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| 001 | 283063 | ||
| 005 | 20251230103620.0 | ||
| 024 | 7 | _ | |a 10.1002/alz70856_099685 |2 doi |
| 024 | 7 | _ | |a pmid:41445344 |2 pmid |
| 024 | 7 | _ | |a pmc:PMC12739343 |2 pmc |
| 024 | 7 | _ | |a 1552-5260 |2 ISSN |
| 024 | 7 | _ | |a 1552-5279 |2 ISSN |
| 037 | _ | _ | |a DZNE-2025-01470 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Roemer-Cassiano, Sebastian |b 0 |
| 111 | 2 | _ | |a Alzheimer’s Association International Conference |g AAIC 25 |c Toronto |d 2025-07-27 - 2025-07-31 |w Canada |
| 245 | _ | _ | |a Amyloid‐induced neuronal hyperactivity and ‐metabolism are associated with faster tau accumulation in Alzheimer's Disease |
| 260 | _ | _ | |c 2025 |
| 336 | 7 | _ | |a Abstract |b abstract |m abstract |0 PUB:(DE-HGF)1 |s 1767013451_31206 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a Conference Paper |0 33 |2 EndNote |
| 336 | 7 | _ | |a INPROCEEDINGS |2 BibTeX |
| 336 | 7 | _ | |a conferenceObject |2 DRIVER |
| 336 | 7 | _ | |a Journal Article |0 PUB:(DE-HGF)16 |2 PUB:(DE-HGF) |m journal |
| 336 | 7 | _ | |a Output Types/Conference Abstract |2 DataCite |
| 336 | 7 | _ | |a OTHER |2 ORCID |
| 520 | _ | _ | |a 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% 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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| 650 | _ | 7 | |a Biomarkers |2 NLM Chemicals |
| 650 | _ | 7 | |a tau Proteins |2 NLM Chemicals |
| 650 | _ | 7 | |a Amyloid beta-Peptides |2 NLM Chemicals |
| 650 | _ | 7 | |a Fluorodeoxyglucose F18 |0 0Z5B2CJX4D |2 NLM Chemicals |
| 650 | _ | 2 | |a Humans |2 MeSH |
| 650 | _ | 2 | |a Alzheimer Disease: metabolism |2 MeSH |
| 650 | _ | 2 | |a Alzheimer Disease: diagnostic imaging |2 MeSH |
| 650 | _ | 2 | |a Alzheimer Disease: pathology |2 MeSH |
| 650 | _ | 2 | |a Positron-Emission Tomography |2 MeSH |
| 650 | _ | 2 | |a Female |2 MeSH |
| 650 | _ | 2 | |a Male |2 MeSH |
| 650 | _ | 2 | |a Biomarkers: metabolism |2 MeSH |
| 650 | _ | 2 | |a Magnetic Resonance Imaging |2 MeSH |
| 650 | _ | 2 | |a Aged |2 MeSH |
| 650 | _ | 2 | |a tau Proteins: metabolism |2 MeSH |
| 650 | _ | 2 | |a Amyloid beta-Peptides: metabolism |2 MeSH |
| 650 | _ | 2 | |a Brain: metabolism |2 MeSH |
| 650 | _ | 2 | |a Brain: diagnostic imaging |2 MeSH |
| 650 | _ | 2 | |a Brain: pathology |2 MeSH |
| 650 | _ | 2 | |a Fluorodeoxyglucose F18 |2 MeSH |
| 650 | _ | 2 | |a Neurons: metabolism |2 MeSH |
| 650 | _ | 2 | |a Aged, 80 and over |2 MeSH |
| 700 | 1 | _ | |a Zhang, Shaoshi |b 1 |
| 700 | 1 | _ | |a Evangelista, Lisa |b 2 |
| 700 | 1 | _ | |a Dehsarvi, Amir |b 3 |
| 700 | 1 | _ | |a Klonowksi, Madleen |b 4 |
| 700 | 1 | _ | |a Frontzkowski, Lukas |b 5 |
| 700 | 1 | _ | |a Rauchmann, Boris-Stephan |0 P:(DE-2719)9001808 |b 6 |u dzne |
| 700 | 1 | _ | |a Steward, Anna |b 7 |
| 700 | 1 | _ | |a Dewenter, Anna |b 8 |
| 700 | 1 | _ | |a Biel, Davina |b 9 |
| 700 | 1 | _ | |a Zhu, Zeyu |b 10 |
| 700 | 1 | _ | |a Hirsch, Fabian |b 11 |
| 700 | 1 | _ | |a Pescoller, Julia |b 12 |
| 700 | 1 | _ | |a Perneczky, Robert |0 P:(DE-2719)2812234 |b 13 |u dzne |
| 700 | 1 | _ | |a Malpetti, Maura |b 14 |
| 700 | 1 | _ | |a Palleis, Carla |0 P:(DE-2719)9000852 |b 15 |u dzne |
| 700 | 1 | _ | |a Gnoerich, Johannes |0 P:(DE-2719)9001652 |b 16 |u dzne |
| 700 | 1 | _ | |a Schöll, Michael |b 17 |
| 700 | 1 | _ | |a Dichgans, Martin |0 P:(DE-2719)2000030 |b 18 |u dzne |
| 700 | 1 | _ | |a Jäkel, Sarah |b 19 |
| 700 | 1 | _ | |a Höglinger, Günter U |0 P:(DE-2719)2811373 |b 20 |u dzne |
| 700 | 1 | _ | |a Brendel, Matthias |0 P:(DE-2719)9001539 |b 21 |u dzne |
| 700 | 1 | _ | |a Yeo, Thomas |b 22 |
| 700 | 1 | _ | |a Franzmeier, Nicolai |b 23 |
| 773 | _ | _ | |a 10.1002/alz70856_099685 |g Vol. 21 Suppl 2, no. Suppl 2, p. e099685 |0 PERI:(DE-600)2201940-6 |n Suppl 2 |p e099685 |t Alzheimer's and dementia |v 21 |y 2025 |x 1552-5260 |
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