cerebral amyloid angiopathy, APP-related

Summary

cerebral amyloid angiopathy, APP-related (MONDO:0011583) is a disease (an umbrella term covering 6 Mondo subtypes) caused by APP (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: APP (GenCC Strong)
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 28

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebral amyloid angiopathy, APP-related
Mondo ID	MONDO:0011583
OMIM	605714
DOID	DOID:0070028
NCIT	C157147
UMLS	C2751536
MedGen	414044
GARD	0024810
Is cancer (heuristic)	no

Also known as: amyloidosis, Cerebroarterial, APP-related · cerebral amyloid angiopathy, APP-related · cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants · HCHWAD

Data availability: 28 ClinVar variants · 2 GenCC gene-disease records · 8 cell lines.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › cerebrovascular disorder › cerebral amyloid angiopathy › cerebral amyloid angiopathy, APP-related

Related subtypes (3): ACys amyloidosis, ADan amyloidosis, ABri amyloidosis

Subtypes (6): ABeta amyloidosis, dutch type, ABetaL34V amyloidosis, ABeta amyloidosis, Iowa type, ABeta amyloidosis, Italian type, ABetaA21G amyloidosis, ABeta amyloidosis, Arctic type

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

28 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 6 pathogenic, 4 likely pathogenic, 3 conflicting classifications of pathogenicity, 3 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
18087	NM_000484.4(APP):c.2077G>C (p.Glu693Gln)	APP	Pathogenic	criteria provided, multiple submitters, no conflicts
18088	NM_000484.4(APP):c.2149G>A (p.Val717Ile)	APP	Pathogenic	criteria provided, multiple submitters, no conflicts
18101	NM_000484.4(APP):c.2080G>A (p.Asp694Asn)	APP	Pathogenic	criteria provided, multiple submitters, no conflicts
3338917	NC_000021.8:g.(?27252860)(27543089_?)dup	APP	Pathogenic	criteria provided, single submitter
127268	NC_000021.7:g.13636378_28138533dup	CYYR1	Pathogenic	no assertion criteria provided
1112	NM_025137.4(SPG11):c.733_734del (p.Met245fs)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
18094	NM_000484.4(APP):c.2137G>A (p.Ala713Thr)	APP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
18103	NM_000484.4(APP):c.2113C>G (p.Leu705Val)	APP	Likely pathogenic	criteria provided, single submitter
2628367	NM_000484.4(APP):c.2061A>C (p.Lys687Asn)	APP	Likely pathogenic	criteria provided, single submitter
3382968	NM_000484.4(APP):c.2059A>C (p.Lys687Gln)	APP	Likely pathogenic	criteria provided, single submitter
1522518	NM_000484.4(APP):c.1450C>T (p.Pro484Ser)	APP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
638317	NM_000484.4(APP):c.2125G>A (p.Gly709Ser)	APP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898004	NM_000484.4(APP):c.704C>T (p.Ala235Val)	APP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1299705	NM_000484.4(APP):c.1409G>A (p.Arg470His)	APP	Uncertain significance	criteria provided, single submitter
1502417	NM_000484.4(APP):c.1754G>A (p.Arg585Lys)	APP	Uncertain significance	criteria provided, multiple submitters, no conflicts
3254698	NM_000484.4(APP):c.752G>T (p.Gly251Val)	APP	Uncertain significance	criteria provided, single submitter
3393136	NM_000484.4(APP):c.892G>A (p.Gly298Arg)	APP	Uncertain significance	criteria provided, single submitter
339642	NM_000484.4(APP):c.674T>C (p.Val225Ala)	APP	Uncertain significance	criteria provided, multiple submitters, no conflicts
339656	NM_000484.4(APP):c.-170C>A	APP	Uncertain significance	criteria provided, single submitter
339658	NM_000484.3(APP):c.-199G>A	APP	Uncertain significance	criteria provided, single submitter
3781337	NM_000484.4(APP):c.1958G>A (p.Arg653Gln)	APP	Uncertain significance	criteria provided, single submitter
851473	NM_000484.4(APP):c.1037C>A (p.Ser346Tyr)	APP	Uncertain significance	criteria provided, multiple submitters, no conflicts
894989	NM_000484.4(APP):c.47G>A (p.Arg16Gln)	APP	Uncertain significance	criteria provided, multiple submitters, no conflicts
4086198	NM_002113.3(CFHR1):c.59C>A (p.Ala20Glu)	CFHR1	Uncertain significance	criteria provided, single submitter
1643179	NM_000484.4(APP):c.1458+18C>T	APP	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
339629	NM_000484.4(APP):c.2124C>T (p.Gly708=)	APP	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
339631	NM_000484.4(APP):c.1840A>G (p.Ser614Gly)	APP	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
705044	NM_000484.4(APP):c.2148C>T (p.Ile716=)	APP	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 12 · 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	cerebral amyloid angiopathy, APP-related	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare 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
SPG11	Orphanet:2822	Autosomal recessive spastic paraplegia type 11
SPG11	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
SPG11	Orphanet:466775	Autosomal recessive Charcot-Marie-Tooth disease type 2X
CFHR1	Orphanet:329931	C3 glomerulonephritis
CFHR1	Orphanet:93571	Dense deposit disease

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
APP	HGNC:620	ENSG00000142192	P05067	Amyloid-beta precursor protein	gencc,clinvar
SPG11	HGNC:11226	ENSG00000104133	Q96JI7	Spatacsin	clinvar
CYYR1	HGNC:16274	ENSG00000166265	Q96J86	Cysteine and tyrosine-rich protein 1	clinvar
CFHR1	HGNC:4888	ENSG00000244414	Q03591	Complement factor H-related protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
SPG11	Spatacsin	May play a role in neurite plasticity by maintaining cytoskeleton stability and regulating synaptic vesicle transport.
CFHR1	Complement factor H-related protein 1	Involved in complement regulation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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
Complement	1	67.0×	0.030
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APP	Other/Unknown	no		Kunitz_BPTI, Amyloid_glyco_extra, Amyloid_glyco
SPG11	Other/Unknown	no		Spatacsin, Spatacsin_C_dom
CYYR1	Other/Unknown	no		CYYR1
CFHR1	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, ComplSys_Reg/VirEntry_Med

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
Brodmann (1909) area 9	1
prefrontal cortex	1
renal medulla	1
bronchial epithelial cell	1
calcaneal tendon	1
granulocyte	1
left ventricle myocardium	1
parietal pleura	1
visceral pleura	1
liver	1
male germ line stem cell (sensu Vertebrata) in testis	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APP	295	ubiquitous	marker	prefrontal cortex, renal medulla, Brodmann (1909) area 9
SPG11	295	ubiquitous	marker	bronchial epithelial cell, granulocyte, calcaneal tendon
CYYR1	241	broad	marker	visceral pleura, left ventricle myocardium, parietal pleura
CFHR1	125		marker	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APP	11,686
SPG11	1,691
CYYR1	714
CFHR1	599

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APP	P05067	256
SPG11	Q96JI7	3
CFHR1	Q03591	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CYYR1	Q96J86	59.39

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 70. Enrichment computed across 4 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
Aggregated β-amyloid induces FXII autocatalysis	1	2855.0×	0.022	APP
Aggregated β-amyloid interacts with fibrinogen	1	1427.5×	0.022	APP
Formyl peptide receptors bind formyl peptides and many other ligands	1	713.8×	0.022	APP
Inflammasomes	1	571.0×	0.022	APP
Cell recruitment (pro-inflammatory response)	1	571.0×	0.022	APP
Neurodegenerative Diseases	1	439.2×	0.022	APP
Defective Intrinsic Pathway for Apoptosis	1	380.7×	0.022	APP
Advanced glycosylation endproduct receptor signaling	1	356.9×	0.022	APP
The NLRP3 inflammasome	1	335.9×	0.022	APP
Diseases of programmed cell death	1	317.2×	0.022	APP
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	259.6×	0.022	APP
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	1	237.9×	0.022	APP
TRAF6 mediated NF-kB activation	1	228.4×	0.022	APP
Purinergic signaling in leishmaniasis infection	1	211.5×	0.022	APP
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1	178.4×	0.022	APP
Lysosome Vesicle Biogenesis	1	163.1×	0.022	APP
TAK1-dependent IKK and NF-kappa-B activation	1	150.3×	0.022	APP
Interleukin-1 family signaling	1	135.9×	0.022	APP
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1	126.9×	0.022	APP
trans-Golgi Network Vesicle Budding	1	126.9×	0.022	APP
Regulation of clotting cascade	1	116.5×	0.022	APP
Regulation of Complement cascade	1	116.5×	0.022	CFHR1
Toll Like Receptor 10 (TLR10) Cascade	1	107.7×	0.022	APP
Toll Like Receptor 5 (TLR5) Cascade	1	107.7×	0.022	APP
MyD88 cascade initiated on plasma membrane	1	102.0×	0.022	APP
Toll Like Receptor 3 (TLR3) Cascade	1	96.8×	0.022	APP
TRIF (TICAM1)-mediated TLR4 signaling	1	95.2×	0.022	APP
Protein localization	1	95.2×	0.022	APP
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1	95.2×	0.022	APP
MyD88 dependent cascade initiated on endosome	1	95.2×	0.022	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
axo-dendritic transport	2	2808.7×	1e-05	APP, SPG11
axonogenesis	2	107.0×	0.005	APP, SPG11
phagosome-lysosome fusion involved in apoptotic cell clearance	1	5617.3×	0.006	SPG11
collateral sprouting in absence of injury	1	1872.4×	0.006	APP
localization within membrane	1	1872.4×	0.006	SPG11
astrocyte activation involved in immune response	1	1404.3×	0.006	APP
microglia development	1	1404.3×	0.006	APP
cellular response to norepinephrine stimulus	1	1404.3×	0.006	APP
regulation of spontaneous synaptic transmission	1	1404.3×	0.006	APP
axon midline choice point recognition	1	1123.5×	0.006	APP
swimming behavior	1	1123.5×	0.006	APP
hippocampal neuron apoptotic process	1	1123.5×	0.006	APP
autophagosome organization	1	1123.5×	0.006	SPG11
positive regulation of amyloid fibril formation	1	1123.5×	0.006	APP
mating behavior	1	936.2×	0.006	APP
regulation of synapse structure or activity	1	936.2×	0.006	APP
walking behavior	1	936.2×	0.006	SPG11
response to insulin-like growth factor stimulus	1	936.2×	0.006	APP
corticospinal tract morphogenesis	1	802.5×	0.006	SPG11
cellular response to manganese ion	1	802.5×	0.006	APP
NMDA selective glutamate receptor signaling pathway	1	802.5×	0.006	APP
obsolete cytolysis by host of symbiont cells	1	702.2×	0.006	CFHR1
modulation of excitatory postsynaptic potential	1	702.2×	0.006	APP
ionotropic glutamate receptor signaling pathway	1	432.1×	0.009	APP
negative regulation of long-term synaptic potentiation	1	432.1×	0.009	APP
neuron remodeling	1	401.2×	0.009	APP
motor neuron apoptotic process	1	374.5×	0.009	SPG11
neuron projection maintenance	1	374.5×	0.009	APP
regulation of store-operated calcium entry	1	351.1×	0.009	SPG11
astrocyte activation	1	330.4×	0.009	APP

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
APP	FLORBETAPIR F 18

Top cohort targets by molecule count

Symbol	Molecules	Max phase
APP	40	4
SPG11	0	0
CYYR1	0	0
CFHR1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
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
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
PARAROSANILINE	2	APP
LUTEOLIN	2	APP
PITTSBURGH COMPOUND B	2	APP
AFTOBETIN	2	APP

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
SPG11	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
APP	1,744

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)
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
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
PARAROSANILINE	2	APP
LUTEOLIN	2	APP
PITTSBURGH COMPOUND B	2	APP
AFTOBETIN	2	APP

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	APP
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	CFHR1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SPG11, CYYR1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SPG11	1	—
CYYR1	0	—
CFHR1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.