APP (103)

APP encodes amyloid precursor protein, a transmembrane protein which is cleaved to form amyloidogenic Aβ peptides. Mutations in APP are associated with familial forms of early onset Alzheimer's disease as well as with Cerebral Amyloid Angiopathy (CAA). Pathogenic mutations generally alter processing by secretases, leading in an overall increase in Aβ production and/or a change in the ratio of specific Aβ peptides.

Mutation	Clinical Phenotype	Pathogenicity	Neuropathology	Biological Effect	Genomic Position	Genomic Region	Mutation Type Codon Change	Research Models	Primary Papers
IVS17 83-88delAAGTAT	Alzheimer's Disease, None	AD : Benign	Unknown; at least one affected deletion carrier had neuropathology consistent with AD.	Unknown; deletion does not appear to affect APP splicing.	rs367709245, rs367709245	Intron 17	Deletion	0	Kamino et al., 1992
H733P	None	AD : Not Classified	Not applicable.	Increased Aβ42 moderately, without significantly altering the Aβ42/Aβ40 ratio in cells.		Exon 17	Point, Missense CAT to CCT	0	Guerreiro et al., 2010
K724N (Belgian)	Alzheimer's Disease	AD : Not Classified	Significant amyloid across the cerebral cortex as measured by PiB-PET.	Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.	rs63750151, rs63750151	Exon 17	Point, Missense AAG to AAC	0	Theuns et al., 2006
L723P (Australian)	Alzheimer's Disease	AD : Pathogenic	Unknown.	Increased Aβ48 levels, reduced Aβ48 trimming. Decreased ε-cleavage; Aβ49 production nearly abrogated.	rs63751122, rs63751122	Exon 17	Point, Missense CTG to CCG	0	Kwok et al., 2000
M722K	Alzheimer's Disease, None	AD : Pathogenic	Unknown; MRI of the proband at age 42 showed moderate cerebral atrophy, especially in the hippocampus.	Increase Aβ42/Aβ40 ratio; increased Aβ42; unchanged Aβ40; More phospho-tau.		Exon 17	Point, Missense ATG to AAG	0	Wang et al., 2015
T719N	Alzheimer's Disease	AD : Pathogenic	Unknown.	In a heterologous expression system, the T719N mutation led to increased levels of Aβ42 and an elevated Aβ42:Aβ40 ratio, compared with wild-type APP.		Exon 17	Point, Missense ACC to AAC	0	Hsu et al., 2018
T719P	Alzheimer's Disease	AD : Not Classified	Unknown; atrophy of the temporal lobes by MRI.	Increased levels of membrane-anchored Aβ49 and Aβ46; increase in the Aβ49 → Aβ46 → Aβ43 → Aβ40 pathway over the Aβ48 → Aβ45 → Aβ42 → Aβ38 pathway. Favors ε-cleavage at Aβ49 over Aβ48. Stalls γ-secretase-APP complex which appears to be toxic per se.		Exon 17	Point, Missense ACC to CCC	0	Ghidoni et al., 2009
V717G	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD in at least one case.	Increased Aβ42/Aβ40 ratio; increased total Aβ, Aβ48, Aβ46, Aβ45, Aβ42, and Aβ38; decreased Aβ40. Increased long, membrane-anchored Aβ peptides. Increased ε-cleavage, including cleavage at a novel site.	rs63749964, rs63749964	Exon 17	Point, Missense GTC to GGC	0	Chartier-Harlin et al., 1991
V717F (Indiana)	Alzheimer's Disease, Myoclonus, Parkinsonism	AD : Pathogenic	In one case, neuropathology was consistent with AD.	In vitro, increased long Aβ peptides (Aβ48, 46, 45), ε-cleavage, Aβ48 pathway. In cells, increased Aβ42/Aβ40 ratio. Altered endocytosis and transport of lipoproteins and APP to axons, possibly via increased β-CTF.	rs63750264, rs63750264	Exon 17	Point, Missense GTC to TTC	13	Murrell et al., 1991
V717I (London)	Alzheimer's Disease, Cerebral Amyloid Angiopathy, Spastic Paraparesis	AD : Pathogenic	Variable: AD plaques and tangles with some reports of mild to severe CAA, cortical and brainstem Lewy bodies, TDP-43 pathology in hippocampus and amygdala, striatal amyloid deposition.	Increased Aβ42/Aβ40 ratio; increased Aβ42; little effect on Aβ40. In yeast system, reduced ε-cleavage.	rs63750264, rs63750264	Exon 17	Point, Missense GTC to ATC	27	Goate et al., 1991
V717L	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI in the Japanese family showed relatively minor atrophic changes in the bilateral hippocampus and cerebral cortices.	Increased total Aβ, Aβ42, Aβ42/Aβ40 ratio; decreased Aβ40. Increased Aβ48 → Aβ45 → Aβ42 → Aβ38 pathway; decreased Aβ49 → Aβ46 → Aβ43 → Aβ40 pathway. Inefficient processing of longer, membrane-anchored peptides: increases in Aβ48, Aβ46, and Aβ45. ε-cleavage also increased.	rs63750264, rs63750264	Exon 17	Point, Missense GTC to CTC	0	Murrell et al., 2000
I716M	Alzheimer's Disease	AD : Not Classified	Unknown; MRI showed mild bilateral hippocampal atrophy.	Unknown; predicted damaging in silico (PHRED-scaled CADD score > 20).		Exon 17	Point, Missense ATC to ATG	0	Blauwendraat et al., 2016
I716T	Alzheimer's Disease	AD : Not Classified	Unknown.	Increased Aβ42/Aβ40 and Aβ38/Aβ42 ratios and increased levels of longer Aβ peptides, including membrane-anchored Aβ49. Decreased total Aβ and AICD. Decreased ε-cleavage and shifted towards the Aβ48 → Aβ45 → Aβ42 → Aβ38 pathway. Stalled the γ-secretase-substrate complex in the membrane.	rs63750851, rs63750851	Exon 17	Point, Missense ATC to ACC	0	Terreni et al., 2002
I716F (Iberian)	Alzheimer's Disease	AD : Pathogenic	Extensive mixed neuropathology, including neurofibrillary changes, amyloid deposits, and Lewy bodies.	Increased Aβ42/Aβ40 ratio; decreased Aβ40 and AICD; increased Aβ1-38, Aβ1-39, Aβ1-42 and APP C-terminal fragments. Also, stalled γ-secretase-substrate complex tied to synaptic loss.		Exon 17	Point, Missense ATC to TTC	5	Guerreiro et al., 2010
I716V (Florida)	Alzheimer's Disease	AD : Not Classified	Diffuse cortical atrophy, most prominant in the left anterior temporal lobe.	Increased Aβ42(43)/Aβ40 ratio; increased Aβ42(43) and membrane-anchored Aβ48. Decreased Aβ48 → Aβ45 → Aβ42 → Aβ38 pathway.	rs63750399, rs63750399	Exon 17	Point, Missense ATC to GTC	15	Eckman et al., 1997
V715A (German)	Alzheimer's Disease	AD : Pathogenic	Hypoperfusion in the parieto-occipital region.	Increased Aβ42/Aβ40 ratio in cells and in vitro. Also increased Aβ38/40 ratio, and inhibited production of AICD50–99. ε-cleavage sites, particularly T48, appear to be affected.	rs63750868, rs63750868	Exon 17	Point, Missense GTG to GCG	0	Cruts et al., 2003
V715M (French)	Alzheimer's Disease	AD : Pathogenic	Progressive cortical atrophy; Hypometabolism.	Decreased total Aβ; unchanged Aβ42; significantly decreased Aβ40.	rs63750734, rs63750734	Exon 17	Point, Missense GTG to ATG	0	Ancolio et al., 1999
T714I (Austrian)	Alzheimer's Disease	AD : Pathogenic	Extensive neuronal loss; Diffuse gliosis; Neurofibrillary tangles; Amyloid plaques including diffuse "cloudy" plaques.	Increased Aβ42/Aβ40 and Aβ38/Aβ40 ratios, increased Aβ48 → Aβ45 → Aβ42 → Aβ38 pathway; decreased Aβ49 → Aβ46 → Aβ43 → Aβ40 pathway. Inefficient processing of Aβ; increased levels of membrane-anchored Aβ48.	rs63750973, rs63750973	Exon 17	Point, Missense ACA to ATA	2	Kumar-Singh et al., 2000
T714A (Iranian)	Alzheimer's Disease	AD : Pathogenic	Progressive cortical atrophy; White matter lesions.	Increased longer Aβ peptides: Aβ42, Aβ46, Aβ48. Increased Aβ38+Aβ42+Aβ45+Aβ48; decreased Aβ40+Aβ43+Aβ46+Aβ49.	rs63750643, rs63750643	Exon 17	Point, Missense ACA to GCA	0	Pasalar et al., 2002
A713V	None	AD : Benign	Not applicable.	Decreased Aβ42 and Aβ40 secretion in cells; no effect on Aβ42/Aβ40 ratio.	rs1800557, rs1800557	Exon 17	Point, Missense GCG to GTG	0	Jones et al., 1992
A713T	Alzheimer's Disease, Cerebral Amyloid Angiopathy, Frontotemporal Dementia, None	AD : Uncertain Significance	Variable: Generalized atrophy of the cerebral cortex; Widespread neurofibrillary tangles; Neuritic plaques; Variable cerebral amyloid angiopathy.	In vitro, increased long forms of Aβ (Aβ45 and Aβ46); decreased short forms. Increased Aβ42/Aβ40 ratio due to decreased Aβ40 secretion in cells. In vitro, promoted aggregation.	rs63750066, rs63750066	Exon 17	Point, Missense GCG to ACG	0	Carter et al., 1992; Armstrong et al., 2004
G708G	None	AD : Benign	Not applicable.	Increased Aβ42 secretion without significantly affecting the Aβ42/Aβ40 ratio in cells.	rs148888161, rs148888161	Exon 17	Point, Silent GGC to GGT	0	Balbín et al., 1992
V695M	Alzheimer's Disease	AD : Not Classified	Unknown.	Unknown. In silico algorithms yielded mixed results, but integrative PHRED-scaled CADD score was > 20, suggesting deleterious effect.		Exon 17	Point, Missense GTG to ATG	0	Gao et al., 2019
E693G (Arctic, E22G)	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD in several carriers. Plaques have a "targetoid: shape, with heterogenous truncated Aβ peptides in the center surrounded by Aβ42. Very low cortical PiB retention. No hemorrhage, but severe congophilic angiopathy.	Increased propensity to form protofibrils, and at a faster rate. Aβ40 and Aβ42 production reduced or unchanged; increased Aβ5-29 and Aβ5-33. Decreased proteolytic degradation of Aβ by neprilysin. Neuronal toxicity.	rs63751039, rs63751039	Exon 17	Point, Missense GAA to GGA	9	Kamino et al., 1992; Nilsberth et al., 2001
E693del (Osaka, E693∆, E693delta)	Alzheimer's Disease	AD : Pathogenic	Unknown; remarkably low levels of amyloid by PiB-PET imaging in multiple carriers, but high tau-PET signal in one case.	Enhanced oligomerization and nucleation of Aβ aggregates in vitro; altered production, secretion, localization, and clearance of Aβ peptides in cells; cognitive impairment, synaptic deficits, neuronal loss, glial activation, and tau hyperphosphorylation in animal models.		Exon 17	Deletion GAA to ---	1	Tomiyama et al., 2008
A692G (Flemish)	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic	Severe CAA and AD pathology. Numerous senile plaques; Dystrophic neurites; Congophilic angiopathy; Hemorrhagic infarction.	Increased secreted Aβ42 and Aβ40 in CHO, HEK-293, and H4 cells. Increased β-CTF which correlated with endosomal dysfunction. Increased Aβ1-19 and Aβ5-40. Altered oligomerization, reduced aggregation.	rs63750671, rs63750671	Exon 17	Point, Missense GCA to GGA	0	Hendriks et al., 1992
F690_V695del (Uppsala deletion, APP Δ690-695, APP delta690–695, Uppsala APP deletion)	Alzheimer's Disease	AD : Pathogenic	One reported carrier of this variant had autopsy-confirmed AD.	Appears to largely eliminate non-amyloidogenic processing of APP and leads to the generation of rapidly aggregating Aβ peptides lacking amino acids 19-24. In mice, Aβ fibrils barely evoke a glial response.		Exon 17	Deletion TTC to ---, TTT to ---, GCA to ---, GAA to ---, GAT to ---, GTG to ---	0	Pagnon de la Vega et al., 2021
K687N (A>T)	Alzheimer's Disease	AD : Not Classified	Unknown; MRI showed mild global brain atrophy without focal or vascular lesions. CSF biomarker profile consistent with AD, specifically elevated total tau and phosphorylated tau, along with reduced levels of Aβ1-42.	Reduces APP cleavage by α-secretase. Reduced production of total sAPP and especially sAPPα. Increased Aβ40 and Aβ42. Alone, mutant Aβ was less toxic to neuroblastoma cells than wild-type Aβ42, but mixed in equimolar amounts with wild-type, toxicity increased. Alone, mutant Aβ formed predominantly low-n oligomers in vitro, but mixed with wild-type Aβ, it aggregated into high-n oligomers.		Exon 16	Point, Missense AAA to AAT	0	Kaden et al., 2012
K687Q	Alzheimer's Disease	AD : Pathogenic	Unknown, but imaging revealed white matter hyperintensities.	Increased nucleation of Aβ aggregation in yeast cell-based assay.		Exon 16	Point, Missense AAA to CAA	0	Jiang et al., 2019; Yi et al., 2020
K687N (A>C)	Alzheimer's Disease	AD : Likely Pathogenic	Unknown, but MRI showed brain atrophy and PET showed cortical amyloid accumulation. CSF biomarkers were consistent with AD.	Unknown, but K687N (A>T) increased Ab40 and Ab42, and when mixed with wildtype Ab, generated large oligomers; highly toxic in cells. Reduced degradation by neprilysin.		Exon 16	AAA to AAC	0	Liang et al., 2023
E682V	Alzheimer's Disease	AD : Not Classified	Unknown, but in one case MRI revealed cerebral infarctions and leukoaraiosis and SWI showed microbleeds and amyloidosis.	Unknown, but predicted in silico to be deleterious. PHRED-scaled CADD = 33.		Exon 16	GAA to GTA	0	Zhaoxia et al., 2023
E682K (Leuven)	Alzheimer's Disease	AD : Not Classified	Bilateral hippocampal volume loss; Cortical PiB uptake.	Significantly increased total Aβ and Aβ42/Aβ40 levels; Shifts BACE1 cleavage toward the β-site. May also accelerate aggregation.		Exon 16	Point, Missense GAA to AAA	0	Zhou et al., 2011
D678N (Tottori)	Alzheimer's Disease	AD : Pathogenic	Marked cortical atrophy, bilateral hippocampal atrophy, absence of focal cerebral infarction or hemorrhagic lesions in heterozygous carrier; small lacunar lesions in temporoparietal cortex and subcortical white matter in homozygous carrier.	Accelerated oligomerization kinetics and greater cytotoxicity than wild-type Aβ.	rs63750064, rs63750064	Exon 16	Point, Missense GAC to AAC	0	Wakutani et al., 2004
D678H (Taiwanese)	Alzheimer's Disease	AD : Pathogenic	Unknown; amyloid-PET showed an initial increase followed by a decrease in amyloid burden; SPECT imaging showed hypoperfusion in the bilateral parietal cortices and the left temporal lobe.	Increased Aβ42/Aβ40 ratio in conditioned media; increased secreted Aβ42 and Aβ40. Increased nucleation of Aβ aggregates/oligomers. Increased toxicity in vitro compared with wild-type Aβ42.		Exon 16	Point, Missense GAC to CAC	0	Chen et al., 2012
H677R (English)	Alzheimer's Disease	AD : Not Classified	Unknown.	Accelerated oligomerization kinetics and greater cytotoxicity than wild-type Aβ.	rs63749953, rs63749953	Exon 16	Point, Missense CAT to CGT	0	Janssen et al., 2003
A673V	Alzheimer's Disease	AD : Not Classified	Definite AD by CERAD criteria, with extensive deposition of Aβ and tau pathology (Braak stage VI). Cerebral amyloid angiopathy. Deposits contained high levels of Aβ40 and were noted to be unusually large, with few preamyloid deposits. Localization was frequently perivascular.	In vitro, A673V shifts β-secretase processing of APP toward the amyloidogenic pathway and may increase Aβ aggregation; however, co-incubation of mutant and wild-type Aβ inhibits amyloidogenesis and toxicity.		Exon 16	Point, Missense GCA to GTA	0	Di Fede et al., 2009
A673T (Icelandic)	None	AD : Protective	This variant is associated with minimal amyloid deposition. In three carriers, biopsies showed no Aβ, phospho-tau, or p62 pathology. Low sAPPβ and Aβ42 in CSF.	Shifts APP processing towards non-amyloidogenic pathway, making APP a less-favorable substrate for β-secretase, resulting in less Aβ production. Also, Aβ peptides less prone to aggregation. Mutant Aβ peptides may have neuroprotective properties.	rs63750847, rs63750847	Exon 16	Point, Missense GCA to ACA	1	Peacock et al., 1993; Jonsson et al., 2012
K670_M671delinsNL (Swedish)	Alzheimer's Disease	AD : Pathogenic	Generalized atrophy with sulcal widening and mild ventricular enlargement.	Increased BACE1 cleavage resulting in elevated total Aβ, Aβ43, Aβ42, Aβ40, β-CTF, and multiple short N-terminal Aβ peptides. Synaptic alterations, defective endocytosis, altered axonal and soma-axon transport of APP and lipoproteins. Increased glucose metabolism, impaired glutamate transport in astrocytes.	rs63751263, rs63751263, rs63750445	Exon 16	Point, Double AAG to AAT, ATG to CTG	82	Mullan et al., 1992
V669L (Seoul)	Alzheimer's Disease	AD : Not Classified	Unknown, although MRI showed pronounced cerebral atrophy that included the hippocampus.	Unknown. Although results were mixed, an integrative in silico prediction tool predicted damaging effects (PHRED-scaled CADD score >20).	rs1259157720, rs1259157720	Exon 16	Point, Missense GTG to CTG	0	Bagyinszky et al., 2019
E665D	None	AD : Benign	Not applicable.	Aβ42, Aβ40, and the Aβ42/Aβ40 ratio were not significantly different from those of cells expressing wildtype APP.	rs63750363, rs63750363	Exon 16	Point, Missense GAG to GAC	0	Peacock et al., 1994
P620L	Alzheimer's Disease	AD : Uncertain Significance	One reported carrier of the variant had autopsy-confirmed AD.	Increased Aβ40 and Aβ42 secretion in cells, without significantly altering the Aβ42/Aβ40 ratio in cells.		Exon 14	Point, Missense CCG to CTG	0	Sassi et al., 2014
P620A	Alzheimer's Disease	AD : Not Classified	Unknown.	Increased Aβ42 and the Aβ42/Aβ40 ratio in cells.		Exon 14	Point, Missense CCG to GCG	0	Nicolas et al., 2015
S614G	Alzheimer's Disease	AD : Uncertain Significance	Unknown.	Increased Aβ42/Aβ40 ratio, with a decrease in Aβ40 and an increase in Aβ42 secretion in a cellular assay.	rs112263157, rs112263157	Exon 14	Point, Missense AGC to GGC	0	Lee et al., 2014
V604M	Alzheimer's Disease, Progressive Nonfluent Aphasia	AD : Benign	Unknown, but MRI showed atrophy of the frontoparietal cortex and hippocampus of one carrier.	Unknown. Predicted in silico to be deleterious (PHRED-scaled CADD score >20).	rs199887707, rs199887707	Exon 14	Point, Missense GTG to ATG	0	Van Giau et al., 2018
T600M	None	AD : Benign	Not applicable.	In cells, secreted less Aβ40, but Aβ42 secretion and the Aβ42/Aβ40 ratio were not significantly altered.	rs200088099, rs200088099	Exon 14	Point, Missense ACG to ATG	0	Schulte et al., 2015
E599K	Alzheimer's Disease, Parkinson's Disease	AD : Benign, PD : Not Classified	Not applicable.	In cells, reduced Aβ40 secretion, but did not significantly alter Aβ42 secretion nor the Aβ42/Aβ40 ratio.	rs140304729, rs140304729	Exon 14	Point, Missense GAA to AAA	0	Sassi et al., 2014
V562I	None	AD : Not Classified	Not applicable.	In cells, Aβ40 secretion was slightly decreased with no change in Aβ42 secretion. Aβ42/Aβ40 was not significantly different from controls.	rs199586073, rs199586073	Exon 13	Point, Missense GTT to ATT	0	Sassi et al., 2014
Y538H	Alzheimer's Disease	AD : Benign	Neuropathology consistent with AD, but not thought to be attributed to this variant.	Decreased Aβ42 and Aβ40 in cells, without altering Aβ42/Aβ40 ratio.	rs45537238, rs45537238	Exon 13	Point, Missense TAT to CAT	0	Sassi et al., 2014
A500T	None	AD : Not Classified	Not applicable.	In cells, Aβ40 and Aβ42 production was similar to wildtype APP.	rs201547994, rs201547994	Exon 12	Point, Missense GCA to ACA	0	Schulte et al., 2015
K496Q	Alzheimer's Disease	AD : Not Classified	One reported carrier of this variant had autopsy-confirmed AD.	In cells, slight increase in Aβ40, but Aβ42/Aβ40 ratio not significantly different from controls.	rs201384815, rs201384815	Exon 12	Point, Missense AAG to CAG	0	Sassi et al., 2014
R486W	Alzheimer's Disease	AD : Not Classified	Unknown.	Unknown, but predicted to be probably damaging by in silico algorithms (PHRED-scaled CADD score > 20).	rs201085152, rs201085152	Exon 11	Point, Missense CGG to TGG	0	Wang et al., 2019
A479S	None	AD : Benign	Not applicable.	In cells, no significant effect on Aβ40 or Aβ42 production.	rs143794560, rs143794560	Exon 11	Point, Missense GCT to TCT	0	Sala Frigerio et al., 2015
R468H	None	AD : Benign	Not applicable.	In cells, neither Aβ40 nor Aβ42 production significantly affected.		Exon 11	Point, Missense CGC to CAC	0	Schulte et al., 2015
E380K	Alzheimer's Disease	AD : Uncertain Significance	Unknown, but imaging revealed brain atrophy.	Unknown, but predicted to be probably damaging by PolyPhen-2, damaging by SIFT, and neutral by PROVEAN. PHRED-scaled CADD score > 20.	rs755703063, rs755703063	Exon 9	Point, Missense GAG to AAG	0	El Bitar et al., 2019
G342S	Alzheimer's Disease	AD : Uncertain Significance	Unknown.	Unknown, but in silico data suggest a damaging effect (PHRED-CADD = 22.5).		Exon 7	GGC to AGC	0	Jiang et al., 2019
V340M	Alzheimer's Disease	AD : Uncertain Significance	Unknown.	Unknown, but its PHRED-scaled CADD score was >20 suggesting a deleterious effect.	rs768499633, rs768499633	Exon 7	GTG to ATG	0	Lee et al., 2014
D332G	Alzheimer's Disease	AD : Uncertain Significance	Unknown, but MRI showed atrophy of the hippocampus and of the temporal and parietal lobes in one case.	Unknown, but predicted to be damaging (PHRED-CADD = 22.8).	rs773998162, rs773998162	Exon 7	Point, Missense GAC to GGC	0	Jiang et al., 2019
P299L	Alzheimer's Disease	AD : Not Classified	Unknown.	Unknown, but predicted to be damaging in silico (PHRED-scaled CADD score >20).	rs202074408, rs202074408	Exon 7	Point, Missense CCG to CTG	0	Nicolas et al., 2015
T297M	Alzheimer's Disease	AD : Uncertain Significance	Unknown.	Unknown, but predicted to be damaging by PolyPhen-2 and deleterious by SIFT (PHRED-scaled CADD score > 20).	rs557227002, rs557227002	Exon 7	Point, Missense ACG to ATG	0	Jiang et al., 2019
E296K	Alzheimer's Disease	AD : Not Classified	Unknown.	Unknown, but in silico PHRED-CADD score >20, suggesting damaging effect.	rs751737009, rs751737009	Exon 7	Point, Missense GAG to AAG	0	Nicolas et al., 2015
E246K	Alzheimer's Disease	AD : Likely Benign	Unknown.	In cells, no significant effect on Aβ40 or Aβ42 production.	rs147485129, rs147485129	Exon 6	Point, Missense GAG to AAG	0	Sala Frigerio et al., 2015
D244G	Alzheimer's Disease	AD : Not Classified	Unknown.	Unknown, but predicted to be probably damaging by PolyPhen-2 and tolerated by SIFT. PHRED-scaled CADD score > 20.	rs1347585131, rs1347585131	Exon 6	Point, Missense GAT to GGT	0	Jiang et al., 2019
D243N	Alzheimer's Disease	AD : Benign	Unknown.	No effect on Aβ42 or Aβ40 production in cells.		Exon 6	Point, Missense GAT to AAT	0	Nicolas et al., 2015
A235V	Alzheimer's Disease	AD : Benign	Unknown.	Decreased aβ40 and Aβ42 without changing Aβ42/Aβ40 ratio in cells.		Exon 6	Point, Missense GCT to GTT	0	Nicolas et al., 2015
A201V	None, Parkinson's Disease Dementia	AD : Benign, PDD : Not Classified	Not applicable.	In cells, no effect on Aβ42, Aβ40, and Aβ42/Aβ40.	rs149995579, rs149995579	Exon 5	Point, Missense GCG to GTG	0	Sassi et al., 2014
S198P	Alzheimer's Disease	AD : Benign	Unknown.	The S198P mutation increased the production of Aβ in cultured cells and in a transgenic mouse model of amyloidosis.	rs145081708, rs145081708	Exon 5	Point, Missense TCT to CCT	0	Zhang et al., 2021
c.-111G> C	Alzheimer's Disease	AD : Benign	Unknown.	Unknown, but in silico algorithm suggested the variant is not damaging (PHRED-CADD = 10.41).	rs459543, rs459543	Exon 1, 5'UTR		0	Xiao et al., 2023
c.-265C>A (-118C>A)	Alzheimer's Disease	AD : Not Classified	Unknown.	Increased APP transcription in a neuronal cell-based reporter system.		2kb upstream		0	Theuns et al., 2006
c.-516C>G (-369C>G)	Alzheimer's Disease	AD : Uncertain Significance	Unkown.	Increased APP transcription in a neuronal cell-based reporter system.	rs539645405, rs539645405	2		0	Theuns et al., 2006
c.-681G>A (-534G>A)	Alzheimer's Disease	AD : Uncertain Significance	Unknown.	Increased APP transcription in a neuronal cell-based reporter system.	rs187510057, rs187510057	2kb upstream		0	Theuns et al., 2006
Duplication 1104 [APP-APP]	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic, CAA :	In one carrier, examination of the brain at autopsy revealed neuropathology consistent with AD and CAA.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood. This duplication includes a single gene: APP.		Chromosome 21		0	Sleegers et al., 2006
Duplication ALZ-254 [POTED-ADAMTS5] (EXT-254 [POTED-ADAMTS5])	Alzheimer's Disease	AD : Not Classified	Unknown.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Wallon et al., 2012
Duplication ALZ-478 [LINC00158-EIF4A1P]	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic, CAA :	Unknown, but an MRI scan of one carrier revealed probable CAA.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood. This duplication includes a single gene: APP.		Chromosome 21		0	Grangeon et al., 2023
Duplication [APP-CYYR1]	Alzheimer's Disease	AD : Pathogenic	Unknown, but CT and MRI scans of 4 affected and 6 asymptomatic carriers revealed white matter lesions or some form of vascular alteration.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Kalfon et al., 2022
Duplication EXT-006 [HSPA13-GRIK1]	Dementia	AD : Not Classified	Unknown.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood. This duplication includes a single gene: APP.		Chromosome 21		0	Grangeon et al., 2023
Duplication EXT-019 [LINC00158-USP16]	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic, CAA :	Consistent with AD and CAA.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood. This duplication includes a single gene: APP.		Chromosome 21		0	Grangeon et al., 2023
Duplication EXT-054 [USP25-ADAMTS1]	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic, CAA :	Neuropathology unknown, but MRI of one carrier revealed CAA with 2 intracerebral hemorrhages, 6 cerebral microbleeds, and cortical superficial siderosis.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Wallon et al., 2012
Duplication EXT-144 [BTG3-EIF4A1P]	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic, CAA :	Consistent with severe CAA in 1 carrier and probable CAA detected by MRI in another. Absence of neurofibrillary tangles.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Wallon et al., 2012
Duplication EXT-145 [NCAM2-EIF4A1P]	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Not Classified, CAA :	Unknown, but MRI of one carrier revealed probable CAA with 3 intracerebral hemorrhages and 13 cerebral microbleeds.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Wallon et al., 2012
Duplication EXT-187 [POTED-ADAMTS5]	Alzheimer's Disease	AD : Not Classified	Unknown.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Wallon et al., 2012
Duplication EXT-262 [JAM2-APP] (BES-262 [JAM2-APP])	Alzheimer's Disease, Cerebral Amyloid Angiopathy, Dementia with Lewy Bodies	AD : Pathogenic, CAA : , DLB : Not Classified	In one carrier, neuropathology was consistent with AD with severe CAA and LBD. CAA and Lewy bodies were widespread. MRI of 3 carriers suggests neuropathology is heterogenous.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Guyant-Marechal et al., 2008
Duplication EXT-279 [GABPA-ADAMTS1]	Alzheimer's Disease	AD : Not Classified	Unknown.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Wallon et al., 2012
Duplication EXT-298 [GABPA-CYYR1]	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic, CAA :	Consistent with AD and CAA in one case, and MRI revealed probable CAA in another.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Wallon et al., 2012
Duplication EXT-773 [LINC00158-CYYR1]	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Not Classified, CAA :	Neuropathology consistent with AD and severe CAA in cortex, insula, and basal ganglia. Also, Lewy bodies in the amygdala, locus niger, nucleus basalis of Meynert, and entorhinal cortex.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Rovelet-Lecrux et al., 2015
Duplication EXT-814 [NCAM2-ADAMTS5]	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Not Classified, CAA :	Unknown, but CSF biomarkers were consistent with AD and MRI revealed probable CAA in one carrier.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Lanoiselée et al., 2017
Duplication EXT-857 [MRPL39-ADAMTS5]	Alzheimer's Disease	AD : Pathogenic	Unknown, but CSF biomarkers were consistent with AD in one carrier. MRI showed no signs of CAA.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Lanoiselée et al., 2017
Duplication EXT-1093 [AK124194-CYYR1]	Alzheimer's Disease	AD : Not Classified	Unknown, but CSF biomarkers were consistent with AD in one carrier.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Lanoiselée et al., 2017
Duplication EXT-1230 [BTG3- ADAMTS5]	Alzheimer's Disease	AD : Not Classified	Unknown.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood. This duplication includes a single gene: APP.				0	Grangeon et al., 2023
Duplication EXT-1252 [LINC00158-ADAMTS1]	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Not Classified, CAA :	Unknown, but CSF biomarkers were consistent with AD in one carrier and MRI showed probable CAA.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood		Chromosome 21		0	Lanoiselée et al., 2017
Duplication EXT-1516 [APP-ADAMTS1]	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Not Classified, CAA :	Unknown, but MRI of one carrier revealed probable CAA.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood. This duplication includes a single gene: APP.		Chromosome 21		0	Grangeon et al., 2023
Duplication EXT 1853 [MRPL39-CYYR1]	Alzheimer's Disease	AD : Not Classified	Unknown. In one carrier, MRI revealed no sign of CAA.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood. This duplication includes a single gene: APP.		Chromosome 21		0	Grangeon et al., 2023
Duplication EXT-1864 [TUBAP-ADAMTS1]	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Not Classified, CAA :	Unknown, but MRI of one carrier revealed probable CAA.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood. This duplication includes a single gene: APP.		Chromosome 21		0	Grangeon et al., 2023
Duplication EXT 2066 [MRPL39-APP]	Alzheimer's Disease	AD : Not Classified	Unknown.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood. This duplication includes a single gene: APP.		Chromosome 21		0	Grangeon et al., 2023
Duplication F009 [LINC00158-EIF4A1P]	Alzheimer's Disease	AD : Pathogenic	Unknown.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Rovelet-Lecrux et al., 2006
Duplication F019 [LINC00158-BACH1]	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic, CAA :	Neuropathology consistent with AD and severe CAA in two carriers.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Rovelet-Lecrux et al., 2006
Duplication F028 [MRPL39-APP] (ALZ-028 [MRPL39-APP])	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic, CAA :	Neuropathology was consistent with AD and severe CAA in two carriers.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Rovelet-Lecrux et al., 2006
Duplication F037 [LINC00158-APP] (ROU-037 [LINC00158-APP])	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic, CAA :	Neuropathology was consistent with AD and severe CAA in 3 carriers.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Rovelet-Lecrux et al., 2006
Duplication F229 [NCAM2-EIF4A1P] (ALZ-229 [NCAM2-EIF4A1P])	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic, CAA :	Unknown, but hypoperfusion was seen in cortex of 1 carrier and was diffuse in another. MRI showed parieto-occipital and frontal white matter changes in the former. Atrophy was severe in the parieto-temporal cortices of both carriers.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Rovelet-Lecrux et al., 2006
Duplication [JAM2-APP]	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic, CAA :	Neuropathology consistent with AD and severe CAA in 3 carriers.	Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood.		Chromosome 21		0	Rovelet-Lecrux et al., 2007; Remes et al., 2004
Duplication PED 2945 [APP-CYYR1]	Alzheimer's Disease	AD : Not Classified	Unknown, but CSF biomarkers were consistent with AD. MRI of one carrier showed mild cortical atrophy without cerebrovascular alterations.	Levels of APP mRNA in the proband's blood were elevated ~1.5-fold.		Chromosome 21		0	Kasuga et al., 2009
Duplication PED 3281 [LINC00158-ADAMTS5] (PED 3281 [C21orf42-ADAMTS5])	Alzheimer's Disease	AD : Not Classified	Unknown, but CSF biomarkers were consistent with AD and brain imaging revealed sucbcortical white matter microbleeds and hyperintensities in one carrier.	Increased APP mRNA in blood ~1.5-fold.		Chromosome 21		0	Kasuga et al., 2009
Triplication [APP-APP]	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic, CAA :	CAA observed in a non-genotyped family member. One carrier had brain vascular alterations as revealed by MRI and CSF biomarkers (Aβ42, Aβ40, tau, phospho-tau) consistent with AD.	APP mRNA levels in blood were increased 2-fold in the proband.		Chromosome 21		0	Grangeon et al., 2021
Trisomy 21	Alzheimer's Disease, Cerebral Amyloid Angiopathy, Down's Syndrome	AD : Pathogenic, CAA : , Down's Syndrome :	Neuropathology consistent with AD, usually developing by age 40 and often accompanied by CAA. Cerebrovascular disease appears to correlate with the severity of amyloid and tau pathologies, suggesting it is a core feature of DS AD tied to AD progression.	APP overexpression, possible modification of pathology/vulnerability by increased expression of other genes on chromosome 21.		Chromosome 21		0	JERVIS, 1948

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APP (103)