Primary progressive aphasia

Summary

Primary progressive aphasia (MONDO:0019806) is a disease with 1 cohort gene and 64 clinical trials. Top therapeutic interventions include florbetaben f18, florbetapir f 18, and nabilone.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide)
• Cohort genes: 1
• ClinVar variants: 2
• Clinical trials: 64

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	7	Worldwide	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	primary progressive aphasia
Mondo ID	MONDO:0019806
EFO	EFO:0009053
MeSH	D018888
Orphanet	95432
DOID	DOID:0081388
NCIT	C85024
UMLS	C0282513
MedGen	79466
GARD	0008541
Is cancer (heuristic)	no

Also known as: Mesulam syndrome · PPA · primary progressive aphasia syndrome

Data availability: 2 ClinVar variants.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › primary progressive aphasia

Related subtypes (21): synucleinopathy, eyelid degenerative disorder, senile degeneration of brain, olivopontocerebellar atrophy, neuroaxonal dystrophy, demyelinating disease, choroidal sclerosis, tauopathy, secondary Parkinson disease, infantile bilateral striatal necrosis, Marchiafava-Bignami disease, superficial siderosis, primary progressive apraxia of speech, human prion disease, primary progressive freezing gait, motor neuron disorder, brachial amyotrophic diplegia, cerebellar degeneration, inherited neurodegenerative disorder, cerebral degeneration, hypertrophic olivary degeneration

Subtypes (2): GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, logopenic progressive aphasia

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:

1 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
98150	NM_002087.4(GRN):c.709-2A>G	GRN	Pathogenic	criteria provided, multiple submitters, no conflicts
1429250	NM_002087.4(GRN):c.1735C>T (p.Arg579Cys)	GRN	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GRN	Orphanet:100069	Semantic dementia
GRN	Orphanet:100070	Progressive non-fluent aphasia
GRN	Orphanet:275864	Behavioral variant of frontotemporal dementia
GRN	Orphanet:314629	CLN11 disease

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GRN	HGNC:4601	ENSG00000030582	P28799	Progranulin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GRN	Progranulin	Secreted protein that acts as a key regulator of lysosomal function and as a growth factor involved in inflammation, wound healing and cell proliferation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GRN	Other/Unknown	no		Granulin, Granulin_sf, Granulin_fam

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
monocyte	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GRN	301	ubiquitous	marker	monocyte, granulocyte, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GRN	1,490

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GRN	P28799	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Neutrophil degranulation	1	23.1×	0.043	GRN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 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 aspartic-type peptidase activity	1	16852.0×	9e-04	GRN
positive regulation of inflammatory response to wounding	1	8426.0×	9e-04	GRN
positive regulation of trophectodermal cell proliferation	1	8426.0×	9e-04	GRN
positive regulation of protein folding	1	5617.3×	9e-04	GRN
astrocyte activation involved in immune response	1	4213.0×	9e-04	GRN
positive regulation of lysosome organization	1	4213.0×	9e-04	GRN
trophectodermal cell proliferation	1	3370.4×	9e-04	GRN
microglial cell activation involved in immune response	1	3370.4×	9e-04	GRN
positive regulation of axon regeneration	1	3370.4×	9e-04	GRN
negative regulation of respiratory burst involved in inflammatory response	1	3370.4×	9e-04	GRN
negative regulation of neutrophil activation	1	2407.4×	0.001	GRN
negative regulation of microglial cell activation	1	2106.5×	0.001	GRN
positive regulation of defense response to bacterium	1	1872.4×	0.001	GRN
maintenance of synapse structure	1	1532.0×	0.001	GRN
lysosomal protein catabolic process	1	1053.2×	0.002	GRN
locomotory exploration behavior	1	991.3×	0.002	GRN
lysosomal transport	1	702.2×	0.003	GRN
lysosomal lumen acidification	1	674.1×	0.003	GRN
blastocyst hatching	1	543.6×	0.003	GRN
embryo implantation	1	351.1×	0.005	GRN
epithelial cell proliferation	1	312.1×	0.005	GRN
lysosome organization	1	306.4×	0.005	GRN
positive regulation of neuron apoptotic process	1	271.8×	0.005	GRN
retina development in camera-type eye	1	255.3×	0.005	GRN
positive regulation of endothelial cell migration	1	251.5×	0.005	GRN
positive regulation of epithelial cell proliferation	1	244.2×	0.005	GRN
regulation of inflammatory response	1	168.5×	0.007	GRN
positive regulation of angiogenesis	1	115.4×	0.010	GRN
negative regulation of neuron apoptotic process	1	110.9×	0.010	GRN
protein stabilization	1	66.9×	0.016	GRN

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GRN	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GRN	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	GRN

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)
GRN	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 64.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	55
PHASE2	5
PHASE1	2
PHASE4	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01818661	PHASE4	RECRUITING	Longitudinal Multi-Modality Imaging in Progressive Apraxia of Speech
NCT05386394	PHASE2	RECRUITING	Transcranial Direct Current Stimulation in the Treatment of Primary Progressive Aphasia
NCT05742698	PHASE2	RECRUITING	Nabilone for Agitation in Frontotemporal Dementia
NCT06191198	PHASE2	RECRUITING	Communication Bridge 3 Study
NCT04046991	PHASE2	COMPLETED	Treating Primary Progressive Aphasia (PPA) Using High-definition tDCS
NCT05615922	PHASE2	COMPLETED	Remotely Supervised Transcranial Direct Current Stimulation (tDCS) for Primary Progressive Aphasia (PPA)
NCT01623284	PHASE1	COMPLETED	PiB PET Scanning in Speech and Language Based Dementias
NCT02736695	PHASE1	COMPLETED	Assessment of Hyperphosphorylated Tau PET Binding in Primary Progressive Aphasia and Frontotemporal Dementia
NCT06511752	EARLY_PHASE1	RECRUITING	Educational Support Group Program for Bilingual and Spanish-speaking Carepartners and People With Progressive Aphasia
NCT00537004	Not specified	RECRUITING	Language in Primary Progressive Aphasia
NCT03313011	Not specified	RECRUITING	The Neurobiology of Two Distinct Types of Progressive Apraxia of Speech
NCT03887481	Not specified	RECRUITING	Targeting Language-specific and Executive-control Networks With Transcranial Direct Current Stimulation in Logopenic Variant PPA
NCT04680130	Not specified	ENROLLING_BY_INVITATION	Clinico-Pathologic-Genetic-Imaging Study of Neurodegenerative and Related Disorders
NCT04715399	Not specified	RECRUITING	UPenn Observational Research Repository on Neurodegenerative Disease
NCT04881617	Not specified	ACTIVE_NOT_RECRUITING	Treatment for Speech and Language in Primary Progressive Aphasia
NCT04920318	Not specified	RECRUITING	Enhancing Language Function in Primary Progressive Aphasia
NCT04957537	Not specified	RECRUITING	Semantic Rehabilitation for Patients With Primary Progressive Semantic Aphasia
NCT05368350	Not specified	ACTIVE_NOT_RECRUITING	Treating Primary Progressive Aphasia and Apraxia of Speech Using Non-invasive Brain Stimulation
NCT05443633	Not specified	RECRUITING	Enhancing Language Function in Aphasia
NCT05730023	Not specified	RECRUITING	A Multimodal Approach for Clinical Diagnosis and Treatment of Primary Progressive Aphasia, MAINSTREAM ID:3430931
NCT05741853	Not specified	RECRUITING	Cognitive Reserve and Response to Speech-Language Intervention in Bilingual Speakers With Primary Progressive Aphasia
NCT05901233	Not specified	ENROLLING_BY_INVITATION	Speech-Language Treatment With Remotely Supervised Transcranial Direct Current Stimulation in Primary Progressive Aphasia
NCT06211374	Not specified	ACTIVE_NOT_RECRUITING	Communication Bridge Pilot Study
NCT06529744	Not specified	RECRUITING	Improving Prognostic Confidence in Neurodegenerative Diseases Causing Dementia Using Peripheral Biomarkers and Integrative Modeling
NCT06613204	Not specified	RECRUITING	STELLA-FTD: Examination of a Behavior Change Intervention for FTD Family Care Partners
NCT06649084	Not specified	ENROLLING_BY_INVITATION	Primary Progressive Aphasia Multicomponent Language Treatment Study
NCT06739967	Not specified	RECRUITING	Speech and Language Interventions for Italian People With PPA
NCT06870838	Not specified	ACTIVE_NOT_RECRUITING	Neuroinflammation in FTLD
NCT06921265	Not specified	ENROLLING_BY_INVITATION	Targeted Transcranial Magnetic Stimulation to Improve Language and Speech in Patients With Primary Progressive Aphasia
NCT07158216	Not specified	RECRUITING	Long Term Effect of Brain Stimulation in PPA
NCT07219680	Not specified	RECRUITING	Intervention for Communication Quality of Life in Primary Progressive Aphasia
NCT07260253	Not specified	RECRUITING	Remotely-supervised Neuromodulation in PPA
NCT07316413	Not specified	RECRUITING	Repetitive Transcranial Magnetic Stimulation in Frontotemporal Lobar Degeneration
NCT07511179	Not specified	NOT_YET_RECRUITING	Personalized Closed-Loop Brain Stimulation for Patients With Primary Progressive Aphasia
NCT07567664	Not specified	ENROLLING_BY_INVITATION	Tracking and Predicting How Brain Damage Spreads in Neurodegenerative Diseases
NCT00957710	Not specified	COMPLETED	Language Treatment for Progressive Aphasia
NCT01465360	Not specified	COMPLETED	Performance of AclarusDx™, a Blood-Based Transcriptomic Test for AD, in US Patients Newly Referred to a Memory Center
NCT02439853	Not specified	COMPLETED	Communication Bridge Speech Therapy Research Study
NCT02541097	Not specified	COMPLETED	Preventing Language Decline in Dementia
NCT02606422	Not specified	COMPLETED	tDCS Intervention in Primary Progressive Aphasia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLORBETABEN F18	4	1
FLORBETAPIR F 18	4	1
NABILONE	4	1
CHEMBL46909	0	1