%0 Conference Paper
%A Roemer-Cassiano, Sebastian
%A Zhang, Shaoshi
%A Evangelista, Lisa
%A Dehsarvi, Amir
%A Klonowksi, Madleen
%A Frontzkowski, Lukas
%A Rauchmann, Boris-Stephan
%A Steward, Anna
%A Dewenter, Anna
%A Biel, Davina
%A Zhu, Zeyu
%A Hirsch, Fabian
%A Pescoller, Julia
%A Perneczky, Robert
%A Malpetti, Maura
%A Palleis, Carla
%A Gnoerich, Johannes
%A Schöll, Michael
%A Dichgans, Martin
%A Jäkel, Sarah
%A Höglinger, Günter U
%A Brendel, Matthias
%A Yeo, Thomas
%A Franzmeier, Nicolai
%T Amyloid‐induced neuronal hyperactivity and ‐metabolism are associated with faster tau accumulation in Alzheimer's Disease
%J Alzheimer's and dementia
%V 21
%N Suppl 2
%@ 1552-5260
%M DZNE-2025-01470
%P e099685
%D 2025
%X The 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
%B Alzheimer’s Association International Conference
%C 27 Jul 2025 - 31 Jul 2025, Toronto (Canada)
Y2 27 Jul 2025 - 31 Jul 2025
M2 Toronto, Canada
%K Humans
%K Alzheimer Disease: metabolism
%K Alzheimer Disease: diagnostic imaging
%K Alzheimer Disease: pathology
%K Positron-Emission Tomography
%K Female
%K Male
%K Biomarkers: metabolism
%K Magnetic Resonance Imaging
%K Aged
%K tau Proteins: metabolism
%K Amyloid beta-Peptides: metabolism
%K Brain: metabolism
%K Brain: diagnostic imaging
%K Brain: pathology
%K Fluorodeoxyglucose F18
%K Neurons: metabolism
%K Aged, 80 and over
%K Biomarkers (NLM Chemicals)
%K tau Proteins (NLM Chemicals)
%K Amyloid beta-Peptides (NLM Chemicals)
%K Fluorodeoxyglucose F18 (NLM Chemicals)
%F PUB:(DE-HGF)1 ; PUB:(DE-HGF)16
%9 AbstractJournal Article
%$ pmid:41445344
%2 pmc:PMC12739343
%R 10.1002/alz70856_099685
%U https://pub.dzne.de/record/283063