Alzheimer disease 2

Summary

Alzheimer disease 2 (MONDO:0007089) is a disease caused by APOE (GenCC Definitive), with 1 cohort gene and 9 clinical trials. Top therapeutic interventions include brexanolone and eltanolone.

At a glance

• Causal gene: APOE (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 19
• Clinical trials: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Alzheimer disease 2
Mondo ID	MONDO:0007089
MeSH	C536595
OMIM	104310
DOID	DOID:0110035
UMLS	C1863051
MedGen	400197
Is cancer (heuristic)	no

Also known as: AD2 · Alzheimer disease 2 · Alzheimer disease associated with APOE E4 · Alzheimer disease associated with APOE4 · Alzheimer disease type 2 · Alzheimer’s disease 2 · Alzheimer’s disease type 2 · late onset Alzheimer disease · late onset familial Alzheimer disease · late-onset familial alzheimer disease · LOFAD

Data availability: 19 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › cognitive disorder › dementia › Alzheimer disease › familial Alzheimer disease › Alzheimer disease 2

Related subtypes (1): early-onset autosomal dominant Alzheimer disease

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

19 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 6 conflicting classifications of pathogenicity, 2 likely benign, 1 conflicting classifications of pathogenicity; other; risk factor, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
17880	NM_000041.4(APOE):c.127C>T (p.Arg43Cys)	APOE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1722323	NM_000041.4(APOE):c.-24+82G>A	APOE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
17851	NM_000041.4(APOE):c.487C>T (p.Arg163Cys)	APOE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
17864	NM_000041.4(APOE):c.388T>C (p.Cys130Arg)	APOE	Conflicting classifications of pathogenicity; other; risk factor	criteria provided, conflicting classifications
3572888	NM_000041.4(APOE):c.460C>T (p.Arg154Cys)	APOE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
440842	NM_000041.4(APOE):c.91G>A (p.Glu31Lys)	APOE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
478832	NM_000041.4(APOE):c.784G>A (p.Glu262Lys)	APOE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
478838	NM_000041.4(APOE):c.787G>A (p.Glu263Lys)	APOE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1315806	NM_000041.4(APOE):c.688G>A (p.Glu230Lys)	APOE	Uncertain significance	criteria provided, multiple submitters, no conflicts
3779927	NM_000041.4(APOE):c.109G>A (p.Glu37Lys)	APOE	Uncertain significance	criteria provided, single submitter
3779929	NM_000041.4(APOE):c.31A>T (p.Thr11Ser)	APOE	Uncertain significance	criteria provided, single submitter
3779932	NM_000041.4(APOE):c.513T>G (p.Asp171Glu)	APOE	Uncertain significance	criteria provided, single submitter
3779933	NM_000041.4(APOE):c.541C>A (p.Gln181Lys)	APOE	Uncertain significance	criteria provided, single submitter
3779934	NM_000041.4(APOE):c.574C>G (p.Leu192Val)	APOE	Uncertain significance	criteria provided, single submitter
478884	NM_000041.4(APOE):c.805C>G (p.Arg269Gly)	APOE	Uncertain significance	criteria provided, multiple submitters, no conflicts
478904	NM_000041.4(APOE):c.434G>A (p.Gly145Asp)	APOE	Uncertain significance	criteria provided, multiple submitters, no conflicts
1210034	NM_000041.4(APOE):c.69G>A (p.Ala23=)	APOE	Likely benign	criteria provided, multiple submitters, no conflicts
760030	NM_000041.4(APOE):c.249C>T (p.Asp83=)	APOE	Likely benign	criteria provided, multiple submitters, no conflicts
779286	NM_000041.4(APOE):c.651C>T (p.Ala217=)	APOE	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
APOE	Definitive	Autosomal dominant	Alzheimer disease 2	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
APOE	Orphanet:329481	Lipoprotein glomerulopathy
APOE	Orphanet:412	Dysbetalipoproteinemia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
APOE	HGNC:613	ENSG00000130203	P02649	Apolipoprotein E	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
APOE	Apolipoprotein E	APOE is an apolipoprotein, a protein associating with lipid particles, that mainly functions in lipoprotein-mediated lipid transport between organs via the plasma and interstitial fluids.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APOE	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	1
left adrenal gland cortex	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APOE	267	ubiquitous	marker	left adrenal gland, left adrenal gland cortex, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOE	6,793

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APOE	P02649	29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 34. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Chylomicron clearance	1	2284.0×	0.007	APOE
Chylomicron assembly	1	1142.0×	0.007	APOE
Chylomicron remodeling	1	1142.0×	0.007	APOE
HDL remodeling	1	1142.0×	0.007	APOE
Plasma lipoprotein assembly	1	713.8×	0.007	APOE
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1	634.4×	0.007	APOE
Scavenging by Class A Receptors	1	601.0×	0.007	APOE
Binding and Uptake of Ligands by Scavenger Receptors	1	543.8×	0.007	APOE
Plasma lipoprotein remodeling	1	475.8×	0.007	APOE
Plasma lipoprotein clearance	1	475.8×	0.007	APOE
NR1H2 and NR1H3-mediated signaling	1	393.8×	0.007	APOE
Metabolism of fat-soluble vitamins	1	380.7×	0.007	APOE
Nuclear signaling by ERBB4	1	346.1×	0.008	APOE
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	308.6×	0.008	APOE
Signaling by ERBB4	1	271.9×	0.008	APOE
Visual phototransduction	1	259.6×	0.008	APOE
Retinoid metabolism and transport	1	248.3×	0.008	APOE
Plasma lipoprotein assembly, remodeling, and clearance	1	228.4×	0.008	APOE
Metabolism of vitamins and cofactors	1	116.5×	0.015	APOE
Amyloid fiber formation	1	102.9×	0.015	APOE
Signaling by Nuclear Receptors	1	102.0×	0.015	APOE
Post-translational protein phosphorylation	1	100.2×	0.015	APOE
Sensory Perception	1	95.2×	0.016	APOE
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.016	APOE
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.026	APOE
Vesicle-mediated transport	1	34.8×	0.038	APOE
Transport of small molecules	1	25.1×	0.050	APOE
RNA Polymerase II Transcription	1	22.5×	0.054	APOE
Post-translational protein modification	1	19.2×	0.061	APOE
Gene expression (Transcription)	1	17.8×	0.064	APOE

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lipid transport involved in lipid storage	1	16852.0×	0.001	APOE
maintenance of location in cell	1	16852.0×	0.001	APOE
intermediate-density lipoprotein particle clearance	1	16852.0×	0.001	APOE
positive regulation of lipid transport across blood-brain barrier	1	16852.0×	0.001	APOE
regulation of cellular response to very-low-density lipoprotein particle stimulus	1	16852.0×	0.001	APOE
triglyceride-rich lipoprotein particle clearance	1	8426.0×	0.001	APOE
regulation of amyloid-beta clearance	1	8426.0×	0.001	APOE
regulation of amyloid fibril formation	1	8426.0×	0.001	APOE
positive regulation of low-density lipoprotein particle receptor catabolic process	1	5617.3×	0.001	APOE
negative regulation of triglyceride metabolic process	1	4213.0×	0.001	APOE
positive regulation of phospholipid efflux	1	4213.0×	0.001	APOE
regulation of behavioral fear response	1	4213.0×	0.001	APOE
very-low-density lipoprotein particle clearance	1	3370.4×	0.001	APOE
acylglycerol homeostasis	1	3370.4×	0.001	APOE
cellular response to lipoprotein particle stimulus	1	3370.4×	0.001	APOE
AMPA glutamate receptor clustering	1	3370.4×	0.001	APOE
NMDA glutamate receptor clustering	1	3370.4×	0.001	APOE
positive regulation of lipoprotein transport	1	3370.4×	0.001	APOE
positive regulation of dendritic spine maintenance	1	3370.4×	0.001	APOE
regulation of amyloid precursor protein catabolic process	1	3370.4×	0.001	APOE
positive regulation of amyloid fibril formation	1	3370.4×	0.001	APOE
chylomicron remnant clearance	1	2808.7×	0.002	APOE
lipoprotein biosynthetic process	1	2808.7×	0.002	APOE
high-density lipoprotein particle clearance	1	2407.4×	0.002	APOE
lipoprotein catabolic process	1	2407.4×	0.002	APOE
negative regulation of cholesterol biosynthetic process	1	2407.4×	0.002	APOE
very-low-density lipoprotein particle remodeling	1	2106.5×	0.002	APOE
regulation of protein metabolic process	1	2106.5×	0.002	APOE
negative regulation of protein metabolic process	1	2106.5×	0.002	APOE
positive regulation of cholesterol metabolic process	1	2106.5×	0.002	APOE

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
APOE	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	APOE

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
APOE	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	7
PHASE2	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04838301	PHASE2	RECRUITING	Allopregnanolone Regenerative Therapeutic for Mild Alzheimer’s Disease
NCT03806478	PHASE2	UNKNOWN	Study of APH-1105 in Patients With Mild to Moderate Alzheimer’s Disease
NCT00064870	Not specified	RECRUITING	Alzheimer’s Disease Genetics Study
NCT05637801	Not specified	ACTIVE_NOT_RECRUITING	A Pivotal Study of Sensory Stimulation in Alzheimer’s Disease (HOPE Study)
NCT01222351	Not specified	COMPLETED	Measuring Brain Amyloid Plaque Load in Older Adults Using BAY 94-9172
NCT03349320	Not specified	COMPLETED	Response to Donepezil, Drug Plasma Concentration and the CYP2D6 and APOE Genetic Polymorphisms
NCT03624842	Not specified	NO_LONGER_AVAILABLE	Expanded Access With Trappsol(R) Cyclo (TM) for an Individual Patient With Late Onset Alzheimer’s Disease
NCT04100889	Not specified	WITHDRAWN	A Non-Interventional Pilot Study to Explore the Role of Gut Flora in Alzheimer’s Disease
NCT07294586	Not specified	COMPLETED	Exploratory Clinical Study and Validation of Blood Biomarkers for Alzheimer’s Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BREXANOLONE	4	1
ELTANOLONE	2	1
CHEMBL38856	0	1