Campaign run · Alzheimer's disease
alzheimer-bbb-pericyte-vascular-r1
Does pericyte-specific SMAD3 upregulation co-occur with astrocytic VEGFA downregulation in a spatially coherent manner across AD Braak stages, and does this vascular transcriptional programme precede or follow parenchymal amyloid deposition in human brain?
Status
- How far it got
- Stopped before planning
Stopped before writing any hypotheses: a dry-run test, a launch superseded by an immediate relaunch, a usage limit or a process failure.
- Why it stopped
This run stopped before the planning stage for an operational reason, not a scientific one. Runs in this group are dry-run tests, launches superseded by an immediate relaunch, runs that hit a usage limit, or one process failure. The released data do not say which of these applies to an individual run. No run in the campaign stopped before planning because data were unavailable.
- Recorded status
Stopped without a final status. The run stopped without recording a final status.
- Census class
Partial. Census class is a label from an earlier, process-level census of the campaign. It does not map one-to-one onto the stages above. How the classes compare.
Research question
The sentence under the run id is quoted from this brief.
Full research brief given to the run
Direction d2 from the second Alzheimer's-mechanism IDEATE run.
Does pericyte-specific SMAD3 upregulation co-occur with astrocytic VEGFA downregulation in a spatially coherent manner across AD Braak stages, and does this vascular transcriptional programme precede or follow parenchymal amyloid deposition in human brain?
No prior lab run has examined vascular cells. The "Gliovascular transcriptional perturbations" Nature Communications 2024 paper identified pericyte SMAD3 upregulation and astrocytic VEGFA downregulation as the dominant blood-brain-barrier (BBB) disruption signals in AD, with blood SMAD3 levels associating with AD neuroimaging outcomes in a separate human cohort. A companion paper found HIF1A/VEGFA angiogenic failure in AD endothelial cells in the same open dataset (GSE157827, Lau 2020), which is confirmed to contain pericyte, endothelial, and astrocyte populations. This OmiCairn run stratifies donors by Braak stage, applies per-donor pseudobulk DE to vascular cell types, and asks whether the SMAD3/VEGFA axis changes before or after amyloid threshold.
Hypotheses (pre-registered, lifted from d2):
H1 (primary — pericyte SMAD3 upregulation by Braak): Pericyte SMAD3 expression is significantly elevated (pseudobulk, FDR < 0.05, fold-change > 1.5) in Braak III-IV vs. Braak 0 donors in GSE157827. Decision rule: per-donor pseudobulk DE within the pericyte compartment, Braak III-IV vs Braak 0; report log2FC + Benjamini-Hochberg FDR + 95% bootstrap CI for SMAD3. H1 passes if SMAD3 is up with fold-change > 1.5 at FDR<0.05 and the 95% CI excludes 0. Report astrocytic VEGFA in parallel (expected down) with the same statistics as a paired vascular-axis readout.
H2 (secondary — vascular programme precedes amyloid threshold): SMAD3 upregulation in pericytes precedes the amyloid plaque density threshold by at least one Braak stage in the GSE157827 donor series, supporting vascular dysfunction as a trigger rather than a consequence. Decision rule: order donors by Braak stage; locate the Braak stage at which pericyte SMAD3 first rises significantly above Braak 0 baseline and the Braak stage at which amyloid plaque density (or its closest available neuropathology proxy) first crosses its threshold; report the Braak-stage offset with a bootstrap 95% CI. H2 passes if the SMAD3-rise stage is at least one Braak stage earlier than the amyloid-threshold stage and the 95% CI of the offset excludes 0.
IMPORTANT — covariate dependency: H1 requires Braak/tau staging in the fetched donors; H2 additionally requires an amyloid plaque-density (or equivalent Aβ) neuropathology measure in the same donors. EXECUTE MUST first verify these are present. If Braak staging is missing, H1 cannot be tested as specified — report that honestly and fall back to an AD-vs-control pericyte SMAD3 contrast without Braak ordering. If amyloid neuropathology is missing, H2 (the precedence question) is untestable — say so and report the Braak-ordered SMAD3 trajectory descriptively without claiming precedence over amyloid. Do NOT impute or fabricate Braak stage or amyloid measures.
A negative or partial result is fully informative. If pericyte SMAD3 is not elevated, or its rise does not precede amyloid, that must be the headline rather than re-tuning cluster definitions until H1/H2 pass.
The research question comes from the topic's current research brief. All attempts at a topic share it; earlier attempts may have started from an earlier wording.