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| Item Type: | Preprint |
|---|---|
| Title: | Disrupted forward connectivity in parieto-temporal network impairs memory performance in alzheimer's disease |
| Creators Name: | Suksangkharn, Y., Schott, B.H., Zeidman, P., Vockert, N., Lattmann, R., Schütze, H., Yakupov, R., Peters, O., Hellmann-Regen, J., Preis, L., Ersözlü, E., Priller, J., Spruth, E.J., Gemenetzi, M., Schneider, A., Fliessbach, K., Wiltfang, J., Bartels, C., Rostamzadeh, A., Glanz, W., Incesoy, E.I., Teipel, S., Kilimann, I., Goerss, D., Laske, C., Spottke, A., Kronmüller, M., Brosseron, F., Lüsebrink, F., Schmid, M., Kleineidam, L., Stark, M., Hetzer, S., Dechent, P., Scheffler, K., Jessen, F., Maass, A., Düzel, E. and Ziegler, G. |
| Abstract: | Alzheimer’s disease (AD) is characterised by the accumulation of beta-amyloid (Aβ) and tau proteins, leading to neurodegeneration and cognitive decline. While Aβ and tau are known to disrupt synaptic function, the mechanisms linking these molecular pathologies to network-level dysfunction and memory impairment remain poorly understood. Here we investigated the effects of Aβ and tau pathology (CSF Aβ42/40 ratio and tau phosphorylated at position 181, ptau-181, respectively) on effective connectivity (EC) related to memory encoding, which may constitute a link between synaptic pathology and cognitive outcomes. Functional magnetic resonance imaging (fMRI) during visual memory encoding was acquired from participants of the multicentric DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE), including 203 cognitively normal older participants (CN) as well as individuals with subjective cognitive decline (SCD; N = 204), mild cognitive impairment (MCI; N = 65), and early dementia due to AD (DAT; N = 21). EC was assessed by applying Dynamic causal modelling (DCM) to the fMRI data, using brain regions previously implicated in memory-encoding: the parahippocampal place area (PPA), the hippocampus (HC) and the precuneus (PCU). Disruptions in forward connectivity from the PPA to the HC and PCU were associated with both memory impairment and indices of AD pathology. Specifically, reduced excitatory EC from the PPA to the HC was associated with higher p-tau-181 levels and correlated with poorer memory performance. Diminished inhibitory EC from the PPA to the PCU was driven by both tau and amyloid pathology and was likewise linked to memory decline. Our findings suggest that disrupted forward connectivity within the temporo-parietal memory network constitutes a candidate mechanism mediating the relationship between molecular pathology and cognitive dysfunction. |
| Keywords: | Alzheimer's Disease, Memory Impairment, Synaptic Aberration, Beta-Amyloid, Tau, Neurodegeneration |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2025.06.05.658022 |
| Date: | 8 June 2025 |
| Official Publication: | https://doi.org/10.1101/2025.06.05.658022 |
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