TY  - CONF
AU  - Roemer-Cassiano, Sebastian
AU  - Zhang, Shaoshi
AU  - Evangelista, Lisa
AU  - Dehsarvi, Amir
AU  - Klonowksi, Madleen
AU  - Frontzkowski, Lukas
AU  - Rauchmann, Boris-Stephan
AU  - Steward, Anna
AU  - Dewenter, Anna
AU  - Biel, Davina
AU  - Zhu, Zeyu
AU  - Hirsch, Fabian
AU  - Pescoller, Julia
AU  - Perneczky, Robert
AU  - Malpetti, Maura
AU  - Palleis, Carla
AU  - Gnoerich, Johannes
AU  - Schöll, Michael
AU  - Dichgans, Martin
AU  - Jäkel, Sarah
AU  - Höglinger, Günter U
AU  - Brendel, Matthias
AU  - Yeo, Thomas
AU  - Franzmeier, Nicolai
TI  - Amyloid‐induced neuronal hyperactivity and ‐metabolism are associated with faster tau accumulation in Alzheimer's Disease
JO  - Alzheimer's and dementia
VL  - 21
IS  - Suppl 2
SN  - 1552-5260
M1  - DZNE-2025-01470
SP  - e099685
PY  - 2025
AB  - 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
T2  - Alzheimer’s Association International Conference
CY  - 27 Jul 2025 - 31 Jul 2025, Toronto (Canada)
Y2  - 27 Jul 2025 - 31 Jul 2025
M2  - Toronto, Canada
KW  - Humans
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: diagnostic imaging
KW  - Alzheimer Disease: pathology
KW  - Positron-Emission Tomography
KW  - Female
KW  - Male
KW  - Biomarkers: metabolism
KW  - Magnetic Resonance Imaging
KW  - Aged
KW  - tau Proteins: metabolism
KW  - Amyloid beta-Peptides: metabolism
KW  - Brain: metabolism
KW  - Brain: diagnostic imaging
KW  - Brain: pathology
KW  - Fluorodeoxyglucose F18
KW  - Neurons: metabolism
KW  - Aged, 80 and over
KW  - Biomarkers (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Fluorodeoxyglucose F18 (NLM Chemicals)
LB  - PUB:(DE-HGF)1 ; PUB:(DE-HGF)16
C6  - pmid:41445344
C2  - pmc:PMC12739343
DO  - DOI:10.1002/alz70856_099685
UR  - https://pub.dzne.de/record/283063
ER  -