Alzheimer disease 3

Summary

Alzheimer disease 3 (MONDO:0011913) is a disease caused by PSEN1 (GenCC Strong), with 2 cohort genes and 19 clinical trials. Top therapeutic interventions include methylene blue cation, phenazopyridine, and flortaucipir.

At a glance

• Causal gene: PSEN1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 404
• Clinical trials: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Alzheimer disease 3
Mondo ID	MONDO:0011913
MeSH	C536598
OMIM	607822
DOID	DOID:0110042
NCIT	C123412
UMLS	C1843013
MedGen	334304
GARD	0016513
Is cancer (heuristic)	no

Also known as: AD · AD3 · Alzheimer disease 3 · Alzheimer disease early onset type 3 · Alzheimer disease type 3 · Alzheimer disease, protection against, due to APOE3-Christchurch · Alzheimer disease, type 3 · Alzheimer disease, type 3, with spastic paraparesis and apraxia · Alzheimer disease, type 3, with spastic paraparesis and unusual plaques · Alzheimer’s disease 3 · Alzheimer’s disease type 3 · early-onset autosomal dominant Alzheimer disease caused by mutation in PSEN1 · familial Alzheimer disease, type 3 · familial Alzheimer’s disease, type 3 · PSEN1 early-onset autosomal dominant Alzheimer disease

Data availability: 404 ClinVar variants · 4 GenCC gene-disease records · 328 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 3

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 4, Alzheimer disease 8, 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

404 retrieved; paginated sample, class counts are floors:

156 uncertain significance, 63 pathogenic, 52 likely benign, 51 conflicting classifications of pathogenicity, 25 likely pathogenic, 24 benign/likely benign, 19 pathogenic/likely pathogenic, 11 benign, 3 not provided

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
1027511	NM_000021.4(PSEN1):c.300dup (p.Lys101Ter)	PSEN1	Pathogenic	criteria provided, single submitter
1045636	NM_000021.4(PSEN1):c.667C>A (p.Gln223Lys)	PSEN1	Pathogenic	criteria provided, single submitter
1178342	NM_000021.4(PSEN1):c.1247T>C (p.Ile416Thr)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1450587	NM_000021.4(PSEN1):c.1129A>T (p.Arg377Trp)	PSEN1	Pathogenic	criteria provided, single submitter
1453682	NM_000021.4(PSEN1):c.750G>T (p.Leu250Phe)	PSEN1	Pathogenic	criteria provided, single submitter
1458372	NM_000021.4(PSEN1):c.838G>A (p.Glu280Lys)	PSEN1	Pathogenic	criteria provided, single submitter
1459049	NC_000014.8:g.(?73673074)(73673200_?)del	PSEN1	Pathogenic	criteria provided, single submitter
18123	NM_000021.4(PSEN1):c.436A>C (p.Met146Leu)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18124	NM_000021.4(PSEN1):c.488A>G (p.His163Arg)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18125	NM_000021.4(PSEN1):c.737C>A (p.Ala246Glu)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18126	NM_000021.4(PSEN1):c.856C>G (p.Leu286Val)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18127	NM_000021.4(PSEN1):c.1229G>A (p.Cys410Tyr)	PSEN1	Pathogenic	criteria provided, single submitter
18128	NM_000021.4(PSEN1):c.415A>G (p.Met139Val)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18129	NM_000021.4(PSEN1):c.436A>G (p.Met146Val)	PSEN1	Pathogenic	criteria provided, single submitter
18130	NM_000021.4(PSEN1):c.487C>T (p.His163Tyr)	PSEN1	Pathogenic	criteria provided, single submitter
18131	NM_000021.4(PSEN1):c.839A>C (p.Glu280Ala)	PSEN1	Pathogenic	criteria provided, single submitter
18132	NM_000021.4(PSEN1):c.839A>G (p.Glu280Gly)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18135	NM_000021.4(PSEN1):c.360A>T (p.Glu120Asp)	PSEN1	Pathogenic	no assertion criteria provided
18136	NM_000021.4(PSEN1):c.1276G>C (p.Ala426Pro)	PSEN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18137	NM_000021.4(PSEN1):c.438G>A (p.Met146Ile)	PSEN1	Pathogenic	no assertion criteria provided
18138	NM_000021.4(PSEN1):c.749T>C (p.Leu250Ser)	PSEN1	Pathogenic	no assertion criteria provided
18141	NM_000021.4(PSEN1):c.1300_1301delinsTG (p.Ala434Cys)	PSEN1	Pathogenic	criteria provided, single submitter
18142	NM_000021.4(PSEN1):c.275G>C (p.Cys92Ser)	PSEN1	Pathogenic	no assertion criteria provided
18143	NM_000021.4(PSEN1):c.617G>C (p.Gly206Ala)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18146	NM_000021.4(PSEN1):c.497T>C (p.Leu166Pro)	PSEN1	Pathogenic	criteria provided, single submitter
18147	NM_000021.4(PSEN1):c.520C>A (p.Leu174Met)	PSEN1	Pathogenic	no assertion criteria provided
18148	NM_000021.4(PSEN1):c.811C>G (p.Leu271Val)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18149	NM_000021.4(PSEN1):c.548G>T (p.Gly183Val)	PSEN1	Pathogenic	no assertion criteria provided
18150	NM_000021.4(PSEN1):c.1307C>A (p.Pro436Gln)	PSEN1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 7 · 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
PSEN1	Strong	Autosomal dominant	Alzheimer disease 3	12

Orphanet rare-disease linkage (cohort genes)

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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

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

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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).
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: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	1	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

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

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
corpus callosum	1
middle frontal gyrus	1
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
PSEN1	287	ubiquitous	marker	middle frontal gyrus, corpus callosum, C1 segment of cervical spinal cord
APOE	267	ubiquitous	marker	left adrenal gland, left adrenal gland cortex, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOE	6,793
PSEN1	3,732

Intra-cohort edges

A	B	Sources
APOE	PSEN1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APOE	P02649	29
PSEN1	P49768	27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 47. Enrichment computed across 2 evidence-associated genes (2 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 2 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	2	346.1×	4e-04	PSEN1, APOE
Chylomicron clearance	1	1142.0×	0.011	APOE
Noncanonical activation of NOTCH3	1	713.8×	0.011	PSEN1
Chylomicron assembly	1	571.0×	0.011	APOE
Chylomicron remodeling	1	571.0×	0.011	APOE
HDL remodeling	1	571.0×	0.011	APOE
Regulated proteolysis of p75NTR	1	519.1×	0.011	PSEN1
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	519.1×	0.011	PSEN1
TGFBR3 PTM regulation	1	475.8×	0.011	PSEN1
NRIF signals cell death from the nucleus	1	356.9×	0.012	PSEN1
Plasma lipoprotein assembly	1	356.9×	0.012	APOE
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1	317.2×	0.012	APOE
Scavenging by Class A Receptors	1	300.5×	0.012	APOE
Binding and Uptake of Ligands by Scavenger Receptors	1	271.9×	0.012	APOE
Plasma lipoprotein remodeling	1	237.9×	0.012	APOE
Plasma lipoprotein clearance	1	237.9×	0.012	APOE
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	237.9×	0.012	PSEN1
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	219.6×	0.012	PSEN1
NR1H2 and NR1H3-mediated signaling	1	196.9×	0.012	APOE
Metabolism of fat-soluble vitamins	1	190.3×	0.012	APOE
Activated NOTCH1 Transmits Signal to the Nucleus	1	178.4×	0.013	PSEN1
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	154.3×	0.014	APOE
Signaling by ERBB4	1	135.9×	0.015	APOE
Visual phototransduction	1	129.8×	0.015	APOE
Retinoid metabolism and transport	1	124.1×	0.015	APOE
Plasma lipoprotein assembly, remodeling, and clearance	1	114.2×	0.016	APOE
EPH-ephrin mediated repulsion of cells	1	109.8×	0.016	PSEN1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	98.5×	0.016	PSEN1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	98.5×	0.016	PSEN1
Degradation of the extracellular matrix	1	58.9×	0.026	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 2 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	3370.4×	1e-05	PSEN1, APOE
amyloid precursor protein metabolic process	2	1296.3×	5e-05	PSEN1, APOE
positive regulation of dendritic spine development	2	766.0×	9e-05	PSEN1, APOE
lipid transport involved in lipid storage	1	8426.0×	0.003	APOE
maintenance of location in cell	1	8426.0×	0.003	APOE
intermediate-density lipoprotein particle clearance	1	8426.0×	0.003	APOE
positive regulation of lipid transport across blood-brain barrier	1	8426.0×	0.003	APOE
regulation of cellular response to very-low-density lipoprotein particle stimulus	1	8426.0×	0.003	APOE
positive regulation of L-glutamate import across plasma membrane	1	4213.0×	0.003	PSEN1
Cajal-Retzius cell differentiation	1	4213.0×	0.003	PSEN1
smooth endoplasmic reticulum calcium ion homeostasis	1	4213.0×	0.003	PSEN1
triglyceride-rich lipoprotein particle clearance	1	4213.0×	0.003	APOE
regulation of amyloid-beta clearance	1	4213.0×	0.003	APOE
regulation of amyloid fibril formation	1	4213.0×	0.003	APOE
negative regulation of gene expression	2	69.1×	0.003	PSEN1, APOE
positive regulation of low-density lipoprotein particle receptor catabolic process	1	2808.7×	0.003	APOE
protein catabolic process at postsynapse	1	2808.7×	0.003	PSEN1
astrocyte activation involved in immune response	1	2106.5×	0.003	PSEN1
obsolete synaptic vesicle targeting	1	2106.5×	0.003	PSEN1
negative regulation of triglyceride metabolic process	1	2106.5×	0.003	APOE
positive regulation of phospholipid efflux	1	2106.5×	0.003	APOE
regulation of behavioral fear response	1	2106.5×	0.003	APOE
very-low-density lipoprotein particle clearance	1	1685.2×	0.003	APOE
obsolete sequestering of calcium ion	1	1685.2×	0.003	PSEN1
acylglycerol homeostasis	1	1685.2×	0.003	APOE
cellular response to lipoprotein particle stimulus	1	1685.2×	0.003	APOE
AMPA glutamate receptor clustering	1	1685.2×	0.003	APOE
NMDA glutamate receptor clustering	1	1685.2×	0.003	APOE
positive regulation of lipoprotein transport	1	1685.2×	0.003	APOE
positive regulation of dendritic spine maintenance	1	1685.2×	0.003	APOE

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
PSEN1	NIROGACESTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSEN1	8	4
APOE	0	0

Drugs targeting cohort genes (top 30)

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

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

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PSEN1	557

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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
TARENFLURBIL	3	PSEN1
SEMAGACESTAT	3	PSEN1
AVAGACESTAT	2	PSEN1
RG-4733	2	PSEN1
BEGACESTAT	2	PSEN1
E-2212	1	PSEN1
MK-0752	1	PSEN1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	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: 19.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	9
PHASE2	4
PHASE4	2
PHASE1	2
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04520308	PHASE4	UNKNOWN	An Open-label, Single-arm Longitudinal Study With Dupilumab for Patients With Atopic Dermatitis
NCT05969054	PHASE4	UNKNOWN	Improvement Effect of Lacosamide and Levetiracetam on Cognitive in Alzheimer’s Disease Patients With Epilepsy
NCT07011706	PHASE2	ACTIVE_NOT_RECRUITING	ATI-045 Versus Placebo in Patients With Moderate-to-Severe Atopic Dermatitis
NCT07252440	PHASE2	RECRUITING	A Study to Evaluate the Efficacy and Safety of TTYP01 Tablets in Early Symptomatic Alzheimer’s Disease
NCT02380573	PHASE2	COMPLETED	Effects of Methylene Blue in Healthy Aging, Mild Cognitive Impairment and Alzheimer’s Disease
NCT03806478	PHASE2	UNKNOWN	Study of APH-1105 in Patients With Mild to Moderate Alzheimer’s Disease
NCT05984784	PHASE1/PHASE2	TERMINATED	A Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of IMG-007 in Adults With Atopic Dermatitis (AD)
NCT03932916	PHASE1	COMPLETED	Safety and Pharmacokinetic of Donepezil Pamoate in Healthy Subjects
NCT06593626	PHASE1	COMPLETED	A Phase I Clinical Study on the Safety and Pharmacokinetics of [18F]Florbetazine Injection
NCT01733355	EARLY_PHASE1	TERMINATED	A Phase 0, Open Label, Multi-center Exploratory and Safety Study of [F-18]T807
NCT05637801	Not specified	ACTIVE_NOT_RECRUITING	A Pivotal Study of Sensory Stimulation in Alzheimer’s Disease (HOPE Study)
NCT06245031	Not specified	ENROLLING_BY_INVITATION	Extension to a Pivotal Study of Sensory Stimulation in Alzheimer’s Disease (OLE Hope Study, CA-0015)
NCT06335836	Not specified	RECRUITING	The Effects of Social Isolation and Social Interaction on the Risk of Dementia Progression and Brain Function in SCD (Subjective Cognitive Decline, SCD)
NCT07100470	Not specified	NOT_YET_RECRUITING	Metabolic Characterization of Alzheimer’s Disease and Frontotemporal Dementia by 23Na-MRI and FDG-PET
NCT01190904	Not specified	COMPLETED	Hormones and Sexual Function Predict Outcomes in Revascularized Men With Diabetes
NCT02273895	Not specified	COMPLETED	The Use of EEG in Alzheimer’s Disease, With and Without Scopolamine - A Pilot Study
NCT04100889	Not specified	WITHDRAWN	A Non-Interventional Pilot Study to Explore the Role of Gut Flora in Alzheimer’s Disease
NCT05372458	Not specified	UNKNOWN	The Mechanism Study of Diabetic Pancreatic Amyloid Deposition on Cognitive Dysfunction in Alzheimer’s Disease
NCT06155201	Not specified	UNKNOWN	Development and Application of Intelligent Diagnosis and Treatment Norms for Children and Adolescents With Mental Disorders

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
METHYLENE BLUE CATION	4	3
PHENAZOPYRIDINE	4	3
FLORTAUCIPIR	4	1
LACOSAMIDE	4	1
LEVETIRACETAM	4	1
SCOPOLAMINE	4	1
ETIRACETAM	2	1
CHEMBL1187846	0	1
CHEMBL3084722	0	1
LEVITIRACETAM	0	1