Posterior cortical atrophy

disease
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Also known as Benson syndromebiparietal Alzheimer diseasePCA

Summary

Posterior cortical atrophy (MONDO:0018899) is a disease with 5 cohort genes (18 GWAS associations across 1 studies) and 18 clinical trials. Top therapeutic interventions include gallium ga 68 gozetotide.

At a glance

  • Prevalence: Unknown (Worldwide) [Orphanet-validated]
  • Cohort genes: 5
  • GWAS associations: 18
  • Phenotypes (HPO): 21
  • Clinical trials: 18

Clinical features

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO IDTermFrequency
HP:0000657Oculomotor apraxiaVery frequent (80-99%)
HP:0000739AnxietyVery frequent (80-99%)
HP:0001251AtaxiaVery frequent (80-99%)
HP:0001289ConfusionVery frequent (80-99%)
HP:0002442DyscalculiaVery frequent (80-99%)
HP:0010523AlexiaVery frequent (80-99%)
HP:0010524AgnosiaVery frequent (80-99%)
HP:0010525Finger agnosiaVery frequent (80-99%)
HP:0010526DysgraphiaVery frequent (80-99%)
HP:0100704Cerebral visual impairmentVery frequent (80-99%)
HP:0000504Abnormality of visionFrequent (30-79%)
HP:0000551Color vision defectFrequent (30-79%)
HP:0000613PhotophobiaFrequent (30-79%)
HP:0010522DyslexiaFrequent (30-79%)
HP:0030217Limb apraxiaFrequent (30-79%)
HP:0002354Memory impairmentOccasional (5-29%)
HP:0002367Visual hallucinationsOccasional (5-29%)
HP:0002463Language impairmentOccasional (5-29%)
HP:0002494Abnormal rapid eye movement sleepOccasional (5-29%)
HP:0011098Speech apraxiaOccasional (5-29%)
HP:0030216InertiaOccasional (5-29%)

Identifiers

Disease identifiers

FieldValue
Canonical nameposterior cortical atrophy
Mondo IDMONDO:0018899
Orphanet54247
ICD-11377572273
SNOMED CT715574002
UMLSC4275079
MedGen909667
GARD0018846
Is cancer (heuristic)no

Also known as: Benson syndrome · biparietal Alzheimer disease · PCA

Data availability: 18 GWAS associations (1 study).

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disordercognitive disorderdementiahereditary dementiaposterior cortical atrophy

Related subtypes (14): neuronal intranuclear inclusion disease, hereditary sensory neuropathy-deafness-dementia syndrome, Alzheimer disease 17, Alzheimer disease 18, Huntington disease-like syndrome, frontotemporal dementia with motor neuron disease, frontotemporal dementia, neurodegeneration with brain iron accumulation, PRKAR1B-related neurodegenerative dementia with intermediate filaments, adrenoleukodystrophy, corticobasal syndrome, metachromatic leukodystrophy, autosomal dominant cerebellar ataxia, familial Alzheimer disease

Genetics & variants

GWAS landscape

18 GWAS associations across 1 studies. Top hits map to 12 distinct genes (as reported by GWAS).

Top associations by p-value

rsIDp-valueGeneRisk alleleOdds ratio
rs20756506e-14TOMM40?2.03
rs768543448e-10RN7SKP102 - CNTNAP5-DT?1.9
rs729070461e-09RPSAP72 - TENT5A?3.2
rs25257761e-08SEMA3C - EIF4EP4?3.3
rs67147101e-06ZAP70?1.49
rs49650064e-06PUS1?1.6
rs27778026e-06ABCA1?1.48
rs116374456e-06MAP2K5?1.49
rs10148976e-06ANGPT4?1.48
rs80387346e-06ARIH1?2.14
rs49979507e-06LINC01098, LINC01099?1.67
rs100610747e-06HIGD1AP3 - MSX2?2.74
rs171254398e-06BCL10-AS1?1.51
rs4338528e-06FAM83E?1.68
rs78050538e-06PER3P1 - CPAMD8P1?1.53
rs13404258e-06RNU4ATAC8P - LRRIQ3?1.63
rs121341339e-06LINC02942?1.46
rs100719329e-06GPBP1 - RMEL3?1.45

Top studies (by case count)

StudyLead authorYearCasesControlsTitle
GCST003452Schott JM201629310,547Genetic risk factors for the posterior cortical atrophy variant of Alzheimer’s disease.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

TierVariants
Tier 1: coding0
Tier 2: splice/UTR1
Tier 3: regulatory0
Tier 4: intronic/intergenic17

MAF distribution

BucketVariants
common (>=0.05)18
low_freq (0.01-0.05)0
rare (<0.01)0
unknown0

Functional consequences

ConsequenceCount
intron_variant11
intergenic_variant6
5_prime_UTR_variant1

Top variants

rsIDChrPosAllelesMAFConsequenceGenep-valueTier
rs20756501944892362A>C,G0.05intron_variantTOMM406e-14Tier 4: intronic/intergenic
rs768543442123995579G>T0.05intergenic_variantRN7SKP102 - CNTNAP5-DT8e-10Tier 4: intronic/intergenic
rs72907046681418166A>G0.05intergenic_variantRPSAP72 - TENT5A1e-09Tier 4: intronic/intergenic
rs2525776781272303C>T0.05intergenic_variantSEMA3C - EIF4EP41e-08Tier 4: intronic/intergenic
rs6714710297728623T>A,G0.05intron_variantZAP701e-06Tier 4: intronic/intergenic
rs496500612131934988C>T0.05intron_variantPUS14e-06Tier 4: intronic/intergenic
rs27778029104807056T>A,C,G0.05intron_variantABCA16e-06Tier 4: intronic/intergenic
rs116374451567699268G>T0.05intron_variantMAP2K56e-06Tier 4: intronic/intergenic
rs101489720914814C>G,T0.05intron_variantANGPT46e-06Tier 4: intronic/intergenic
rs80387341572519061G>A,C0.05intron_variantARIH16e-06Tier 4: intronic/intergenic
rs49979504177819494G>C,T0.05intron_variantLINC01098, LINC010997e-06Tier 4: intronic/intergenic
rs100610745174705751A>G0.05intergenic_variantHIGD1AP3 - MSX27e-06Tier 4: intronic/intergenic
rs17125439185302696C>A0.05intron_variantBCL10-AS18e-06Tier 4: intronic/intergenic
rs4338521948613847C>A,T0.055_prime_UTR_variantFAM83E8e-06Tier 2: splice/UTR
rs780505379684086C>A,G,T0.05intron_variantPER3P1 - CPAMD8P18e-06Tier 4: intronic/intergenic
rs1340425173920165C>A,G,T0.05intergenic_variantRNU4ATAC8P - LRRIQ38e-06Tier 4: intronic/intergenic
rs121341331207284500G>A0.05intron_variantLINC029429e-06Tier 4: intronic/intergenic
rs10071932557358044T>C0.05intergenic_variantGPBP1 - RMEL39e-06Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
SEMA3COrphanet:388Hirschsprung disease
TOMM40Orphanet:1020Early-onset autosomal dominant Alzheimer disease
TENT5AOrphanet:216812Osteogenesis imperfecta type 3
APOEOrphanet:329481Lipoprotein glomerulopathy
APOEOrphanet:412Dysbetalipoproteinemia

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

SubsetGenes
gwas_only5

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
SEMA3CHGNC:10725ENSG00000075223Q99985Semaphorin-3Cgwas
TOMM40HGNC:18001ENSG00000130204O96008Mitochondrial import receptor subunit TOM40 homologgwas
TENT5AHGNC:18345ENSG00000112773Q96IP4Terminal nucleotidyltransferase 5Agwas
CNTNAP5HGNC:18748ENSG00000155052Q8WYK1Contactin-associated protein-like 5gwas
APOEHGNC:613ENSG00000130203P02649Apolipoprotein Egwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
SEMA3CSemaphorin-3CBinds to plexin family members and plays an important role in the regulation of developmental processes.
TOMM40Mitochondrial import receptor subunit TOM40 homologChannel-forming protein that forms part of the translocase of the outer mitochondrial membrane (TOM) complex essential for the recognition and translocation of cytosolically synthesized mitochondrial preproteins.
TENT5ATerminal nucleotidyltransferase 5ACytoplasmic non-canonical poly(A) RNA polymerase that catalyzes the transfer of one adenosine molecule from an ATP to an mRNA poly(A) tail bearing a 3’-OH terminal group and participates in the cytoplasmic polyadenylation.
CNTNAP5Contactin-associated protein-like 5May play a role in the correct development and proper functioning of the peripheral and central nervous system and be involved in cell adhesion and intercellular communication.
APOEApolipoprotein EAPOE 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: 2 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.4

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.

FamilyGenesFoldFDR
Antibody/Immunoglobulin15.8×0.480
Enzyme (other)12.4×0.530
Other/Unknown31.1×0.608

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
SEMA3CAntibody/ImmunoglobulinyesSemap_dom, Ig_sub, Ig-like_dom
TOMM40Other/UnknownnoPorin_dom_sf, Porin_Euk/Tom40, Tom40
TENT5AEnzyme (other)yes2.7.7.19TET5
CNTNAP5Other/UnknownnoFA58C, EGF, Laminin_G
APOEOther/UnknownnoApoA_E, Apolipoprotein_A1/A4/E

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)0
broad (>20)5
unknown0

Top tissues across cohort

TissueCohort genes
calcaneal tendon1
mammary duct1
synovial joint1
mucosa of transverse colon1
olfactory bulb1
type B pancreatic cell1
parotid gland1
pericardium1
tibia1
corpus callosum1
cortical plate1
male germ line stem cell (sensu Vertebrata) in testis1
left adrenal gland1
left adrenal gland cortex1
right adrenal gland cortex1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
SEMA3C289ubiquitousmarkermammary duct, synovial joint, calcaneal tendon
TOMM40295ubiquitousmarkerolfactory bulb, type B pancreatic cell, mucosa of transverse colon
TENT5A270ubiquitousmarkerparotid gland, tibia, pericardium
CNTNAP598tissue_specificmarkermale germ line stem cell (sensu Vertebrata) in testis, cortical plate, corpus callosum
APOE267ubiquitousmarkerleft 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)

SymbolInteractor count
APOE6,793
TOMM403,210
SEMA3C1,257
TENT5A991
CNTNAP5967

Intra-cohort edges

ABSources
APOETOMM40string_interaction

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
APOEP0264929
TOMM40O9600812
TENT5AQ96IP42

AlphaFold-only cohort genes (top 30 by pLDDT)

SymbolUniProtpLDDT
SEMA3CQ9998585.69
CNTNAP5Q8WYK184.06

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 36. Enrichment computed across 5 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.

PathwayCohort genesFoldFDRSample cohort genes
Chylomicron clearance11142.0×0.015APOE
Chylomicron assembly1571.0×0.015APOE
Chylomicron remodeling1571.0×0.015APOE
HDL remodeling1571.0×0.015APOE
Plasma lipoprotein assembly1356.9×0.015APOE
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors1317.2×0.015APOE
Scavenging by Class A Receptors1300.5×0.015APOE
Binding and Uptake of Ligands by Scavenger Receptors1271.9×0.015APOE
Plasma lipoprotein remodeling1237.9×0.015APOE
Plasma lipoprotein clearance1237.9×0.015APOE
NR1H2 and NR1H3-mediated signaling1196.9×0.015APOE
Metabolism of fat-soluble vitamins1190.3×0.015APOE
PINK1-PRKN Mediated Mitophagy1178.4×0.015TOMM40
Nuclear signaling by ERBB41173.0×0.015APOE
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux1154.3×0.016APOE
Signaling by ERBB41135.9×0.016APOE
Visual phototransduction1129.8×0.016APOE
Retinoid metabolism and transport1124.1×0.016APOE
Plasma lipoprotein assembly, remodeling, and clearance1114.2×0.017APOE
Mitochondrial protein import184.0×0.021TOMM40
Metabolism of vitamins and cofactors158.3×0.029APOE
Amyloid fiber formation151.4×0.030APOE
Signaling by Nuclear Receptors151.0×0.030APOE
Post-translational protein phosphorylation150.1×0.030APOE
Sensory Perception147.6×0.030APOE
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)143.3×0.032APOE
Signaling by Receptor Tyrosine Kinases125.8×0.051APOE
Vesicle-mediated transport117.4×0.073APOE
Transport of small molecules112.6×0.097APOE
RNA Polymerase II Transcription111.3×0.104APOE

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO termCohort genesFoldFDRSample cohort genes
lipid transport involved in lipid storage13370.4×0.006APOE
maintenance of location in cell13370.4×0.006APOE
intermediate-density lipoprotein particle clearance13370.4×0.006APOE
cardiac endothelial to mesenchymal transition13370.4×0.006SEMA3C
positive regulation of lipid transport across blood-brain barrier13370.4×0.006APOE
regulation of cellular response to very-low-density lipoprotein particle stimulus13370.4×0.006APOE
triglyceride-rich lipoprotein particle clearance11685.2×0.007APOE
regulation of amyloid-beta clearance11685.2×0.007APOE
regulation of amyloid fibril formation11685.2×0.007APOE
pulmonary myocardium development11123.5×0.007SEMA3C
positive regulation of low-density lipoprotein particle receptor catabolic process11123.5×0.007APOE
positive regulation of cardiac neural crest cell migration involved in outflow tract morphogenesis11123.5×0.007SEMA3C
dichotomous subdivision of terminal units involved in salivary gland branching1842.6×0.007SEMA3C
negative regulation of triglyceride metabolic process1842.6×0.007APOE
positive regulation of phospholipid efflux1842.6×0.007APOE
regulation of behavioral fear response1842.6×0.007APOE
very-low-density lipoprotein particle clearance1674.1×0.007APOE
acylglycerol homeostasis1674.1×0.007APOE
cellular response to lipoprotein particle stimulus1674.1×0.007APOE
AMPA glutamate receptor clustering1674.1×0.007APOE
NMDA glutamate receptor clustering1674.1×0.007APOE
positive regulation of lipoprotein transport1674.1×0.007APOE
positive regulation of dendritic spine maintenance1674.1×0.007APOE
regulation of amyloid precursor protein catabolic process1674.1×0.007APOE
positive regulation of amyloid fibril formation1674.1×0.007APOE
chylomicron remnant clearance1561.7×0.008APOE
lipoprotein biosynthetic process1561.7×0.008APOE
high-density lipoprotein particle clearance1481.5×0.009APOE
lipoprotein catabolic process1481.5×0.009APOE
negative regulation of cholesterol biosynthetic process1481.5×0.009APOE

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

SymbolMoleculesMax phase
SEMA3C00
TOMM4000
TENT5A00
CNTNAP500
APOE00

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

SymbolAssaysType breakdown
TOMM403Binding:3

Cohort enzymes (BRENDA EC)

SymbolEC numbersNames
TENT5A2.7.7.19polynucleotide adenylyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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):

TierDefinitionGenesSymbols
AApproved (phase 4 drug)0
BPhased (≥1) drug, not yet approved0
CDruggable family + PDB, no drug1TENT5A
DDruggable family + AlphaFold only, no drug1SEMA3C
EDifficult family or no structure, no drug3TOMM40, CNTNAP5, APOE

Undrugged target profiles

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

SymbolChEMBL assaysDrugged partners (top 3)
SEMA3C0
TOMM403
TENT5A0
CNTNAP50
APOE0

Clinical trials & evidence

Clinical trials

Clinical trials: 18.

Phase distribution (across all retrieved trials)

PhaseTrials
Not specified16
PHASE31
PHASE11

Top trials by phase / activity

NCTPhaseStatusTitle
NCT07052214PHASE3RECRUITINGPSMA PET Combined With MRI for the Detection of PCa
NCT01723553PHASE1COMPLETEDAmyloid-related Imaging Abnormalities (Microbleeds) in Atypical AD
NCT02740634Not specifiedACTIVE_NOT_RECRUITINGMolecular and Structural Imaging in Alzheimer’s Disease: A Longitudinal Study
NCT04150198Not specifiedRECRUITINGMECHANISMS OF NEURONAL RESILIENCE IN ALZHEIMER’S DISEASE AND ITS FOCAL VARIANTS: A PET/MR STUDY
NCT04680130Not specifiedENROLLING_BY_INVITATIONClinico-Pathologic-Genetic-Imaging Study of Neurodegenerative and Related Disorders
NCT04715399Not specifiedRECRUITINGUPenn Observational Research Repository on Neurodegenerative Disease
NCT06820190Not specifiedRECRUITINGAnalgesic Efficacy of Multiple Mid-Transverse Process to Pleura (MTP) Block and PCA in Idiopathic Scoliosis Patients Undergoing Posterior Spinal Fusion
NCT07049341Not specifiedENROLLING_BY_INVITATIONPilot Trial Evaluating Patient Experience With the MemorEM for Patients With Neurological Diseases
NCT07051109Not specifiedRECRUITINGDual-chamber Patient-controlled Analgesia for Postoperative Recovery
NCT07191327Not specifiedRECRUITINGTesting Personalized High-Definition Transcranial Direct Current Stimulation (HD-tDCS) as a Treatment of Posterior Cortical Atrophy
NCT07222605Not specifiedENROLLING_BY_INVITATIONResearch Study for Patients With Neurological Diseases Which Evaluates the Patient Experience of the MemorEM Device
NCT01095744Not specifiedCOMPLETEDInfluence of Age on Amyloid Load in Alzheimer’s Disease and in Atypical Focal Cortical Alzheimer’s Disease
NCT02289118Not specifiedCOMPLETEDTau Imaging in Young Onset Dementia
NCT03153371Not specifiedCOMPLETEDEarly-onset Alzheimer’s Disease Phenotypes: Neuropsychology and Neural Networks
NCT04041089Not specifiedCOMPLETEDDevelopment of the Effectiveness of Rehabilitation Tools for Neurovisual Disorders in Patients With Posterior Cortical Atrophy
NCT04929054Not specifiedUNKNOWNPCR Based CEUS in BI RADS 4A Nodules
NCT05688371Not specifiedUNKNOWNDexmedetomidine Plus Low Dose Morphine Versus Standard Dose of Morphine in PCA in Children .
NCT05845281Not specifiedCOMPLETEDComparison of Erector Spinae Plane Block and Intravenous Patient-controlled Analgesia in Percutaneous Nephrolithotomy

Drugs tested across these trials (top 30)

MoleculeMax phaseTrials referencing
GALLIUM GA 68 GOZETOTIDE41
CHEMBL458922601