. Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer's disease. Sci Transl Med. 2025 Jan 22;17(782):eadp2564. Epub 2025 Jan 22 PubMed.

Recommends

Please login to recommend the paper.

Comments

  1. Roemer, Wagner, and Franzmeier conducted a comprehensive study that integrates some hypothesized pathophysiological concepts regarding the link between amyloid and tangle spread into a single model. Previous research has suggested that amyloid promotes hyperconnectivity, drives tau pathology, and that tau pathology progresses across connected brain regions/neurons. The novelty of this study lies in its integration of these concepts into a unified model by statically linking these processes. The replication of results in an independent cohort strengthens the conclusions.

    Another interesting aspect of this project is the group's intention to bridge their phenomenological findings with an interventional study. They are currently planning to repurpose drugs used in epilepsy to modulate neuronal excitability induced by amyloid and observe the effects on tau propagation. This is a very nice example of how we can rapidly translate observational study outcomes to clinical testing.

    View all comments by Tharick Pascoal
  2. This is a great paper. Its conclusions and implications are clear, making a brief comment challenging.

    As the authors state, their finding that "Aβ-associated neuronal activity and connectivity changes may be a key missing link between the accumulation of Aβ and the subsequent spreading of tau pathology in AD" converges with a lot of prior preclinical work, as well as with emerging human-based research, including a recent paper from our group (Giorgio et al., 2024). 

    The authors do a good job outlining some of the new therapeutic opportunities for this work. From my point of view, with high-precision neuroimaging (task and resting-state fMRI, plus Aβ and tau PET), we are looking at the very real possibility of staging individual patients and optimizing interventions for each, including anti-Aβ monoclonal antibodies but also lifestyle interventions.

    The authors mention anti-epileptic medications but there are also neuromodulatory therapeutics, such as targeted transcranial magnetic stimulation and ultrasound, that could be used to reduce the toxic burden on neurons of the Aβ-induced hyperexcitability and increased functional connectivity networks.

    I think there is strong consensus in the field that the new anti-Aβ antibodies are just the first in what will be combination therapies, adding neuromodulation, but also agents that protect neurons against hyper-phosphorylation of tau due to their hyper-excitability. Understanding the mechanisms of the amyloid cascade—as this paper helps to do—is key to this process.

    References:

    . Amyloid induced hyperexcitability in default mode network drives medial temporal hyperactivity and early tau accumulation. Neuron. 2024 Feb 21;112(4):676-686.e4. Epub 2023 Dec 13 PubMed.

    View all comments by Michael Breakspear
  3. This fascinating research highlights a critical element of AD pathophysiology that has been observed in multiple studies. It shows a link between Aβ deposition in heteromodal association cortices and hyperconnectivity between the medial temporal lobe and systems in the medial parietal and posterior temporal cortices. These same brain regions involved in the hyperconnectivity are selectively vulnerable to tau deposition.

    The findings align with the growing body of evidence supporting a cascading network failure model in AD, where early functional disruption in MTL-connected neocortical systems leads to spatially distant Aβ pathology. These same MTL-connected neocortical systems then accumulate large amounts of tau about 13.3 years later, in an accelerated failure time model. At this phase, measures of brain function, such as FDG-PET, can be used to fully synthesize and predict spatial patterns of tau deposition, as measured by tau-PET.

    A biological model that includes this global-network physiology allows for a clear description of the spatial and temporal discrepancies between amyloid and tangles. Others have emphasized amyloid-induced hyperexcitability as the key physiologic connection, but the relationship is bidirectional, and relevant network changes occur throughout the aging process and must logically precede plaque formation. This line of work underscores the importance of addressing network-level changes, not just molecular targets, in therapeutic development.

    From a clinical perspective, the implications are profound. Targeting functional physiology early in the disease process—potentially alongside protein-based therapies—could attenuate tau-associated neurodegeneration, preserve network integrity, and ultimately delay cognitive decline. Future longitudinal studies incorporating functional measures (e.g., neuropsychological testing, FDG-PET, fMRI, and/or electrophysiology) alongside molecular biomarkers could provide even more granular insights into the interplay between Aβ, large-scale functional brain physiology, clinical symptoms, and tau spatiotemporal dynamics.

    References:

    . Cascading network failure across the Alzheimer's disease spectrum. Brain. 2016 Feb;139(Pt 2):547-62. Epub 2015 Nov 19 PubMed.

    . Tau, amyloid, and cascading network failure across the Alzheimer's disease spectrum. Cortex. 2017 Dec;97:143-159. Epub 2017 Oct 3 PubMed.

    . A robust biomarker of large-scale network failure in Alzheimer's disease. Alzheimers Dement (Amst). 2017;6:152-161. Epub 2017 Jan 25 PubMed.

    . Default mode network failure and neurodegeneration across aging and amnestic and dysexecutive Alzheimer's disease. Brain Commun. 2023;5(2):fcad058. Epub 2023 Mar 8 PubMed.

    . Relationships between β-amyloid and tau in an elderly population: An accelerated failure time model. Neuroimage. 2021 Nov 15;242:118440. Epub 2021 Jul 29 PubMed.

    . Synthesizing images of tau pathology from cross-modal neuroimaging using deep learning. Brain. 2024 Mar 1;147(3):980-995. PubMed.

    . A computational model of neurodegeneration in Alzheimer's disease. Nat Commun. 2022 Mar 28;13(1):1643. PubMed.

    . Amyloid induced hyperexcitability in default mode network drives medial temporal hyperactivity and early tau accumulation. Neuron. 2024 Feb 21;112(4):676-686.e4. Epub 2023 Dec 13 PubMed.

    . Anterior-temporal network hyperconnectivity is key to Alzheimer's disease: from ageing to dementia. Brain. 2025 Jan 15; Epub 2025 Jan 15 PubMed.

    View all comments by David Jones

Make a Comment

To make a comment you must login or register.

This paper appears in the following:

News

  1. Plaques Spur Spread of Tangles by Sending Synapses into Overdrive