APOEε4 drives microglial activation in the medial temporal cortex in individuals across the AD spectrum
Bibliographic record
Abstract
Abstract Background Microglial activation is an early phenomenon in Alzheimer’s disease (AD) that may occur prior to and independently of amyloid‐β (Aβ) aggregation. Compelling experimental evidence suggests that the apolipoprotein E ε4 (APOEε4) allele may be a culprit of early microglial activation in AD. However, it is unclear whether the APOEε4 genotype is associated with microglial reactivity in the living human brain. In individuals across the aging and AD spectrum, we tested the hypothesis that APOEε4 associates with microglial activation. Method We studied 118 individuals (79 cognitively unimpaired [CU], 23 with mild cognitive impairment [MCI], and 16 with AD dementia) from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Individuals had available [18F]AZD4694 Aβ PET, [18F]MK6240 tau PET, [11C]PBR28 microglial activation PET, and magnetic resonance imaging (MRI), as well as APOE genotyping. To increase the reliability of our results, we only included high‐affinity binders for the [11C]PBR28 radiotracer. In a subgroup of 42 individuals with longitudinal clinical and MRI data, we further assessed longitudinal hippocampal atrophy and clinical deterioration. Result Voxel‐wise analysis revealed that APOEε4 carriership was associated with increased [11C]PBR28 uptake mainly in the medial temporal cortex (Figure 1A and B), and this effect of APOEε4 was independent of Aβ and tau accumulation. Region‐wise analyses demonstrated that APOEε4 carriers presented increased [11C]PBR28 SUVR relative to noncarriers only in Braak I‐II regions (Figure 1C), which further supports that APOEε4‐related microglial activation occurs specifically in medial temporal structures. Lastly, we found that [11C]PBR28 uptake in brain regions vulnerable to APOEε4 effects is associated with subsequent hippocampal atrophy and clinical decline over 2 years (Figure 2). Conclusion These results support a model in which APOEε4 plays a role in early AD progression by contributing to microglial activation in medial temporal regions. Our findings provide a rationale for the development of novel AD therapies targeting the interplay between ApoE and neuroinflammation.
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".