Microglial activation interacts with amyloid‐β to drive longitudinal tau tangle accumulation and cognitive decline
Bibliographic record
Abstract
Abstract Background Activation of microglial cells in the brain, more commonly known as neuroinflammation, has often been linked to the pathophysiology of Alzheimer’s disease (AD). However, how microglial activation is associated with longitudinal tau tangle accumulation and consequent cognitive decline is poorly understood. Here, we aimed to investigate whether baseline microglial activation impacts tau tangle deposition and cognitive decline in individuals across the AD continuum. Method We assessed 92 individuals from the TRIAD cohort (57 cognitively unimpaired and 35 cognitively impaired) with available baseline [11C]PBR28‐PET, a measure of microglial activation and [18F]NAV4694 Aß‐PET, and longitudinal [18F]MK6240 Tau‐PET (mean follow‐up time = 1.93 years) and Mini‐Mental State Exam (MMSE) (mean follow‐up time = 1.84 years). We performed voxel‐wise associations using linear regressions accounting for age and sex and adjusted for multiple comparisons using Random Field Theory (RFT) (p < 0.05). We used the cuneus and superior temporal cortex as a composite ROI for [11C]PBR28‐PET and Aß‐PET since these regions showed a higher association with longitudinal tau accumulation in the temporal meta‐ROI. Result Voxel‐wise analysis showed that baseline levels of [11C]PBR28‐PET alone are not sufficient to predict longitudinal tau tangle accumulation (Fig. 1a). However, the interaction between [11C]PBR28‐PET levels and Aß burden predicted an increased accumulation of tau tangle, mainly in the cuneus, inferior frontal and lateral occipital regions (Fig. 1b).Individuals with higher baseline [11C]PBR28‐PET and Aß‐PET levels present higher rates of longitudinal tau accumulation in the temporal meta‐ROI (ß = 0.36, t = 3.46, p = 0.0009; Fig. 1c). Similarly, while [11C]PBR28‐PET levels alone did not correlate with longitudinal changes in MMSE score (ß = ‐0.17, t = ‐1.69, p = 0.10), a significant interaction between [11C]PBR28‐PET and Aß‐PET levels on MMSE annual decline was observed (ß = ‐0.24, t = ‐2.25, p = 0.028; Fig. 1d). Conclusion We found that baseline levels of microglial activation was associated with longitudinal tau tangle accumulation and cognitive decline in individuals across the AD continuum in the presence of Aß burden. Our results indicate that microglial activation might act potentiating the deleterious effects of Aß on forthcoming tau tangle deposition.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".