Alzheimer disease-relevant human pathway modules

A project-level decomposition of normal human pathway modules represented by the Alzheimer disease review gene set. The module groups gene products by evolved biological roles in APP processing and amyloid-beta handling, lipid/lipoprotein transport, microglial lipid-debris sensing, tau/cytoskeletal kinase biology, and endocytic/adhesion adaptor systems. It is not a causal disease-progression model.

MODULE:alzheimer_disease_relevant_pathwaysDRAFTModulemodules/alzheimer_disease_pathways.yaml
Alzheimer disease-relevant pathway curation set
file:projects/ALZHEIMER_DISEASE.md
Alzheimer disease project review log
Project-level curation record listing the 34 reviewed human genes and the second-pass review status for each gene.
file:genes/human/APP/APP-ai-review.yaml
APP gene review
Supports APP as the central precursor/cargo for amyloidogenic and non-amyloidogenic processing branches, adhesion-related functions, and amyloid-beta biology.
file:genes/human/TREM2/TREM2-ai-review.yaml
TREM2 gene review
Supports the microglial lipid/apolipoprotein/apoptotic-cell receptor branch and its coupling to TYROBP/SYK/PLC signaling.
file:genes/human/MAPT/MAPT-ai-review.yaml
MAPT gene review
Supports tau microtubule binding, microtubule stabilization, axonal localization, and pathological tau self-assembly as a separate module from APP processing.

This module is deliberately conservative. It groups reviewed genes into reusable pathway modules but does not assert that every connection is a direct disease-causal edge. Disease-progression hypotheses should be handled in a separate disease-mechanism artifact.

6Nodes
5Parts
0Variant Sets
0Variants
21Annotons
4Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:alzheimer_disease_relevant_pathways deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Gene-review completeness (0/0 grounded genes reviewed)

No concrete UniProt-grounded genes in this module.

Details

Context
Homo sapiensNCBITaxon:9606
neuron microglial cell astrocyte brain endothelial cell macrophage or myeloid-lineage cell
central nervous system brain vasculature and immune interfaces
Alzheimer disease-relevant human pathway modulesModulealzheimer_disease_relevant_pathways
Alzheimer disease-relevant pathway curation set
Context
Homo sapiensNCBITaxon:9606
neuron microglial cell astrocyte brain endothelial cell macrophage or myeloid-lineage cell
central nervous system brain vasculature and immune interfaces

Connections

Endocytic adaptors and membrane-remodeling proteins influence APP, BACE1, LRP1, and amyloid-beta compartment access and routing.
APOE/CLU/lipoprotein particles and lipidated debris provide ligands or cargo context for TREM2- and receptor-mediated microglial handling.
APP-derived amyloid-beta peptides and amyloid-lipoprotein complexes can become cargo or ligands for microglial uptake and receptor signaling.
Tau and tau-regulating kinases intersect with cytoskeletal, synaptic, and adaptor proteins such as BIN1 and PICALM, but these links should be curated as context-specific unless direct molecular evidence supports a gene-level GO annotation.
Part 1: APP processing, trafficking, and amyloid-beta handling
APP processing and amyloid-beta handlingBiological Processapp_processing_and_amyloid_handling

Regulated trafficking and proteolysis of APP, plus receptor- and transporter-linked handling of amyloid-beta peptides and APP-derived cargos. This module separates alpha-secretase, beta-secretase, gamma-secretase, sorting, and clearance roles.

Annotons

APP precursor and processed cargo
app_precursor_cargo
Participant: Gene: APP
Gene:
APP

Processes

APP processing and amyloid-beta peptide generation

Substrate and signaling/adhesion precursor whose ectodomain and intramembrane cleavage products connect non-amyloidogenic and amyloidogenic processing branches.

ADAM10 alpha-secretase branch
adam10_alpha_secretase
Participant: Gene: ADAM10
Gene:
ADAM10

Function

membrane metalloendopeptidase sheddase activity

Processes

non-amyloidogenic APP ectodomain shedding

Membrane sheddase that contributes to alpha-secretase cleavage of APP and other cell-surface substrates.

BACE1 beta-secretase branch
bace1_beta_secretase
Participant: Gene: BACE1
Gene:
BACE1

Function

membrane aspartyl endopeptidase activity

Processes

amyloidogenic APP beta-site cleavage

Endosomal/TGN-accessed beta-secretase that initiates amyloidogenic APP processing.

Presenilin gamma-secretase complex
gamma_secretase_complex
Participant: Protein Complex: presenilin-containing gamma-secretase complex
Protein Complex:
presenilin-containing gamma-secretase complex
Active units:
PSEN1 catalytic subunit option
Participant: Gene: PSEN1
Gene:
PSEN1
Role: catalytic presenilin subunit
PSEN2 catalytic subunit option
Participant: Gene: PSEN2
Gene:
PSEN2
Role: catalytic presenilin subunit in alternative complexes
NCSTN substrate-recognition subunit
Participant: Gene: NCSTN
Gene:
NCSTN
Role: nicastrin substrate-recruitment subunit
APH1A scaffold subunit
Participant: Gene: APH1A
Gene:
APH1A
Role: APH-1 scaffold/adaptor subunit
APH1B scaffold subunit option
Participant: Gene: APH1B
Gene:
APH1B
Role: APH-1 paralog in alternative complexes
PSENEN/PEN-2 maturation subunit
Participant: Gene: PSENEN
Gene:
PSENEN
Role: presenilin maturation and complex-stability subunit

Function

intramembrane aspartyl endopeptidase complex activity

Processes

APP and Notch intramembrane proteolysis

Four-subunit membrane protease complex that performs presenilin-dependent intramembrane cleavage of APP and many other type I membrane substrates.

APP and amyloid-beta sorting/clearance receptors and adaptors
app_sorting_receptors_and_adaptors
Participant: Any Participant: SORL1, LRP1, PICALM, BIN1, ABCA7, and CD2AP roles in APP, BACE1, or amyloid-beta routing.
SORL1, LRP1, PICALM, BIN1, ABCA7, and CD2AP roles in APP, BACE1, or amyloid-beta routing.

Processes

endocytic sorting and amyloid-beta clearance

Sorting receptors and membrane/adaptor proteins regulate APP/BACE1 compartment access, amyloid-beta uptake or transcytosis, and clearance-related trafficking.

file:genes/human/SORL1/SORL1-ai-review.yaml
SORL1 supports APP sorting and amyloid-beta lysosomal routing.
file:genes/human/LRP1/LRP1-ai-review.yaml
LRP1 supports amyloid-beta clearance/transcytosis and cargo endocytosis.
file:genes/human/PICALM/PICALM-ai-review.yaml
PICALM supports clathrin-mediated endocytic routing of amyloid-beta/LRP1 and other cargo.
file:genes/human/BIN1/BIN1-ai-review.yaml
BIN1 supports BACE1 trafficking and membrane remodeling.
file:genes/human/ABCA7/ABCA7-ai-review.yaml
ABCA7 supports phospholipid transport, phagocytosis, and amyloid processing/clearance.
file:genes/human/CD2AP/CD2AP-ai-review.yaml
CD2AP supports actin/endocytic adaptor biology and tau-release context.
Part 2: lipid, lipoprotein, and cholesterol transport
Lipid and lipoprotein transportTransport Steplipoprotein_lipid_transport

Exchangeable apolipoproteins, ABC lipid transporters, and endocytic receptors coordinate phospholipid/cholesterol efflux, HDL-like particle assembly, APOE/clusterin lipidation, and receptor-mediated particle uptake.

Annotons

APOE lipoprotein carrier
apoe_lipoprotein_carrier
Participant: Gene: APOE
Gene:
APOE

Function

exchangeable apolipoprotein lipid carrier activity

Processes

lipoprotein particle remodeling and receptor-mediated clearance

Secreted apolipoprotein that binds lipids and receptors to mediate peripheral and CNS lipoprotein transport.

CLU extracellular holdase and lipoprotein-associated chaperone
clu_extracellular_chaperone
Participant: Gene: CLU
Gene:
CLU

Function

extracellular holdase chaperone activity

Processes

extracellular protein/lipoprotein client handling

Secreted glycoprotein chaperone associated with lipoproteins, amyloid-beta handling, and complement-related extracellular protection.

ABCA1 lipid efflux transporter
abca1_lipid_efflux
Participant: Gene: ABCA1
Gene:
ABCA1

Function

ATP-coupled phospholipid and cholesterol transporter activity

Processes

apolipoprotein-dependent cholesterol and phospholipid efflux

ATP-binding cassette transporter required for apolipoprotein lipidation and HDL biogenesis.

ABCA7 phospholipid transporter
abca7_phospholipid_transport
Participant: Gene: ABCA7
Gene:
ABCA7

Function

ATP-coupled phospholipid transporter activity

Processes

phospholipid efflux and phagocytic membrane support

ABCA-family transporter with strong support for phospholipid and lysophosphatidylcholine transport, phagocytosis, and amyloid processing/clearance effects.

LRP1 lipoprotein and cargo endocytic receptor
lrp1_lipoprotein_endocytic_receptor
Participant: Gene: LRP1
Gene:
LRP1

Function

multifunctional cargo receptor activity

Processes

receptor-mediated endocytosis of lipoprotein and ligand complexes

LDLR-family receptor mediating endocytosis and clearance of apolipoprotein, amyloid-beta, tau, and other ligand complexes.

Part 3: microglial and complement lipid-debris sensing
Microglial lipid-debris sensing and immune signalingSignaling Pathwaymicroglial_lipid_debris_sensing

Myeloid and microglial receptors/adaptors convert lipid, apoptotic-cell, complement, and immune-complex information into phagocytic, metabolic, and inflammatory state changes.

Annotons

TREM2 lipid/apolipoprotein receptor axis
trem2_receptor_axis
Participant: Gene: TREM2
Gene:
TREM2

Function

damage-associated lipid and apolipoprotein receptor activity

Processes

microglial phagocytosis and lipid-responsive signaling

Microglial/myeloid receptor for apolipoprotein, lipoprotein, amyloid-associated, apoptotic-cell, and myelin lipid ligands.

PLCG2 and INPP5D phosphoinositide signaling balance
plc_inositol_signaling_balance
Participant: Any Participant: PLCG2 generates downstream phospholipase-C signals, while INPP5D/SHIP1 dampens PI3K/phosphoinositide signaling.
PLCG2 generates downstream phospholipase-C signals, while INPP5D/SHIP1 dampens PI3K/phosphoinositide signaling.

Processes

immunoreceptor phosphoinositide signaling control

Coupled activation and inhibitory phosphoinositide enzymes tune myeloid receptor outputs downstream of TREM2 and related receptors.

file:genes/human/PLCG2/PLCG2-ai-review.yaml
PLCG2 review supports phospholipase C signaling downstream of immune receptors including TREM2.
file:genes/human/INPP5D/INPP5D-ai-review.yaml
INPP5D review supports SHIP1 inhibitory phosphoinositide phosphatase signaling in immune cells.
CD33, ABI3, SPI1, and MS4A-family microglial state modulators
inhibitory_and_actin_adaptors
Participant: Any Participant: CD33, ABI3, SPI1, MS4A4A, and MS4A6A roles in myeloid state, membrane, actin, and receptor modulation.
CD33, ABI3, SPI1, MS4A4A, and MS4A6A roles in myeloid state, membrane, actin, and receptor modulation.

Processes

myeloid receptor state and actin/membrane remodeling

Immunoreceptor, actin-regulatory, transcriptional, and membrane proteins that modulate microglial/myeloid state rather than acting as amyloid-processing enzymes.

CR1 and CLU complement/immune-complex handling
complement_clearance_axis
Participant: Any Participant: CR1 complement receptor/cofactor and CLU complement-protective extracellular chaperone roles.
CR1 complement receptor/cofactor and CLU complement-protective extracellular chaperone roles.

Processes

complement-opsonized particle handling and complement regulation

Complement receptor and extracellular chaperone functions that influence immune-complex, complement, and extracellular-client handling.

Part 4: tau, cytoskeleton, and neuronal kinase regulation
Tau cytoskeleton and kinase moduleBiological Processtau_cytoskeleton_kinase_module

Tau microtubule binding and stabilization, tau self-assembly, and neuronal kinases/adaptors that regulate cytoskeletal and synaptic substrate states.

Annotons

MAPT/tau microtubule-associated protein
mapt_tau_microtubule
Participant: Gene: MAPT
Gene:
MAPT

Function

microtubule binding and stabilization

Processes

axonal microtubule organization and tau assembly

Neuronal microtubule-associated protein whose physiological role is microtubule binding/stabilization and whose pathological branch includes tau self-assembly.

GSK3B tau and beta-catenin kinase
gsk3b_tau_wnt_kinase
Participant: Gene: GSK3B
Gene:
GSK3B

Function

protein serine/threonine kinase activity

Processes

tau phosphorylation and Wnt/beta-catenin regulation

Broad serine/threonine kinase with central substrate branches including tau and beta-catenin destruction-complex regulation.

CDK5-CDK5R1 neuronal kinase complex
cdk5_cdk5r1_kinase_complex
Participant: Protein Complex: CDK5-p35/p25 protein kinase complex
Protein Complex:
CDK5-p35/p25 protein kinase complex
Active units:
CDK5 catalytic kinase
Participant: Gene: CDK5
Gene:
CDK5
Role: catalytic serine/threonine kinase
CDK5R1 p35/p25 regulatory subunit
Participant: Gene: CDK5R1
Gene:
CDK5R1
Role: non-catalytic activator and localization/substrate-context regulator

Function

activated neuronal protein serine/threonine kinase complex activity

Processes

neuronal substrate phosphorylation, autophagy induction, and synaptic receptor regulation

CDK5 activity depends on p35/p25-family activators that determine localization, stability, and substrate context.

Part 5: endocytic, adhesion, and cytoskeletal adaptor systems
Endocytic, adhesion, and cytoskeletal adaptor systemsBiological Processendocytic_adhesion_adaptor_systems

Membrane-remodeling, clathrin, focal-adhesion, and cytoskeletal scaffold proteins that tune cargo routing, adhesion, and cellular morphology.

Annotons

PICALM clathrin/SNARE adaptor
picalm_clathrin_snr_adaptor
Participant: Gene: PICALM
Gene:
PICALM

Function

clathrin assembly and SNARE cargo adaptor activity

Processes

clathrin-mediated endocytosis and cargo sorting

ANTH-domain adaptor for clathrin-coated pit maturation and selected cargo/SNARE endocytosis.

BIN1 BAR-domain membrane-remodeling adaptor
bin1_bar_adaptor
Participant: Gene: BIN1
Gene:
BIN1

Function

membrane curvature sensing and remodeling

Processes

endocytic membrane remodeling and BACE1 trafficking context

BAR/SH3 adaptor that shapes membranes and contributes to muscle, neuronal, BACE1-trafficking, and tau-interaction contexts.

CD2AP actin/endocytic adaptor
cd2ap_actin_endocytic_adaptor
Participant: Gene: CD2AP
Gene:
CD2AP

Function

actin-associated adaptor activity

Processes

endocytosis, actin organization, and podocyte/immune adaptor biology

SH3-domain adaptor linking membrane protein complexes to actin and endocytic trafficking.

EPHA1, FERMT2, and CASS4 adhesion-signaling axis
eph_kindlin_cas_adhesion_axis
Participant: Any Participant: EPHA1 receptor tyrosine kinase, FERMT2/kindlin-2 integrin adaptor, and CASS4 focal-adhesion scaffold.
EPHA1 receptor tyrosine kinase, FERMT2/kindlin-2 integrin adaptor, and CASS4 focal-adhesion scaffold.

Processes

contact-dependent signaling, integrin activation, focal adhesion, and cytoskeletal remodeling

Adhesion and cytoskeletal signaling proteins whose primary roles are receptor-kinase signaling, integrin activation, and focal-adhesion scaffolding rather than amyloid or tau catalysis.