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.
Larissa Fischer, N. Vockert, Joseph Höpker Fernandes et al.· bioRxiv· 0 citations
Episodic memory decline is a common feature of cognitively normal aging, but its extent varies markedly across individuals. Although entorhinal tau pathology is thought to be a key contributor to episodic memory impairment, the neural mechanisms linking early tau accumulation to memory differences remain unclear. Grid-cell computations in the entorhinal cortex, which provide scaffolds for organizing experiences into episodic memories, offer one candidate mechanism. Here, we combined virtual-reality functional MRI, multivariate analysis, tau PET, and delayed word-list recall in cognitively normal older adults to test whether tau-related alterations in entorhinal coding are associated with worse episodic memory. Weaker left entorhinal grid-cell-like signal was associated with poorer memory performance, and individuals with higher left entorhinal tau burden showed weaker grid-cell-like signal. This association was specific to the canonical six-fold signal and was not explained by entorhinal volume, mean diffusivity, or intracortical myelination. A cross-sectional Bayesian mediation analysis further demonstrated that bilateral medial temporal tau burden is related to memory indirectly through left entorhinal grid-cell-like signal. Together, these findings provide evidence that entorhinal grid codes may constitute a functional pathway linking tau accumulation to memory variability in normal aging.
V. Segen, Tuğçe Belge Bernard, Gerard Callau Navarro et al.· bioRxiv· 0 citations
Alzheimer’s disease (AD) is characterised by the accumulation of β-amyloid (Aβ) and tau proteins, resulting in neurodegeneration and cognitive decline. Although Aβ and tau disrupt synaptic function, the association linking these molecular pathologies to network-level dysfunction and memory impairment remains poorly understood. Here, we investigated the effects of Aβ and tau pathology (CSF Aβ42/40 ratio and tau phosphorylated at position 181, p-tau-181, respectively) on effective connectivity related to memory encoding, which may provide a link between synaptic pathology and cognitive outcomes. Functional magnetic resonance imaging (fMRI) during visual memory encoding was acquired from 205 participants in the multicentric DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE) across the AD spectrum. Effective connectivity was assessed using Dynamic Causal Modelling (DCM) of task-fMRI data, focusing on the parahippocampal place area (PPA), hippocampus (HC), and precuneus (PCU)—regions central to memory encoding. Disruptions in connectivity between temporal and parietal lobes were associated with both memory impairment and indices of AD pathology. Specifically, reduced positive effective connectivity from the PCU to the PPA and from the HC to the PCU were linked to higher p-tau-181 levels, with an amplification effect observed in the presence of amyloid accumulation for the latter connectivity. The disruption from the PCU to the PPA was found to be associated with decreased memory performance. Together, these findings indicate that temporo-parietal connectivity is associated with both AD molecular pathology and, for a subset of connections, with memory performance.
Yanin Suksangkharn, B. Schott, P. Zeidman et al.· Alzheimer's Research & Thera...· 0 citations
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