Alzheimer disease 4

Summary

Alzheimer disease 4 (MONDO:0011743) is a disease caused by PSEN2 (GenCC Strong), with 3 cohort genes and 2 clinical trials. The dominant Reactome pathway is Nuclear signaling by ERBB4 (3 cohort genes).

At a glance

• Causal gene: PSEN2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 253
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Alzheimer disease 4
Mondo ID	MONDO:0011743
MeSH	C536596
OMIM	606889
DOID	DOID:0110040
NCIT	C123413
UMLS	C1847200
MedGen	376072
GARD	0016511
Is cancer (heuristic)	no

Also known as: AD4 · Alzheimer disease 4 · Alzheimer disease familial type 4 · Alzheimer disease type 4 · Alzheimer disease-4 · Alzheimer’s disease 4 · Alzheimer’s disease type 4 · familial Alzheimer disease, type 4 · familial Alzheimer’s disease, type 4

Data availability: 253 ClinVar variants · 2 GenCC gene-disease records · 21 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › early-onset autosomal dominant Alzheimer disease › Alzheimer disease 4

Related subtypes (13): Alzheimer disease type 1, Alzheimer disease 5, Alzheimer disease without neurofibrillary tangles, Alzheimer disease, familial early-onset, with coexisting amyloid and prion pathology, Alzheimer disease 6, Alzheimer disease 7, Alzheimer disease 8, Alzheimer disease 3, Alzheimer disease 10, Alzheimer disease 11, Alzheimer disease 12, Alzheimer disease 13, Alzheimer disease 14

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

253 retrieved; paginated sample, class counts are floors:

112 uncertain significance, 70 likely benign, 22 conflicting classifications of pathogenicity, 21 benign/likely benign, 13 benign, 10 pathogenic, 2 pathogenic/likely pathogenic, 2 likely pathogenic, 1 conflicting classifications of pathogenicity; other; risk factor

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
533784	NC_000001.11:g.(?226881888)(226895599_?)del	LOC129932680	Pathogenic	criteria provided, single submitter
38296	NM_000021.4(PSEN1):c.869-1624_956-2452del	PSEN1	Pathogenic	no assertion criteria provided
38297	NM_000021.4(PSEN1):c.806G>A (p.Arg269His)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
3720283	NM_000447.3(PSEN2):c.342_343del (p.Lys115fs)	PSEN2	Pathogenic	criteria provided, single submitter
4763759	NM_000447.3(PSEN2):c.524C>T (p.Ser175Phe)	PSEN2	Pathogenic	criteria provided, single submitter
8845	NM_000447.3(PSEN2):c.422A>T (p.Asn141Ile)	PSEN2	Pathogenic	criteria provided, multiple submitters, no conflicts
8846	NM_000447.3(PSEN2):c.715A>G (p.Met239Val)	PSEN2	Pathogenic	criteria provided, single submitter
8849	NM_000447.3(PSEN2):c.364A>C (p.Thr122Pro)	PSEN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8850	NM_000447.3(PSEN2):c.717G>A (p.Met239Ile)	PSEN2	Pathogenic	no assertion criteria provided
8851	NM_000447.3(PSEN2):c.365C>G (p.Thr122Arg)	PSEN2	Pathogenic	no assertion criteria provided
8853	NM_000447.3(PSEN2):c.254C>T (p.Ala85Val)	PSEN2	Pathogenic	no assertion criteria provided
465218	NM_000447.3(PSEN2):c.886+2_886+4del	PSEN2	Likely pathogenic	criteria provided, single submitter
4726843	NM_000447.3(PSEN2):c.356+2T>C	PSEN2	Likely pathogenic	criteria provided, single submitter
17864	NM_000041.4(APOE):c.388T>C (p.Cys130Arg)	APOE	Conflicting classifications of pathogenicity; other; risk factor	criteria provided, conflicting classifications
242765	NM_000041.4(APOE):c.137T>C (p.Leu46Pro)	APOE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180476	NM_000447.3(PSEN2):c.149A>G (p.Gln50Arg)	PSEN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191770	NM_000447.3(PSEN2):c.166G>A (p.Gly56Ser)	PSEN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191771	NM_000447.3(PSEN2):c.205C>G (p.Pro69Ala)	PSEN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191773	NM_000447.3(PSEN2):c.1139C>A (p.Thr380Lys)	PSEN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
192129	NM_000447.3(PSEN2):c.208G>A (p.Gly70Arg)	PSEN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295988	NM_000447.3(PSEN2):c.222C>G (p.Gly74=)	PSEN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295989	NM_000447.3(PSEN2):c.336C>T (p.Tyr112=)	PSEN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295991	NM_000447.3(PSEN2):c.690C>G (p.Ala230=)	PSEN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295994	NM_000447.3(PSEN2):c.954C>T (p.Pro318=)	PSEN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295995	NM_000447.3(PSEN2):c.1077C>T (p.Gly359=)	PSEN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295999	NM_000447.3(PSEN2):c.*120G>A	PSEN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
296002	NM_000447.3(PSEN2):c.*306G>A	PSEN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2985383	NM_000447.3(PSEN2):c.850A>G (p.Arg284Gly)	PSEN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3251598	NM_000447.3(PSEN2):c.1305G>T (p.Arg435=)	PSEN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 9 · 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
PSEN2	Strong	Autosomal dominant	Alzheimer disease 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PSEN2	Orphanet:1020	Early-onset autosomal dominant Alzheimer disease
PSEN2	Orphanet:154	Familial isolated dilated cardiomyopathy
APOE	Orphanet:329481	Lipoprotein glomerulopathy
APOE	Orphanet:412	Dysbetalipoproteinemia
PSEN1	Orphanet:100069	Semantic dementia
PSEN1	Orphanet:100070	Progressive non-fluent aphasia
PSEN1	Orphanet:1020	Early-onset autosomal dominant Alzheimer disease
PSEN1	Orphanet:154	Familial isolated dilated cardiomyopathy
PSEN1	Orphanet:275864	Behavioral variant of frontotemporal dementia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PSEN2	HGNC:9509	ENSG00000143801	P49810	Presenilin-2	gencc,clinvar
APOE	HGNC:613	ENSG00000130203	P02649	Apolipoprotein E	clinvar
PSEN1	HGNC:9508	ENSG00000080815	P49768	Presenilin-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PSEN2	Presenilin-2	Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein).
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.
PSEN1	Presenilin-1	Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein).

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Protease	2	24.4×	0.004
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PSEN2	Protease	yes		Peptidase_A22A, Pept_A22A_PS2, Preselin/SPP
APOE	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E
PSEN1	Protease	yes		Peptidase_A22A, Pept_A22A_PS1, Preselin/SPP

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
male germ line stem cell (sensu Vertebrata) in testis	1
pancreas	1
left adrenal gland	1
left adrenal gland cortex	1
right adrenal gland cortex	1
C1 segment of cervical spinal cord	1
corpus callosum	1
middle frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PSEN2	134	ubiquitous	marker	body of pancreas, male germ line stem cell (sensu Vertebrata) in testis, pancreas
APOE	267	ubiquitous	marker	left adrenal gland, left adrenal gland cortex, right adrenal gland cortex
PSEN1	287	ubiquitous	marker	middle frontal gyrus, corpus callosum, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOE	6,793
PSEN1	3,732
PSEN2	2,338

Intra-cohort edges

A	B	Sources
APOE	PSEN1	string_interaction
APOE	PSEN2	string_interaction
PSEN1	PSEN2	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APOE	P02649	29
PSEN1	P49768	27
PSEN2	P49810	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 47. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Nuclear signaling by ERBB4	3	346.1×	1e-06	PSEN2, APOE, PSEN1
Noncanonical activation of NOTCH3	2	951.7×	3e-05	PSEN2, PSEN1
Regulated proteolysis of p75NTR	2	692.1×	3e-05	PSEN2, PSEN1
NOTCH4 Activation and Transmission of Signal to the Nucleus	2	692.1×	3e-05	PSEN2, PSEN1
TGFBR3 PTM regulation	2	634.4×	3e-05	PSEN2, PSEN1
NRIF signals cell death from the nucleus	2	475.8×	4e-05	PSEN2, PSEN1
NOTCH3 Activation and Transmission of Signal to the Nucleus	2	317.2×	9e-05	PSEN2, PSEN1
NOTCH2 Activation and Transmission of Signal to the Nucleus	2	292.8×	9e-05	PSEN2, PSEN1
Activated NOTCH1 Transmits Signal to the Nucleus	2	237.9×	1e-04	PSEN2, PSEN1
EPH-ephrin mediated repulsion of cells	2	146.4×	3e-04	PSEN2, PSEN1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	2	131.3×	3e-04	PSEN2, PSEN1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	2	131.3×	3e-04	PSEN2, PSEN1
Chylomicron clearance	1	761.3×	0.005	APOE
Chylomicron assembly	1	380.7×	0.008	APOE
Chylomicron remodeling	1	380.7×	0.008	APOE
HDL remodeling	1	380.7×	0.008	APOE
Plasma lipoprotein assembly	1	237.9×	0.012	APOE
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1	211.5×	0.012	APOE
Scavenging by Class A Receptors	1	200.3×	0.012	APOE
Binding and Uptake of Ligands by Scavenger Receptors	1	181.3×	0.013	APOE
Plasma lipoprotein remodeling	1	158.6×	0.013	APOE
Plasma lipoprotein clearance	1	158.6×	0.013	APOE
NR1H2 and NR1H3-mediated signaling	1	131.3×	0.015	APOE
Metabolism of fat-soluble vitamins	1	126.9×	0.015	APOE
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	102.9×	0.018	APOE
Signaling by ERBB4	1	90.6×	0.020	APOE
Visual phototransduction	1	86.5×	0.020	APOE
Retinoid metabolism and transport	1	82.8×	0.020	APOE
Plasma lipoprotein assembly, remodeling, and clearance	1	76.1×	0.021	APOE
Degradation of the extracellular matrix	1	39.2×	0.039	PSEN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of amyloid fibril formation	2	2246.9×	4e-05	APOE, PSEN1
Notch receptor processing	2	1248.3×	5e-05	PSEN2, PSEN1
amyloid-beta formation	2	1248.3×	5e-05	PSEN2, PSEN1
amyloid precursor protein metabolic process	2	864.2×	7e-05	APOE, PSEN1
amyloid precursor protein catabolic process	2	802.5×	7e-05	PSEN2, PSEN1
positive regulation of dendritic spine development	2	510.7×	1e-04	APOE, PSEN1
membrane protein ectodomain proteolysis	2	432.1×	2e-04	PSEN2, PSEN1
calcium ion homeostasis	2	295.6×	3e-04	PSEN2, PSEN1
protein processing	2	113.5×	0.002	PSEN2, PSEN1
lipid transport involved in lipid storage	1	5617.3×	0.002	APOE
maintenance of location in cell	1	5617.3×	0.002	APOE
intermediate-density lipoprotein particle clearance	1	5617.3×	0.002	APOE
positive regulation of lipid transport across blood-brain barrier	1	5617.3×	0.002	APOE
regulation of cellular response to very-low-density lipoprotein particle stimulus	1	5617.3×	0.002	APOE
Notch signaling pathway	2	94.4×	0.002	PSEN2, PSEN1
positive regulation of L-glutamate import across plasma membrane	1	2808.7×	0.003	PSEN1
Cajal-Retzius cell differentiation	1	2808.7×	0.003	PSEN1
smooth endoplasmic reticulum calcium ion homeostasis	1	2808.7×	0.003	PSEN1
triglyceride-rich lipoprotein particle clearance	1	2808.7×	0.003	APOE
regulation of amyloid-beta clearance	1	2808.7×	0.003	APOE
regulation of amyloid fibril formation	1	2808.7×	0.003	APOE
positive regulation of low-density lipoprotein particle receptor catabolic process	1	1872.4×	0.004	APOE
regulation of calcium import into the mitochondrion	1	1872.4×	0.004	PSEN2
protein catabolic process at postsynapse	1	1872.4×	0.004	PSEN1
astrocyte activation involved in immune response	1	1404.3×	0.004	PSEN1
obsolete synaptic vesicle targeting	1	1404.3×	0.004	PSEN1
negative regulation of triglyceride metabolic process	1	1404.3×	0.004	APOE
positive regulation of phospholipid efflux	1	1404.3×	0.004	APOE
regulation of behavioral fear response	1	1404.3×	0.004	APOE
very-low-density lipoprotein particle clearance	1	1123.5×	0.004	APOE

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PSEN2	NIROGACESTAT
PSEN1	NIROGACESTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSEN2	8	4
PSEN1	8	4
APOE	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIROGACESTAT	4	PSEN1, PSEN2
TARENFLURBIL	3	PSEN1, PSEN2
SEMAGACESTAT	3	PSEN1, PSEN2
AVAGACESTAT	2	PSEN1, PSEN2
RG-4733	2	PSEN1, PSEN2
BEGACESTAT	2	PSEN1, PSEN2
E-2212	1	PSEN1, PSEN2
MK-0752	1	PSEN1, PSEN2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PSEN1	557	Binding:538, Functional:12, ADMET:6, Unclassified:1
PSEN2	479	Binding:460, Functional:12, ADMET:6, Unclassified:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PSEN2	479
PSEN1	557

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

8 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.

Compound	Max phase	Cohort target (bioactivity)
NIROGACESTAT	4	PSEN1, PSEN2
TARENFLURBIL	3	PSEN1, PSEN2
SEMAGACESTAT	3	PSEN1, PSEN2
AVAGACESTAT	2	PSEN1, PSEN2
RG-4733	2	PSEN1, PSEN2
BEGACESTAT	2	PSEN1, PSEN2
E-2212	1	PSEN1, PSEN2
MK-0752	1	PSEN1, PSEN2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	PSEN2, PSEN1
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: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05637801	Not specified	ACTIVE_NOT_RECRUITING	A Pivotal Study of Sensory Stimulation in Alzheimer’s Disease (HOPE Study)
NCT04100889	Not specified	WITHDRAWN	A Non-Interventional Pilot Study to Explore the Role of Gut Flora in Alzheimer’s Disease