Plaques Spur Spread of Tangles by Sending Synapses into Overdrive
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Scientists consider Alzheimer’s disease to be a secondary tauopathy induced by amyloid plaques. Given that Aβ and tau start aggregating in different regions of the brain, how does one set off the other? Combining functional MRI, Aβ-PET, and tau-PET, scientists led by Nicolai Franzmeier, Ludwig-Maximilians University in Munich, found that amyloid intensifies connectivity between tangle epicenters in the medial temporal lobe and areas in the cortex that are destined to fall prey to these fibrils later. The stronger these connections, the more tau accumulates. Their findings, reported in the January 22 Science Translational Medicine, cast neuronal hyperactivity as a critical link between Aβ and tau pathologies, and suggests that calming amyloid-rattled neurons might stem the tide of tangles.
- Amyloid amps up connectivity between brain regions.
- Cortical regions with strongest connectivity to tangle epicenters in medial temporal lobe accumulated tau fibrils fastest.
- Becalming those connections might slow the spread of tangles.
“Previous research has suggested that amyloid promotes hyperconnectivity, drives tau pathology, and that tau pathology progresses across connected brain regions/neurons,” commented Tharick Pascoal of the University of Pittsburg in Pennsylvania. “The novelty of this study lies in its integration of these concepts into a unified model by statistically linking these processes.”
The study dovetails with numerous others in the field. For example, researchers have long known that amyloid boosts neuronal activity, and that hyperactive neurons release more hyperphosphorylated tau (Feb 2014 news; Jun 2016 news; Rodriguez et al., 2020). Upticks in epileptic seizures and sub-epileptic spikes in people with AD are another indication that neuronal circuits go haywire. More recently, scientists found that Aβ-riled neurons in the default mode network coaxed tangle-laden neurons in the medial temporal lobe to spread their proteopathic seeds (Dec 2023 news). Missing from these prior studies is how amyloid skews connectivity between brain regions, and how that might steer the spread of tau pathology.
To investigate if amyloid-induced changes in neural circuitry might push tangles beyond the entorhinal cortex, co-first authors Sebastian Roemer and Fabian Wagner and colleagues integrated different types of neuroimaging data from the Alzheimer’s Disease Neuroimaging Network (ADNI). Specifically, they looked at resting-state functional MRI, Aβ-PET, and tau-PET scans from 69 cognitively normal controls who had amyloid in their brain, and 140 amyloid-positive people who spanned the AD clinical spectrum. First, they asked if regional amyloid accumulation relates to how strongly regions with highest levels of tangles connect with other areas of the brain. These “tau epicenters” were determined individually for each volunteer. These tangle hotbeds most commonly lay in the inferior temporal lobe; based on resting-state fMRI, they strongly connected to posterior areas of the brain.
The scientists used amyloid PET scans to take stock of plaque burden in each tau epicenter, as well as in cortical regions connected to it. In short, they found that higher Aβ load correlated with stronger connectivity between the tau epicenters and posterior regions that typically accumulate tau in the early stages of AD. This suggests that amyloid dials up connectivity between those regions early in the disease, which, in turn, might kick-start the spread of the pathology.
The scientists replicated their findings in a preclinical cohort, using baseline neuroimaging data from the A4 study. These volunteers have amyloid, and in many cases, tau pathology, but are cognitively normal at baseline. Here, too, tangle epicenters in the inferior temporal lobe tightly connected with posterior regions known to accumulate tau in the early stages of AD.
Does how strongly connected a tau epicenter is predict how fast tangles will accumulate? Yes, according to longitudinal tau-PET scans from the ADNI cohort. Particularly for temporo-parietal, occipital, and superior frontal brain regions, the stronger their connectivity with a tau epicenter, the faster tangles accumulated there. Notably, many of these regions also displayed amyloid-related hyperconnectivity.
So far, the neuroimaging data suggested strong correlations among amyloid pathology, tau epicenter hyperconnectivity, and the subsequent spread of tau pathology to connected regions. To go beyond these correlations and infer causal relationships, the scientists ran a mediation analysis. Using this computational technique, the scientists asked to what extent hyperconnectivity explains the relationship between Aβ plaques and tau tangle spread. This statistical modeling suggested that amyloid-dependent hyperconnectivity between a tau epicenter and a given region sped up tau pathology in the latter. In other words, hyperconnectivity mediated at least some of the relationship between Aβ pathology and tau tangle spread (image below).
The Amyloid—Tangle Connection. Aβ aggregates (green) hyper-excite neurons in tau epicenters and connected regions, strengthening that connectivity. This pushes tau propagation from one region to another, explaining up to 25 percent of tangle accumulation in posterior cortex (right). [Courtesy of Roemer et al., Science Translational Medicine, 2025.]
“Taken together, these results favor a pathophysiological disease model in which regional Aβ induces stronger functional connectivity to the tau epicenter, which in turn facilitates the spreading of tau from the epicenters to connected brain regions,” the authors wrote.
This is consistent with the idea that hyperactivated neurons actively secrete hyperphosphorylated tau, which can be readily taken up within the synaptic cleft by connected neurons (Mar 2018 news). Franzmeier thinks p-tau in CSF directly reflects this process.
He predicts that dialing down this amyloid-induced hyperactivity might nip tau spread in the bud. Low doses of anti-epileptic drugs, such as levetiracetam or AGB101, are being tested in clinical trials, thus far to no avail. Yet, Franzmeier noted that volunteers in most of these studies already had mild cognitive impairment or dementia, suggesting that tau tangles had already run amok. He proposes comparing other anti-epileptic drugs in people with preclinical AD. Using p-tau as a proxy for squelching Aβ-induced hyperactivity, these early phase studies could run in mere weeks, instead of months or years, he said.
Michael Breakspear of Newcastle University in Sydney noted that other therapeutic strategies, such as targeted transcranial magnetic stimulation, might tame hyperexcited neurons, as well.
“This line of work underscores the importance of addressing network-level changes, not just molecular targets, in therapeutic development,” wrote David Jones of the Mayo Clinic in Rochester, Minnesota. “From a clinical perspective, the implications are profound,” Jones added. “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.” Comments below.—Jessica Shugart
References
News Citations
- Neurons Release Tau in Response to Excitation
- Excited Neurons Release More Aberrant Tau
- Plaques Kick Neocortical Neurons into Overdrive, Entangling Tau
- Isotope Labeling Links Tau Production to Aβ Burden
Therapeutics Citations
Paper Citations
- Rodriguez GA, Barrett GM, Duff KE, Hussaini SA. Chemogenetic attenuation of neuronal activity in the entorhinal cortex reduces Aβ and tau pathology in the hippocampus. PLoS Biol. 2020 Aug;18(8):e3000851. Epub 2020 Aug 21 PubMed.
Further Reading
Primary Papers
- Roemer-Cassiano SN, Wagner F, Evangelista L, Rauchmann BS, Dehsarvi A, Steward A, Dewenter A, Biel D, Zhu Z, Pescoller J, Gross M, Perneczky R, Malpetti M, Ewers M, Schöll M, Dichgans M, Höglinger GU, Brendel M, Jäkel S, Franzmeier N. 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.
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Comments
University of Pittsburgh
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.
University of Newcastle
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:
Giorgio J, Adams JN, Maass A, Jagust WJ, Breakspear M. 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.
Mayo Clinic
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:
Jones DT, Knopman DS, Gunter JL, Graff-Radford J, Vemuri P, Boeve BF, Petersen RC, Weiner MW, Jack CR Jr, Alzheimer’s Disease Neuroimaging Initiative. Cascading network failure across the Alzheimer's disease spectrum. Brain. 2016 Feb;139(Pt 2):547-62. Epub 2015 Nov 19 PubMed.
Jones DT, Graff-Radford J, Lowe VJ, Wiste HJ, Gunter JL, Senjem ML, Botha H, Kantarci K, Boeve BF, Knopman DS, Petersen RC, Jack CR Jr. Tau, amyloid, and cascading network failure across the Alzheimer's disease spectrum. Cortex. 2017 Dec;97:143-159. Epub 2017 Oct 3 PubMed.
Wiepert DA, Lowe VJ, Knopman DS, Boeve BF, Graff-Radford J, Petersen RC, Jack CR Jr, Jones DT. A robust biomarker of large-scale network failure in Alzheimer's disease. Alzheimers Dement (Amst). 2017;6:152-161. Epub 2017 Jan 25 PubMed.
Corriveau-Lecavalier N, Gunter JL, Kamykowski M, Dicks E, Botha H, Kremers WK, Graff-Radford J, Wiepert DA, Schwarz CG, Yacoub E, Knopman DS, Boeve BF, Ugurbil K, Petersen RC, Jack CR, Terpstra MJ, Jones DT. 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.
Therneau TM, Knopman DS, Lowe VJ, Botha H, Graff-Radford J, Jones DT, Vemuri P, Mielke MM, Schwarz CG, Senjem ML, Gunter JL, Petersen RC, Jack CR Jr. 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.
Lee J, Burkett BJ, Min HK, Senjem ML, Dicks E, Corriveau-Lecavalier N, Mester CT, Wiste HJ, Lundt ES, Murray ME, Nguyen AT, Reichard RR, Botha H, Graff-Radford J, Barnard LR, Gunter JL, Schwarz CG, Kantarci K, Knopman DS, Boeve BF, Lowe VJ, Petersen RC, Jack CR Jr, Jones DT. Synthesizing images of tau pathology from cross-modal neuroimaging using deep learning. Brain. 2024 Mar 1;147(3):980-995. PubMed.
Jones D, Lowe V, Graff-Radford J, Botha H, Barnard L, Wiepert D, Murphy MC, Murray M, Senjem M, Gunter J, Wiste H, Boeve B, Knopman D, Petersen R, Jack C. A computational model of neurodegeneration in Alzheimer's disease. Nat Commun. 2022 Mar 28;13(1):1643. PubMed.
Giorgio J, Adams JN, Maass A, Jagust WJ, Breakspear M. 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.
Chauveau L, Landeau B, Dautricourt S, Turpin AL, Delarue M, Hébert O, de La Sayette V, Chételat G, de Flores R. Anterior-temporal network hyperconnectivity is key to Alzheimer's disease: from ageing to dementia. Brain. 2025 Jan 15; Epub 2025 Jan 15 PubMed.
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