Change in functional connectivity strength during rest and encoding is differentially related to Alzheimer's pathology and memory depending on <i>APOE</i> genotype
Bibliographic record
Abstract
Abstract Background The medial temporal lobe (MTL) and posteromedial cortex (PMC) are essential for episodic memory and affected early by Alzheimer's pathology, particularly in APOE4 carriers. Functional connectivity (FC) changes within and between MTL and PMC could be detrimental or beneficial for cognition. However, the relation of those changes to Alzheimer's pathology and memory performance is unclear and most studies assess FC only during rest. We hypothesized that increasing FC strength would be associated with higher pathology burden, especially in APOE4 carriers. Method In this preregistered study, we analysed longitudinal 3‐Tesla fMRI over up to 4 years and cross‐sectional amyloid‐beta and tau PET (PREVENT‐AD cohort; details in Figure 1). We assessed changes in resting‐state FC (RSFC) and task‐FC during intentional object‐location encoding within (ΔFC PMC, ΔFC MTL ) and between MTL and PMC (ΔFC MTL‐PMC ). The sample included 152 cognitively unimpaired older adults (63±5years, 102 female, 59 APOE4 ). We investigated associations between ΔFC strength with i) pathology burden and ii) change in delayed memory (RBANS composite score and fMRI‐task object recognition), and interactions with APOE genotype. We used multiple regression and linear mixed models including APOE , age, sex and education. Result We found ΔFC by APOE interactions predicting pathology. Specifically, declining RSFC PMC ( p = 0.038; Figure 2a) was related to more global amyloid in APOE4 carriers only. In contrast, increasing encoding‐FC MTL was related to more entorhinal tau in APOE4 carriers only ( p = 0.032, Figure 2b). Regarding cognition, regardless of APOE status, increasing encoding‐FC PMC was related to decreasing RBANS ( p = 0.018) performance and object recognition ( p = 0.001). Finally, increasing RSFC MTL‐PMC was related to increasing RBANS performance ( p = 0.032; Figure 3a), but increasing encoding‐FC MTL‐PMC was related to decreasing object recognition ( p = 0.014; Figure 3b). Conclusion Our study shows APOE‐ dependent and region‐specific associations of ΔFC strength within and between episodic memory areas with pathology burden and memory performance. Notably, associations differed between RSFC and task‐FC. In APOE4 carriers, longitudinally increasing FC or “hyperconnectivity” within MTL during encoding was related to tau in line with our hypothesis. However, in PMC, longitudinally decreasing FC during rest was related to more amyloid, indicating a disconnection in PMC regions. Our study highlights that pathology‐related network changes manifest differentially during rest and task (memory encoding).
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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 | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 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".