alzheimer-ligrec-braak-breakdown-r1

Direction d5 from the Alzheimer's-mechanism IDEATE run.

Which ligand-receptor (L-R) communication axes between microglia, astrocytes, and excitatory/inhibitory neurons are most disrupted with advancing Braak stage in human AD snRNA-seq atlases; do the disrupted signals cluster in pathways encoded by AD GWAS risk genes; and can the identity of disrupted signals predict the next region of tau spread (EC→hippocampus→PFC sequence)?

De Strooper's "network disease" framing motivates this: AD emerges from the breakdown of coordinated glial-neuronal responses, not from any single cell-autonomous lesion. Prior work identified dysregulated L-R interactions in AD PFC and integrated GWAS risk into that framework, but did not address the TEMPORAL dynamics across Braak stage. This OmiCairn run quantifies cell-cell communication across Braak stage in open human AD snRNA-seq using open L-R inference frameworks (e.g. CellChat / NicheNet), tests GWAS enrichment of the disrupted axes, and explores whether disrupted signals presage tau spread.

Hypotheses (pre-registered, lifted from d5):

H1 (primary — three most-disrupted axes, monotone with Braak): Complement-related signaling (C1Q-C3-CR3 axis: microglia→neuron), SPP1 (microglia→astrocyte/oligodendrocyte), and CXCL10-CXCR3 (glia→T-cell recruitment) are the three most disrupted communication axes in AD, with disruption magnitude increasing monotonically with Braak stage. Decision rule: per-donor pseudobulk L-R interaction scores (CellChat communication probability or equivalent) regressed on Braak stage (ordinal); report slope + p-value + 95% CI per axis. H1 passes if the three named axes rank among the top disrupted interactions AND each shows a positive monotone slope with Braak (p<0.05, 95% CI excluding 0). Report the full ranked disruption table regardless — if a different axis dominates, that is the finding.

H2 (secondary — GWAS enrichment of disrupted axes): Disrupted L-R interactions at Braak stage III-IV are significantly enriched in pathways encoded by genes in the top 20 AD GWAS loci (specifically BIN1, CLU, CR1, MS4A, PICALM, TREM2), indicating that GWAS-identified risk converges on inter-cellular communication failure rather than purely cell-autonomous dysfunction. Decision rule: hypergeometric / permutation enrichment test of the Braak III-IV disrupted-interaction gene set against the top-20 AD GWAS locus gene set; report odds ratio / enrichment statistic + p-value + 95% CI. H2 passes if enrichment is significant (p<0.05) with a 95% CI excluding the null.

A negative or partial result is fully informative. If complement / SPP1 / CXCL10 are NOT the top disrupted axes, report the actual ranking as the headline. If GWAS enrichment is absent, report that the disrupted communication network does not preferentially involve GWAS loci. Do not re-tune the L-R inference until H1/H2 pass.

The tau-spread prediction (EC→hippocampus→PFC) is exploratory and multi-region: with a single-region primary atlas it can only be framed as a hypothesis-generating direction, not tested. Report it as such unless a multi-region open atlas (SEA-AD) is successfully fetched and harmonised.

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.