Mesoscale medial temporal lobe connectivity patterns relate to tau pathology and memory in older adults

Fischer, L.; Vockert, N.; Hoepker Fernandes, J.; Garcia-Garcia, B.; Roemer-Cassiano, S. N.; Franzmeier, N.; Gellersen, H. M.; Schumann-Werner, B.; Behrenbruch, N.; Schwarck, S.; Molloy, E. N.; Behnisch, G.; Seidenbecher, C.; Schott, B. H.; Morgado, B.; Esselmann, H.; Wiltfang, J.; Barthel, H.; Sabri, O.; Kreissl, M. C.; Duezel, E.; Schreiber, S.; Kuehn, E.; Maass, A.

doi:10.64898/2026.08.18.745399

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bioRxiv · 10.64898/2026.08.18.745399

Mesoscale medial temporal lobe connectivity patterns relate to tau pathology and memory in older adults

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Abstract

The medial temporal lobe (MTL) is crucial for episodic memory. Tau pathology is a hallmark of Alzheimer's disease (AD) and accumulates in layer-specific patterns in the MTL during aging. It is, however, unclear whether early AD pathology relates to mesoscale network signatures distinct from non-pathological aging. To address this gap, we acquired 7 Tesla submillimeter-resolution resting-state fMRI, plasma-based AD biomarkers, glial fibrillary acidic protein (GFAP) levels, APOE genotype, regional [18F]PI-2620 tau PET burden, and longitudinal episodic memory data in 75 cognitively unimpaired older adults. Older age was associated with lower perirhinal-hippocampal connectivity and lower network segregation, whereas higher plasma-based AD pathology was associated with higher perirhinal-hippocampal connectivity. Furthermore, temporal-lobe tau burden was related to altered connectivity patterns in tau-vulnerable MTL subfields and layers, dependent on GFAP levels. Retrosplenial tau burden was associated with higher hippocampal-retrosplenial connectivity consistent with tau spread along canonical hippocampal output pathways. Finally, higher connectivity within the hippocampus attenuated the negative association between temporal-lobe tau burden and memory performance but predicted unfavorable memory trajectories. Our findings show differential associations of age and AD pathology with mesoscale MTL-connectivity patterns. Importantly, increased hippocampal connectivity may support memory function in the short term while contributing to subsequent memory decline.

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Fischer, L., Vockert, N., Hoepker Fernandes, J., Garcia-Garcia, B., Roemer-Cassiano, S. N., Franzmeier, N., Gellersen, H. M., Schumann-Werner, B., Behrenbruch, N., Schwarck, S., Molloy, E. N., Behnisch, G., Seidenbecher, C., Schott, B. H., Morgado, B., Esselmann, H., Wiltfang, J., Barthel, H., Sabri, O., Kreissl, M. C., Duezel, E., Schreiber, S., Kuehn, E., Maass, A.. 2026-08-21. Mesoscale medial temporal lobe connectivity patterns relate to tau pathology and memory in older adults. https://doi.org/10.64898/2026.08.18.745399

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