Pick disease

Summary

Pick disease (MONDO:0008243) is a disease caused by variants in MAPT and PSEN1, with 2 cohort genes and 5 clinical trials. Top therapeutic interventions include rotigotine.

At a glance

• Causal genes: MAPT (GenCC Strong), PSEN1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 270
• Clinical trials: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Pick disease
Mondo ID	MONDO:0008243
EFO	EFO:0003096
MeSH	D020774
OMIM	172700
DOID	DOID:11870
ICD-10-CM	G31.01
NCIT	C85008
SNOMED CT	13092008
UMLS	C0236642
MedGen	116020
GARD	0024611
Anatomy (UBERON)	UBERON:0001870, UBERON:0001871
Is cancer (heuristic)	no

Also known as: lobar atrophy of brain · lobar atrophy of the brain · Pick disease · PICK disease of brain · Pick disease of the brain

Data availability: 270 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › cognitive disorder › dementia › hereditary dementia › frontotemporal dementia › Pick disease

Related subtypes (3): inclusion body myopathy with Paget disease of bone and frontotemporal dementia, GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, behavioral variant of frontotemporal dementia

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

270 retrieved; paginated sample, class counts are floors:

91 uncertain significance, 53 pathogenic, 51 likely benign, 32 conflicting classifications of pathogenicity, 18 pathogenic/likely pathogenic, 10 likely pathogenic, 8 benign, 7 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
14245	NM_001377265.1(MAPT):c.2078C>T (p.Pro693Leu)	MAPT	Pathogenic	criteria provided, multiple submitters, no conflicts
14247	NM_001377265.1(MAPT):c.2392C>T (p.Arg798Trp)	MAPT	Pathogenic	criteria provided, multiple submitters, no conflicts
14253	NM_001377265.1(MAPT):c.2013T>G (p.Asn671Lys)	MAPT	Pathogenic	criteria provided, multiple submitters, no conflicts
14255	NM_001377265.1(MAPT):c.2341G>A (p.Gly781Arg)	MAPT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14259	NM_001377265.1(MAPT):c.1946A>C (p.Lys649Thr)	MAPT	Pathogenic	no assertion criteria provided
14260	NM_001377265.1(MAPT):c.2282A>T (p.Lys761Ile)	MAPT	Pathogenic	no assertion criteria provided
14262	NM_001377265.1(MAPT):c.2135C>T (p.Ser712Phe)	MAPT	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
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
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
18136	NM_000021.4(PSEN1):c.1276G>C (p.Ala426Pro)	PSEN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18143	NM_000021.4(PSEN1):c.617G>C (p.Gly206Ala)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
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
18152	NM_000021.4(PSEN1):c.833G>T (p.Arg278Ile)	PSEN1	Pathogenic	criteria provided, single submitter
18153	NM_000021.4(PSEN1):c.254T>C (p.Leu85Pro)	PSEN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18155	NM_000021.4(PSEN1):c.1292C>A (p.Ala431Glu)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18157	NM_000021.4(PSEN1):c.236C>T (p.Ala79Val)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1917985	NM_000021.4(PSEN1):c.845T>C (p.Leu282Pro)	PSEN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2028849	NM_000021.4(PSEN1):c.274T>A (p.Cys92Ser)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 13 · 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
MAPT	Strong	Autosomal dominant	Pick disease	8
PSEN1	Strong	Autosomal dominant	Pick disease	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAPT	Orphanet:100069	Semantic dementia
MAPT	Orphanet:100070	Progressive non-fluent aphasia
MAPT	Orphanet:240071	Classic progressive supranuclear palsy syndrome
MAPT	Orphanet:240085	Progressive supranuclear palsy-predominant parkinsonism syndrome
MAPT	Orphanet:240094	Progressive supranuclear palsy-pure akinesia with gait freezing syndrome
MAPT	Orphanet:240103	Progressive supranuclear palsy-corticobasal syndrome
MAPT	Orphanet:240112	Progressive supranuclear palsy-progressive non-fluent aphasia syndrome
MAPT	Orphanet:275864	Behavioral variant of frontotemporal dementia
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

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MAPT	HGNC:6893	ENSG00000186868	P10636	Microtubule-associated protein tau	gencc,clinvar
PSEN1	HGNC:9508	ENSG00000080815	P49768	Presenilin-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAPT	Microtubule-associated protein tau	Promotes microtubule assembly and stability, and might be involved in the establishment and maintenance of neuronal polarity.
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: 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)
MAPT	Other/Unknown	no		MAP_tubulin-bd_rpt, Tau, MAP2/MAP4/Tau
PSEN1	Protease	yes		Peptidase_A22A, Pept_A22A_PS1, Preselin/SPP

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
cortical plate	1
prefrontal cortex	1
superior frontal gyrus	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
MAPT	141	broad	marker	cortical plate, superior frontal gyrus, prefrontal cortex
PSEN1	287	ubiquitous	marker	middle frontal gyrus, corpus callosum, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAPT	7,289
PSEN1	3,732

Intra-cohort edges

A	B	Sources
MAPT	PSEN1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MAPT	P10636	293
PSEN1	P49768	27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. 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
Noncanonical activation of NOTCH3	1	713.8×	0.009	PSEN1
Regulated proteolysis of p75NTR	1	519.1×	0.009	PSEN1
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	519.1×	0.009	PSEN1
Caspase-mediated cleavage of cytoskeletal proteins	1	475.8×	0.009	MAPT
TGFBR3 PTM regulation	1	475.8×	0.009	PSEN1
NRIF signals cell death from the nucleus	1	356.9×	0.009	PSEN1
Apoptotic cleavage of cellular proteins	1	237.9×	0.009	MAPT
Apoptotic execution phase	1	237.9×	0.009	MAPT
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	237.9×	0.009	PSEN1
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	219.6×	0.009	PSEN1
Activation of AMPK downstream of NMDARs	1	190.3×	0.009	MAPT
Activated NOTCH1 Transmits Signal to the Nucleus	1	178.4×	0.009	PSEN1
Nuclear signaling by ERBB4	1	173.0×	0.009	PSEN1
EPH-ephrin mediated repulsion of cells	1	109.8×	0.013	PSEN1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	98.5×	0.013	PSEN1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	98.5×	0.013	PSEN1
Apoptosis	1	84.0×	0.015	MAPT
Programmed Cell Death	1	73.2×	0.016	MAPT
PKR-mediated signaling	1	70.5×	0.016	MAPT
Degradation of the extracellular matrix	1	58.9×	0.018	PSEN1
Neutrophil degranulation	1	11.5×	0.085	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
astrocyte activation	2	991.3×	1e-04	MAPT, PSEN1
synapse organization	2	280.9×	5e-04	MAPT, PSEN1
regulation of synaptic plasticity	2	259.3×	5e-04	MAPT, PSEN1
learning or memory	2	240.7×	5e-04	MAPT, PSEN1
memory	2	183.2×	7e-04	MAPT, PSEN1
plus-end-directed organelle transport along microtubule	1	8426.0×	0.002	MAPT
positive regulation of L-glutamate import across plasma membrane	1	4213.0×	0.002	PSEN1
Cajal-Retzius cell differentiation	1	4213.0×	0.002	PSEN1
smooth endoplasmic reticulum calcium ion homeostasis	1	4213.0×	0.002	PSEN1
neurofibrillary tangle assembly	1	4213.0×	0.002	MAPT
negative regulation of protein localization to mitochondrion	1	4213.0×	0.002	MAPT
negative regulation of gene expression	2	69.1×	0.002	MAPT, PSEN1
protein catabolic process at postsynapse	1	2808.7×	0.003	PSEN1
astrocyte activation involved in immune response	1	2106.5×	0.003	PSEN1
rRNA metabolic process	1	2106.5×	0.003	MAPT
obsolete synaptic vesicle targeting	1	2106.5×	0.003	PSEN1
axonal transport	1	2106.5×	0.003	MAPT
positive regulation of protein localization to synapse	1	2106.5×	0.003	MAPT
DNA damage response	2	53.5×	0.003	MAPT, PSEN1
obsolete sequestering of calcium ion	1	1685.2×	0.003	PSEN1
negative regulation of mitochondrial fission	1	1685.2×	0.003	MAPT
regulation of long-term synaptic depression	1	1685.2×	0.003	MAPT
positive regulation of amyloid fibril formation	1	1685.2×	0.003	PSEN1
positive regulation of coagulation	1	1404.3×	0.004	PSEN1
regulation of microtubule-based movement	1	1404.3×	0.004	MAPT
intracellular distribution of mitochondria	1	1203.7×	0.004	MAPT
regulation of mitochondrial fission	1	1053.2×	0.004	MAPT
Notch receptor processing	1	936.2×	0.004	PSEN1
amyloid-beta formation	1	936.2×	0.004	PSEN1
L-glutamate import across plasma membrane	1	936.2×	0.004	PSEN1

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Tolcapone.

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
MAPT	BEPRIDIL
PSEN1	NIROGACESTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAPT	449	4
PSEN1	8	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	MAPT
PHENYLBUTAZONE	4	MAPT
CEFOTAXIME SODIUM	4	MAPT
DIENESTROL	4	MAPT
PROGESTERONE	4	MAPT
CLOTRIMAZOLE	4	MAPT
CHOLECALCIFEROL	4	MAPT
LATANOPROST	4	MAPT
CHLORTHALIDONE	4	MAPT
FLUORESCEIN	4	MAPT
OXCARBAZEPINE	4	MAPT
NABUMETONE	4	MAPT
GLIPIZIDE	4	MAPT
AMIODARONE HYDROCHLORIDE	4	MAPT
TRICLABENDAZOLE	4	MAPT
MESORIDAZINE	4	MAPT
INDIGOTINDISULFONATE	4	MAPT
TRIHEXYPHENIDYL HYDROCHLORIDE	4	MAPT
IMIPRAMINE	4	MAPT
FURAZOLIDONE	4	MAPT
DROPERIDOL	4	MAPT
ARIPIPRAZOLE	4	MAPT
RALOXIFENE HYDROCHLORIDE	4	MAPT
IDARUBICIN	4	MAPT
ACETAMINOPHEN	4	MAPT
ACITRETIN	4	MAPT
CISPLATIN	4	MAPT
CLOBETASOL PROPIONATE	4	MAPT
AMINOSALICYLIC ACID	4	MAPT
TETRABENAZINE	4	MAPT

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
MAPT	184	Binding:180, Functional:4

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MAPT	184
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

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)
BEPRIDIL	4	MAPT
PHENYLBUTAZONE	4	MAPT
CEFOTAXIME SODIUM	4	MAPT
DIENESTROL	4	MAPT
PROGESTERONE	4	MAPT
CLOTRIMAZOLE	4	MAPT
CHOLECALCIFEROL	4	MAPT
LATANOPROST	4	MAPT
CHLORTHALIDONE	4	MAPT
FLUORESCEIN	4	MAPT
OXCARBAZEPINE	4	MAPT
NABUMETONE	4	MAPT
GLIPIZIDE	4	MAPT
AMIODARONE HYDROCHLORIDE	4	MAPT
TRICLABENDAZOLE	4	MAPT
MESORIDAZINE	4	MAPT
INDIGOTINDISULFONATE	4	MAPT
TRIHEXYPHENIDYL HYDROCHLORIDE	4	MAPT
IMIPRAMINE	4	MAPT
FURAZOLIDONE	4	MAPT
DROPERIDOL	4	MAPT
ARIPIPRAZOLE	4	MAPT
RALOXIFENE HYDROCHLORIDE	4	MAPT
IDARUBICIN	4	MAPT
ACETAMINOPHEN	4	MAPT
ACITRETIN	4	MAPT
CISPLATIN	4	MAPT
CLOBETASOL PROPIONATE	4	MAPT
AMINOSALICYLIC ACID	4	MAPT
TETRABENAZINE	4	MAPT

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	MAPT, 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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	2
Not specified	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04937452	PHASE2	COMPLETED	Dopaminergic Therapy for Frontotemporal Dementia Patients
NCT00077896	PHASE1	COMPLETED	Direct Current Brain Polarization in Frontotemporal Dementia
NCT00674960	PHASE1	UNKNOWN	Far Infrared Irradiation for the Management, Control and Treatment of Frontotemporal Dementia
NCT02194816	Not specified	RECRUITING	Modifiable Variables in Parkinsonism (MVP)
NCT04165213	Not specified	COMPLETED	Care of Persons With Dementia in Their Environments (COPE) in Programs of All-Inclusive Care of the Elderly (PACE)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ROTIGOTINE	4	1
CHEMBL104383	0	1