early-onset autosomal dominant Alzheimer disease

Summary

early-onset autosomal dominant Alzheimer disease (MONDO:0015140) is a disease (an umbrella term covering 14 Mondo subtypes) with 4 cohort genes.

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Umbrella term: 14 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 2
• Phenotypes (HPO): 26

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000713	Agitation	Very frequent (80-99%)
HP:0000726	Dementia	Very frequent (80-99%)
HP:0000738	Hallucinations	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001276	Hypertonia	Very frequent (80-99%)
HP:0001289	Confusion	Very frequent (80-99%)
HP:0001300	Parkinsonism	Very frequent (80-99%)
HP:0001336	Myoclonus	Very frequent (80-99%)
HP:0002120	Cerebral cortical atrophy	Very frequent (80-99%)
HP:0002185	Neurofibrillary tangles	Very frequent (80-99%)
HP:0002354	Memory impairment	Very frequent (80-99%)
HP:0002463	Language impairment	Very frequent (80-99%)
HP:0003791	Deposits immunoreactive to beta-amyloid protein	Very frequent (80-99%)
HP:0012433	Abnormal social behavior	Very frequent (80-99%)
HP:0012759	Neurodevelopmental abnormality	Very frequent (80-99%)
HP:0000734	Disinhibition	Frequent (30-79%)
HP:0000504	Abnormality of vision	Occasional (5-29%)
HP:0000657	Oculomotor apraxia	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0002186	Apraxia	Occasional (5-29%)
HP:0002381	Aphasia	Occasional (5-29%)
HP:0010525	Finger agnosia	Occasional (5-29%)
HP:0010526	Dysgraphia	Occasional (5-29%)
HP:0011446	Abnormality of higher mental function	Occasional (5-29%)
HP:0030219	Semantic dementia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	early-onset autosomal dominant Alzheimer disease
Mondo ID	MONDO:0015140
Orphanet	1020
GARD	0012798
Is cancer (heuristic)	no

Also known as: early-onset familial autosomal dominant Alzheimer disease · early-onset, autosomal dominant Alzheimer disease · EOFAD

Data availability: 2 ClinVar variants · 4 GenCC gene-disease records · 475 cell lines.

Disease family

An umbrella term covering 14 Mondo subtypes.

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

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Subtypes (14): 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 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

2 retrieved; paginated sample, class counts are floors:

2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
18126	NM_000021.4(PSEN1):c.856C>G (p.Leu286Val)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
98091	NM_000021.4(PSEN1):c.854C>T (p.Ala285Val)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 28 · Orphanet: 15 · 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
APP	Strong	Autosomal dominant	Alzheimer disease type 1	11
PSEN1	Strong	Autosomal dominant	Alzheimer disease 3	12
PSEN2	Strong	Autosomal dominant	Alzheimer disease 4	4
SORL1	Supportive	Autosomal dominant	early-onset autosomal dominant Alzheimer disease

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
SORL1	Orphanet:1020	Early-onset autosomal dominant Alzheimer disease
APP	Orphanet:100006	ABeta amyloidosis, Dutch type
APP	Orphanet:1020	Early-onset autosomal dominant Alzheimer disease
APP	Orphanet:324703	ABetaL34V amyloidosis
APP	Orphanet:324708	ABeta amyloidosis, Iowa type
APP	Orphanet:324713	ABeta amyloidosis, Italian type
APP	Orphanet:324718	ABetaA21G amyloidosis
APP	Orphanet:324723	ABeta amyloidosis, Arctic type
PSEN2	Orphanet:1020	Early-onset autosomal dominant Alzheimer disease
PSEN2	Orphanet:154	Familial isolated dilated cardiomyopathy

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PSEN1	HGNC:9508	ENSG00000080815	P49768	Presenilin-1	gencc,clinvar
SORL1	HGNC:11185	ENSG00000137642	Q92673	Sortilin-related receptor	gencc
APP	HGNC:620	ENSG00000142192	P05067	Amyloid-beta precursor protein	gencc
PSEN2	HGNC:9509	ENSG00000143801	P49810	Presenilin-2	gencc

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).
SORL1	Sortilin-related receptor	Sorting receptor that directs several proteins to their correct location within the cell.
APP	Amyloid-beta precursor protein	Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.
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).

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.75

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	18.3×	0.013
Antibody/Immunoglobulin	1	7.3×	0.195
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PSEN1	Protease	yes		Peptidase_A22A, Pept_A22A_PS1, Preselin/SPP
SORL1	Antibody/Immunoglobulin	yes		LDLR_classB_rpt, LDrepeatLR_classA_rpt, FN3_dom
APP	Other/Unknown	no		Kunitz_BPTI, Amyloid_glyco_extra, Amyloid_glyco
PSEN2	Protease	yes		Peptidase_A22A, Pept_A22A_PS2, Preselin/SPP

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
middle frontal gyrus	2
C1 segment of cervical spinal cord	1
corpus callosum	1
frontal pole	1
paraflocculus	1
Brodmann (1909) area 9	1
prefrontal cortex	1
renal medulla	1
body of pancreas	1
male germ line stem cell (sensu Vertebrata) in testis	1
pancreas	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
SORL1	293	ubiquitous	marker	frontal pole, paraflocculus, middle frontal gyrus
APP	295	ubiquitous	marker	prefrontal cortex, renal medulla, Brodmann (1909) area 9
PSEN2	134	ubiquitous	marker	body of pancreas, male germ line stem cell (sensu Vertebrata) in testis, pancreas

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APP	11,686
PSEN1	3,732
SORL1	2,524
PSEN2	2,338

Intra-cohort edges

A	B	Sources
APP	PSEN1	intact, string_interaction
APP	PSEN2	intact, string_interaction
APP	SORL1	biogrid_interaction, intact, string_interaction
PSEN1	PSEN2	string_interaction
PSEN1	SORL1	string_interaction
PSEN2	SORL1	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APP	P05067	256
PSEN1	P49768	27
SORL1	Q92673	7
PSEN2	P49810	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 83. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Noncanonical activation of NOTCH3	2	713.8×	1e-04	PSEN1, PSEN2
Regulated proteolysis of p75NTR	2	519.1×	1e-04	PSEN1, PSEN2
NOTCH4 Activation and Transmission of Signal to the Nucleus	2	519.1×	1e-04	PSEN1, PSEN2
TGFBR3 PTM regulation	2	475.8×	1e-04	PSEN1, PSEN2
NRIF signals cell death from the nucleus	2	356.9×	2e-04	PSEN1, PSEN2
NOTCH3 Activation and Transmission of Signal to the Nucleus	2	237.9×	4e-04	PSEN1, PSEN2
NOTCH2 Activation and Transmission of Signal to the Nucleus	2	219.6×	4e-04	PSEN1, PSEN2
Activated NOTCH1 Transmits Signal to the Nucleus	2	178.4×	4e-04	PSEN1, PSEN2
Nuclear signaling by ERBB4	2	173.0×	4e-04	PSEN1, PSEN2
EPH-ephrin mediated repulsion of cells	2	109.8×	0.001	PSEN1, PSEN2
Constitutive Signaling by NOTCH1 PEST Domain Mutants	2	98.5×	0.001	PSEN1, PSEN2
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	2	98.5×	0.001	PSEN1, PSEN2
Amyloid fiber formation	2	51.4×	0.004	SORL1, APP
Aggregated β-amyloid induces FXII autocatalysis	1	1427.5×	0.004	APP
Aggregated β-amyloid interacts with fibrinogen	1	713.8×	0.008	APP
Formyl peptide receptors bind formyl peptides and many other ligands	1	356.9×	0.015	APP
Inflammasomes	1	285.5×	0.016	APP
Cell recruitment (pro-inflammatory response)	1	285.5×	0.016	APP
Neurodegenerative Diseases	1	219.6×	0.020	APP
Defective Intrinsic Pathway for Apoptosis	1	190.3×	0.022	APP
Advanced glycosylation endproduct receptor signaling	1	178.4×	0.022	APP
The NLRP3 inflammasome	1	167.9×	0.022	APP
Diseases of programmed cell death	1	158.6×	0.023	APP
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	129.8×	0.027	APP
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	1	119.0×	0.028	APP
TRAF6 mediated NF-kB activation	1	114.2×	0.028	APP
Purinergic signaling in leishmaniasis infection	1	105.7×	0.029	APP
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1	89.2×	0.033	APP
Lysosome Vesicle Biogenesis	1	81.6×	0.035	APP
TAK1-dependent IKK and NF-kappa-B activation	1	75.1×	0.037	APP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
astrocyte activation involved in immune response	2	2106.5×	4e-05	PSEN1, APP
positive regulation of amyloid fibril formation	2	1685.2×	4e-05	PSEN1, APP
Notch receptor processing	2	936.2×	5e-05	PSEN1, PSEN2
amyloid-beta formation	2	936.2×	5e-05	PSEN1, PSEN2
Notch signaling pathway	3	106.2×	5e-05	PSEN1, APP, PSEN2
amyloid precursor protein catabolic process	2	601.9×	1e-04	PSEN1, PSEN2
neuron projection maintenance	2	561.7×	1e-04	PSEN1, APP
astrocyte activation	2	495.6×	1e-04	PSEN1, APP
positive regulation of glycolytic process	2	337.0×	2e-04	PSEN1, APP
membrane protein ectodomain proteolysis	2	324.1×	2e-04	PSEN1, PSEN2
calcium ion homeostasis	2	221.7×	5e-04	PSEN1, PSEN2
cellular response to amyloid-beta	2	195.9×	6e-04	PSEN1, APP
synapse organization	2	140.4×	1e-03	PSEN1, APP
learning or memory	2	120.4×	0.001	PSEN1, APP
protein processing	2	85.1×	0.002	PSEN1, PSEN2
obsolete positive regulation of early endosome to recycling endosome transport	1	4213.0×	0.002	SORL1
negative regulation of neurofibrillary tangle assembly	1	4213.0×	0.002	SORL1
positive regulation of tumor necrosis factor production	2	76.6×	0.002	PSEN1, APP
positive regulation of L-glutamate import across plasma membrane	1	2106.5×	0.004	PSEN1
Cajal-Retzius cell differentiation	1	2106.5×	0.004	PSEN1
smooth endoplasmic reticulum calcium ion homeostasis	1	2106.5×	0.004	PSEN1
positive regulation of glial cell-derived neurotrophic factor production	1	2106.5×	0.004	SORL1
collateral sprouting in absence of injury	1	1404.3×	0.005	APP
regulation of calcium import into the mitochondrion	1	1404.3×	0.005	PSEN2
protein catabolic process at postsynapse	1	1404.3×	0.005	PSEN1
axo-dendritic transport	1	1053.2×	0.005	APP
microglia development	1	1053.2×	0.005	APP
obsolete synaptic vesicle targeting	1	1053.2×	0.005	PSEN1
insulin receptor recycling	1	1053.2×	0.005	SORL1
cellular response to norepinephrine stimulus	1	1053.2×	0.005	APP

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
APP	FLORBETAPIR F 18
PSEN2	NIROGACESTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
APP	40	4
PSEN1	8	4
PSEN2	8	4
SORL1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIROGACESTAT	4	PSEN1, PSEN2
FLORBETAPIR F 18	4	APP
FLORBETAPIR	4	APP
METHYLENE BLUE CATION	4	APP
FLUTEMETAMOL F 18	4	APP
TRETINOIN	4	APP
METHYLENE BLUE ANHYDROUS	4	APP
CLIOQUINOL	4	APP
DONEPEZIL	4	APP
FLORBETABEN F18	4	APP
NIACIN	4	APP
FLUTEMETAMOL	4	APP
GENTIAN VIOLET	4	APP
AMODIAQUINE	4	APP
CARVEDILOL	4	APP
CHLOROQUINE	4	APP
TACRINE	4	APP
RETINOL	4	APP
TARENFLURBIL	3	PSEN1, PSEN2
SEMAGACESTAT	3	PSEN1, PSEN2
CURCUMIN	3	APP
CAFFEIC ACID	3	APP
TRAMIPROSATE	3	APP
RESVERATROL	3	APP
FLUTAFURANOL	3	APP
EPIGALOCATECHIN GALLATE	3	APP
LANABECESTAT	3	APP
QUERCETIN	3	APP
EDETIC ACID	3	APP
AVAGACESTAT	2	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
APP	1,744	Binding:1699, Functional:44, ADMET:1
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
PSEN1	557
APP	1,744
PSEN2	479

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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
FLORBETAPIR F 18	4	APP
FLORBETAPIR	4	APP
METHYLENE BLUE CATION	4	APP
FLUTEMETAMOL F 18	4	APP
TRETINOIN	4	APP
METHYLENE BLUE ANHYDROUS	4	APP
CLIOQUINOL	4	APP
DONEPEZIL	4	APP
FLORBETABEN F18	4	APP
NIACIN	4	APP
FLUTEMETAMOL	4	APP
GENTIAN VIOLET	4	APP
AMODIAQUINE	4	APP
CARVEDILOL	4	APP
CHLOROQUINE	4	APP
TACRINE	4	APP
RETINOL	4	APP
TARENFLURBIL	3	PSEN1, PSEN2
SEMAGACESTAT	3	PSEN1, PSEN2
CURCUMIN	3	APP
CAFFEIC ACID	3	APP
TRAMIPROSATE	3	APP
RESVERATROL	3	APP
FLUTAFURANOL	3	APP
EPIGALOCATECHIN GALLATE	3	APP
LANABECESTAT	3	APP
QUERCETIN	3	APP
EDETIC ACID	3	APP
AVAGACESTAT	2	PSEN1, PSEN2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	PSEN1, APP, PSEN2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	SORL1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
SORL1	0	APP

Clinical trials & evidence

Clinical trials

Clinical trials: 0.