Mutations
APP
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.
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APP (114)
| Mutation | Pathogenicity | DNA Change | Expected RNA | Protein Consequence | Coding/Non-Coding | Genomic Region | Neuropathology | Biological Effect | Primary Papers |
|---|---|---|---|---|---|---|---|---|
| c.-681G>A (-534G>A) |
AD : Uncertain Significance | Substitution | Non-Coding | 2kb upstream | Unknown. |
Increased APP transcription in a neuronal cell-based reporter system. |
Theuns et al., 2006 | |
| c.-516C>G (-369C>G) |
AD : Uncertain Significance | Substitution | Non-Coding | 2 | Unkown. |
Increased APP transcription in a neuronal cell-based reporter system. |
Theuns et al., 2006 | |
| c.-265C>A (-118C>A) |
AD : Not Classified | Substitution | Non-Coding | 2kb upstream | Unknown. |
Increased APP transcription in a neuronal cell-based reporter system. |
Theuns et al., 2006 | |
| c.-111G> C |
AD : Benign | Substitution | Substitution | | Non-Coding | Exon 1, 5'UTR | Unknown. |
Unknown, but in silico algorithm suggested the variant is not damaging (PHRED-CADD = 10.41). |
Xiao et al., 2023 |
| S198P |
AD : Benign | Substitution | Substitution | Missense | Coding | Exon 5 | Unknown. |
The S198P mutation increased the production of Aβ in cultured cells and in a transgenic mouse model of amyloidosis. |
Zhang et al., 2021 |
| A201V |
AD : Benign, PDD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 5 | Not applicable. |
In cells, no effect on Aβ42, Aβ40, and Aβ42/Aβ40. |
Sassi et al., 2014 |
| A235V |
AD : Benign | Substitution | Substitution | Missense | Coding | Exon 6 | Unknown. |
Decreased aβ40 and Aβ42 without changing Aβ42/Aβ40 ratio in cells. |
Nicolas et al., 2015 |
| D243N |
AD : Benign | Substitution | Substitution | Missense | Coding | Exon 6 | Unknown. |
No effect on Aβ42 or Aβ40 production in cells. |
Nicolas et al., 2015 |
| D244G |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 6 | Unknown. |
Unknown, but predicted to be probably damaging by PolyPhen-2 and tolerated by SIFT. PHRED-scaled CADD score > 20. |
Jiang et al., 2019 |
| E246K |
AD : Likely Benign | Substitution | Substitution | Missense | Coding | Exon 6 | Unknown. |
In cells, no significant effect on Aβ40 or Aβ42 production. |
Sala Frigerio et al., 2015 |
| E296K |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 7 | Unknown. |
Unknown, but in silico PHRED-CADD score >20, suggesting damaging effect. |
Nicolas et al., 2015 |
| T297M |
AD : Uncertain Significance | Substitution | Substitution | Missense | Coding | Exon 7 | Unknown. |
Unknown, but predicted to be damaging by PolyPhen-2 and deleterious by SIFT (PHRED-scaled CADD score > 20). |
Jiang et al., 2019 |
| P299L |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 7 | Unknown. |
Unknown, but predicted to be damaging in silico (PHRED-scaled CADD score >20). |
Nicolas et al., 2015 |
| D332G |
AD : Uncertain Significance | Substitution | Substitution | Missense | Coding | Exon 7 | 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). |
Jiang et al., 2019 |
| V340M |
AD : Uncertain Significance | Substitution | Substitution | Missense | Coding | Exon 7 | Unknown. |
Unknown, but its PHRED-scaled CADD score was >20 suggesting a deleterious effect. |
Lee et al., 2014 |
| G342S |
AD : Uncertain Significance | Substitution | Substitution | Missense | Coding | Exon 7 | Unknown. |
Unknown, but in silico data suggest a damaging effect (PHRED-CADD = 22.5). |
Jiang et al., 2019 |
| E380K |
AD : Uncertain Significance | Substitution | Substitution | Missense | Coding | Exon 9 | 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. |
El Bitar et al., 2019 |
| R468H |
AD : Benign | Substitution | Substitution | Missense | Coding | Exon 11 | Not applicable. |
In cells, neither Aβ40 nor Aβ42 production significantly affected. |
Schulte et al., 2015 |
| A479S |
AD : Benign | Substitution | Substitution | Missense | Coding | Exon 11 | Not applicable. |
In cells, no significant effect on Aβ40 or Aβ42 production. |
Sala Frigerio et al., 2015 |
| R486W |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 11 | Unknown. |
Unknown, but predicted to be probably damaging by in silico algorithms (PHRED-scaled CADD score > 20). |
Wang et al., 2019 |
| K496Q |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 12 | 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. |
Sassi et al., 2014 |
| A500T |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 12 | Not applicable. |
In cells, Aβ40 and Aβ42 production was similar to wildtype APP. |
Schulte et al., 2015 |
| Y538H |
AD : Benign | Substitution | Substitution | Missense | Coding | Exon 13 | Neuropathology consistent with AD, but not thought to be attributed to this variant. |
Decreased Aβ42 and Aβ40 in cells, without altering Aβ42/Aβ40 ratio. |
Sassi et al., 2014 |
| V562I |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 13 | Not applicable. |
In cells, Aβ40 secretion was slightly decreased with no change in Aβ42 secretion. Aβ42/Aβ40 was not significantly different from controls. |
Sassi et al., 2014 |
| E599K |
AD : Benign, PD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 14 | Not applicable. |
In cells, reduced Aβ40 secretion, but did not significantly alter Aβ42 secretion nor the Aβ42/Aβ40 ratio. |
Sassi et al., 2014 |
| T600M |
AD : Benign | Substitution | Substitution | Missense | Coding | Exon 14 | Not applicable. |
In cells, secreted less Aβ40, but Aβ42 secretion and the Aβ42/Aβ40 ratio were not significantly altered. |
Schulte et al., 2015 |
| V604M |
AD : Benign | Substitution | Substitution | Missense | Coding | Exon 14 | 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). |
Van Giau et al., 2018 |
| S614G |
AD : Uncertain Significance | Substitution | Substitution | Missense | Coding | Exon 14 | Unknown. |
Increased Aβ42/Aβ40 ratio, with a decrease in Aβ40 and an increase in Aβ42 secretion in a cellular assay. |
Lee et al., 2014 |
| P620A |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 14 | Unknown. |
Increased Aβ42 and the Aβ42/Aβ40 ratio in cells. |
Nicolas et al., 2015 |
| P620L |
AD : Uncertain Significance | Substitution | Substitution | Missense | Coding | Exon 14 | 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. |
Sassi et al., 2014 |
| T663M |
PDD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 16 | Unknown. |
Unknown, but in silico predicted to be deleterious (PHRED-scaled CADD score >20). |
Schulte et al., 2015 |
| E665D |
AD : Benign | Substitution | Substitution | Missense | Coding | Exon 16 | Not applicable. |
Aβ42, Aβ40, and the Aβ42/Aβ40 ratio were not significantly different from those of cells expressing wildtype APP. |
Peacock et al., 1994 |
| V669L (Seoul) |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 16 | 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). |
Bagyinszky et al., 2019 |
| K670_M671delinsNL (Swedish) |
AD : Pathogenic | Deletion-Insertion | Deletion-Insertion | Deletion-Insertion | Coding | Exon 16 | 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. |
Mullan et al., 1992 |
| A673T (Icelandic) |
AD : Protective | Substitution | Substitution | Missense | Coding | Exon 16 | 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. |
Reduced production of amyloidogenic Aβ peptides. The Aβ generated is less prone to aggregation. |
Peacock et al., 1993; Jonsson et al., 2012 |
| A673V |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 16 | 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. |
Di Fede et al., 2009 |
| H677R (English) |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 16 | Unknown. |
Accelerated oligomerization kinetics and greater cytotoxicity than wild-type Aβ. |
Janssen et al., 2003 |
| D678H (Taiwanese) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 16 | 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. |
Chen et al., 2012 |
| D678N (Tottori) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 16 | 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. |
Wakutani et al., 2004 |
| E682K (Leuven) |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 16 | 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. |
Zhou et al., 2011 |
| E682V |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 16 | 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. |
Zhaoxia et al., 2023 |
| K687Q |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 16 | Unknown, but imaging revealed white matter hyperintensities. |
Increased nucleation of Aβ aggregation in yeast cell-based assay. |
Jiang et al., 2019; Yi et al., 2020 |
| K687N (A>T) |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 16 | 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. |
Kaden et al., 2012 |
| K687N (A>C) |
AD : Likely Pathogenic | Substitution | Substitution | Missense | Coding | Exon 16 | 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. |
Liang et al., 2023 |
| L688V (Greek) |
VaD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 16 | In one case, CADASIL-like pathology with CAA was observed. In another, white matter damage and brain atrophy, particularly in the temporal lobe and hippocampus, were reported. CSF biomarkers were consistent with AD 4 years afterwards. |
Accelerated nucleation of Aβ aggregation in yeast cell-based assay. |
Psychogios et al., 2021; Kalampokini et al., 2021 |
| A692G (Flemish) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | 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. |
Hendriks et al., 1992 |
| E693K (Italian) |
CAA : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | Small to large hematomas, subarachnoid bleeding, scars with hemosiderin deposits, small infarcts, cortical calicifications; Aβ immunoreactivity in vessel walls and neuropil; Absence of neurofibrillary changes and neuritic plaques. |
Although reduced Aβ42/Aβ40 ratio and decreased Aβ42, the mutant peptide is toxic in cells and aggregates faster. |
Tagliavini et al., 1999; Bugiani et al., 2010 |
| E693Q (Dutch) |
CAA : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | Extensive amyloid deposition in the cerebral vasculature; Hemorrhages; Some diffuse plaques in brain parenchyma. |
Accelerates Aβ aggregation in vitro, increasing fibril formation; may alter APP processing. |
Levy et al., 1990; Van Broeckhoven et al., 1990; Fernandez-Madrid et al., 1991 |
| E693G (Arctic, E22G) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | 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. |
Kamino et al., 1992; Nilsberth et al., 2001 |
| E693del (Osaka, E693∆, E693delta) |
AD : Pathogenic | Deletion | Deletion | Deletion | Coding | Exon 17 | 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. |
Tomiyama et al., 2008 |
| D694N (Iowa) |
CAA : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | Extensive CAA with cortical, particularly occipital, calcifications and AD pathology; hemorrhagic lesions. |
Increased fibrillogenesis of the Aβ peptide; greater Aβ-induced toxicity; decreased α-secretase cleavage, increased Aβ5-29, Aβ5-33, Aβ1-19, Aβ1-33. |
Grabowski et al., 2001 |
| V695M |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 17 | Unknown. |
Unknown. In silico algorithms yielded mixed results, but integrative PHRED-scaled CADD score was > 20, suggesting deleterious effect. |
Gao et al., 2019 |
| F690_V695del (Uppsala deletion, APP Δ690-695, APP delta690–695, Uppsala APP deletion) |
AD : Pathogenic | Deletion | Deletion | Deletion | Coding | Exon 17 | 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. |
Pagnon de la Vega et al., 2021 |
| N698D (Ghent mutation, p.[Asn698Asp]) |
CAA : Not Classified | Substitution | Substitution | Missense | Coding | Exon 17 | Unknown, but in one case MRI showed widespread cerebral microangiopathy consistent with CAA and CSVD. |
Unknown, but in silico analysis predicted damaging effect (PHRED-scaled CADD = 25.6). |
Schuermans et al., 2023 |
| L705V |
CAA : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | Severe CAA; Hemorrhages originating from affected vessels; “Vessel-within-vessel” morphology; Absence of parenchymal amyloid deposits and neurofibrillary tangles. |
Accelerated nucleation of Aβ aggregates in vitro |
Obici et al., 2005 |
| G708G |
AD : Benign | Substitution | Substitution | Silent | Coding | Exon 17 | Not applicable. |
Increased Aβ42 secretion without significantly affecting the Aβ42/Aβ40 ratio in cells. |
Balbín et al., 1992 |
| G709S |
PDD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 17 | Unknown. |
Unknown, but in silico analysis predicted it is deleterious (PHRED-scaled CADD score >20). |
Schulte et al., 2015 |
| A713T |
AD : Uncertain Significance | Substitution | Substitution | Missense | Coding | Exon 17 | 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. |
Carter et al., 1992; Armstrong et al., 2004 |
| A713V |
AD : Benign | Substitution | Substitution | Missense | Coding | Exon 17 | Not applicable. |
Decreased Aβ42 and Aβ40 secretion in cells; no effect on Aβ42/Aβ40 ratio. |
Jones et al., 1992 |
| T714A (Iranian) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | Progressive cortical atrophy; White matter lesions. |
Increased longer Aβ peptides: Aβ42, Aβ46, Aβ48. Increased Aβ38+Aβ42+Aβ45+Aβ48; decreased Aβ40+Aβ43+Aβ46+Aβ49. |
Pasalar et al., 2002 |
| T714I (Austrian) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | 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. |
Kumar-Singh et al., 2000 |
| V715M (French) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | Progressive cortical atrophy; Hypometabolism. |
Decreased total Aβ; unchanged Aβ42; significantly decreased Aβ40. |
Ancolio et al., 1999 |
| V715A (German) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | 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. |
Cruts et al., 2003 |
| I716F (Iberian) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | 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. |
Guerreiro et al., 2010 |
| I716V (Florida) |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 17 | 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. |
Eckman et al., 1997 |
| I716T |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 17 | 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. |
Terreni et al., 2002 |
| I716M |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 17 | Unknown; MRI showed mild bilateral hippocampal atrophy. |
Unknown; predicted damaging in silico (PHRED-scaled CADD score > 20). |
Blauwendraat et al., 2016 |
| V717F (Indiana) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | 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. |
Murrell et al., 1991 |
| V717L |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | 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. |
Murrell et al., 2000 |
| V717I (London) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | 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. |
Goate et al., 1991 |
| V717G |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | 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. |
Chartier-Harlin et al., 1991 |
| T719P |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 17 | 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.
|
Ghidoni et al., 2009 |
| T719N |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | 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. |
Hsu et al., 2018 |
| M722K |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | 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. |
Wang et al., 2015 |
| L723P (Australian) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | Unknown. |
Increased Aβ48 levels, reduced Aβ48 trimming. Decreased ε-cleavage; Aβ49 production nearly abrogated. |
Kwok et al., 2000 |
| K724N (Belgian) |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 17 | Significant amyloid across the cerebral cortex as measured by PiB-PET. |
Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40. |
Theuns et al., 2006 |
| H733P |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 17 | Not applicable. |
Increased Aβ42 moderately, without significantly altering the Aβ42/Aβ40 ratio in cells. |
Guerreiro et al., 2010 |
| IVS17 83-88delAAGTAT |
AD : Benign | Deletion | Deletion | | Non-Coding | Intron 17 | Unknown; at least one affected deletion carrier had neuropathology consistent with AD. |
Unknown; deletion does not appear to affect APP splicing. |
Kamino et al., 1992 |
| c.*18 C>T |
CAA : Likely Benign | Substitution | Substitution | | Non-Coding | Exon 18, 3' UTR | Unknown; imaging showed an ischemic stroke in the right middle cerebral artery and hematomas in the right temporal and parietal lobes. MRI showed numerous cortical microbleeds and white-matter hyperintensities. |
Unknown. Failed to reach commonly used threshold for in silico deleteriousness classification (PHRED-scaled CADD score = 19.09). |
Nicolas et al., 2015 |
| c.*331_*332del |
CAA : Likely Pathogenic | Deletion | Deletion | | Non-Coding | Exon 18, 3' UTR | Unknown; imaging revealed multiple subarachnoid hemorrhages and hematomas in the temporal, frontal, and parietal regions of the cortex, as well as diffuse superficial siderosis, cortical microbleeds, and white matter hyperintensities. |
This deletion of two base pairs (TA) occurs in a highly conserved region of the UTR. When cloned into a luciferase reporter, the variant increased APP expression (~1.5-fold over WT). APP upregulation was at least partially attributable to changes in miRNA binding. |
Nicolas et al., 2015 |
| c.*372 A>G |
CAA : Benign | Substitution | Substitution | | Non-Coding | Exon 18, 3' UTR | Unknown; at least two mutation carriers had hemorrhages and microbleeds consistent with CAA. However, this variant has also been detected in controls. |
Unknown. |
Nicolas et al., 2015 |
| Duplication 1104 [APP-APP] |
AD : Pathogenic, CAA : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Sleegers et al., 2006 |
| Duplication ALZ-254 [POTED-ADAMTS5] (EXT-254 [POTED-ADAMTS5]) |
AD : Not Classified | Duplication | Duplication | Duplication | Both | Chromosome 21 | Unknown. |
Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood. |
Wallon et al., 2012 |
| Duplication ALZ-478 [LINC00158-EIF4A1P] |
AD : Pathogenic, CAA : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Grangeon et al., 2023 |
| Duplication [APP-CYYR1] |
AD : Pathogenic | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Kalfon et al., 2022 |
| Duplication EXT-006 [HSPA13-GRIK1] |
AD : Not Classified | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Grangeon et al., 2023 |
| Duplication EXT-019 [LINC00158-USP16] |
AD : Pathogenic, CAA : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Grangeon et al., 2023 |
| Duplication EXT-054 [USP25-ADAMTS1] |
AD : Pathogenic, CAA : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Wallon et al., 2012 |
| Duplication EXT-144 [BTG3-EIF4A1P] |
AD : Pathogenic, CAA : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Wallon et al., 2012 |
| Duplication EXT-145 [NCAM2-EIF4A1P] |
AD : Not Classified, CAA : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Wallon et al., 2012 |
| Duplication EXT-187 [POTED-ADAMTS5] |
AD : Not Classified | Duplication | Duplication | Duplication | Both | Chromosome 21 | Unknown. |
Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood. |
Wallon et al., 2012 |
| Duplication EXT-262 [JAM2-APP] (BES-262 [JAM2-APP]) |
AD : Pathogenic, CAA : , DLB : Not Classified | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Guyant-Marechal et al., 2008 |
| Duplication EXT-279 [GABPA-ADAMTS1] |
AD : Not Classified | Duplication | Duplication | Duplication | Both | Chromosome 21 | Unknown. |
Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood. |
Wallon et al., 2012 |
| Duplication EXT-298 [GABPA-CYYR1] |
AD : Pathogenic, CAA : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Wallon et al., 2012 |
| Duplication EXT-773 [LINC00158-CYYR1] |
AD : Not Classified, CAA : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Rovelet-Lecrux et al., 2015 |
| Duplication EXT-814 [NCAM2-ADAMTS5] |
AD : Not Classified, CAA : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Lanoiselée et al., 2017 |
| Duplication EXT-857 [MRPL39-ADAMTS5] |
AD : Pathogenic | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Lanoiselée et al., 2017 |
| Duplication EXT-1093 [AK124194-CYYR1] |
AD : Not Classified | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Lanoiselée et al., 2017 |
| Duplication EXT-1230 [BTG3- ADAMTS5] |
AD : Not Classified | Duplication | Duplication | Duplication | Both | 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. |
Grangeon et al., 2023 | |
| Duplication EXT-1252 [LINC00158-ADAMTS1] |
AD : Not Classified, CAA : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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 |
Lanoiselée et al., 2017 |
| Duplication EXT-1516 [APP-ADAMTS1] |
AD : Not Classified, CAA : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Grangeon et al., 2023 |
| Duplication EXT 1853 [MRPL39-CYYR1] |
AD : Not Classified | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Grangeon et al., 2023 |
| Duplication EXT-1864 [TUBAP-ADAMTS1] |
AD : Not Classified, CAA : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Grangeon et al., 2023 |
| Duplication EXT 2066 [MRPL39-APP] |
AD : Not Classified | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Grangeon et al., 2023 |
| Duplication F009 [LINC00158-EIF4A1P] |
AD : Pathogenic | Duplication | Duplication | Duplication | Both | Chromosome 21 | Unknown. |
Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP expression by ~1.5 in blood. |
Rovelet-Lecrux et al., 2006 |
| Duplication F019 [LINC00158-BACH1] |
AD : Pathogenic, CAA : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Rovelet-Lecrux et al., 2006 |
| Duplication F028 [MRPL39-APP] (ALZ-028 [MRPL39-APP]) |
AD : Pathogenic, CAA : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Rovelet-Lecrux et al., 2006 |
| Duplication F037 [LINC00158-APP] (ROU-037 [LINC00158-APP]) |
AD : Pathogenic, CAA : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Rovelet-Lecrux et al., 2006 |
| Duplication F229 [NCAM2-EIF4A1P] (ALZ-229 [NCAM2-EIF4A1P]) |
AD : Pathogenic, CAA : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Rovelet-Lecrux et al., 2006 |
| Duplication [JAM2-APP] |
AD : Pathogenic, CAA : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Rovelet-Lecrux et al., 2007; Remes et al., 2004 |
| Duplication PED 2945 [APP-CYYR1] |
AD : Not Classified | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Kasuga et al., 2009 |
| Duplication PED 3281 [LINC00158-ADAMTS5] (PED 3281 [C21orf42-ADAMTS5]) |
AD : Not Classified | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
Kasuga et al., 2009 |
| Triplication [APP-APP] |
AD : Pathogenic, CAA : | Triplication | Triplication | Triplication | Both | Chromosome 21 | 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. |
Grangeon et al., 2021 |
| Trisomy 21 |
AD : Pathogenic, CAA : , Down's Syndrome : | Duplication | Duplication | Duplication | Both | Chromosome 21 | 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. |
JERVIS, 1948 |