Epigenomic alterations and neural development anomalies in induced pluripotent stem cells from sporadic Alzheimer's disease
Bibliographic record
Abstract
Reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs) resets the aging clock. However, primed iPSCs can retain cell-of-origin epigenomic marks, especially those linked to heterochromatin. Here, we show that iPSCs produced from fibroblasts of late-onset sporadic Alzheimer's disease (AD) cases retain epigenomic alterations that correlate with developmental anomalies and neurodegeneration. Compared to controls, AD iPSCs show reduced BMI1 expression and H3K9me3 levels and an altered DNA methylome. Gene Ontology analysis of differentially methylated DNA regions reveals terms linked to cell-cell adhesion and synapses, with MEF2C-binding sites being the most enriched at differentially methylated DNA regions. Upon noggin exposure, AD iPSCs show less-efficient neural induction and forebrain specification, together with elevated WNT signaling. Mature AD neurons present a mixed cell lineage identity phenotype and reduced MEF2C expression. AD glial cells express neuronal, cell proliferation, and stem cell-related genes. Despite these anomalies, AD iPSCs generate cortical neurons in normal proportion and readily form cerebral organoids showing AD-related pathologies. These findings implicate reprogramming-resistant epigenomic alterations or genetic variants working in trans on the epigenome in AD pathophysiology.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| 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) | 0.000 | 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 teacher head, 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".