Between-networks hyperconnectivity is induced by beta-amyloid and may facilitate tau spread

Alzheimer’s disease (AD) is characterized by the buildup of neurofibrillary tau tangles and beta-amyloid (Aβ) plaques. While it has been hypothesized that Aβ facilitates the spread of tau outside of the medial temporal lobe (MTL), the specific pathological processes and mechanisms by which this occurs remain poorly understood. Our study employed advanced neuroimaging techniques, integrating 18F-Florbetaben Aβ and 18F-MK6240 tau positron emission tomography (PET) with resting-state functional magnetic resonance imaging (rs-fMRI) to characterize these mechanisms in two distinct datasets, that included 481 healthy elderly subjects, 46 of whom came with longitudinal data. Our research highlighted an intricate internetwork relationship between Aβ and tau accumulation, across spatially distinct functional networks. Additionally, we observed compelling evidence supporting the existence of a compensatory mechanism triggered by Aβ accumulation, resulting in hyperconnectivity between functional networks. Finally, the longitudinal findings indicate that between-networks hyperconnectivity is associated with future tau elevation and mediates the relationship between cortical Aβ and early-stage tau. Understanding this early brain alteration in response to the accumulation of Aβ could guide treatments early in the disease course and potentially prevent future tau accumulation. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Our data and any subsequent studies derived from it have undergone thorough ethical approval through the processes of two Institutional Review Boards (IRBs), located at Columbia University Irving Medical Center and Weill Cornell Medicine. These regulatory bodies play a crucial role in ensuring the integrity of our research by safeguarding the rights, well-being, and confidentiality of research participants. The approval from IRBs signifies that our research design, methodology, and associated procedures adhere to stringent ethical standards and regulatory guidelines. This comprehensive review process assures that our research is conducted with the utmost consideration for ethical principles, addressing critical factors such as participant consent, data confidentiality, and the overall welfare of individuals involved in the study. This approval underscores our commitment to ethical research practices and reinforces the credibility and reliability of our data and subsequent studies. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors