Dysfunction of the episodic memory network in the Alzheimer’s disease cascade
DOI: 10.1038/s41467-026-71831-z
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Summary
This study investigates the relationship between episodic memory (EM) network dysfunction and the longitudinal progression of Alzheimer’s disease (AD) biomarkers, neurodegeneration, and cognitive decline. Motivated by the need to understand how synaptic dysfunction contributes to cognitive impairment independent of structural neurodegeneration, the authors utilized data from the DZNE DELCODE study, which includes over 1,000 longitudinal functional magnetic resonance imaging (fMRI) measurements. The research aims to determine if EM network abnormalities, measured via task-based fMRI, precede cognitive decline and operate as an independent driver of disease progression within the amyloid-tau-neurodegeneration (ATN) framework. The researchers employed a multivariate disease progression model (DPM) to generate continuous disease stage scores for participants ranging from cognitively normal older adults to those with mild dementia. This model integrated longitudinal cerebrospinal fluid biomarkers (amyloid-β42/40 and phosphorylated tau181), volumetric MRI data (hippocampal and entorhinal volume), and cognitive scores. The study analyzed encoding-related brain activity during an incidental learning task, focusing on both activation and deactivation patterns. Voxel-wise analyses and mediation models were used to assess the unique contributions of biomarkers to fMRI activity changes, controlling for factors such as vascular pathology and effective connectivity. Results indicated that disease progression was associated with widespread loss of both deactivation and activation in EM networks. Specifically, trajectories for the loss of deactivation were nonlinear, showing early abnormalities associated with amyloid and tau positivity that visually preceded cognitive decline. While activation changes followed a more monotonic trajectory, deactivation abnormalities emerged in the earliest disease stages. Crucially, the relationship between deactivation and cognitive decline was partly independent of neurodegeneration. Mediation analyses revealed that hippocampal volume and effective connectivity mediated the association between activation and cognition, but deactivation remained significantly associated with cognitive scores even after controlling for volume and other biomarkers. Furthermore, residual variability in fMRI signals increased with disease stage, overlapping with regions of significant activity differences. The findings provide evidence that synaptic dysfunction, reflected by EM network deactivation abnormalities, and neurodegeneration are independent drivers of cognitive decline in AD. The study demonstrates that brain activity abnormalities can precede structural atrophy and cognitive impairment, supporting the hypothesis that synaptic dysfunction is a distinct pathological process. These results suggest that targeting synaptic dysfunction along the AD cascade could be a viable therapeutic strategy to delay cognitive decline, independent of interventions aimed at reducing amyloid or tau pathology or preventing neurodegeneration.
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| Stage | Outcome | Tool | Model | Prompt | Attempts | Completed |
|---|---|---|---|---|---|---|
| discover | success | DOAJ | — | — | 1 | 2026-06-25 |
| archive | success | unpaywall | — | — | 1 | 2026-06-26 |
| extract | success | cached | — | — | 2 | 2026-06-26 |
| clean | success | clean | — | — | 1 | 2026-06-25 |
| chunk | success | chunk | — | — | 1 | 2026-06-25 |
| embed | success | embed | Qwen/Qwen3-Embedding-8B | — | 1 | 2026-06-25 |
| promote | success | — | — | — | 1 | 2026-06-25 |
| summarize | success | llm | qwen3.6-27b-prismaquant | summ-v5 | 1 | 2026-06-26 |
| tag | success | vector_similarity | — | — | 6 | 2026-06-25 |
| verify | success | — | — | — | 1 | 2026-06-26 |
Summary generated by qwen3.6-27b-prismaquant on 2026-06-26; verification: verified.
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