Stage-Progressive Subcortical BOLD Signal Dynamics in Alzheimer's Disease: Hippocampal Hyperactivation, Thalamic Rigidification, and Pallidal Gate Dysregulation
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2026
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| _version_ | 1866901269626486784 |
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| author | Malone, Ryan |
| author_facet | Malone, Ryan |
| contents | <p>Background: The thalamus has been identified as an early site of Alzheimer’s disease (AD)<br>pathology, but its functional trajectory relative to hippocampal degeneration and its specificity for<br>distinct cognitive domains remain incompletely characterised in large-scale longitudinal data.<br>Objective: To test the Thalamic Filter Model prediction that thalamic hardware (filter layer)<br>degrades before hippocampal hardware (memory buffer) across the AD spectrum, with thalamic<br>integrity specifically predicting executive function but not memory, language, or visuospatial<br>domains.<br>Methods: Longitudinal structural MRI and diffusion tensor imaging (DTI) data were drawn from<br>the Alzheimer’s Disease Neuroimaging Initiative (ADNI), encompassing 804 participants (222<br>cognitively normal [CN], 391 mild cognitive impairment [MCI], 191 dementia) with 2,412<br>longitudinal observations and 1,232 DTI observations. Thalamic volume, posterior thalamic<br>radiation fractional anisotropy (PTR-FA), and hippocampal volume were extracted and compared<br>across disease stages. Partial correlations examined the independent relationship between thalamic<br>volume and specific cognitive domains after controlling for hippocampal volume. APOE4 carrier<br>effects were examined within each disease stage.<br>Results: Thalamic volume showed monotonic, statistically significant decline across the<br>CN→MCI→Dementia spectrum (F(2,801)=13.11, η²=0.032, Cohen’s d=0.61). PTR-FA declined<br>concurrently (F(2,653)=8.90, d=0.73). Hippocampal volume showed a larger overall effect<br>(d=1.15) but with decline concentrated at the MCI→Dementia transition rather than CN→MCI,<br>consistent with filter-before-transmitter degradation. Thalamic volume independently predicted<br>executive function (partial r=0.094, p=0.010) after controlling for hippocampal volume, with zero<br>independent relationship with memory (partial r=0.011, p=0.78), language (partial r=0.019,<br>p=0.61), or visuospatial domains (partial r=0.024, p=0.51). APOE4 specifically amplified thalamic<br>atrophy at the MCI stage (d=−0.224, p=0.039) with null effects at CN and Dementia stages and<br>null hippocampal APOE4 effects at all stages.<br>Conclusion: Thalamic filter hardware degrades before hippocampal memory hardware across the<br>AD spectrum, specifically predicting executive function loss. APOE4 amplifies thalamic atrophy<br>during the transitional MCI vulnerability window. These findings identify a potential early<br>intervention window targeting thalamic integrity, with implications for patient stratification in<br>clinical trials.</p> |
| format | Recurso digital |
| id | zenodo_https___doi_org_10_5281_zenodo_19817112 |
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| publishDate | 2026 |
| publisher | Zenodo |
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| spellingShingle | Stage-Progressive Subcortical BOLD Signal Dynamics in Alzheimer's Disease: Hippocampal Hyperactivation, Thalamic Rigidification, and Pallidal Gate Dysregulation Malone, Ryan Alzheimer's disease thalamus hippocampus ADNI longitudinal MRI diffusion tensor imaging APOE4 executive function mild cognitive impairment thalamic filter subcortical <p>Background: The thalamus has been identified as an early site of Alzheimer’s disease (AD)<br>pathology, but its functional trajectory relative to hippocampal degeneration and its specificity for<br>distinct cognitive domains remain incompletely characterised in large-scale longitudinal data.<br>Objective: To test the Thalamic Filter Model prediction that thalamic hardware (filter layer)<br>degrades before hippocampal hardware (memory buffer) across the AD spectrum, with thalamic<br>integrity specifically predicting executive function but not memory, language, or visuospatial<br>domains.<br>Methods: Longitudinal structural MRI and diffusion tensor imaging (DTI) data were drawn from<br>the Alzheimer’s Disease Neuroimaging Initiative (ADNI), encompassing 804 participants (222<br>cognitively normal [CN], 391 mild cognitive impairment [MCI], 191 dementia) with 2,412<br>longitudinal observations and 1,232 DTI observations. Thalamic volume, posterior thalamic<br>radiation fractional anisotropy (PTR-FA), and hippocampal volume were extracted and compared<br>across disease stages. Partial correlations examined the independent relationship between thalamic<br>volume and specific cognitive domains after controlling for hippocampal volume. APOE4 carrier<br>effects were examined within each disease stage.<br>Results: Thalamic volume showed monotonic, statistically significant decline across the<br>CN→MCI→Dementia spectrum (F(2,801)=13.11, η²=0.032, Cohen’s d=0.61). PTR-FA declined<br>concurrently (F(2,653)=8.90, d=0.73). Hippocampal volume showed a larger overall effect<br>(d=1.15) but with decline concentrated at the MCI→Dementia transition rather than CN→MCI,<br>consistent with filter-before-transmitter degradation. Thalamic volume independently predicted<br>executive function (partial r=0.094, p=0.010) after controlling for hippocampal volume, with zero<br>independent relationship with memory (partial r=0.011, p=0.78), language (partial r=0.019,<br>p=0.61), or visuospatial domains (partial r=0.024, p=0.51). APOE4 specifically amplified thalamic<br>atrophy at the MCI stage (d=−0.224, p=0.039) with null effects at CN and Dementia stages and<br>null hippocampal APOE4 effects at all stages.<br>Conclusion: Thalamic filter hardware degrades before hippocampal memory hardware across the<br>AD spectrum, specifically predicting executive function loss. APOE4 amplifies thalamic atrophy<br>during the transitional MCI vulnerability window. These findings identify a potential early<br>intervention window targeting thalamic integrity, with implications for patient stratification in<br>clinical trials.</p> |
| title | Stage-Progressive Subcortical BOLD Signal Dynamics in Alzheimer's Disease: Hippocampal Hyperactivation, Thalamic Rigidification, and Pallidal Gate Dysregulation |
| topic | Alzheimer's disease thalamus hippocampus ADNI longitudinal MRI diffusion tensor imaging APOE4 executive function mild cognitive impairment thalamic filter subcortical |
| url | https://doi.org/10.5281/zenodo.19817112 |