Cell type vulnerability in Alzheimers Disease (SEA-AD transcriptomic data)¶
Notebook ID: nb-SDA-2026-04-03-gap-seaad-v4-20260402065846 · Analysis: SDA-2026-04-03-gap-seaad-v4-20260402065846 · Generated: 2026-04-26T23:48:52
Research question¶
What cell types are most vulnerable in Alzheimers Disease based on SEA-AD transcriptomic data from the Allen Brain Cell Atlas? Identify mechanisms of cell-type-specific vulnerability in neurons, microglia, astrocytes, and oligodendrocytes. Focus on gene expression patterns, pathway dysregulation, and therapeutic implications.
Approach¶
This notebook is generated programmatically from real Forge tool calls and SciDEX debate data. Forge tools used: PubMed Search, MyGene, STRING PPI, Reactome pathways, Enrichr.
Debate Summary¶
Quality score: 0.9 · Rounds: 4
1. Target gene annotations (MyGene + Human Protein Atlas)¶
import pandas as pd
ann_rows = [{'gene': 'ACSL4', 'name': 'acyl-CoA synthetase long chain family member 4', 'protein_class': "['Disease related genes', 'Enzymes', 'Human disease related ", 'disease_involvement': "['Alport syndrome', 'Deafness', 'Disease variant', 'Elliptocytosis', 'Hereditary"}, {'gene': 'ALOX15', 'name': 'arachidonate 15-lipoxygenase', 'protein_class': "['Disease related genes', 'Enzymes', 'Metabolic proteins', '", 'disease_involvement': '—'}, {'gene': 'APOE', 'name': 'apolipoprotein E', 'protein_class': "['Cancer-related genes', 'Candidate cardiovascular disease g", 'disease_involvement': "['Alzheimer disease', 'Amyloidosis', 'Cancer-related genes', 'Disease variant', "}, {'gene': 'CLDN5', 'name': 'claudin 5', 'protein_class': "['Predicted membrane proteins', 'Transporters']", 'disease_involvement': '—'}, {'gene': 'GENES', 'name': 'MIR142 host genes', 'protein_class': '—', 'disease_involvement': '—'}, {'gene': 'LPCAT3', 'name': 'lysophosphatidylcholine acyltransferase 3', 'protein_class': "['Enzymes', 'Metabolic proteins', 'Predicted membrane protei", 'disease_involvement': '—'}, {'gene': 'MAPT', 'name': 'microtubule associated protein tau', 'protein_class': '—', 'disease_involvement': '—'}, {'gene': 'PARP1', 'name': 'poly(ADP-ribose) polymerase 1', 'protein_class': "['Cancer-related genes', 'Enzymes', 'FDA approved drug targe", 'disease_involvement': "['Cancer-related genes', 'FDA approved drug targets']"}, {'gene': 'PPARA', 'name': 'peroxisome proliferator activated receptor alpha', 'protein_class': "['FDA approved drug targets', 'Nuclear receptors', 'Predicte", 'disease_involvement': "['FDA approved drug targets']"}, {'gene': 'REGIONAL', 'name': 'dihydrouridine synthase 2', 'protein_class': '—', 'disease_involvement': '—'}, {'gene': 'SIRT3', 'name': 'sirtuin 3', 'protein_class': "['Enzymes', 'Metabolic proteins', 'Predicted intracellular p", 'disease_involvement': '—'}, {'gene': 'SLC16A1', 'name': 'solute carrier family 16 member 1', 'protein_class': "['Disease related genes', 'Human disease related genes', 'Me", 'disease_involvement': "['Disease variant']"}, {'gene': 'TREM2', 'name': 'triggering receptor expressed on myeloid cells 2', 'protein_class': "['Disease related genes', 'Human disease related genes', 'Po", 'disease_involvement': "['Alzheimer disease', 'Amyloidosis', 'Disease variant', 'Neurodegeneration']"}, {'gene': 'VULNERABILITY', 'name': 'TM2 domain containing 1', 'protein_class': '—', 'disease_involvement': '—'}]
pd.DataFrame(ann_rows)
| gene | name | protein_class | disease_involvement | |
|---|---|---|---|---|
| 0 | ACSL4 | acyl-CoA synthetase long chain family member 4 | ['Disease related genes', 'Enzymes', 'Human di... | ['Alport syndrome', 'Deafness', 'Disease varia... |
| 1 | ALOX15 | arachidonate 15-lipoxygenase | ['Disease related genes', 'Enzymes', 'Metaboli... | — |
| 2 | APOE | apolipoprotein E | ['Cancer-related genes', 'Candidate cardiovasc... | ['Alzheimer disease', 'Amyloidosis', 'Cancer-r... |
| 3 | CLDN5 | claudin 5 | ['Predicted membrane proteins', 'Transporters'] | — |
| 4 | GENES | MIR142 host genes | — | — |
| 5 | LPCAT3 | lysophosphatidylcholine acyltransferase 3 | ['Enzymes', 'Metabolic proteins', 'Predicted m... | — |
| 6 | MAPT | microtubule associated protein tau | — | — |
| 7 | PARP1 | poly(ADP-ribose) polymerase 1 | ['Cancer-related genes', 'Enzymes', 'FDA appro... | ['Cancer-related genes', 'FDA approved drug ta... |
| 8 | PPARA | peroxisome proliferator activated receptor alpha | ['FDA approved drug targets', 'Nuclear recepto... | ['FDA approved drug targets'] |
| 9 | REGIONAL | dihydrouridine synthase 2 | — | — |
| 10 | SIRT3 | sirtuin 3 | ['Enzymes', 'Metabolic proteins', 'Predicted i... | — |
| 11 | SLC16A1 | solute carrier family 16 member 1 | ['Disease related genes', 'Human disease relat... | ['Disease variant'] |
| 12 | TREM2 | triggering receptor expressed on myeloid cells 2 | ['Disease related genes', 'Human disease relat... | ['Alzheimer disease', 'Amyloidosis', 'Disease ... |
| 13 | VULNERABILITY | TM2 domain containing 1 | — | — |
2. GO Biological Process enrichment (Enrichr)¶
go_bp = [{'rank': 1, 'term': 'Microglial Cell Activation (GO:0001774)', 'p_value': 2.676276080527817e-13, 'odds_ratio': 1109.6666666666667, 'genes': ['APP', 'TYROBP', 'TREM2', 'MAPT', 'CLU']}, {'rank': 2, 'term': 'Astrocyte Activation (GO:0048143)', 'p_value': 2.4448023088239226e-11, 'odds_ratio': 1427.2142857142858, 'genes': ['APP', 'TREM2', 'MAPT', 'PSEN1']}, {'rank': 3, 'term': 'Astrocyte Development (GO:0014002)', 'p_value': 6.736219018143865e-11, 'odds_ratio': 1037.8181818181818, 'genes': ['APP', 'TREM2', 'MAPT', 'PSEN1']}, {'rank': 4, 'term': 'Regulation Of Amyloid Fibril Formation (GO:1905906)', 'p_value': 6.736219018143865e-11, 'odds_ratio': 1037.8181818181818, 'genes': ['APP', 'TREM2', 'PSEN1', 'CLU']}, {'rank': 5, 'term': 'Positive Regulation Of Supramolecular Fiber Organization (GO:1902905)', 'p_value': 1.0354136710554012e-09, 'odds_ratio': 182.21611721611723, 'genes': ['APP', 'MAPT', 'APOE', 'PSEN1', 'CLU']}, {'rank': 6, 'term': 'Macrophage Activation (GO:0042116)', 'p_value': 2.5696934344337086e-09, 'odds_ratio': 367.889400921659, 'genes': ['APP', 'TREM2', 'MAPT', 'CLU']}, {'rank': 7, 'term': 'Negative Regulation Of Long-Term Synaptic Potentiation (GO:1900272)', 'p_value': 6.919481814980666e-09, 'odds_ratio': 1498.8, 'genes': ['APP', 'TYROBP', 'APOE']}, {'rank': 8, 'term': 'Memory (GO:0007613)', 'p_value': 2.0688966159515193e-08, 'odds_ratio': 210.95238095238096, 'genes': ['TREM2', 'MAPT', 'APOE', 'PSEN1']}, {'rank': 9, 'term': 'Positive Regulation Of ERK1 And ERK2 Cascade (GO:0070374)', 'p_value': 2.4015108691702915e-08, 'odds_ratio': 94.89942528735632, 'genes': ['PDGFRB', 'APP', 'PDGFRA', 'TREM2', 'APOE']}, {'rank': 10, 'term': 'Regulation Of Amyloid-Beta Clearance (GO:1900221)', 'p_value': 5.610477788412988e-08, 'odds_ratio': 624.28125, 'genes': ['TREM2', 'APOE', 'CLU']}]
go_df = pd.DataFrame(go_bp)[['term','p_value','odds_ratio','genes']]
go_df['p_value'] = go_df['p_value'].apply(lambda p: f'{p:.2e}')
go_df['odds_ratio'] = go_df['odds_ratio'].round(1)
go_df['term'] = go_df['term'].str[:60]
go_df['n_hits'] = go_df['genes'].apply(len)
go_df['genes'] = go_df['genes'].apply(lambda g: ', '.join(g))
go_df[['term','n_hits','p_value','odds_ratio','genes']]
| term | n_hits | p_value | odds_ratio | genes | |
|---|---|---|---|---|---|
| 0 | Microglial Cell Activation (GO:0001774) | 5 | 2.68e-13 | 1109.7 | APP, TYROBP, TREM2, MAPT, CLU |
| 1 | Astrocyte Activation (GO:0048143) | 4 | 2.44e-11 | 1427.2 | APP, TREM2, MAPT, PSEN1 |
| 2 | Astrocyte Development (GO:0014002) | 4 | 6.74e-11 | 1037.8 | APP, TREM2, MAPT, PSEN1 |
| 3 | Regulation Of Amyloid Fibril Formation (GO:190... | 4 | 6.74e-11 | 1037.8 | APP, TREM2, PSEN1, CLU |
| 4 | Positive Regulation Of Supramolecular Fiber Or... | 5 | 1.04e-09 | 182.2 | APP, MAPT, APOE, PSEN1, CLU |
| 5 | Macrophage Activation (GO:0042116) | 4 | 2.57e-09 | 367.9 | APP, TREM2, MAPT, CLU |
| 6 | Negative Regulation Of Long-Term Synaptic Pote... | 3 | 6.92e-09 | 1498.8 | APP, TYROBP, APOE |
| 7 | Memory (GO:0007613) | 4 | 2.07e-08 | 211.0 | TREM2, MAPT, APOE, PSEN1 |
| 8 | Positive Regulation Of ERK1 And ERK2 Cascade (... | 5 | 2.40e-08 | 94.9 | PDGFRB, APP, PDGFRA, TREM2, APOE |
| 9 | Regulation Of Amyloid-Beta Clearance (GO:1900221) | 3 | 5.61e-08 | 624.3 | TREM2, APOE, CLU |
import matplotlib.pyplot as plt
import numpy as np
go_bp = [{'rank': 1, 'term': 'Microglial Cell Activation (GO:0001774)', 'p_value': 2.676276080527817e-13, 'odds_ratio': 1109.6666666666667, 'genes': ['APP', 'TYROBP', 'TREM2', 'MAPT', 'CLU']}, {'rank': 2, 'term': 'Astrocyte Activation (GO:0048143)', 'p_value': 2.4448023088239226e-11, 'odds_ratio': 1427.2142857142858, 'genes': ['APP', 'TREM2', 'MAPT', 'PSEN1']}, {'rank': 3, 'term': 'Astrocyte Development (GO:0014002)', 'p_value': 6.736219018143865e-11, 'odds_ratio': 1037.8181818181818, 'genes': ['APP', 'TREM2', 'MAPT', 'PSEN1']}, {'rank': 4, 'term': 'Regulation Of Amyloid Fibril Formation (GO:1905906)', 'p_value': 6.736219018143865e-11, 'odds_ratio': 1037.8181818181818, 'genes': ['APP', 'TREM2', 'PSEN1', 'CLU']}, {'rank': 5, 'term': 'Positive Regulation Of Supramolecular Fiber Organization (GO:1902905)', 'p_value': 1.0354136710554012e-09, 'odds_ratio': 182.21611721611723, 'genes': ['APP', 'MAPT', 'APOE', 'PSEN1', 'CLU']}, {'rank': 6, 'term': 'Macrophage Activation (GO:0042116)', 'p_value': 2.5696934344337086e-09, 'odds_ratio': 367.889400921659, 'genes': ['APP', 'TREM2', 'MAPT', 'CLU']}, {'rank': 7, 'term': 'Negative Regulation Of Long-Term Synaptic Potentiation (GO:1900272)', 'p_value': 6.919481814980666e-09, 'odds_ratio': 1498.8, 'genes': ['APP', 'TYROBP', 'APOE']}, {'rank': 8, 'term': 'Memory (GO:0007613)', 'p_value': 2.0688966159515193e-08, 'odds_ratio': 210.95238095238096, 'genes': ['TREM2', 'MAPT', 'APOE', 'PSEN1']}]
terms = [t['term'][:45] for t in go_bp][::-1]
neglogp = [-np.log10(max(t['p_value'], 1e-300)) for t in go_bp][::-1]
fig, ax = plt.subplots(figsize=(9, 4.5))
ax.barh(terms, neglogp, color='#4fc3f7')
ax.set_xlabel('-log10(p-value)')
ax.set_title('Top GO:BP enrichment (Enrichr)')
ax.grid(axis='x', alpha=0.3)
plt.tight_layout(); plt.show()
3. STRING protein interaction network¶
ppi = [{'protein1': 'APOE', 'protein2': 'MAPT', 'score': 0.879, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.57, 'dscore': 0, 'tscore': 0.731}, {'protein1': 'APOE', 'protein2': 'TREM2', 'score': 0.986, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.514, 'dscore': 0, 'tscore': 0.974}, {'protein1': 'APOE', 'protein2': 'CLU', 'score': 0.991, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0, 'dscore': 0.72, 'tscore': 0.971}, {'protein1': 'APOE', 'protein2': 'APP', 'score': 0.995, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.621, 'dscore': 0.72, 'tscore': 0.96}, {'protein1': 'PDGFRA', 'protein2': 'PDGFRB', 'score': 0.969, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.457, 'dscore': 0.9, 'tscore': 0.477}, {'protein1': 'TYROBP', 'protein2': 'TREM2', 'score': 0.998, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.526, 'dscore': 0.8, 'tscore': 0.982}, {'protein1': 'APP', 'protein2': 'TREM2', 'score': 0.491, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.359, 'dscore': 0, 'tscore': 0.239}, {'protein1': 'APP', 'protein2': 'MAPT', 'score': 0.886, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.57, 'dscore': 0, 'tscore': 0.746}, {'protein1': 'APP', 'protein2': 'CLU', 'score': 0.972, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.483, 'dscore': 0.72, 'tscore': 0.827}, {'protein1': 'APP', 'protein2': 'PSEN1', 'score': 0.975, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.946, 'dscore': 0, 'tscore': 0.571}, {'protein1': 'CLU', 'protein2': 'TREM2', 'score': 0.954, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.292, 'dscore': 0, 'tscore': 0.938}]
ppi_df = pd.DataFrame(ppi).sort_values('score', ascending=False)
display_cols = [c for c in ['protein1','protein2','score','escore','tscore'] if c in ppi_df.columns]
print(f'{len(ppi_df)} STRING edges')
ppi_df[display_cols].head(20)
11 STRING edges
| protein1 | protein2 | score | escore | tscore | |
|---|---|---|---|---|---|
| 5 | TYROBP | TREM2 | 0.998 | 0.526 | 0.982 |
| 3 | APOE | APP | 0.995 | 0.621 | 0.960 |
| 2 | APOE | CLU | 0.991 | 0.000 | 0.971 |
| 1 | APOE | TREM2 | 0.986 | 0.514 | 0.974 |
| 9 | APP | PSEN1 | 0.975 | 0.946 | 0.571 |
| 8 | APP | CLU | 0.972 | 0.483 | 0.827 |
| 4 | PDGFRA | PDGFRB | 0.969 | 0.457 | 0.477 |
| 10 | CLU | TREM2 | 0.954 | 0.292 | 0.938 |
| 7 | APP | MAPT | 0.886 | 0.570 | 0.746 |
| 0 | APOE | MAPT | 0.879 | 0.570 | 0.731 |
| 6 | APP | TREM2 | 0.491 | 0.359 | 0.239 |
import math
ppi = [{'protein1': 'APOE', 'protein2': 'MAPT', 'score': 0.879, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.57, 'dscore': 0, 'tscore': 0.731}, {'protein1': 'APOE', 'protein2': 'TREM2', 'score': 0.986, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.514, 'dscore': 0, 'tscore': 0.974}, {'protein1': 'APOE', 'protein2': 'CLU', 'score': 0.991, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0, 'dscore': 0.72, 'tscore': 0.971}, {'protein1': 'APOE', 'protein2': 'APP', 'score': 0.995, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.621, 'dscore': 0.72, 'tscore': 0.96}, {'protein1': 'PDGFRA', 'protein2': 'PDGFRB', 'score': 0.969, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.457, 'dscore': 0.9, 'tscore': 0.477}, {'protein1': 'TYROBP', 'protein2': 'TREM2', 'score': 0.998, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.526, 'dscore': 0.8, 'tscore': 0.982}, {'protein1': 'APP', 'protein2': 'TREM2', 'score': 0.491, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.359, 'dscore': 0, 'tscore': 0.239}, {'protein1': 'APP', 'protein2': 'MAPT', 'score': 0.886, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.57, 'dscore': 0, 'tscore': 0.746}, {'protein1': 'APP', 'protein2': 'CLU', 'score': 0.972, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.483, 'dscore': 0.72, 'tscore': 0.827}, {'protein1': 'APP', 'protein2': 'PSEN1', 'score': 0.975, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.946, 'dscore': 0, 'tscore': 0.571}, {'protein1': 'CLU', 'protein2': 'TREM2', 'score': 0.954, 'nscore': 0, 'fscore': 0, 'pscore': 0, 'ascore': 0, 'escore': 0.292, 'dscore': 0, 'tscore': 0.938}]
if ppi:
nodes = sorted({p for e in ppi for p in (e['protein1'], e['protein2'])})
n = len(nodes)
pos = {n_: (math.cos(2*math.pi*i/n), math.sin(2*math.pi*i/n)) for i, n_ in enumerate(nodes)}
fig, ax = plt.subplots(figsize=(7, 7))
for e in ppi:
x1,y1 = pos[e['protein1']]; x2,y2 = pos[e['protein2']]
ax.plot([x1,x2],[y1,y2], color='#888', alpha=0.3+0.5*e.get('score',0))
for name,(x,y) in pos.items():
ax.scatter([x],[y], s=450, color='#ffd54f', edgecolors='#333', zorder=3)
ax.annotate(name, (x,y), ha='center', va='center', fontsize=8, fontweight='bold', zorder=4)
ax.set_aspect('equal'); ax.axis('off')
ax.set_title(f'STRING PPI network ({len(ppi)} edges)')
plt.tight_layout(); plt.show()
4. Reactome pathway footprint¶
pw_rows = [{'gene': 'ACSL4', 'n_pathways': 2, 'top_pathway': 'Intracellular metabolism of fatty acids regulates insulin secretion'}, {'gene': 'ALOX15', 'n_pathways': 8, 'top_pathway': 'Synthesis of Leukotrienes (LT) and Eoxins (EX)'}, {'gene': 'APOE', 'n_pathways': 8, 'top_pathway': 'Nuclear signaling by ERBB4'}, {'gene': 'CLDN5', 'n_pathways': 2, 'top_pathway': 'Tight junction interactions'}, {'gene': 'GENES', 'n_pathways': 0, 'top_pathway': '—'}, {'gene': 'LPCAT3', 'n_pathways': 3, 'top_pathway': 'Acyl chain remodelling of PC'}, {'gene': 'MAPT', 'n_pathways': 3, 'top_pathway': 'Caspase-mediated cleavage of cytoskeletal proteins'}, {'gene': 'PARP1', 'n_pathways': 8, 'top_pathway': 'POLB-Dependent Long Patch Base Excision Repair'}, {'gene': 'PPARA', 'n_pathways': 8, 'top_pathway': 'BMAL1:CLOCK,NPAS2 activates circadian expression'}, {'gene': 'REGIONAL', 'n_pathways': 0, 'top_pathway': '—'}, {'gene': 'SIRT3', 'n_pathways': 5, 'top_pathway': 'Transcriptional activation of mitochondrial biogenesis'}, {'gene': 'SLC16A1', 'n_pathways': 4, 'top_pathway': 'Basigin interactions'}, {'gene': 'TREM2', 'n_pathways': 4, 'top_pathway': 'Immunoregulatory interactions between a Lymphoid and a non-Lymphoid ce'}, {'gene': 'VULNERABILITY', 'n_pathways': 0, 'top_pathway': '—'}]
pd.DataFrame(pw_rows).sort_values('n_pathways', ascending=False)
| gene | n_pathways | top_pathway | |
|---|---|---|---|
| 1 | ALOX15 | 8 | Synthesis of Leukotrienes (LT) and Eoxins (EX) |
| 2 | APOE | 8 | Nuclear signaling by ERBB4 |
| 8 | PPARA | 8 | BMAL1:CLOCK,NPAS2 activates circadian expression |
| 7 | PARP1 | 8 | POLB-Dependent Long Patch Base Excision Repair |
| 10 | SIRT3 | 5 | Transcriptional activation of mitochondrial bi... |
| 11 | SLC16A1 | 4 | Basigin interactions |
| 12 | TREM2 | 4 | Immunoregulatory interactions between a Lympho... |
| 6 | MAPT | 3 | Caspase-mediated cleavage of cytoskeletal prot... |
| 5 | LPCAT3 | 3 | Acyl chain remodelling of PC |
| 0 | ACSL4 | 2 | Intracellular metabolism of fatty acids regula... |
| 3 | CLDN5 | 2 | Tight junction interactions |
| 4 | GENES | 0 | — |
| 9 | REGIONAL | 0 | — |
| 13 | VULNERABILITY | 0 | — |
5. Hypothesis ranking (19 hypotheses)¶
hyp_data = [('ACSL4-Mediated Neuroinflammatory Amplification in Disea', 0), ('ACSL4-Driven Ferroptotic Priming in Disease-Associated ', 0.869), ('ACSL4-Ferroptotic Priming in Stressed Oligodendrocytes ', 0.801), ('40 Hz Gamma Entrainment Gates ACSL4-Mediated Ferroptoti', 0.801), ('Microglial TREM2-SYK Pathway Enhancement', 0.798), ('ACSL4-Driven Ferroptotic Priming in Disease-Associated ', 0.779), ('LPCAT3-Mediated Lands Cycle Remodeling as the Primary F', 0.779), ('ALOX15-Driven Enzymatic Ferroptosis in AD Oligodendrocy', 0.777), ('LPCAT3-Mediated Lands Cycle Amplification of Ferroptoti', 0.776), ('LPCAT3-Mediated Lands Cycle Amplification of Ferroptoti', 0.77), ('SIRT3-Mediated Mitochondrial Deacetylation Failure with', 0.738), ('Selective Tau Kinase Inhibition in Vulnerable Neuronal ', 0.676), ('Astrocyte MCT1/MCT4 Ratio Disruption with Metabolic Unc', 0.668), ('Astrocyte APOE4-Specific Lipid Metabolism Correction', 0.651), ('Cell-Type Specific Metabolic Reprogramming', 0.643), ('Disease-Associated Microglia Metabolic Reprogramming', 0.631), ('Spatially-Targeted Regional Vulnerability Prevention', 0.616), ('Vascular-Glial Interface Restoration', 0.566), ('Oligodendrocyte DNA Repair Enhancement', 0.55)]
titles = [h[0] for h in hyp_data][::-1]
scores = [h[1] for h in hyp_data][::-1]
fig, ax = plt.subplots(figsize=(10, max(8, len(titles)*0.4)))
colors = ['#ef5350' if s >= 0.6 else '#ffa726' if s >= 0.5 else '#66bb6a' for s in scores]
ax.barh(range(len(titles)), scores, color=colors)
ax.set_yticks(range(len(titles))); ax.set_yticklabels(titles, fontsize=7)
ax.set_xlabel('Composite Score'); ax.set_title('Cell type vulnerability in Alzheimers Disease (SEA-AD transcriptomic data)')
ax.grid(axis='x', alpha=0.3)
plt.tight_layout(); plt.show()
6. Score dimension heatmap (top 10)¶
labels = ['ACSL4-Mediated Neuroinflammatory Amplifi', 'ACSL4-Driven Ferroptotic Priming in Dise', 'ACSL4-Ferroptotic Priming in Stressed Ol', '40 Hz Gamma Entrainment Gates ACSL4-Medi', 'Microglial TREM2-SYK Pathway Enhancement', 'ACSL4-Driven Ferroptotic Priming in Dise', 'LPCAT3-Mediated Lands Cycle Remodeling a', 'ALOX15-Driven Enzymatic Ferroptosis in A', 'LPCAT3-Mediated Lands Cycle Amplificatio', 'LPCAT3-Mediated Lands Cycle Amplificatio']
matrix = np.array([[0, 0, 0, 0.84, 0.36, 0, 0.82, 0, 0.48], [0.85, 0.75, 0.85, 0.84, 0.36, 0, 0.82, 0, 0.48], [0.56, 0.6, 0, 0.74, 0.36, 0, 0.72, 0, 0.42], [0.63, 0.5, 0, 0.52, 0.36, 0, 0.72, 0, 0.61], [0.6, 0.7, 0.8, 0.8, 0.81, 0.7, 0.7, 0.8, 0.6], [0, 0.6, 0, 0.73, 0.36, 0, 0.88, 0, 0.44], [0.58, 0.58, 0, 0.78, 0.36, 0, 0.85, 0, 0.46], [0.62, 0, 0, 0.75, 0.36, 0, 0.88, 0, 0], [0.52, 0.58, 0, 0.77, 0.36, 0, 0.85, 0, 0.46], [0.51, 0, 0, 0.77, 0.36, 0, 0.85, 0, 0]])
dims = ['novelty_score', 'feasibility_score', 'impact_score', 'mechanistic_plausibility_score', 'clinical_relevance_score', 'data_availability_score', 'reproducibility_score', 'druggability_score', 'safety_profile_score']
if matrix.size:
fig, ax = plt.subplots(figsize=(10, 5))
im = ax.imshow(matrix, cmap='RdYlGn', aspect='auto', vmin=0, vmax=1)
ax.set_xticks(range(len(dims)))
ax.set_xticklabels([d.replace('_score','').replace('_',' ').title() for d in dims],
rotation=45, ha='right', fontsize=8)
ax.set_yticks(range(len(labels))); ax.set_yticklabels(labels, fontsize=7)
ax.set_title('Score dimensions — top hypotheses')
plt.colorbar(im, ax=ax, shrink=0.8)
plt.tight_layout(); plt.show()
else:
print('No score data available')
7. PubMed literature per hypothesis¶
Hypothesis 1: ACSL4-Mediated Neuroinflammatory Amplification in Disease-Associated M¶
Target genes: ACSL4 · Composite score: 0.0
ACSL4 (acyl-CoA synthetase long-chain family member 4) drives neuroinflammatory amplification in disease-associated microglia through arachidonic acid (AA) metabolism and eicosanoid signaling rather than ferroptotic cell death. In this mechanism, ACSL4 upregulation in DAM microglia increases AA-CoA
lit_data = [{'year': '2025', 'journal': 'Phytomedicine', 'title': 'Integrating metagenomics, lipidomics and proteomics to explore the effect and me', 'pmid': '41014671'}]
if lit_data:
df = pd.DataFrame(lit_data)
print(f'{len(lit_data)} PubMed results')
display(df)
else:
print('No PubMed results')
1 PubMed results
| year | journal | title | pmid | |
|---|---|---|---|---|
| 0 | 2025 | Phytomedicine | Integrating metagenomics, lipidomics and prote... | 41014671 |
Hypothesis 2: ACSL4-Driven Ferroptotic Priming in Disease-Associated Microglia¶
Target genes: ACSL4 · Composite score: 0.869
Mechanistic Overview¶
ACSL4-Driven Ferroptotic Priming in Disease-Associated Microglia starts from the claim that modulating ACSL4 within the disease context of Alzheimer's Disease can redirect a disease-relevant process. The original description reads: "## 1. Molecular Mechanism and Rationale ACS
lit_data = [{'year': '2025', 'journal': 'Phytomedicine', 'title': 'Integrating metagenomics, lipidomics and proteomics to explore the effect and me', 'pmid': '41014671'}]
if lit_data:
df = pd.DataFrame(lit_data)
print(f'{len(lit_data)} PubMed results')
display(df)
else:
print('No PubMed results')
1 PubMed results
| year | journal | title | pmid | |
|---|---|---|---|---|
| 0 | 2025 | Phytomedicine | Integrating metagenomics, lipidomics and prote... | 41014671 |
Hypothesis 3: ACSL4-Ferroptotic Priming in Stressed Oligodendrocytes Drives White Ma¶
Target genes: ACSL4 · Composite score: 0.801
Mechanistic Overview¶
ACSL4-Ferroptotic Priming in Stressed Oligodendrocytes Drives White Matter Degeneration in Alzheimer's Disease starts from the claim that modulating ACSL4 within the disease context of Alzheimer's Disease can redirect a disease-relevant process. The original description reads
lit_data = [{'year': '2025', 'journal': 'Phytomedicine', 'title': 'Integrating metagenomics, lipidomics and proteomics to explore the effect and me', 'pmid': '41014671'}]
if lit_data:
df = pd.DataFrame(lit_data)
print(f'{len(lit_data)} PubMed results')
display(df)
else:
print('No PubMed results')
1 PubMed results
| year | journal | title | pmid | |
|---|---|---|---|---|
| 0 | 2025 | Phytomedicine | Integrating metagenomics, lipidomics and prote... | 41014671 |
Hypothesis 4: 40 Hz Gamma Entrainment Gates ACSL4-Mediated Ferroptotic Priming to Se¶
Target genes: ACSL4 · Composite score: 0.801
Mechanistic Overview¶
40 Hz Gamma Entrainment Gates ACSL4-Mediated Ferroptotic Priming to Selectively Eliminate Disease-Associated Microglia starts from the claim that modulating ACSL4 within the disease context of Alzheimer's Disease can redirect a disease-relevant process. The original descripti
lit_data = [{'year': '2025', 'journal': 'Phytomedicine', 'title': 'Integrating metagenomics, lipidomics and proteomics to explore the effect and me', 'pmid': '41014671'}]
if lit_data:
df = pd.DataFrame(lit_data)
print(f'{len(lit_data)} PubMed results')
display(df)
else:
print('No PubMed results')
1 PubMed results
| year | journal | title | pmid | |
|---|---|---|---|---|
| 0 | 2025 | Phytomedicine | Integrating metagenomics, lipidomics and prote... | 41014671 |
Hypothesis 5: Microglial TREM2-SYK Pathway Enhancement¶
Target genes: TREM2 · Composite score: 0.798
Mechanistic Overview¶
Microglial TREM2-SYK Pathway Enhancement starts from the claim that modulating TREM2 within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "## Mechanistic Overview Microglial TREM2-SYK Pathway Enhancement star
print('No PubMed results for hypothesis h-48858e2a')
No PubMed results for hypothesis h-48858e2a
Hypothesis 6: ACSL4-Driven Ferroptotic Priming in Disease-Associated Oligodendrocyte¶
Target genes: ACSL4 · Composite score: 0.779
Mechanistic Overview¶
ACSL4-Driven Ferroptotic Priming in Disease-Associated Oligodendrocytes Underlies White Matter Degeneration in Alzheimer's Disease starts from the claim that modulating ACSL4 within the disease context of Alzheimer's Disease can redirect a disease-relevant process. The origin
print('No PubMed results for hypothesis h-var-f96e38ec20')
No PubMed results for hypothesis h-var-f96e38ec20
Hypothesis 7: LPCAT3-Mediated Lands Cycle Remodeling as the Primary Ferroptotic Prim¶
Target genes: LPCAT3 · Composite score: 0.779
Mechanistic Overview¶
LPCAT3-Mediated Lands Cycle Remodeling as the Primary Ferroptotic Priming Engine in Disease-Associated Microglia starts from the claim that modulating LPCAT3 within the disease context of Alzheimer's Disease can redirect a disease-relevant process. The original description re
lit_data = [{'year': '2025', 'journal': 'Phytomedicine', 'title': 'Integrating metagenomics, lipidomics and proteomics to explore the effect and me', 'pmid': '41014671'}]
if lit_data:
df = pd.DataFrame(lit_data)
print(f'{len(lit_data)} PubMed results')
display(df)
else:
print('No PubMed results')
1 PubMed results
| year | journal | title | pmid | |
|---|---|---|---|---|
| 0 | 2025 | Phytomedicine | Integrating metagenomics, lipidomics and prote... | 41014671 |
Hypothesis 8: ALOX15-Driven Enzymatic Ferroptosis in AD Oligodendrocytes via PUFA-PE¶
Target genes: ALOX15 · Composite score: 0.777
Mechanistic Overview¶
ALOX15-Driven Enzymatic Ferroptosis in AD Oligodendrocytes via PUFA-PE Peroxidation starts from the claim that modulating ALOX15 within the disease context of Alzheimer's Disease can redirect a disease-relevant process. The original description reads: "## Mechanistic Overview
lit_data = [{'year': '2025', 'journal': 'Phytomedicine', 'title': 'Integrating metagenomics, lipidomics and proteomics to explore the effect and me', 'pmid': '41014671'}]
if lit_data:
df = pd.DataFrame(lit_data)
print(f'{len(lit_data)} PubMed results')
display(df)
else:
print('No PubMed results')
1 PubMed results
| year | journal | title | pmid | |
|---|---|---|---|---|
| 0 | 2025 | Phytomedicine | Integrating metagenomics, lipidomics and prote... | 41014671 |
Hypothesis 9: LPCAT3-Mediated Lands Cycle Amplification of Ferroptotic Substrate Poo¶
Target genes: LPCAT3 · Composite score: 0.776
Mechanistic Overview¶
LPCAT3-Mediated Lands Cycle Amplification of Ferroptotic Substrate Pools in Disease-Associated Microglia starts from the claim that modulating LPCAT3 within the disease context of Alzheimer's Disease can redirect a disease-relevant process. The original description reads: "##
print('No PubMed results for hypothesis h-var-c56b26facf')
No PubMed results for hypothesis h-var-c56b26facf
Hypothesis 10: LPCAT3-Mediated Lands Cycle Amplification of Ferroptotic Vulnerability¶
Target genes: LPCAT3 · Composite score: 0.77
Mechanistic Overview¶
LPCAT3-Mediated Lands Cycle Amplification of Ferroptotic Vulnerability in Disease-Associated Microglia starts from the claim that modulating LPCAT3 within the disease context of Alzheimer's Disease can redirect a disease-relevant process. The original description reads: "**Mo
lit_data = [{'year': '2025', 'journal': 'Phytomedicine', 'title': 'Integrating metagenomics, lipidomics and proteomics to explore the effect and me', 'pmid': '41014671'}]
if lit_data:
df = pd.DataFrame(lit_data)
print(f'{len(lit_data)} PubMed results')
display(df)
else:
print('No PubMed results')
1 PubMed results
| year | journal | title | pmid | |
|---|---|---|---|---|
| 0 | 2025 | Phytomedicine | Integrating metagenomics, lipidomics and prote... | 41014671 |
Hypothesis 11: SIRT3-Mediated Mitochondrial Deacetylation Failure with PINK1/Parkin M¶
Target genes: SIRT3 · Composite score: 0.738
Mechanistic Overview¶
SIRT3-Mediated Mitochondrial Deacetylation Failure with PINK1/Parkin Mitophagy Dysfunction starts from the claim that modulating SIRT3 within the disease context of Alzheimer's Disease can redirect a disease-relevant process. The original description reads: "## Mechanistic Ov
print('No PubMed results for hypothesis h-seaad-v4-5a7a4079')
No PubMed results for hypothesis h-seaad-v4-5a7a4079
Hypothesis 12: Selective Tau Kinase Inhibition in Vulnerable Neuronal Subtypes¶
Target genes: MAPT · Composite score: 0.676
Mechanistic Overview¶
Selective Tau Kinase Inhibition in Vulnerable Neuronal Subtypes starts from the claim that modulating MAPT within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Background and Rationale Alzheimer's diseas
print('No PubMed results for hypothesis h-3fdee932')
No PubMed results for hypothesis h-3fdee932
Hypothesis 13: Astrocyte MCT1/MCT4 Ratio Disruption with Metabolic Uncoupling¶
Target genes: SLC16A1 · Composite score: 0.668
Mechanistic Overview¶
Astrocyte MCT1/MCT4 Ratio Disruption with Metabolic Uncoupling starts from the claim that modulating SLC16A1 within the disease context of Alzheimer's Disease can redirect a disease-relevant process. The original description reads: "## 1. Molecular Mechanism and Rationale The
print('No PubMed results for hypothesis h-seaad-v4-29e81bbc')
No PubMed results for hypothesis h-seaad-v4-29e81bbc
Hypothesis 14: Astrocyte APOE4-Specific Lipid Metabolism Correction¶
Target genes: APOE · Composite score: 0.651
Mechanistic Overview¶
Astrocyte APOE4-Specific Lipid Metabolism Correction starts from the claim that modulating APOE within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "## Mechanistic Overview Astrocyte APOE4-Specific Lipid Met
lit_data = [{'year': '2025', 'journal': 'Phytomedicine', 'title': 'Integrating metagenomics, lipidomics and proteomics to explore the effect and me', 'pmid': '41014671'}]
if lit_data:
df = pd.DataFrame(lit_data)
print(f'{len(lit_data)} PubMed results')
display(df)
else:
print('No PubMed results')
1 PubMed results
| year | journal | title | pmid | |
|---|---|---|---|---|
| 0 | 2025 | Phytomedicine | Integrating metagenomics, lipidomics and prote... | 41014671 |
Hypothesis 15: Cell-Type Specific Metabolic Reprogramming¶
Target genes: PPARA · Composite score: 0.643
Mechanistic Overview¶
Cell-Type Specific Metabolic Reprogramming starts from the claim that modulating PPARA within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "## Mechanistic Overview Cell-Type Specific Metabolic Reprogramming
print('No PubMed results for hypothesis h-b34120a1')
No PubMed results for hypothesis h-b34120a1
Hypothesis 16: Disease-Associated Microglia Metabolic Reprogramming¶
Target genes: TREM2 · Composite score: 0.631
Mechanistic Overview¶
Disease-Associated Microglia Metabolic Reprogramming starts from the claim that modulating TREM2 within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "# Disease-Associated Microglia Metabolic Reprogramming vi
print('No PubMed results for hypothesis h-2531ed61')
No PubMed results for hypothesis h-2531ed61
Hypothesis 17: Spatially-Targeted Regional Vulnerability Prevention¶
Target genes: Regional vulnerability genes · Composite score: 0.616
Mechanistic Overview¶
Spatially-Targeted Regional Vulnerability Prevention starts from the claim that modulating Regional vulnerability genes within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "## Mechanistic Overview Spatially-
print('No PubMed results for hypothesis h-80ff3fd6')
No PubMed results for hypothesis h-80ff3fd6
Hypothesis 18: Vascular-Glial Interface Restoration¶
Target genes: CLDN5 · Composite score: 0.566
Mechanistic Overview¶
Vascular-Glial Interface Restoration starts from the claim that modulating CLDN5 within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "## Mechanistic Overview Vascular-Glial Interface Restoration starts from
print('No PubMed results for hypothesis h-6cfb4671')
No PubMed results for hypothesis h-6cfb4671
Hypothesis 19: Oligodendrocyte DNA Repair Enhancement¶
Target genes: PARP1 · Composite score: 0.55
Mechanistic Overview¶
Oligodendrocyte DNA Repair Enhancement starts from the claim that modulating PARP1 within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "## Mechanistic Overview Oligodendrocyte DNA Repair Enhancement starts f
print('No PubMed results for hypothesis h-43ec636e')
No PubMed results for hypothesis h-43ec636e
8. Knowledge graph edges (201 total)¶
edge_data = [{'source': 'neuron', 'relation': 'implicated_in', 'target': "Alzheimer's disease", 'strength': 0.9}, {'source': 'DAM', 'relation': 'associated_with', 'target': 'microglia', 'strength': 0.85}, {'source': 'excitatory_neuron', 'relation': 'implicated_in', 'target': "Alzheimer's disease", 'strength': 0.85}, {'source': 'microglia', 'relation': 'associated_with', 'target': "Alzheimer's disease", 'strength': 0.85}, {'source': 'ACSL4', 'relation': 'associated_with', 'target': "Alzheimer's Disease", 'strength': 0.82}, {'source': 'ACSL4', 'relation': 'participates_in', 'target': 'ferroptosis', 'strength': 0.82}, {'source': 'astrocyte', 'relation': 'associated_with', 'target': "Alzheimer's disease", 'strength': 0.8}, {'source': 'inhibitory_neuron', 'relation': 'implicated_in', 'target': "Alzheimer's disease", 'strength': 0.8}, {'source': 'reactive_astrocyte', 'relation': 'associated_with', 'target': 'astrocyte', 'strength': 0.8}, {'source': 'diseases-atypical-parkinsonism', 'relation': 'investigated_in', 'target': 'h-b34120a1', 'strength': 0.75}, {'source': 'oligodendrocyte', 'relation': 'implicated_in', 'target': "Alzheimer's disease", 'strength': 0.75}, {'source': 'OPC', 'relation': 'associated_with', 'target': 'oligodendrocyte', 'strength': 0.75}, {'source': 'astrocytes', 'relation': 'regulates', 'target': 'lipid_metabolism', 'strength': 0.7}, {'source': 'microglia', 'relation': 'performs', 'target': 'amyloid_clearance', 'strength': 0.7}, {'source': 'oligodendrocytes', 'relation': 'vulnerable_to', 'target': 'myelin_breakdown', 'strength': 0.7}, {'source': 'MAPT', 'relation': 'associated_with', 'target': 'GSK3B', 'strength': 0.7}, {'source': 'APOE4', 'relation': 'dysregulates', 'target': 'cholesterol_metabolism', 'strength': 0.7}, {'source': 'CLDN5', 'relation': 'maintains', 'target': 'blood_brain_barrier', 'strength': 0.7}, {'source': 'SIRT3', 'relation': 'associated_with', 'target': "Alzheimer's Disease", 'strength': 0.68}, {'source': 'SIRT3', 'relation': 'participates_in', 'target': 'mitochondrial quality control', 'strength': 0.68}, {'source': 'SLC16A1', 'relation': 'associated_with', 'target': "Alzheimer's Disease", 'strength': 0.58}, {'source': 'SLC16A1', 'relation': 'participates_in', 'target': 'astrocyte-neuron lactate shutt', 'strength': 0.58}, {'source': 'PVALB', 'relation': 'co_discussed', 'target': 'ACSL4', 'strength': 0.4}, {'source': 'PVALB', 'relation': 'co_discussed', 'target': 'SLC16A1', 'strength': 0.4}, {'source': 'C3', 'relation': 'co_discussed', 'target': 'PARP1', 'strength': 0.4}]
if edge_data:
pd.DataFrame(edge_data).head(25)
else:
print('No KG edge data available')
Caveats¶
This notebook uses real Forge tool calls from live APIs:
- Enrichment is against curated gene-set libraries (Enrichr)
- STRING/Reactome/HPA/MyGene reflect curated knowledge
- PubMed literature is search-relevance ranked, not systematic review
The cached evidence bundle is the minimum viable real-data analysis for this topic.