Longitudinal hippocampal iron accumulation predicts episodic memory in presymptomatic Alzheimer's disease with additional influences of tau and APOE geneotype
Bibliographic record
Abstract
Abstract Background Elevated brain iron deposition is recognized as a characteristic of normal aging and neurodegenerative diseases, particularly Alzheimer's disease (AD), where it correlated with amyloid‐β plaques and neurofibrillary tangles. Our study aimed to investigate the relationship between longitudinal changes in hippocampal iron deposition and episodic memory, and how this relationship is impacted by AD pathology and APOE4 allele carriership. Method We measured longitudinal changes in brain iron levels using quantitative susceptibility mapping (QSM)‐MRI (see Figure 1), in a cohort of old adults at risk of AD ( N =143, 102 females, 41 males; mean age = 67.7 ± 5.0 years; longitudinal duration = 2.7 ± 0.4 years). Cognition was assessed using the RBANS. Plasma was collected from all participants at a single time point (Time 2, T2) and p ‐tau181 measured using in‐house single‐molecule arrays. We examined the relationship between iron accumulation and memory, the mediating effect of plasma p ‐tau181. We also investigated how APOE4 status moderates the relationship between iron deposition and plasma p ‐tau181. Result Hippocampal iron levels demonstrated a significant increase over time (t(142)=2.45, Cohen's d=0.21, p = 0.016). Changes in iron levels were significantly negatively correlated with memory performance (β=‐0.223, p = 0.009, Figure 2A), and positively associated with plasma p ‐tau181 (β=0.217, p = 0.011, Figure 2B). Plasma p ‐tau181 were also negatively associated memory (β=–0.207, p = 0.015, Figure 2C). Furthermore, p ‐tau181 mediated the relationship between hippocampal iron increases and memory performance, accounted for 16.2% of the total association (β = −0.034, p = 0.045, CI: −0.09 to ‐0.004, Figure 2D). APOE4 status moderated the impact of increased hippocampal iron on plasma p ‐tau181 levels (β =0.431, p = 0.021, CI: 0.06 to 0.8, Figure 3). Conclusion These findings underscore the unique effect of hippocampal iron accumulation on cognition, which is additionally impacted by AD pathology. Further, we find a novel association in APOE4 carriers, wherein increases in iron interact with AD pathology, which highlights the need for early detection and intervention strategies tailored to APOE4 carriers. This work deepens our understanding of the interplay among iron dysregulation, tau pathology, and APOE4, offering a promising avenue for precision‐based approaches to AD risk assessment and therapeutic development.
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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 | 0.000 |
| 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 | 0.001 | 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".