mediated by lower tau-PET. Amyloid-PET levels did not differ between KL-VS het carriers versus non-carriers. Together, our findings provide evidence to suggest a protective role of KL-VS het against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia.