ApoE4 associated with higher tau accumulation independent of amyloid burden
Bibliographic record
Abstract
Abstract Background ApoE4 carriage is the strongest genetic risk factor for developing late‐onset AD. Previous studies suggest that ApoE is involved in the amyloid pathway, and that elevated AD risk in ApoE4‐carriers is conferred by higher beta‐amyloid levels. However, recent animal work suggests that ApoE4 is also associated with increased tau pathology (Shi et al, 2017, Nature). Yet, it is unclear whether this association between ApoE4 and tau pathology translates to humans. Thus, the main aim of the current study was to test whether ApoE4 has an amyloid‐independent effect on cross‐sectional and longitudinal tau‐PET in humans. Method For longitudinal analyses, we included baseline AV45 amyloid‐PET and longitudinal AV1451 tau‐PET (∼1.3 years follow‐up) from 111 ADNI participants (42ε4+,69ε4‐) including cognitively normal (CN), mild cognitive impairment (MCI) and AD dementia (ADD). For cross‐sectional analyses, we additionally included tau‐ and amyloid‐PET from 254 CN and MCI participants (83ε4+,171ε4) from ADNI (not overlapping with the longitudinal ADNI sample) plus 128 CN participants (53ε4+,75ε4‐) from the PREVENT‐AD cohort (Table 1). Average baseline PET‐SUVR and annual change rates were quantified within 68 Freesurfer‐defined cortical brain regions (Figure 1). Analysis of covariance (ANCOVA) was used to investigate differences in cross‐sectional tau‐PET or longitudinal tau‐PET changes between ApoE4 carriers versus non‐carriers, controlling continuous measures of global amyloid‐PET. Post‐hoc subgroup analyses tested potential ApoE4 effects with a more rigorous control of amyloid‐PET by including only participants with the same amyloid status. Result For cross‐sectional analyses, we found ApoE4 carriers to show higher tau‐PET compared to non‐carriers after controlling global amyloid‐PET (Figure 2). Across samples, medial temporal areas (entorhinal cortex,parahippocampus) showed the strongest ApoE effect. The amyloid‐independent effect of ApoE4 on medial temporal tau‐PET remained significant in post‐hoc analyses of only amyloid‐positive ADNI or amyloid‐negative PREVENT‐AD participants (data not shown). For longitudinal analyses, we found significantly higher tau‐PET changes in ApoE4 carriers controlled for baseline amyloid‐PET (Figure 3). Strongest effects were found in posterior brain areas (lateral occipital, superior parietal) which remained significant in post‐hoc subgroup analyses. Conclusion The current results suggest that there is an amyloid‐independent association between ApoE4 and elevated tau‐PET specifically in medial temporal regions.
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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 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".