Brain network decoupling with increased serum neurofilament and reduced cognitive function in Alzheimer’s disease
Muriah D. Wheelock, Jeremy F. Strain, Patricia K. Mansfield, Jiaxin Cindy Tu, Aaron Tanenbaum, Oliver Preische, Jasmeer P. Chhatwal, David M. Cash, Carlos Cruchaga, Anne M. Fagan, Nick C. Fox, Neill R. Graff‐Radford, Jason Hassenstab, Clifford R. Jack, Celeste M. Karch, Johannes Levin, Eric McDade, Richard J. Perrin, Peter R. Schofield, Chengjie Xiong, John C. Morris, Randall J. Bateman, Mathias Jucker, Tammie L.S. Benzinger, Beau M. Ances, Adam T. Eggebrecht, Brian A. Gordon, the Dominantly Inherited Alzheimer Network, Sarah Adams, Ricardo Allegri, Aki Araki, Nicolas R. Barthélemy, Randall J. Bateman, Jacob Bechara, Tammie L.S. Benzinger, Sarah Berman, Courtney Bodge, Susan E. Brandon, W. K. Brooks, Jared R. Brosch, Jill Buck, Virginia Buckles, Kathleen Carter, David M. Cash, Lisa Cash, Charlie Chen, Jasmeer P. Chhatwal, Patricio Chrem, Jasmin Chua, Helena Chui, Carlos Cruchaga, Gregory S. Day, Chrismary De La Cruz, Darcy Denner, Anna Diffenbacher, Aylin Dincer, Tamara Donahue, J. Maxwell Douglas, Duc M. Duong, Noelia Egido, Bianca Esposito, Anne M. Fagan, Marty Farlow, Becca Feldman, Colleen Fitzpatrick, Shaney Flores, Nick C. Fox, Erin Franklin, Nelly Friedrichsen, Hisako Fujii, Samantha L. Gardener, Bernardino Ghetti, Alison Goate, Sarah B. Goldberg, Jill Goldman, Alyssa Gonzalez, Brian A. Gordon, Susanne Gräber‐Sultan, Neill R. Graff‐Radford, Morgan Graham, Julia Gray, Emily Gremminger, Miguel L. Grilo, Alex Groves, Christian Haass, Lisa M. Häsler, Jason Hassenstab, Cortaiga Hellm, Elizabeth Herries, Laura Hoechst-Swisher, Anna Hofmann, David M. Holtzman, Russ C. Hornbeck, Yakushev Igor, Ryoko Ihara, Takeshi Ikeuchi, Snežana Ikonomović, Kenji Ishii, Clifford R. Jack, Gina Jerome
Abstract
Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer's disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer's disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer's disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer's disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer's disease.