Alzheimer's disease (AD) is characterized by two hallmark molecular pathologies: amyloid aβ1-42, and Tau neurofibrillary tangles. To date, studies of functional connectivity MRI (fcMRI) in preclinical AD have relied on associations with in-vivo measures of amyloid pathology. With the recent advent of in-vivo Tau-PET tracers it is now possible to extend investigations on fcMRI in a sample of cognitively normal elderly humans to regional measures of Tau. We modeled fcMRI measures across four major cortical association networks (Default Mode (DMN), Salience, Dorsal Attention (DAN), and Frontoparietal Control (FPCN)) as a function of global cortical amyloid (PiB-PET) and regional Tau (AV1451-PET) in entorhinal, inferior temporal (IT), and inferior parietal (IP) cortex. Results showed that the interaction term between PiB and IT AV1451 was significantly associated with connectivity in the DMN and salience. The interaction revealed that amyloid positive (aβ+) individuals show increased connectivity in the DMN and salience when neocortical Tau levels are low, whereas aβ+ individuals demonstrate decreased connectivity in these networks as a function of elevated Tau-PET signal. This pattern suggests a hyper-connectivity phase followed by a hypo-connectivity phase in the course of preclinical AD.
Significance: This paper offers a first look at the relationship between Tau-PET imaging with F18-AV1451 and functional connectivity MRI (fcMRI) in the context of amyloid-PET imaging. The results suggest a non-linear relationship between fcMRI and both Tau-PET and amyloid-PET imaging. The pattern supports recent conjecture that the AD fcMRI trajectory is characterized by periods of both hyper- and hypo- connectivity. Furthermore, this nonlinear pattern can account for the sometimes conflicting reports of associations between amyloid and fcMRI in preclinical AD.
Potential Conflicts of Interest: A. Schultz has been a paid consultant for Janssen Pharmaceuticals and Biogen., E. Mormino received funding from NIH grant from NIH grant K01 AG051718. She has also served as a consultant for Biogen, and has received research support from Eli Lilly and Janssen Pharmaceuticals., B. Hanseeuw received support from the Belgian American Education Foundation (BAEF).,, T. Hedden received funding from NIH grants K01 AG040197, P01 AG036694, P50 AG005134, R01 AG053509, and R01 AG034556., J. Sepulcre received funding from HIH grant K23EB019023, R. Buckley received funding from the Australian National Health and Medical Research Council (NHMRC) and Australian Research Council (ARC) Dementia Research Fellowship APP1105576., K. Johnson has served as paid consultant for Bayer, GE Healthcare, Janssen Alzheimer's Immunotherapy, Siemens Medical Solutions, Genzyme, Novartis, Biogen, Roche, ISIS Pharma, AZTherapy, GEHC, Lundberg, and Abbvie. He is a site coinvestigator for Lilly/Avid, Pfizer, Janssen Immunotherapy, and Navidea. He has spoken at symposia sponsored by Janssen Alzheimer's Immunotherapy and Pfizer. K. Johnson receives funding from NIH grants R01EB014894, R21 AG038994, R01 AG026484, R01 AG034556, P50 AG00513421, U19 AG10483, P01 AG036694, R13 AG042201174210, R01 AG027435, and R01 AG037497 and the Alzheimer's Association grant ZEN-10-174210., R. Sperling has served as a paid consultant for Abbvie, Biogen, Bracket, Genentech, Lundbeck, Roche, and Sanofi. She has served as a co-investigator for Avid, Eli Lilly, and Janssen Alzheimer Immunotherapy clinical trials. She has spoken at symposia sponsored by Eli Lilly, Biogen, and Janssen. R. Sperling receives research support from Janssen Pharmaceuticals, and Eli Lilly and Co. These relationships are not related to the content in the manuscript. She also receives research support from the following grants: P01 AG036694, U01 AG032438, U01 AG024904, R01 AG037497, R01 AG034556, K24 AG035007, P50 AG005134, U19 AG010483, R01 AG027435, Fidelity Biosciences, Harvard NeuroDiscovery Center, and the Alzheimer's Association.
This work was supported in part by shared instrumentation grants and the Martinos Center for Biomedical Imaging: S10OD010364, S10RR023401, and 1S10RR019307-01. The research was supported in major part by the Harvard Aging Brain Study (P01 AG036694).