Resting-State Functional Connectivity Disruption as a Pathological Biomarker in Autosomal Dominant Alzheimer Disease

Robert X. Smith, Jeremy F. Strain, Aaron Tanenbaum, Anne M. Fagan, Jason Hassenstab, Eric McDade, Suzanne E. Schindler, Brian A. Gordon, Chengjie Xiong, Jasmeer Chhatwal, Clifford Jack, Celeste Karch, Sarah Berman, Jared R. Brosch, James J. Lah, Adam M. Brickman, David M. Cash, Nick C. Fox, Neill R. Graff-Radford, Johannes LevinJames Noble, David M. Holtzman, Colin L. Masters, Martin R. Farlow, Christoph Laske, Peter R. Schofield, Daniel S. Marcus, John C. Morris, Tammie L.S. Benzinger, Randall J. Bateman, Beau M. Ances

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Aim: Identify a global resting-state functional connectivity (gFC) signature in mutation carriers (MC) from the Dominantly Inherited Alzheimer Network (DIAN). Assess the gFC with regard to amyloid (A), tau (T), and neurodegeneration (N) biomarkers, and estimated years to symptom onset (EYO). Introduction: Cross-sectional measures were assessed in MC (n = 171) and mutation noncarrier (NC) (n = 70) participants. A functional connectivity (FC) matrix that encompassed multiple resting-state networks was computed for each participant. Methods: A global FC was compiled as a single index indicating FC strength. The gFC signature was modeled as a nonlinear function of EYO. The gFC was linearly associated with other biomarkers used for assessing the AT(N) framework, including cerebrospinal fluid (CSF), positron emission tomography (PET) molecular biomarkers, and structural magnetic resonance imaging. Results: The gFC was reduced in MC compared with NC participants. When MC participants were differentiated by clinical dementia rating (CDR), the gFC was significantly decreased in MC CDR >0 (demented) compared with either MC CDR 0 (cognitively normal) or NC participants. The gFC varied nonlinearly with EYO and initially decreased at EYO =-24 years, followed by a stable period followed by a further decline near EYO = 0 years. Irrespective of EYO, a lower gFC associated with values of amyloid PET, CSF Aβ1-42, CSF p-tau, CSF t-tau, 18F-fluorodeoxyglucose, and hippocampal volume. Conclusions: The gFC correlated with biomarkers used for defining the AT(N) framework. A biphasic change in the gFC suggested early changes associated with CSF amyloid and later changes associated with hippocampal volume.

Original languageEnglish
Pages (from-to)239-249
Number of pages11
JournalBrain connectivity
Issue number3
StatePublished - Apr 2021


  • 18F-fluorodeoxyglucose (FDG)
  • amyloid
  • autosomal dominant Alzheimer disease
  • cerebrospinal fluid (CSF)
  • estimated years to onset (EYO)
  • hippocampus
  • positron emission tomography (PET)
  • resting-state functional connectivity
  • tau


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