Brain network decoupling with increased serum neurofilament and reduced cognitive function in Alzheimer’s disease
Authors: Wheelock Muriah D , Strain Jeremy F , Mansfield Patricia , Tu Jiaxin Cindy , Tanenbaum Aaron , Preische Oliver , Chhatwal Jasmeer P , Cash David M , Cruchaga Carlos , Fagan Anne M , Fox Nick C , Graff-Radford Neill R , Hassenstab Jason , Jack Clifford R , Karch Celeste M , Levin Johannes , McDade Eric M , Perrin Richard J , Schofield Peter R , Xiong Chengjie , Morris John C , Bateman Randal J , Jucker Mathias , Benzinger Tammie L S , Ances Beau M , Eggebrecht Adam T , Gordon Brian A ,   the Dominantly Inherited Alzheimer Network, Adams Sarah , Allegri Ricardo , Araki Aki , Barthelemy Nicolas , Bateman Randall , Bechara Jacob , Benzinger Tammie , Berman Sarah , Bodge Courtney , Brandon Susan , Brooks William (Bill) , Brosch Jared , Buck Jill , Buckles Virginia , Carter Kathleen , Cash Dave , Cash Lisa , Chen Charlie , Chhatwal Jasmeer , Chrem Patricio , Chua Jasmin , Chui Helena , Cruchaga Carlos , Day Gregory S , De La Cruz Chrismary , Denner Darcy , Diffenbacher Anna , Dincer Aylin , Donahue Tamara , Douglas Jane , Duong Duc , Egido Noelia , Esposito Bianca , Fagan Anne , Farlow Marty , Feldman Becca , Fitzpatrick Colleen , Flores Shaney , Fox Nick , Franklin Erin , Friedrichsen Nelly , Fujii Hisako , Gardener Samantha , Ghetti Bernardino , Goate Alison , Goldberg Sarah , Goldman Jill , Gonzalez Alyssa , Gordon Brian , Gräber-Sultan Susanne , Graff-Radford Neill , Graham Morgan , Gray Julia , Gremminger Emily , Grilo Miguel , Groves Alex , Haass Christian , Häsler Lisa , Hassenstab Jason , Hellm Cortaiga , Herries Elizabeth , Hoechst-Swisher Laura , Hofmann Anna , Holtzman David , Hornbeck Russ , Igor Yakushev , Ihara Ryoko , Ikeuchi Takeshi , Ikonomovic Snezana , Ishii Kenji , Jack Clifford , Jerome Gina , Johnson Erik , Jucker Mathias , Karch Celeste , Käser Stephan , Kasuga Kensaku , Keefe Sarah , Klunk William (Bill) , Koeppe Robert , Koudelis Deb , Kuder-Buletta Elke , Laske Christoph , Lee Jae-Hong , Levey Allan , Levin Johannes , Li Yan , Lopez Oscar , Marsh Jacob , Martinez Rita , Martins Ralph , Mason Neal Scott , Masters Colin , Mawuenyega Kwasi , McCullough Austin , McDade Eric , Mejia Arlene , Morenas-Rodriguez Estrella , Mori Hiroshi , Morris John , Mountz James , Mummery Cath , Nadkami Neelesh , Nagamatsu Akemi , Neimeyer Katie , Niimi Yoshiki , Noble James , Norton Joanne , Nuscher Brigitte , O’Connor Antoinette , Obermüller Ulricke , Patira Riddhi , Perrin Richard , Ping Lingyan , Preische Oliver , Renton Alan , Ringman John , Salloway Stephen , Sanchez-Valle Raquel , Schofield Peter , Senda Michio , Seyfried Nick , Shady Kristine , Shimada Hiroyuki , Sigurdson Wendy , Smith Jennifer , Smith Lori , Snitz Beth , Sohrabi Hamid , Stephens Sochenda , Taddei Kevin , Thompson Sarah , Vöglein Jonathan , Wang Peter , Wang Qing , Weamer Elise , Xiong Chengjie , Xu Jinbin , Xu Xiong 
Published: January 2023

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.