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000283063 1001_ $$aRoemer-Cassiano, Sebastian$$b0
000283063 1112_ $$aAlzheimer’s Association International Conference$$cToronto$$d2025-07-27 - 2025-07-31$$gAAIC 25$$wCanada
000283063 245__ $$aAmyloid‐induced neuronal hyperactivity and ‐metabolism are associated with faster tau accumulation in Alzheimer's Disease
000283063 260__ $$c2025
000283063 3367_ $$0PUB:(DE-HGF)1$$2PUB:(DE-HGF)$$aAbstract$$babstract$$mabstract$$s1767013451_31206
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000283063 520__ $$aThe link between amyloid (Aβ) and tau accumulation in Alzheimer's disease (AD) is still unknown, hindering therapeutic efforts to attenuate the Aβ-tau axis. Preclinical studies demonstrated that Aβ promotes hyperexcitatory neuronal activity and that tau spreads trans-synaptically in an activity-dependent manner. We recently showed that tau spreads across connected brain regions, and that Aβ-related connectivity increases promote tau spreading (Roemer-Cassiano et al., 2024). Yet, it is unclear whether Aβ-related hyperconnectivity indeed represents hyperexcitatory neuronal activity. To test this, we combined resting-state fMRI, FDG-PET and post-mortem data, to determine whether Aβ promotes neuronal hyperactivity, thereby driving tau spread in AD.We first assessed the effect Aβ on neuronal hyperactivity with a novel algorithm to estimate the excitatory to inhibitory (E/I) ratio applied to resting-state fMRI in 145 amyloid-negative controls and 441 amyloid-positive subjects across the AD spectrum, who also underwent amyloid-PET. Second, we used glucose metabolism (FDG-PET) as a marker of neuronal activity in 638 amyloid-positive AD spectrum patients, with a subset (n = 215) of them having tau-PET at a later timepoint. Lastly, we analysed post-mortem data of 5 AD patients and 4 controls stained for c-Fos as a marker of ante-mortem neuronal activity.Resting-state fMRI-based E/I-ratio assessment in Aβ- controls showed biologically plausible stronger inhibition in association cortices (Figure 1A). In AD, we found an association between higher amyloid-PET SUVRs and a higher E/I ratio, consistent across diagnostic groups (Figure 1B-D), indicative of Aβ-associated hyperexcitatory neuronal activity. Second, we found within individuals, that higher regional amyloid-PET was linked to higher FDG-PET (correlationamyloid-PET vs. FDG-PET: 95% CI [0.37,0.40] p-value <0.001), suggesting higher neuronal activity in Aβ-harbouring regions (Figure 2A). Similarly, we found post-mortem elevated neuronal c-Fos expression in AD brain tissue vs. controls, indicating higher ante-mortem neuronal activity (Figure 3G). Finally, we found that amyloid-PET-based prediction of subject-level future tau accumulation is improved when including regional FDG-PET (Figure 2B) and that FDG-PET-assessed hypermetabolism mediates subject-level effects of Aβ on subsequent tau accumulation (Figure 2C).Aβ promotes an hyper-excitatory shift in neuronal activity that manifests in glucose hypermetabolism which promotes Aβ-related tau accumulation. Thus, Aβ-associated neuronal hyper-excitability is a potential target for attenuating the Ab-tau axis in AD.
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000283063 650_7 $$2NLM Chemicals$$aBiomarkers
000283063 650_7 $$2NLM Chemicals$$atau Proteins
000283063 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000283063 650_7 $$00Z5B2CJX4D$$2NLM Chemicals$$aFluorodeoxyglucose F18
000283063 650_2 $$2MeSH$$aHumans
000283063 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000283063 650_2 $$2MeSH$$aAlzheimer Disease: diagnostic imaging
000283063 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000283063 650_2 $$2MeSH$$aPositron-Emission Tomography
000283063 650_2 $$2MeSH$$aFemale
000283063 650_2 $$2MeSH$$aMale
000283063 650_2 $$2MeSH$$aBiomarkers: metabolism
000283063 650_2 $$2MeSH$$aMagnetic Resonance Imaging
000283063 650_2 $$2MeSH$$aAged
000283063 650_2 $$2MeSH$$atau Proteins: metabolism
000283063 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000283063 650_2 $$2MeSH$$aBrain: metabolism
000283063 650_2 $$2MeSH$$aBrain: diagnostic imaging
000283063 650_2 $$2MeSH$$aBrain: pathology
000283063 650_2 $$2MeSH$$aFluorodeoxyglucose F18
000283063 650_2 $$2MeSH$$aNeurons: metabolism
000283063 650_2 $$2MeSH$$aAged, 80 and over
000283063 7001_ $$aZhang, Shaoshi$$b1
000283063 7001_ $$aEvangelista, Lisa$$b2
000283063 7001_ $$aDehsarvi, Amir$$b3
000283063 7001_ $$aKlonowksi, Madleen$$b4
000283063 7001_ $$aFrontzkowski, Lukas$$b5
000283063 7001_ $$0P:(DE-2719)9001808$$aRauchmann, Boris-Stephan$$b6$$udzne
000283063 7001_ $$aSteward, Anna$$b7
000283063 7001_ $$aDewenter, Anna$$b8
000283063 7001_ $$aBiel, Davina$$b9
000283063 7001_ $$aZhu, Zeyu$$b10
000283063 7001_ $$aHirsch, Fabian$$b11
000283063 7001_ $$aPescoller, Julia$$b12
000283063 7001_ $$0P:(DE-2719)2812234$$aPerneczky, Robert$$b13$$udzne
000283063 7001_ $$aMalpetti, Maura$$b14
000283063 7001_ $$0P:(DE-2719)9000852$$aPalleis, Carla$$b15$$udzne
000283063 7001_ $$0P:(DE-2719)9001652$$aGnoerich, Johannes$$b16$$udzne
000283063 7001_ $$aSchöll, Michael$$b17
000283063 7001_ $$0P:(DE-2719)2000030$$aDichgans, Martin$$b18$$udzne
000283063 7001_ $$aJäkel, Sarah$$b19
000283063 7001_ $$0P:(DE-2719)2811373$$aHöglinger, Günter U$$b20$$udzne
000283063 7001_ $$0P:(DE-2719)9001539$$aBrendel, Matthias$$b21$$udzne
000283063 7001_ $$aYeo, Thomas$$b22
000283063 7001_ $$aFranzmeier, Nicolai$$b23
000283063 773__ $$0PERI:(DE-600)2201940-6$$a10.1002/alz70856_099685$$gVol. 21 Suppl 2, no. Suppl 2, p. e099685$$nSuppl 2$$pe099685$$tAlzheimer's and dementia$$v21$$x1552-5260$$y2025
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