Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer’s disease

Nicolai Franzmeier, Emrah Düzel, Frank Jessen, Katharina Buerger, Johannes Levin, Marco Duering, Martin Dichgans, Christian Haass, Marc Suárez-Calvet, Anne M. Fagan, Katrina Paumier, Tammie Benzinger, Colin L. Masters, John C. Morris, Robert Perneczky, Daniel Janowitz, Cihan Catak, Steffen Wolfsgruber, Michael Wagner, Stefan TeipelIngo Kilimann, Alfredo Ramirez, Martin Rossor, Mathias Jucker, Jasmeer Chhatwal, Annika Spottke, Henning Boecker, Frederic Brosseron, Peter Falkai, Klaus Fliessbach, Michael T. Heneka, Christoph Laske, Peter Nestor, Oliver Peters, Manuel Fuentes, Felix Menne, Josef Priller, Eike J. Spruth, Christiana Franke, Anja Schneider, Barbara Kofler, Christine Westerteicher, Oliver Speck, Jens Wiltfang, Claudia Bartels, Miguel Ángel Araque Caballero, Coraline Metzger, Daniel Bittner, Michael Weiner, Jae Hong Lee, Stephen Salloway, Adrian Danek, Alison Goate, Peter R. Schofield, Randall J. Bateman, Michael Ewers

Research output: Contribution to journalArticlepeer-review

77 Scopus citations


Patients with Alzheimer’s disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms May support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer’s pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer’s disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer’s disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer’s disease, 55 controls from the Dominantly Inherited Alzheimer’s Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer’s disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer’s disease and cerebrospinal fluid tau levels in sporadic Alzheimer’s disease cases. In both autosomal dominant and sporadic Alzheimer’s disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer’s disease, a significant left frontal cortex connectivity estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer’s disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer’s disease is at least partially attributable to higher left frontal cortex-hub connectivity.

Original languageEnglish
Pages (from-to)1186-1200
Number of pages15
Issue number4
StatePublished - Apr 2018


  • Alzheimer’s disease
  • Cognitive reserve
  • Dementia biomarkers
  • Memory
  • Resting state connectivity


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