Alzheimer disease genes

Reviewing every GO annotation on 34 human genes behind amyloid, tau, lipid and microglial biology

AI Gene Review · projects/ALZHEIMER_DISEASE · 2026

Bottom line

  • AD genetics converges on APP processing, tau, lipid transport, endocytosis and microglial immunity.
  • We reviewed 4,336 GO annotation rows (4,332 existing plus 4 proposed NEW) on 34 human genes; every review is COMPLETE and validates.
  • 54% accepted as core, 630 rows marked over-annotated, only 4 REMOVE: abstract-only experimental rows were left UNDECIDED (34) rather than overruled. The proposed pathway modules are not built yet.

The core mechanism: two routes for APP

Why this gene set

  • Mixed on purpose: familial genes (APP, PSEN1, PSEN2), GWAS and rare-variant risk genes (APOE, TREM2, SORL1, PLCG2, ABI3), and pathway genes (BACE1, the γ-secretase subunits, MAPT, GSK3B, CDK5).
  • Anchored on Open Targets and GWAS Catalog for MONDO:0004975, plus Bellenguez 2022, Kunkle 2019 and Sims 2017.
  • AD genes carry some of the largest annotation sets in human GO: APP 429 rows, GSK3B 390, APOE 293, TREM2 273.
  • The test: can review separate each gene's core molecular function from pleiotropic and disease-context rows?

Actions per gene

What a review looks like

PSEN1 review page: IBA rows for Notch signalling and intramembrane aspartic endopeptidase activity accepted as core γ-secretase function.

APP: isoforms and cleavage products

The APP review separates splice classes and cleavage products (sAPPα, sAPPβ, …) so fragment-specific functions are not pinned on the whole precursor.

Findings

  1. Very few REMOVEs (4): APP Notch signalling (IEA keyword), ADAM10 metallodipeptidase activity (IEA; ADAM10 is an endopeptidase), PLCG2 Wnt signalling (TAS), INPP5D NKG2A protein binding (abstract says SHIP is not associated).
  2. UNDECIDED instead of overruling (34): e.g. PSEN1 unusual locations (16), CD33/CD2AP tau-secretion rows from an FRMD4A-centred screen.
  3. 4 NEW terms: APP cell adhesion mediator activity, cell adhesion molecule binding, copper ion binding; INPP5D phosphotyrosine residue binding.
  4. MODIFY concentrated in signalling genes: SPI1 21, PLCG2 19, INPP5D 12.

Status and next steps

  • ✅ 34/34 gene reviews COMPLETE, most with a second-pass reference_review audit.
  • ⬜ Reusable normal-biology modules: APP processing, γ-secretase intramembrane proteolysis, apolipoprotein transport, microglial lipid sensing, tau microtubule biology, endocytic adaptors.
  • ⬜ Resolve the 34 UNDECIDED rows with full text.

Read more: projects/ALZHEIMER_DISEASE.md · genes/human/<GENE>/