Reelin' from Alzheimer's Disease
Which neurons die first in Alzheimer's, and why those?
Core trick
Fits donor-clustered, depth-controlled models of RELN and RORB co-detection across ten public datasets, testing monotonic association with Braak tau stage.
Description
Which neurons die first in Alzheimer's, and why those? I investigated whether two markers of the selectively vulnerable entorhinal-cortex neurons that seed tau pathology — Reelin (RELN) and the transcription factor RORB — occupy the same individual cells, and whether that co-occupancy tracks disease. Using Claude Science, I built the analysis end to end: harmonizing ten public human datasets across single-cell, spatial (MERFISH), and bulk transcriptomics (>4M cells) and fitting depth-controlled, donor-clustered models that test the two genes as a pair.
The findings show that RELN⁺/RORB⁺ detection is independent in healthy tissue but converges with advancing tau stage — a monotonic six-stage dose-response, independently replicated in an 81-donor cohort with 10× higher depth (exactly the condition that would inflate a detection artifact — which it doesn't), confirmed in intact tissue by MERFISH, absent in other tauopathies, and amplified by APOE-ε4 dose. Regulatory-network, ChIP-seq, and structural analyses rule out a direct molecular link, establishing co-vulnerability rather than partnership.
This sharpens the map of AD's earliest-lost neurons and ties it to APOE4 — the field's strongest genetic risk factor — via Reelin–ApoE receptor competition: a hypothesis-generating finding, with the decisive next experiments specified, that others can build on directly.
TamaraVas/reln_rorb_AD_analysis★ 00 forksPythonNOASSERTIONCreated Jul 13, 2026 · last push Oct 7, 2026
README excerpt
# RELN–RORB convergence in the Alzheimer's entorhinal cortex Analysis code for the study of whether **Reelin (RELN)** and **RORB** co-occupy the *same* entorhinal-cortex (EC) excitatory neurons in Alzheimer's disease (AD), and whether that co-occupancy tracks tau pathology. **Headline finding.** RELN and RORB are expressed independently in EC excitatory neurons in cognitively normal brain, but converge into the *same* neurons with advancing Braak tau stage. The convergence is specific to EC excitatory neurons, tau-graded, module-level (the whole reelin-signalling program co-recruits with the RORB⁺ EC:Exc.4 identity), amplified by APOE-ε4 dose, and absent from non-entorhinal cortex in AD and two other primary tauopathies. All analyses are **secondary analyses of public data**. This is a computational, hypothesis-generating study. ## What's here Each script in `analysis/` is a self-contained analysis that reads from `data/` and writes a figure + result table to the working directory. Run them independently; there is no master pipeline. Scripts are numbered in narrative order, not strict dependency order (02 and 05 consume `cellclass_all_regions.csv` and 14 consumes `staged_ec_all_regions.json`, both produced by 04). | Script | What it does | |--------|--------------| | `01_coexpression_same_cell.py` | Discovery: same-cell RELN×RORB co-occupancy, AD vs normal (Leng EC) | | `02_region_class_specificity.py` | Region × cell-class specificity | | `03_braak_trajectory.py` | Bra