The Multifactorial Impact of ApoE4 on Alzheimer's Pathology and Cognitive Decline
Bibliographic record
Abstract
Abstract Background Apolipoprotein E (ApoE) isoforms differentially regulate Aβ and tau pathology in Alzheimer's disease (AD). However, most preclinical models do not recapitulate the combined impact of Aβ, tau, and ApoE on cognitive function and disease progression. To overcome this, we developed new mouse models harbouring humanized variants of the ApoE genotypes (ApoE3, ApoE4), hApp (App WT , App NL or App NL‐F ) and hMAPT (tau), and evaluated whether their interactions influence cognition, brain structure, and pathological load. Method Methods used include single nuclei RNA sequencing (snRNAseq), magnetic resonance imaging (MRI), immunofluorescence microscopy, ELISAs, and Western Blotting. Attentional function was assessed using the cross‐species Continuous Performance Task, an automated touchscreen test. Result Biochemical and immunofluorescence analyses confirm that ApoE genotype interacts with both Aβ and tau to drive distinct pathogenic trajectories. At 6 months, App NL‐F /ApoE4 mice exhibit higher cortical levels of insoluble Aβ42 compared to their ApoE3 counterparts, indicating that ApoE4 accelerates amyloidogenic processes. This trend persists at 9 and 12 months, where App NL‐F /ApoE4 mice show increased insoluble Aβ42 levels, plaque burden and plaque size compared to App NL‐F /ApoE3 mice. Additionally, cortical levels of soluble and insoluble total tau are elevated in App NL‐F /ApoE4 mice relative to App NL‐F /ApoE3 mice at 9 and 16 months, respectively. MRI reveals reduced grey matter volume in fronto‐cortical regions of 6‐month‐old App NL‐F /ApoE4 mice compared to App NL /ApoE3 mice. snRNA‐seq confirms a reduction in cortical excitatory neurons, and an upregulation of gliosis in App NL‐F /ApoE4 mice. Finally, App NL‐F /ApoE4 mice exhibit attentional deficits on CPT as early as 6 months, with these impairments persisting at 9 and 12 months relative to App NL‐F /ApoE3 mice. Pathology was negligible at all timepoints in App NL (ApoE3 and ApoE4) and App WT mice, suggesting that Aβ toxicity drives the pathogenic interactions with ApoE. Conclusion These findings highlight the multifactorial impact of ApoE4 in AD, demonstrating that humanized App NL‐F /MAPT/ApoE4 mice exhibit biochemical and imaging biomarkers of pathology and a time course of neurodegeneration and cognitive dysfunction that reproduces a human‐like phenotype of late onset AD. This work underscores the value of combining these novel mouse models with translational imaging and cognitive biomarkers for understanding the relationship between pathophysiology and high‐level cognitive function.
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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) | 0.001 | 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 | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| 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".