Mutations

PSEN-1

PSEN1 encodes presenilin-1, a subunit of γ-secretase, the aspartyl protease responsible for Aβ generation. More than 300 mutations in PSEN1 have been reported and mutations in PSEN1 are the most common cause of early onset Alzheimer's disease.

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Search Results

PSEN1 (364)

Mutation Pathogenicity DNA Change Expected RNA | Protein Consequence Coding/Non-Coding Genomic Region Neuropathology Biological Effect Primary
Papers
Q15H
FTD : Not Classified Substitution Substitution | Missense Coding Exon 3

Unknown

Unknown. Multiple in silico algorithms yielded conflicting results.

Koriath et al., 2018
N24S
AD : Not Classified Substitution Substitution | Missense Coding Exon 3

Unknown

Unknown, in silico algorithms yielded mixed predictions.

Jia et al., 2020
N32N
AD : Likely Benign Substitution Substitution | Silent Coding Exon 4

Unknown.

Unknown.

Scacchi et al., 2007
R35Q
AD : Benign Substitution Substitution | Missense Coding Exon 4

Unknown.

Aβ profile very similar to wildtype PSEN1 in cell-based assays.

 

Rogaeva et al., 2001
N39Y
AD : Not Classified Substitution Substitution | Missense Coding Exon 4

Unknown

Unknown. Multiple in silico algorithms yielded conflicting results.

Koriath et al., 2018
D40del (delACG)
AD : Uncertain Significance Deletion Deletion | Deletion Coding Exon 4

Unknown.

Decreased Aβ42 production and undetectable Aβ40 production in vitro. Does not cause a frame-shift.

Nicolas et al., 2015
D40del (delGAC)
AD : Uncertain Significance Deletion Deletion | Deletion Coding Exon 4

Unknown; MRI showed progressive cortical atrophy involving the lateral frontal lobes most prominently. Medial temporal lobe structures were also affected. Imaging by PET with florbetapir showed fibrillary Aβ deposits particularly in the frontal lobes.

Mixed results: two assays showed an increase in the Aβ42/Aβ40 ratio and one showed no effect on either the Aβ42/Aβ40 nor the Aβ37/Aβ42 ratios. Results were inconsistent regarding production levels of each peptide.

Nygaard et al., 2014
R41S
PD : Not Classified Substitution Substitution | Missense Coding Exon 4

Unknown, but in one patient, MRI showed moderate frontal cortex atrophy, PiB-PET no amyloid deposition, FDG-PET mild hypometabolism in the lateral temporal lobe. CSF Aβ and tau were normal; phospho-tau elevated.

Unknown. Multiple in silico algorithms yielded conflicting results.

Gatto et al., 2020
R42L
AD : Not Classified Substitution Substitution | Missense Coding Exon 4

Unknown.

Unknown. Multiple in silico algorithms yielded conflicting results.

Koriath et al., 2018
P49L
AD : Not Classified Substitution Substitution | Missense Coding Exon 4

Neuropathology consistent with AD in a carrier who also had the PSEN1 G183V mutation.

Unknown. Multiple in silico algorithms yielded conflicting results.

Perrone et al., 2020
E69D
AD : Not Classified Substitution Substitution | Missense Coding Exon 4

Unknown.

No changes in either Aβ42/Aβ40 or Aβ37/Aβ40 ratios in 2 cell assays; in one assay both Aβ42 and Aβ40 were increased, in the other both were decreased.

 

Nicolas et al., 2015
G78G
AD : Likely Benign Substitution Splicing Alteration | Silent Coding Exon 4

Unknown.

Unknown. Predicted to potentially affect splicing in silico, but PHRED-scaled CADD = 10.

Jia et al., 2020
A79V
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 4

Neuropathology consistent with AD.

Increased  the Aβ42/Aβ40 ratio, and decreased the Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios in cells. Also, altered transcriptomic profiles in carrier brains and iPSC-derived neurons.

Cruts et al., 1998
V82L
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 4

Unknown.

Results were mixed. Although all indicated little or no change in Aβ42/Aβ40, one assay showed a robust increase in Aβ43 and a decrease in Aβ37, with a decreased Aβ37/Aβ42 ratio.

Campion et al., 1995
I83_M84del
(DelIM, ΔI83/M84, ΔI83/ΔM84)
AD : Not Classified Deletion Deletion | Deletion Coding Exon 4

Accumulation of noncongophilic, Aβ-positive, cotton-wool plaques in brain parenchyma. Widespread cerebral amyloid angiopathy, neurofibrillary tangles, and neuropil threads.

Hexanucleotide deletion resulting in deletion of two amino acids (I and M). Cultured cells expressing mutant PSEN1 have an elevated Aβ42/Aβ40 ratio compared with cells transfected with wild-type PSEN1. In vitro, Aβ40 production is undetectable and Aβ42 production greatly reduced.

Houlden et al., 2000;
Steiner et al., 2001
I83T
AD : Pathogenic Substitution Substitution | Missense Coding Exon 4

Unknown; MRI showed bilateral atrophy, especially in the parietal and temporal lobes in one case, and frontal and temporal atrophy in another.

Increased Aβ42/Aβ40 and decreased Aβ37/Aβ42.

Achouri-Rassas et al., 2015
M84V
AD : Pathogenic Substitution Substitution | Missense Coding Exon 4

Neuropathology consistent with AD in 2 cases. MRI showed cortical and cerebellar atrophy in 2 cases; frontal and temporal lobe atrophy in a third case.

Increased Aβ42 and Aβ42/Aβ40 ratio in cells.

Hooli et al., 2014
M84T
AD : Not Classified Substitution Substitution | Missense Coding Exon 4

Neuropathology consistent with AD. Severe CAA, no Lewy bodies observed.

Unknown. In silico predicted deleterious (CADD-PHRED score = 24).

Lanoiselée et al., 2017
L85P
AD : Pathogenic, Corticobasal Syndrome : Not Classified Substitution Substitution | Missense Coding Exon 4

Neuropathological examination was not available. SPECT and PET showed bilateral hypoperfusion and hypometabolism in the occipital and temporal lobes.

Increased Aβ42/Aβ40 ratio; increased Aβ42 in transfected cells. In vitro, decreased Aβ42 production and abrogated Aβ40 production.

Ataka et al., 2004
P88R
AD : Not Classified Substitution Substitution | Missense Coding Exon 4

Unknown, but MRI in one case showed temporal and parietal atrophy with white matter hyperintensities, and levels of Aβ42 and the Aβ42/Aβ40 ratio were reduced in CSF.

Unknown, but in silico algorithms predicted damaging (PHRED-scaled CADD > 20).

Thomas et al., 2022
P88L
AD : Pathogenic Substitution Substitution | Missense Coding Exon 4

Unknown, but MRI showed generalized cortical atrophy.

Increased ratio of Aβ42,43/Aβ40 and generation of Aβ45 and Aβ46.

Liu et al., 2017
P88H
AD : Not Classified Substitution Substitution | Missense Coding Exon 4

Unknown

Unknown, but multiple in silico algorithms predicted a damaging effect.

Lanoiselée et al., 2017
V89L (G>C)
AD : Pathogenic Substitution Substitution | Missense Coding Exon 4

Typical Alzheimer's disease pathology.

Increased  the Aβ42/Aβ40 ratio in vitro, and decreased the Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios in cells.

Liu et al., 2017
V89L (G>T)
AD : Pathogenic Substitution Substitution | Missense Coding Exon 4

Neurofibrillary tangles and neuritic plaques with dystrophic neurites corresponding to stage VI of Braak and Braak. Plaques abundant in the hippocampus, amygdala, and neocortex. Tangles abundant in the neocortex and hippocampus. Some amyloid angiopathy in cortical vessels. Moderate cortical atrophy and enlarged ventricles.

Decreased Aβ40 and Aβ42 production; increased Aβ42/Aβ40 ratio in vitro.

Queralt et al., 2002
C92S
AD : Pathogenic Substitution Substitution | Missense Coding Exon 4

Unknown.

Increased Aβ42/Aβ40 ratio, and Aβ42 and Aβ43 secretion in cells. Reduced Aβ37/Aβ42 ratio.

Tedde et al., 2003
V94M
AD : Benign Substitution Substitution | Missense Coding Exon 4

Unknown.

Decreased Aβ42 and Aβ40 production; Aβ42/Aβ40 and Aβ37/Aβ42 ratios similar to controls.

Arango et al., 2001
V96F
AD : Pathogenic Substitution Substitution | Missense Coding Exon 4

Unknown, but MRI in two cases showed brain volume loss, particularly in the hippocampus.

In cultured cells, increased Aβ42/Aβ40 ratio and decreased Aβ37/Aβ42 ratio. Inhibited endopeptidase activity.

Kamino et al., 1996
V97L
AD : Pathogenic Substitution Substitution | Missense Coding Exon 4

Unknown; MRI from two mutation carriers showed enlarged lateral ventricles and atrophy of the cerebral cortex, especially the temporal lobes.

MIxed experimental results, but a detailed analysis of Aβ peptide production in cells indicated a deleterious effect with a decrease in the Aβ37/Aβ42 ratio. Alterations of other cellular functions were also reported.

 

 

Jia et al., 2005
T99A
AD : Not Classified Substitution Substitution | Missense Coding Exon 4

Unknown, but MRI showed atrophy of the parietal and frontal lobes.

Three different assays yielded mixed results, but all suggested deleterious effects, including increased Aβ42/Aβ40 and decreased Aβ37/Aβ42 ratios.

Ikeda et al., 2013
I100F
AD : Pathogenic Substitution Substitution | Missense Coding Exon 4

Unknown

Unknown, but 5 in silico algorithms predicted damaging

Jia et al., 2020
V103G
AD : Not Classified Substitution Substitution | Missense Coding Exon 4

Unknown

Unknown, but predicted structural effect and predicted damaging by in silico algorithms (PolyPhen, SIFT, MutationTaster, CADD).

Gao et al., 2019
V103_S104delinsG
AD : Pathogenic Deletion Deletion | Deletion-Insertion Coding Exon 4

Unknown, but in one case, MRI showed global atrophy, and FDG-PET showed hypometabolism in the posterior cingulate cortex, precuneus, and temporoparietal cortices.

Increased Aβ42/40 ratio and decreased Aβ42 and Aβ40 levels in cell-based assay.

Takada et al., 2022
F105I
AD : Pathogenic Substitution Substitution | Missense Coding Exon 4

Unknown.

Increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios in cells, indicating reduced γ-processivity. Also reduced total Aβ secretion.

Raux et al., 2005
F105V
AD : Pathogenic Substitution Substitution | Missense Coding Exon 4

Unknown.

Increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios in cells, indicating reduced γ-processivity. It also reduced total Aβ secretion.

Gómez-Tortosa et al., 2010
F105C
AD : Pathogenic Substitution Substitution | Missense Coding Exon 4

Unknown; neuroimaging showed enlarged ventricles and atrophy in the hippocampus and frontotemporal regions.

Decreased Aβ (37 + 38 + 40) / (42 + 43) ratio.

Jiao et al., 2014;
Deng et al., 2014
F105L
AD : Pathogenic Substitution Substitution | Missense Coding Exon 4

Neuropathology consistent with AD in three individuals.

Increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios in cells, indicating reduced γ-processivity. It also reduced total Aβ secretion.

Finckh et al., 2000
R108Q
AD : Not Classified Substitution Substitution | Missense Coding Exon 4

Unknown.

In cell assay, increased Aβ42 and Aβ40; in vitro, decreased Aβ42 production and undetectable Aβ40 production.

Dobricic et al., 2012
G111W
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 4

Unknown

Unknown, but multiple in silico algorithms predicted a damaging effect.

Lanoiselée et al., 2017
G111V
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 4

Unknown, but an MRI scan of one case revealed bilateral hippocampal atrophy.

Reduced Aβ40, unchanged Aβ42, and elevated Aβ42/Aβ40 ratio in transfected cells. In silico analyses (PANTHER, Mutation Taster, and PolyPhen-2) predict probably pathogenic. 

Qiu et al., 2020
L113Q
AD : Not Classified Substitution Substitution | Missense Coding Exon 4

Neuritic plaques (Braak stage C); Neurofibrillary tangles (stage VI); Severe amyloid angiopathy.

Decreased Aβ40 production in vitro; increased Aβ42/Aβ40 ratio.

 

Finckh et al., 2005
L113P
AD : Pathogenic, FTD : Not Classified Substitution Substitution | Missense Coding Exon 4

AD-like plaques and tangles; CT scans showed predominant frontotemporal atrophy and SPECT showed hypoperfusion including the frontal lobes.

Increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios in cells, indicating reduced γ-processivity. It also reduced total Aβ secretion.

Raux et al., 2000
L113_I114insT
(Intron 4, InsTAC, g.23024delG, p.113+1delG, splice5, int4del)
AD : Pathogenic Deletion Splicing Alteration | Insertion Both Intron 4

Neuropathology consistent with AD, including neuron loss in the hippocampus and entorhinal cortex, neuritic plaques and neurofibrillary tangles in the hippocampus, and amyloid angiopathy, particularly evident in the cerebellum.

Deletion of a G in splice donor site of intron 4 produces three aberrant transcripts. Increased Aβ42 and Aβ42/Aβ40; reduced Aβ40 and Aβ38 production in patient brain membranes. In iPSC-derived neurons, increased Aβ42/Aβ40, Aβ42/Aβ38, and Aβ43/Aβ40 ratios, while decreased Aβ38/Aβ40. Also, increased BACE1–BACE2 products (Aβ19/20) and BACE1–BACE1/BACE2 products (Aβ34).

Tysoe et al., 1998;
De Jonghe et al., 1999
Y115D
AD : Not Classified Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD.

Increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios in cells, indicating reduced γ-processivity. It also reduced total Aβ secretion.

Y115H
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD.

Increased Aβ42/Aβ40 and changed production levels and ratios of Aβ43, Aβ42, Aβ40, Aβ38, and Aβ37 in cells and in vitro, indicating reduced γ-processivity. Suppressed Aβ production by wild-type PSEN1.  

 

Campion et al., 1995
Y115C
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD.

Increased Aβ42:Aβ40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios in cells, indicating reduced γ-processivity. In cells, increased Aβ42 secretion; in vitro, decreased Aβ42, and especially Aβ40, production. Also, disruption of lysosome function and autophagy via accumulation of APP β-C-terminal fragments.

Cruts et al., 1998
T116R
AD : Not Classified | Missense Coding Exon 5

Unknown.

Increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios in cells, indicating reduced γ-processivity. It increased Aβ42 and 43 production at the expense of Aβ37, 38 and 40, and reduced total Aβ secretion.

Mann et al., 2001
T116_P117delinsST
AD : Not Classified Deletion-Insertion Deletion-Insertion | Deletion-Insertion Coding Exon 5

Neuropathology consistent with AD in biopsies from two individuals. 

Unknown. In silico predictions mixed: deleterious (PolyPhen2, SIFT, PROVEAN); uncertain significance (Mutation Taster 2); medium effect (Mutation Assessor); T116S neutral and P117T pathogenic (PredictSNP).

Blanco et al., 2019
T116I
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown, but MRI and FDG-PET showed atrophy and hypometabolism in temporal and parietal regions.

Increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios in cells, indicating reduced γ-processivity. It also reduced total Aβ secretion.

La Bella et al., 2004
T116N
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD.

Increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios in cells and in vitro for Aβ42/40 ratio, indicating reduced γ-processivity. It also reduced total Aβ secretion in cells and production in vitro.

Romero et al., 1999
P117S
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD according to CERAD criteria; Neuronal loss estimated to be greater than 70 percent in one brain; extensive loss of white matter; active gliosis throughout the brain; Lewy bodies.

Increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios in transfected cells, indicating reduced γ-processivity. Increased production of Aβ42 and Aβ43 at the expense of Aβ37 and Aβ40; Aβ38 was only moderately decreased. Reduced neurite outgrowth.

 

Dowjat et al., 2004
P117A
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown.

Increased Aβ42/40 and Aβ42/Aβ total ratios and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios. 

Anheim et al., 2007
P117T
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown

Unknown, but 5 in silico algorithms predicted damaging. PHRED-CADD score: 26.5

Jia et al., 2020
P117Q
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown, but CSF biomarkers (Aβ42, tau, and phospho-tau) were in the AD pathological range in one case.

Unknown, but multiple in silico algorithms predicted a damaging effect.

Lanoiselée et al., 2017
P117L
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD. Unusually high amyloid burden, especially in the molecular layer of the cerebellum and in cerebellar vessels.

Increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios in cells; reduced ε-cleavage; Aβ49→Aβ46 and Aβ43→Aβ40 trimming. In addition, inhibited neurite outgrowth and neurofilament assembly, increased cell-cycle arrest, and decreased neuronal differentiation of progenitor cells.

Wisniewski et al., 1998
P117R
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown.

Increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios in cells, indicating reduced γ-processivity. Also, affected cell cycle in immortalized patient lymphocytes.

Zekanowski et al., 2003
T119I
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown, but in 3 cases, PiB-PET revealed amyloid in frontal, parietal, and temporal regions, and PET-FDG showed hypometabolism in 3 patients including parietal lobe, precuneus, anterior cingulate, dorsal frontal lobe, and temporal lobe. MRI showed atrophy in frontal, parietal, and temporal cortices. CSF Aβ42 was reduced in one case and CSF phospho-tau elevated in another. 

Unknown, but most in silico analyses predict it to be damaging, as do structural data. CADD-PHRED score = 24.

Itzcovich et al., 2019;
Giau et al., 2019
E120K
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD.

Increased Aβ42/40 ratio in cells and in vitro. In cells, also increased Aβ42/Aβ total ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios. In vitro, reduced Aβ40 and Aβ42 production. Cell data suggest reduced γ-processivity. 

Hutton et al., 1996
E120G
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Frequent amyloid plaques and neurofibrillary tangles; Severe amyloid angiopathy.
 

Decreased Aβ38 and Aβ40 production and Aβ38/Aβ42 ratio in patient brain sample. Increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios in cells, indicating reduced γ-processivity. Total Aβ secretion reduced in cells.

Lladó et al., 2009;
Gómez-Tortosa et al., 2010
E120D (A>T)
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown.

Increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios in cells, indicating reduced γ-processivity. It also reduced total Aβ secretion. In vitro, decreased Aβ42, and particularly Aβ40, production.

 

 

Reznik-Wolf et al., 1996
E120D (A>C)
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD.

Increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios in cells, indicating reduced γ-processivity. It also reduced total Aβ secretion. In vitro, decreased Aβ42, and particularly Aβ40, production.

Poorkaj et al., 1998
T122A
FTD : Not Classified Substitution Substitution | Missense Coding Exon 5

Unknown

Unknown, but multiple in silico algorithms predicted a damaging effect.

Koriath et al., 2018
E123K
AD : Uncertain Significance Substitution Substitution | Missense Coding Exon 5

Unknown, but in 2 cases, MRI showed atrophy in the medial temporal lobes, and PET showed hypoperfusion in the temporal and parietal lobes.

In cells, effects on AICD, Aβ38, Aβ40, and Aβ42 were minimal, but increased Aβ43; in vitro, decreased Aβ40 and Aβ42 production, and elevated Aβ42/Aβ40 ratio.

Yasuda et al., 1999
Q127_R128delinsG
AD : Not Classified Deletion-Insertion Deletion-Insertion | Deletion-Insertion Coding Exon 5

Unknown

Increased Aβ42 and decreased Aβ40 secreted from cells, resulting in increased Aβ42/Aβ40 ratio. However, earlier cell-based results suggested no effect on Aβ40 and Aβ42 levels. 

Hsu et al., 2018
H131R
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown, but PiB-PET showed extensive cortical and striatal amyloid deposition in one patient. Also, FDG-PET showed hypometabolism in precuneus and bilateral temporo-parietal region and reduced blood flow in parietal and temporal lobes. In two patients, MRI showed parietal and temporal atrophy.

 

Increased Aβ42/Aβ40 ratio in vitro. Also, abrogated pH-sensitivity of Aβ peptide generation in vitro. In silico algorithms predicted benign (Polyphen) and damaging (SIFT).

 

Ikeda et al., 2013
H131Q
AD : Not Classified Substitution Substitution | Missense Coding Exon 5

Unknown

Unknown. Only 1 of 5 in silico algorithms predicted damaging.

Jia et al., 2020
S132A
AD : Not Classified, DLB : Not Classified, FTD : Not Classified Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD, with severe neocortical Lewy body disease (one case).

Unknown, but CADD score was above 20 suggesting deleterious effects.

Ryan et al., 2016
L134R
AD : Not Classified Substitution Substitution | Missense Coding Exon 5

Unknown; MRI of the Turkish proband showed atrophy of the cerebrum and cerebellum.

Decreased Aβ42, and abrogated Aβ40, production in vitro. Predicted probably damaging in silico.

Lohmann et al., 2012
N135D
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Brain biopsy showed mild loss of neurons and secondary gliosis with multiple neuritic plaques and abundant neurofibrillary tangles.

Increased Aβ42/Aβ40 ratio in cell lines and in vitro; increases intracellular and secreted Aβ42 and decreases Aβ40 in cells; reduces both Aβ42 and Aβ40 production in vitro.

Crook et al., 1997
N135Y
AD : Not Classified Substitution Substitution | Missense Coding Exon 5

Postmortem findings consistent with AD.

Reduced levels of secreted Aβ40 and higher Aβ42/Aβ40 ratio.

Natelson Love et al., 2017
N135S
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD, including widespread neurofibrillary tangles and neuritic plaques. Some cotton-wool plaques; Mild amyloid angiopathy; Corticospinal tract pathology.

Unknown, but multiple in silico algorithms predicted a damaging effect.

Finckh et al., 2005
A136V
AD : Not Classified Substitution Substitution | Missense Coding Exon 5

Unknown, but in one case MRI showed hippocampal atrophy and FDG-PET hypometabolism in temporal, parietal, and occipital cortices. Aβ42 and tau in CSF were consistent with AD.

Unknown, but in silico algorithms (SIFT, Polyphen2) predicted damaging.

Li et al., 2021
A136G
AD : Not Classified Substitution Substitution | Missense Coding Exon 5

In vitro assays showed a moderate decrease in both Aβ40 and Aβ42 production, with the Aβ42/Aβ40 ratio remaining roughly similar to wildtype. Neuroblastoma cells carrying the mutation showed enhanced sensitivity to trophic withdrawal. Also, the mutation enhanced PSEN1 cleavage of ER calcium sensor STIM1, resulting in dendritic spine disruption. 

Xu et al., 2002
A137T
FTD : Not Classified Substitution Substitution | Missense Coding Exon 5

Unknown

Unknown. Multiple in silico algorithms yielded conflicting results.

Koriath et al., 2018
M139L
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown, but MRI in two individuals revealed bilateral atrophy in the hippocampus and cerebral cortex.

 Aβ40 levels moderately decreased; Aβ42/Aβ40 ratio increased in cultured cells.

Qiu et al., 2019;
Gao et al., 2019
M139V
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD.

Increased Aβ42/Aβ40, Aβ42/Aβ38, Aβ43/Aβ40, and Aβ2-40:Aβ40; decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42, Aβ38/Aβ40, Aβ38/Aβ42, Aβ40/Aβ43, and Aβ11-40/Aβ40 ratios. Decreased Aβ40, Aβ38, and Aβ37 levels, while increasing Aβ42 and Aβ43. Mutant protein levels were variable in iPSC-derived neurons suggesting protein instability.

 

Alzheimer's Disease Collaborative Group, 1995
M139K
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown.

Unknown, but multiple in silico algorithms predicted a damaging effect.

Dumanchin et al., 1998
M139R
AD : Not Classified Substitution Substitution | Missense Coding Exon 5

Unknown

Unknown, but an in silico algorithm predicted it is damaging (PHRED-scaled CADD score >20). 

M139T
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown.

Increased Aβ42/Aβ40 ratio and decreased Aβ (37 + 38 + 40) / (42 + 43), Aβ37/Aβ42, and Aβ38/Aβ42 ratios in cells. 

Campion et al., 1995
M139I (G>A)
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Possible mislocalization of presenilin-1 protein; co-localization with tangles.

Increased Aβ42/Aβ total ratio.

Boteva et al., 1996
M139I (G>C)
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Possible mislocalization of presenilin-1 protein; co-localization with tangles.

Increased Aβ42/Aβ total ratio.

Kim et al., 2010
V142I
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown

Unknown, but CADD score above 20 suggesting damaging effect. 

Koriath et al., 2018
V142F
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown, but MRI showed severe cortical atrophy that was most pronounced in frontal and temporal lobes.

Predicted to be pathogenic by MutPred, SNPs&Go, MutationTaster, and SIFT.

Wang et al., 2018
I143F
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD, but in one case, more widespread distribution of plaques in the temporal sulcus compared with sporadic AD, and lower ratio of Ab40 to Ab42/Ab43 in plaques. Also, accelerated NFT formation and neuronal loss.

Increased Aβ42/Aβ40 and decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 indicating a deleterious effect.

 

Rossor et al., 1996;
Palmer et al., 1999
I143V
AD : Not Classified Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD, including abundant amyloid plaques and severe neurofibrillary tangle pathology (stage VI Braak and Braak). Amyloid deposits were comprised largely of Aβ42, with little to no Aβ40. There was minimal amyloid angiopathy in vessels.

Increased Aβ42 and Aβ42/Aβ40 ratio in cells and in vitro.

Gallo et al., 2011
I143T
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD.

Increased the Aβ42/Aβ40 ratio and decreased the Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios. 

Cruts et al., 1995;
Rogaeva et al., 2001
I143N
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown

Increased Aβ42/Aβ40 and decreased Aβ37/Aβ42 in cultured cells.

Raux et al., 2005
I143M
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD in one case.

Unknown, but other mutations at this location alter Aβ peptide production and, in wild-type PSEN1, I143 forms part of the substrate-binding pore.

 

Heckmann et al., 2002
M146L (A>T)
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD. In one case, Lewy body pathology in the amygdala, cingulate gyrus, and substantia nigra. 

Increased Aβ42, Aβ42/Aβ total, Aβ42/Aβ40 in cells and in vitro assays and decreased Aβ37/Aβ42. Impaired calcium dynamics, mitochondrial permeability, expression of synaptic and neuronal differentiation genes.

Mangone et al., 1995;
Morelli et al., 1998
M146L (A>C)
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD in multiple affected mutation carriers. Pick bodies and Lewy body pathology, as assessed by α-synuclein staining, have been noted in some cases.

Increased Aβ42, Aβ42/Aβ total, Aβ42/Aβ40 in cells and in vitro assays and decreased Aβ37/Aβ42. Impaired calcium dynamics, mitochondrial permeability, expression of synaptic and neuronal differentiation genes.

Sherrington et al., 1995;
Sorbi et al., 1995;
Alzheimer's Disease Collaborative Group, 1995
M146V
AD : Pathogenic, FTD : Not Classified Substitution Substitution | Missense Coding Exon 5

Variable: Neuropathology consistent with AD in some cases, but also, in at least one case, mixed pathology including frequent Aβ deposits, tangles, and Pick bodies.

Increased Aβ42/Aβ40 ratio; increased Aβ42 and Aβ43; lowered wild-type PSEN1 gene expression. Disrupted endosomes via accumulation of APP β-CTF. Disrupted calcium channels, triggered cascade resulting in altered axonal transport, damage/loss of neurites. Increased calcineurin activity, impaired trafficking of glutamate AMPA receptors. Disrupted mitochondrial function, altered trophic factor function, and cerebral blood flow.

Alzheimer's Disease Collaborative Group, 1995
M146I (G>A)
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD.

Increased Aβ42/Aβ40 and Aβ42/Aβ38; unchanged Aβ38/Aβ40 and Aβ43/Aβ40 in iPSC-derived neurons. Altered protein stability. Also, disrupted lysosome function and autophagy seemingly due to accumulation of β-C-terminal APP fragments. (M146I, nt change unspecified).

Jørgensen et al., 1996
M146I (G>T)
AD : Not Classified Substitution Substitution | Missense Coding Exon 5

Unknown, but carriers of a different nucleotide change resulting in the same amino acid substitution had neuropathology consistent with AD.

Increased Aβ42/Aβ40 and Aβ42/Aβ38; unchanged Aβ38/Aβ40 and Aβ43/Aβ40 in iPSC-derived neurons. Altered protein stability. Also, disrupted lysosome function and autophagy seemingly due to accumulation of β-C-terminal APP fragments. (M146I, nt change unspecified).

Rogaeva et al., 2001
M146I (G>C)
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD in 3 cases, but more involvement of central grey areas, no vascular lesions, and very mild amyloid angiopathy.

Increased Aβ42/Aβ40 and Aβ42/Aβ38; unchanged Aβ38/Aβ40 and Aβ43/Aβ40 in iPSC-derived neurons. Altered protein stability. Also, disrupted lysosome function and autophagy seemingly due to accumulation of β-C-terminal APP fragments. (M146I, nt change unspecified).

Gustafson et al., 1998
T147P
AD : Not Classified Substitution Substitution | Missense Coding Exon 5

Unknown; neuroimaging showed widespread cortical atrophy, as well as atrophy in the medial temporal lobes, with less severe cerebellar atrophy.

 

In cells, decreased Aβ37/Aβ42 ratio, although Aβ42/Aβ40 was similar to controls.

Testi et al., 2014
T147I
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown.

Unknown; predicted probably damaging in silico.

Campion et al., 1999
L150P
AD : Not Classified Substitution Substitution | Missense Coding Exon 5

Unknown.

Decreased Aβ37/Aβ42 ratio, increased Aβ43. Slightly increased Aβ42/Aβ40 ratio.

Wallon et al., 2012
V151M
AD : Not Classified Substitution Substitution | Missense Coding Exon 5

Unknown

Unknown, but in silico analyses predicted a damaging effect (PHRED-scaled CADD score > 20).

Jiao et al., 2021
V151V
AD : Not Classified Substitution Splicing Alteration | Silent Coding Exon 5

Unknown.

Unknown. Predicted to potentially affect splicing in silico, but PHRED-scaled CADD = 11.

Jia et al., 2020
L153V
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Neuropathology consistent with AD in one case. 

Decreased Aβ40 and Aβ42 production in vitro.

Raux et al., 2000;
Janssen et al., 2001
Y154N
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown, MRI and SPECT showed atrophy and hypoperfusion in occipito-parietal areas and internal temporal lobe areas, including the hippocampus.

Dramatically decreased Aβ40 and Aβ42 production, as well as decreased endopeptidase activity, in vitro.

Hattori et al., 2004
Y154C
AD : Not Classified Substitution Substitution | Missense Coding Exon 5

Unknown

Unknown, but multiple in silico algorithms predicted a damaging effect.

Janssen et al., 2003
Y156delinsFIY
AD : Likely Pathogenic Insertion Insertion | Insertion; Missense Coding Exon 5

Neuropathology in one case was consistent with AD, but more widespread and included cotton-wool plaques. FDG-PET in 2 individuals showed hypometabolism starting in posterior temporo-parietal cortex and spreading rapidly to posterior cingulate, primary motor, and frontal association cortices. 

Unknown

Rogaeva et al., 2001;
Moretti et al., 2004
R157S
AD : Uncertain Significance Substitution Substitution | Missense Coding Exon 5

Unknown, but one patient had posterior cortical atrophy and mild medial temporal atrophy as assessed by MRI.

Unknown, but multiple in silico analyses predicted the mutation is likely pathogenic, CADD score, 31.

Jiang et al., 2019
Y159F
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown, but CSF biomarkers suggestive of AD.

Increased Aβ2 resulting in an increased Aβ42/Aβ40 ratio in cells.

Kerchner and Holbrook, 2012
Y159S
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Unknown, but MRI in one patient revealed mild atrophy of the temporal and parietal lobes, and the hippocampus.

Decreased Aβ40 and moderately increased Aβ42, resulting in a 4-fold increase in the Aβ42/Aβ40 ratio in cells.

Li et al., 2022
Y159C
AD : Not Classified Substitution Substitution | Missense Coding Exon 5

Unknown, but in one case, MRI revealed diffuse parietal and hippocampal atrophy, and FDG-PET showed severe hypometabolism in bilateral frontoparieto-temporal cortex.

Unknown, but in silico algorithms predicted probably damaging (Polyphen2) and not tolerated (SIFT). Cryo-EM suggests structural role in PSEN1-APP interaction. CADD score = 28.3.

Kim et al., 2020
H163Y
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Typical AD neuropathology (one case); decreased glucose metabolism in presymptomatic mutation carriers, especially in the thalamus. Widespread brain amyloid (PiB-PET) and shrunken hippocampi.

Decreased CSF Aβ42 and Aβ38 levels. Increased Aβ42/Aβ total ratio when expressed in COS-1 cells co-transfected with APP695, and increased Aβ42 production in an in vitro assay using purified proteins.

Alzheimer's Disease Collaborative Group, 1995
H163P
AD : Not Classified Substitution Substitution | Missense Coding Exon 5

Brain biopsy of the frontal cortex showed numerous senile plaques and neurofibrillary tangles compatible with a diagnosis of AD. No spongiform changes or abnormal prion proteins were detected.

Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.

Kim et al., 2012
H163R
AD : Pathogenic Substitution Substitution | Missense Coding Exon 5

Data are limited, but neuropathology consistent with AD has been observed in at least one case.

Increased total Aβ, Aβ42, and Aβ43, while reducing Aβ40 and Aβ38 production in cells; drastic reduction of Aβ42 and Aβ40 production in vitro. Affects γ-secretase-dependent neurexin processing.

Campion et al., 1995;
Sherrington et al., 1995;
Tanahashi et al., 1995
A164V
AD : Not Classified Substitution Substitution | Missense Coding Exon 6

Unknown; MRI showed generalized atrophy of the brain with pronounced involvement of the anterior temporal lobe, including the hippocampus.

Both Aβ42/Aβ40 and Aβ37/Aβ42 ratios were similar to wildtype PSEN1.

Roeber et al., 2015
W165G
AD : Not Classified Substitution Substitution | Missense Coding Exon 6

Unknown; but SPECT showed slight decrease in blood flow to parieto-occipital regions and thalamus in one case. Also, EEG alterations, but normal MRI.

In vitro, increased Aβ42 and Aβ42/Aβ40 ratio; reduced Aβ40.

Higuchi et al., 2000
W165C (G>T)
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

Unknown, MRI showed diffuse cerebral and cerebellar atrophy in one case.

Unknown, but in silico analyses (SIFT and polyphen) predict the mutation is deleterious, probably damaging.

Syama et al., 2018
W165C (G>C)
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

Unknown

Campion et al., 1999
L166V
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

SPECT imaging performed four years after symptom onset showed temporoparietal hypoperfusion. Postmortem evaluation revealed neuropathology consistent with AD, including advanced plaques and tangles (CERAD C, Braak stage VI).

Unknown; predicted damaging in silico by multiple algorithms.

Sassi et al., 2014
L166del
AD : Not Classified Deletion Deletion | Deletion Coding Exon 6

Unknown; MRI showed generalized, symmetrical cerebral atrophy, which was most prominent in the medial temporal lobes.

Unknown.

Knight et al., 2007
L166H
AD : Not Classified Substitution Substitution | Missense Coding Exon 6

Unknown; MRI showed marked hippocampal atrophy and cortical atrophy, especially in the insula and the peri-insular temporal lobe. SPECT imaging showed bilateral hypometabolism in the parietal and frontal lobes.

Unknown, but multiple in silico algorithms predicted a damaging effect.

Pantieri et al., 2005
L166R
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

Unknown; MRI in the proband showed cortical atrophy; PET showed parietal hypoperfusion.

Unknown, but multiple in silico algorithms predicted a damaging effect.

Ezquerra et al., 2000
L166P
AD : Pathogenic, ALS-FTD : Not Classified Substitution Substitution | Missense Coding Exon 6

In one individual, numerous Aβ-positive neuritic and cotton-wool plaques throughout the cerebral cortex; abundant Aβ-positive amyloid cores in the cerebellar cortex. In another, robust amyloid pathology in the striatum and cerebellum, and asymmetric tau pathology in the primary sensorimotor cortex contralateral to the side most affected by spasticity.

Decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 and increased Aβ42/Aβ40. Increased Aβ42 and Aβ43; endosomal accumulation of APP β-CTF. Also, interfered with wild-type PSEN1 activity, reduced GLT-1 interaction, inhibited calcium leak in the ER, affected ApoE secretion, altered PSEN1 subcellular localization. Stalled γ-secretase-substrate complex tied to synaptic loss.

Moehlmann et al., 2002
I168del (TTAdel)
(I167del)
AD : Pathogenic Deletion Deletion | Deletion Coding Exon 6

Unknown.

Decreased Aβ37/Aβ42, increased Aβ42/Aβ40, and increased Aβ43 in cultured cells (nucleotide change unspecified).

Jiao et al., 2014
I168del (TATdel)
(I167del)
AD : Not Classified Deletion Deletion | Deletion Coding Exon 6

Unknown

Decreased Aβ37/Aβ42, increased Aβ42/Aβ40, and increased Aβ43 in cultured cells (variant's nucleotide change was unspecified).

Janssen et al., 2003
I168T
AD : Not Classified Substitution Substitution | Missense Coding Exon 6

Neuropathology consistent with AD.

No significant effect on Aβ40 or Aβ42 secretion in cells; decreased Aβ42 and abrogated Aβ40 production in vitro.

Sassi et al., 2014
I168dup
AD : Not Classified Duplication Duplication | Duplication Coding Exon 6

Neuropatholgoy consistent with AD in one case.

Unknown, but in silico algorithms (PROVEAN and SIFT)  predicted pathogenicity and CADD score was 20.2.

O'Connor et al., 2021
S169P
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

Neuropathology consistent with AD, including numerous plaques and neurofibrillary tangles, neuritic irregularities, neuronal lipofuscin, and mild astrocytosis.

Increased Aβ42 and moderately decreased Aβ40 production in vitro; increased Aβ42/Aβ40.

Ezquerra et al., 1999
S169L
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

Neuropathology typical of AD, but also Aβ deposition in the cerebellum and white matter, as well as numerous ectopic neurons, often containing tau-immunopositive neurofibrillary tangles, in the white matter of the frontal and temporal lobes, possibly due to errant migration during development.

Unknown, but cryo-EM analysis of the γ-secretase-complex revealed a direct interaction of the wild-type residue with APP.

Taddei et al., 1998
S169del
(ΔS169, Ser169del, ΔS170)
AD : Pathogenic Deletion Deletion | Deletion Coding Exon 6

Unknown; MRI of the proband showed generalized cerebral atrophy with enlargement of the ventricles and widening of the sulci.

Decreased Aβ42 and abrogation of Aβ40 production in vitro. No effect on Notch.

Guo et al., 2010
S170P
AD : Not Classified, Parkinsonism : Not Classified Substitution Substitution | Missense Coding Exon 6

In AD case, typical AD tau pathology was reported. In parkinsonism case, MRI revealed hypointensity in the putamen, globus pallidus, and substantia nigra, as well as frontotemporal cortical atrophy. SPECT showed severe nigrostriatal dopaminergic deficit bilaterally, and 18F-FDG PET hypometabolism in striatal and posterior cingulate.

Unknown, but multiple in silico algorithms predicted a damaging effect.

Irwin et al., 2013;
Carecchio et al., 2017
S170F
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

Variable: Some cases with typical AD pathology; Extensive Lewy bodies in the substantia nigra and throughout the brain have also been reported. One case had severe cerebellar pathology, including abundant amyloid deposition and loss of Purkinje cells.

Increased Aβ42/Aβ40 ratio in cells and in vitro, but effects on Aβ42 and Aβ40 levels varied between studies. Effects on calcium homeostasis, phospho-tau expression, autophagy, expression of mitochondrial fission and fusion proteins, cell viability, and trophic factor function have also been reported. 

 

 

 

Snider et al., 2005
S170_ L171insY
AD : Not Classified Insertion Insertion | Insertion Coding Exon 6

Unknown

Unknown

Koriath et al., 2018
L171P
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

Unknown

Drastically decreased Aβ42 production and Aβ40 production was undetectable in vitro.

Ramirez-Dueñas et al., 1998
L172W
AD : Not Classified Substitution Substitution | Missense Coding Exon 6

Unknown

Unknown. 4 of 5 in silico algorithms predicted damaging.

Jia et al., 2020
L173W
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

Unknown.

Decreased Aβ40 and increased Aβ42 and the Aβ42/Aβ40 ratio in vitro.

Campion et al., 1999
L173S
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

Unknown

Unknown, predicted to be damaging by multiple in silico analyses, but not all. PHRED-CADD score=24.1

Wang et al., 2019
L173F (G>C)
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

Unknown; MRI from two affected mutation carriers showed atrophy of the medial temporal lobe. SPECT showed hypoperfusion of the posterior cingulate gyri and other cortical areas.

Uncertain. Aβ37/Aβ42 ratio similar to control in one cell-based assay, but increased Aβ42/Aβ40 ratio in two assays. Aβ42 decreased in one assay, but increased in another.

Kasuga et al., 2009
L173F (G>T)
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

Unknown.

Uncertain. Aβ37/Aβ42 ratio similar to control in one cell-based assay, but increased Aβ42/Aβ40 ratio in two assays. Aβ42 decreased in one assay, but increased in another. (One assays did not specify nucleotide change; other involved synonymous variant L173F (G>C)).

Jin et al., 2012
L174M
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

Neuropathology consistent with AD and CAA in one case.

Decreased Aβ40 and increased Aβ42/Aβ40 ratio in in vitro experiments. Conservative mutation in third transmembrane domain.

Bertoli Avella et al., 2002;
Tedde et al., 2003
L174del
AD : Not Classified Deletion Deletion | Deletion Coding Exon 6

Unknown, proband MRI revealed slight temporal lobe atrophy.

Increased Aβ40, and decreased Aβ42 and Aβ42/Aβ40 in proband's CSF

Tiedt et al., 2013
L174R
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

Neuropathology consistent with AD in one case. Also, abundant Lewy bodies in amygdala and entorhinal cortex.

 

Increased Aβ42/Aβ40 and Aβ43 levels; decreased Aβ37/Aβ42.

Klünemann et al., 2004
F175del
AD : Not Classified Deletion Deletion | Deletion Coding Exon 6

Unknown, but MRI and FDG-PET observations, as well as CSF biomarkers, were consistent with AD.

Increased Aβ42 and Aβ39; decreased Aβ40 in cultured cells.

Vöglein et al., 2019
F175S
AD : Not Classified Substitution Substitution | Missense Coding Exon 6

Unknown

No effect on Aβ42 or Aβ40 production in cultured cells. Multiple in silico algorithms yielded conflicting results.

Colacicco et al., 2002
F176V
AD : Not Classified Substitution Substitution | Missense Coding Exon 6

Atrophy of the hippocampus, parahippocampal cortex, and head of the caudate nucleus. Aβ plaques, tau-immunopositive neurons, and neuropil threads throughout the cerebral cortex. Myelinated fiber loss in the hemispheric white matter. Also, amyloid angiopathy and parenchymal Aβ deposition in the cerebellum.

Increased the Aβ42/Aβ40 ratio and decreased the Aβ (37 + 38 + 40) / (42 + 43) ratio.

Ghetti et al.,
F176L
AD : Not Classified Substitution Substitution | Missense Coding Exon 6

Neuropathology consistent with AD, notably abundant amyloid plaques and neurofibrillary tangles in the cortex. In fact, the neuropathology in this individual (Auguste D.) defined these structures as hallmarks of AD.

Variable results, but a comprehensive survey of Aβ peptides in a cell-based assay suggests it is damaging as reflected by its reduction of the Aβ37/Aβ42 ratio.

Müller et al., 2013
F177V
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

Unknown, but MRI showed global brain atrophy, especially in the temporal region and hippocampus in one patient.

Increased Aβ42 and Aβ42/Aβ40 in transfected cells.

Gao et al., 2019
F177L
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

Unknown

Increased Aβ42 production and Aβ42/Aβ40 ratio in vitro. Little impact on total cleavage activity of γ-secretase.

Rogaeva et al., 2001
F177S
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

Unknown, but in one carrier, PET revealed amyloid pathology in the cortex and widespread tau pathology and hypometabolism. MRI showed whole-brain atrophy.

Increased Aβ42/Aβ40 ratio and decreased Aβ37/Aβ42 ratio in cultured cells.

Rogaeva et al., 2001
S178P
AD : Pathogenic Substitution Substitution | Missense Coding Exon 6

Unknown

γ-secretase activity was 32% of wildtype as assessed by production levels of Aβ37, Aβ38, Aβ40, Aβ42, and Aβ43.

Rogaeva et al., 2001
I180N
AD : Not Classified Substitution Substitution | Missense Coding Exon 6

Unknown

Unknown, but multiple in silico algorithms predicted a damaging effect

Lanoiselée et al., 2017
G183V
AD : Not Classified, Other Tauopathy : Not Classified Substitution Splicing Alteration | Deletion; Missense Coding Exon 6

Mixed findings. In one case, severe frontotemporal atrophy; Pick bodies, tau-positive cytoplasmic neuronal inclusions, in the neocortex; A striking absence of extracellular Aβ deposits. Neuropathology was consistent with Pick’s disease. But in double mutation carrier (G138V and P49L), neuropathology consistent with AD.

Increase in Aβ42/Aβ40 ratio in cells and in vitro; reduced production of Aβ40 and Aβ42 in vitro. No effect on Notch cleavage. Generates alternative transcripts mostly degraded by nonsense-mediated decay, but coding for truncated proteins that may cause loss of function. Forms complexes with wild-type PSEN1, possibly suppressing activity.

Dermaut et al., 2004
E184G
AD : Likely Pathogenic Substitution Splicing Alteration | Missense Coding Exon 7

Unknown, but MRI of one patient revelaed global cortical atrophy.

Increased Aβ42/Aβ40 ratio, with decreased Aβ42 and Aβ40 production in vitro. In silico algorithms predicted the mutation is damaging and causes structural alterations. Also, mutation is near splice site.

Wallon et al., 2012
E184D
AD : Pathogenic, DLB : Not Classified, PPA : Not Classified Substitution Substitution | Missense Coding Exon 7

Neuropathology consistent with AD in three cases. In addition, CAA pathology described in two cases. Also, in two cases, robust Lewy body pathology and, in one of these cases, accumulation of the non-Aβ component of AD amyloid (NAC) in plaques and astrocytes.

Increased Aβ42/Aβ40 ratio; reduced Aβ37/Aβ42 ratio in cultured cells.

Yasuda et al., 1997
V191A
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown

Decreased Aβ42 secretion in isolated cells, but decrease in Aβ42/Aβ40 did not reach statistical significance.

Guerreiro et al., 2010
I202F
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Neuropathology was consistent with AD, with severe CAA, in one case. CAA included included chronic inflammatory infiltrate surrounding some cortical and leptomeningeal blood vessels. Lewy pathology was found in the amygdala. 

Reduced Aβ38 and Aβ37 production, as well as Aβ38/Aβ42 and Aβ37/Aβ42 ratios in membranes isolated from patient brains and transgenic cultured cells. 

 

Church et al., 2011
W203C
ALS : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown

Unknown, but multiple n silico algorithm predicted a damaging effect.

Couthouis et al., 2014
F205_G206delinsC
AD : Pathogenic Deletion Deletion | Deletion-Insertion Coding Exon 7

Unknown

Unknown, but in silico algorithms predicted damaging

Lanoiselée et al., 2017
G206R
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Consistent with AD. Also, end-stage TDP-43 and severe α-synuclein pathologies.

Unknown, but in silico algorithm suggests deleterious (PHRED scaled-CADD = 29.2).

Libard et al., 2022
G206S
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown; bilateral frontotemporal and parietal hypometabolism by PET; diffuse brain atrophy with enlarged ventricles by CT.

Decreased Aβ40 and Aβ42 production; increased Aβ42/Aβ40 ratio in vitro.

Rogaeva et al., 2001;
Raux et al., 2005
G206D
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Neuropathology consistent with AD.

Increased Aβ42 production; reduced interaction with Pen2; disrupted ER calcium homeostasis.

Raux et al., 2005
G206A
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Typical AD neuropathology, including extensive plaques and tangles (Braak stage VI). Cortical atrophy revealed by MRI and temporo-parietal hypometabolism revealed by FDG-PET. In one case, MRI alterations were similar to those of limbic encephalitis.

Increased Aβ42/Aβ40 ratio, decreased Aβ37/Aβ42 ratio. γ-secretase activity = 61% of wildtype. 

 

Rogaeva et al., 2001;
Athan et al., 2001
G206V
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown; an early MRI of the proband showed mild atrophy of the brain with normal temporal lobes.

Increased total Aβ and Aβ42, and decreased Aβ43, Aβ40, and Aβ38 in cells.

Goldman et al., 2002
G209R
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown; imaging showed mild brain atrophy in temporal lobes at early stages and diffuse brain atrophy mostly in frontotemporal lobes at advanced stages. Hypoperfusion in frontotemporal areas at early stages extending to parieto-occipital areas at advanced stages. CSF Aβ38, Aβ40, Aβ42, Aβ43 levels and Aβ43/Aβ42 were high vs other FAD carriers.

Abrogated Aβ40 production and drastically reduce Aβ42 production in vitro.

Sugiyama et al., 1999
G209V
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Neuropathology consistent with AD, includin cortical atrophy, extensive amyloid plaques and neurofibrillary tangles, and amyloid angiopathy.

Abrogated Aβ40 production and drastically reduced Aβ42 production in vitro. Also, caused incomplete endoproteolytic processing of PSEN1.

Poorkaj et al., 1998
G209E
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown, but MRI revealed global cerebral atrophy, particularly affecting the hippocampus. FDG-PET showed global hypometabolism, particularly affecting the temporal, parietal, and occipital lobes.

Unknown, but multiple in silico algorithms predicted a damaging effect.

Rogaeva et al., 2001
G209A
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown; MRI showed global cortical atrophy and FDG-PET revealed widespread bilateral hypometabolism.

Unknown; predicted likely damaging in silico by PolyPhen2, SIFT, and Provean.

An et al., 2016
M210R
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown, but levels of AD biomarkers in proband's CSF (Aβ42, tau, phospho-tau) were in the pathological range.

Unknown, but multiple in silico algorithms predicted a damaging effect.

Lanoiselée et al., 2017
S212Y
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Neuropathology consistent with AD in two carriers, including neurofibrillary tangles (Braak stage VI) and frequent neuritic plaques. In one case, severe amyloid angiopathy noted in the cerebellum and occipital cortex, and α-synuclein pathology detected in the amygdala.

Aβ42/Aβ40 ratio increased and Aβ37/Aβ42 ratio decreased in cultured cells.

Ringman et al., 2011
I213F
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown

Increased Aβ40 and Aβ42 secretion, and increased Aβ42/Aβ40 ratio in transfected cells.

Zekanowski et al., 2003
I213L
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown

Increased Aβ40 and Aβ42 production, and an increase in the Aβ42:Aβ40 ratio as assessed in vitro.

Rogaeva et al., 2001
I213T
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown.

 

Decreased short (Aβ38, Aβ40, and Aβ42), and increased long (Aβ43, Aβ45, Aβ46+) Aβ peptides in cell lysates and knockin mouse brains. Increased Aβ42/Aβ40 ratio, and decreased Aβ38/Aβ42 and Aβ40/Aβ43 ratios. Also inhibits neuroprotection by trophic factors and impairs angiogenesis in KI mice.

 

Kamino et al., 1996
H214Y
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown; imaging showed global cortical atrophy with marked frontotemporal atrophy and white-matter lesions.

Increased Aβ42/Aβ40 and decreased Aβ37/Aβ42 in cultured cells.

Raux et al., 2005
H214N
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown; CT scan showed diffuse cerebral atrophy more pronounced in medial temporal lobes.

Increased Aβ42/Aβ40 and decreased Aβ37/Aβ42 ratios in cells.

Piccoli et al., 2016
H214D
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown

Decreased Aβ37/Aβ42 ratio; Aβ42/Aβ40 similar or greater than that of controls. Reduced production of Aβ37, Aβ38, Aβ39, Aβ40, and Aβ42 peptides, but not Aβ43. 

Clarimón et al., 2008;
Guerreiro et al., 2010
H214R
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown, but in one case, MRI showed mild white matter demyelination of the frontal and parietal lobes, with no apparent atrophy of the cerebral cortex or hippocampus.

Unknown, but multiple in silico algorithms predicted it is deleterious.

Li et al., 2019
G217R
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 7

Cotton wool plaques.

Increased Aβ42/Aβ40 in two cell-based assays; decreased Aβ37/Aβ42 in iPSC-derived neurons. 

Norton et al., 2009
G217D
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 7

Cotton wool plaques in the cortex, caudate nucleus, putamen, claustrum, thalamus, substantia innominate, and colliculi.

Decreased Aβ37/Aβ42 ratio; increased Aβ42/Aβ40. Increased Aβ43 and decreased Aβ37 production.

Miravalle et al., 2002;
Takao et al., 2002
P218L
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown

Unknown, but in silico analyses predict damaging (Polyphen) and deleterious (SIFT).

Wojtas et al., 2012
P218P
AD : Likely Benign Substitution Splicing Alteration | Silent Coding Exon 7

Unknown.

Unknown. Predicted to potentially affect splicing in silico, but PHRED-scaled CADD = 5.

Jia et al., 2020
L219F
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown

Decreased Aβ40; increased Aβ42 and the Aβ42/Aβ40 ratio in vitro.

Terreni et al., 2016
L219R
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown, but brain imaging showed atrophy and reduced blood flow in temporal, parietal, and frontal lobes. Also, widespread microbleeds were found in brain, brainstem, and cerebellum. Levels of phospho-tau in CSF were elevated, while those of Aβ42 were reduced.

Unknown, but multiple in silico algorithms predicted a damaging effect.

Ikeda et al., 2013
L219P
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 7

Neuropathology consistent with AD in one case; meningeal CAA in cortex and cerebellum. PET and SPECT show hypoperfusion and hypometabolism in temporal lobes and right parietal lobe.

Increased the Aβ42/Aβ40 ratio and decreased the Aβ (37 + 38 + 40) / (42 + 43) ratio.

Smith et al., 1999
R220P
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown; MRI showed diffuse cortico-subcortical cerebral atrophy with multiple foci in the deep white matter.

Unknown; predicted to be damaging in silico (CADD score > 20).

Piccoli et al., 2016
R220Q
AD : Uncertain Significance Substitution Substitution | Missense Coding Exon 7

Unknown.

Unknown, but in silico algorithms predicted a damaging effect (PHRED-scaled CADD = 22.9).

Wang et al., 2023
Q222P
AD : Uncertain Significance Substitution Substitution | Missense Coding Exon 7

Unknown

Unknown, but predicted to be probably damaging by Polyphen and deleterious by Provean. Conserved between species and PSENs; other pathogenic mutations at this site.

Scahill et al., 2013;
Ryan et al., 2016
Q222R
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown

Increased Aβ40 and Aβ42 production, as well as the Aβ42/Aβ40 ratio in vitro.

Rogaeva et al., 2001
Q222H
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 7

Neuropathology consistent with AD in one case, CSF biomarkers consistent with AD in another case.

Increased Aβ42/Aβ40, decreased Aβ37/Aβ42, and increased Aβ43 levels in cultured cells.

Miklossy et al., 2003
Q223R
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown, but cotton-wool plaques and neurofibrillary tangles were found in two biopsies of family members of a mutation carrier. MRI of mutation carrier revealed white matter lesions in the frontotemporal region. FDG-PET showed progressive decrease in glucose metabolism in the precuneus and posterior cingulate, with parietal regions affected later. 

Increased Aβ42/Aβ40 ratio, decreased Aβ37/Aβ42 ratio, and dramatically increased Aβ43.

Uttner et al., 2010
L226V
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown, but imaging in one case showed a posterior gradient of atrophy including the hippocampus; white matter alterations in cortical and subcortical regions, and hypoperfusion in the right temporal, parietal, and occipital lobes. Also, decreased Aβ42 and Aβ42/Aβ40 ratio in CSF, with normal tau and p-tau levels.

Unknown, but in silico algorithm predicted a damaging effect (PHRED-scaled CADD = 28).

Zilioli et al., 2023
L226F
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Neuropathology consistent with AD.

Increased Aβ42/Aβ40 ratio; increased Aβ42; increased Aβ40.

Zekanowski et al., 2006
L226R
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Neuropathology consistent with AD in one individual, including numerous neuritic plaques and neurofibrillary tangles in the hippocampus and neocortex.

Increased the Aβ42/Aβ40 ratio and decreased the Aβ (37 + 38 + 40) / (42 + 43) ratio.

Coleman et al., 2004
I227V
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown

Unknown. In silico algorithms predicted damaging effect (CADD>20).

Koriath et al., 2018
I227L
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown

Unknown, but the variant's PHRED-scaled CADD score was above 20 suggesting a deleterious effect.

Jiao et al., 2021
I229F
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown

In vitro, increased Aβ42 production and reduced Aβ40; increased Aβ42/Aβ40 ratio

Janssen et al., 2003
S230I
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown.

Drastically decreased Aβ42 production and abrogated Aβ40 production in vitro.

Wallon et al., 2012
S230N
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown, but MRI showed diffuse atrophy, which was most severe in lateral temporal lobes and insulae.

Increased the Aβ42/Aβ40 ratio and decreased the Aβ (37 + 38 + 40) / (42 + 43) ratio.

Ringman et al., 2017
S230R
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

SPECT imaging showed bilateral parietal hypoperfusion, more marked on the left side. Postmortem evaluation revealed neuropathology consistent with AD, including advanced plaque and tangle pathology (CERAD C, Braak VI).

Unknown, but multiple in silico algorithms predicted a damaging effect.

Sassi et al., 2014
A231P
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown.

Unknown, but multiple in silico algorithms predicted a damaging effect.

Nicolas et al., 2015
A231T
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown

Decreased Aβ37/Aβ42; Aβ42/Aβ40 mixed results. Decreased production of all Aβ peptides.

Campion et al., 1995
A231V
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown

Unknown, but multiple in silico algorithms predicted a damaging effect.

Cruts et al., 1998
L232F
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown, but in one carrier, CSF biomarkers consistent with AD.

Unknown, but in silico algorithm predicted deleterious (PHRED-scaled CADD = 26.1).

Küçükali et al., 2023
L232P
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown, but MRI revealed diffuse cortical atrophy, especially in the frontal and parietal lobes.

Unknown, but multiple in silico algorithms predicted a damaging effect.

Park et al., 2017
M233V
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

In one case: neurofibrillary tangles and amyloid plaques throughout the neocortex; occasional plaques in the spinal cord; Lewy bodies in the substantia nigra and cortex; moderate to severe amyloid angiopathy in leptomeningeal, cerebral, and cerebellar vessels. Widespread amyloid deposition in another patient as assessed by PET.

Increased Aβ42/Aβ40 ratio and decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios in cells. 

Houlden et al., 2001
M233L (A>T)
FTD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown, but SPECT revealed hypoperfusion in posterior pariteal areas and a subsequent PET scan showed hypometabolism in prefrontal, parietal, and temporal cortices, in one case. MRI showed global cerebral atrophy.

Increased Aβ42 and decreased Aβ40 production, resulting in increased Aβ42/Aβ40 ratio in vitro. In cells, increased Aβ42/Aβ40 ratio, decreased total Aβ production and elevated levels of Aβ42 and Aβ43. Also, poromotes accumulation of APP β-CTFs which disrupt endosomes.

Mendez and McMurtray, 2006
M233L (A>C)
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown; imaging showed global cerebral atrophy.

In vitro, increased Aβ42 production, decreased Aβ40 production; increased Aβ42:Aβ40 ratio. In cells, increased Aβ42 and Aβ43, decreased total Aβ production, increased Aβ42:Aβ40 ratio. Disrupts endosomes via accumulation of APP β-CTF.

Aldudo et al., 1999
M233T
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Neuropathology consistent with AD in at least one case.

Increased Aβ42, Aβ48, and Aβ39; Decreased Aβ38, Aβ40, Aβ43, and Aβ46.

Kwok et al., 1997
M233I (G>A)
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown.

Decreased the Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios; increased Aβ42/Aβ40 in two cell-based assays (variant's nucleotide change unspecified).

Wallon et al., 2012
M233I (G>C)
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Neuropathology consistent with a diagnosis of AD, including amyloid plaques and tau-positive neurofibrillary tangles. No evidence of astrocytic gliosis, spongiosis, or prion disease.

Decreased the Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios; increased Aβ42/Aβ40 in two cell-based assays (nucleotide change unspecified).

Portet et al., 2003
L235V
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 7

Neuropathology consistent with AD in at least one case.

Modestly decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios in cells, and increased Aβ42/Aβ40 in cells but not in vitro; deleterious effect on monoamine oxidase.

Janssen et al., 2003
L235dup
AD : Not Classified Coding Exon 7

Unknown, but MRI showed hippocampal atrophy and ventricular enlargement. PET revealed amyloid deposition throughout the cortex.

Unknown.

Liang et al., 2023
L235R
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown; MRI showed bilateral atrophy, especially in the temporal and parietal lobes.

Drastically decreased Aβ42 production and abrogated Aβ40 production in vitro. Also, caused incomplete endoproteolytic processing of PSEN1. Predicted possibly damaging in silico.

Antonell et al., 2011
L235P
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Neuropathology consistent with AD.

In transgenic mice, increased production of Aβ, increased tau hyperphosphorylation, and loss of synaptic protein. In cells, decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios.

Campion et al., 1996
F237I
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown, but in proband, PET and SPECT revealed hypometabolism and hypoperfusion in bilateral temporoparietal areas, including primary and sensory motor cortices.

Decreased Aβ37/Aβ42 ratio; Aβ42/Aβ40 ratio similar to wildtype. Decreased levels of Aβ43, Aβ42, Aβ40.

Sodeyama et al., 2001
F237L
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown, but in one carrier CSF AD biomarkers were consistent with AD.

Decreased Aβ37/Aβ42 ratio; Aβ42/Aβ40 ratio similar to wildtype. Decreased levels of Aβ43, Aβ42, Aβ40.

Janssen et al., 2003
F237C
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown.

Unknown. Evolutionarily conserved codon across species and between human PSEN1 and PSEN2.

Lanoiselée et al., 2017
I238M
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown; MRI showed progressive cerebral atrophy. PET showed hypometabolism in the frontal and temporal lobes.

Increased the Aβ42/Aβ40 ratio and decreased the Aβ (37 + 38 + 40) / (42 + 43) ratio. 

Ting et al., 2014
I238_K239insI
AD : Not Classified Insertion Insertion | Insertion Coding Exon 7

Neuropathology consistent with AD (Braak and Braak stage VI, CERAD C). Cortical atrophy, mainly of the frontal lobe; Numerous neurofibrillary tangles and amyloid plaques, as well as ghost tangles, neuropil threads, and neuritic plaques; Cerebral amyloid angiopathy.

Unknown; insertion of the trinucleotide TAA results in the insertion of one amino acid (isoleucine), but does not cause a frameshift. In silico this insertion is predicted to be deleterious.

Roeber et al., 2015
K239N
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown, but MRI in one case showed medial temporal lobe and frontal lobe atrophy.  

In cells, Aβ42 and Aβ42/Aβ40 were increased. However, Aβ40 and Aβ42 production was undetectable in an assay using isolated proteins. Also, cell survival pathways preserved.

Lladó et al., 2010
L241R
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown, but mutation carrier had CSF AD biomarker levels (Aβ42, tau, phospho-tau) in the pathological range. 

Unknown, but multiple in silico algorithms predicted a damaging effect.

Lanoiselée et al., 2017
P242Lfs
Familial Acne Inversa : Not Classified Deletion Deletion | Frame Shift Coding Exon 7

Not applicable.

Decreases PSEN1 mRNA due to premature stop codon, nonsense-mediated decay. No effect on APP cleavage, but enhances Notch signaling. Also enhances cytokine and chemokine expression, and prolongs TNF-α production in monocytes and macrophages. 

T245P
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown, but MRI showed diffuse brain atrophy in one patient, and no abnormalities in 2 others.

Increased the Aβ42/Aβ40 ratio and decreased the Aβ (37 + 38 + 40) / (42 + 43) ratio.

Edwards-Lee et al., 2006
A246P
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Neuropathology consistent with AD (Braak and Braak stage VI, CERAD C) as well as cerebral amyloid angiopathy. Some α-synuclein inclusions were observed in the entorhinal cortex. Aβ42, tau, and phospho-tau levels in CSF consistent with AD

Unknown; predicted probably damaging in silico.

Roeber et al., 2015
A246E
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Generalized atrophy, most prominently in the frontal lobes and hippocampus. Neuronal loss, gliosis, neurofibrillary tangles, and plaques.

Increased Aβ42 and Aβ43 secretion, Aβ42/Aβ40 ratio, Aβ42/Aβ total ratio. Decreased production of Aβ40 and Aβ42 in vitro. Disrupts endosomes via accumulation of APP β-CTF. Impaired neuronal differentiation, neural precursor proliferation, viability, autophagy, mitophagy, lysosomal function, ER calcium flux. 

Sherrington et al., 1995
L248P
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown.

 

Increased Aβ42/Aβ40 and decreased Aβ37/Aβ42 in cultured cells.

Jiao et al., 2014
L248R
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown; in one case, neuroimaging showed prominent atrophy in the lateral fissure, and less prominent in parietofrontal regions

Increased Aβ42/Aβ40 ratio, decreased Aβ37/Aβ42 ratio. Production of all Aβ peptides was decreased.

Clarimón et al., 2008;
Guerreiro et al., 2010
I249L
ALS : Not Classified, AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown, but MRI from one case revealed hippocampal and cortical atrophy.

Increased Aβ42 and Aβ42/Aβ40 ratio, with no effect on PSEN1 endoproteolysis or Aβ43 production, in transfected cells. In silico analyses yielded mixed results: SIFT=tolerated; PolyPhen2=possibly damaging; Mutation Taster=disease causing.

Couthouis et al., 2014;
Shen et al., 2019
L250V
AD : Likely Pathogenic, Myoclonus : Not Classified Substitution Substitution | Missense Coding Exon 7

Unknown, but MRI showed diffuse cerebral atrophy and SPECT showed severe cortical hypoperfusion

Unknown, but multiple in silico algorithms predicted a damaging effect.

Furuya et al., 2003
L250S
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 7

Neuropathology consistent with AD in two cases.

In vitro, decreases Aβ40 and Aβ42 production; increases Aβ42/Aβ40 ratio.

Hutton et al., 1996;
Harvey et al., 1998
L250F
AD : Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown, but CT scans showed frontal, parietal, and temporal atrophy

Unknown, but multiple in silico algorithms predicted a damaging effect.

Butler et al., 2010
Y256N
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 7

Unknown, but MRI revealed temporal lobe and hippocampal atrophy in one case.

Unknown, but in silico algorithms predict the mutation is deleterious.

Li et al., 2019
Y256S
AD : Not Classified Substitution Substitution | Missense Coding Exon 7

Neuropathology consistent with AD in two cases; severe, widespread pathology, including cotton-wool plaques.

Increased Aβ40 and Aβ42 in frontal cortex of one case. In cells, increased Aβ42 and Aβ43. In vitro, decreased production of Aβ42 and Aβ40, increased Aβ42/Aβ40 ratio.

Miklossy et al., 2003
A260G
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 8

Unknown, but CSF bimoarkers were consistent with AD in two patients and MRI revealed mild cortical and hippocampal atrophy in one patient and signs of CAA in two patients. 

Increased the Aβ42/Aβ40 ratio and decreased the Aβ (37 + 38 + 40) / (42 + 43) ratio.

Ryman et al., 2014;
Piaceri et al., 2020
A260V
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Neuropathology consistent with AD. Also, diffuse Lewy body pathology, perivascular amyloid deposits and Pick-like intra-neuronal inclusions in the dentate gyrus.

Increased the Aβ42/Aβ40 ratio and decreased the Aβ (37 + 38 + 40) / (42 + 43) ratio. Reduced production of Aβ40 and Aβ42, disrupted APP intracellular distribution.

Rogaev et al., 1995;
Ikeda et al., 1996
V261F
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 8

Neuropathology consistent with AD, with cotton-wool plaques, CAA, and degeneration of spinal lateral pyramidal tracts.

Increased Aβ43 production (prevailing Aβ species) in cells. Decreased Aβ42 and Aβ40 production, and increased Aβ42/Aβ40 ratio in vitro. Also, abolished autoproteolysis.

Rogaeva et al., 2001;
Farlow et al., 2000;
Farlow et al., 2001
V261L
AD : Not Classified Substitution Substitution | Missense Coding Exon 8

Unknown, but MRI showed cortical and subcortical atrophy, and SPECT revealed temporal hyperperfusion in one patient.

Unknown, but multiple in silico algorithms predicted it is deleterious

Jiménez Caballero et al., 2008;
Gómez-Tortosa et al., 2010
V261I
AD : Not Classified Substitution Substitution | Missense Coding Exon 8

Consistent with AD, with widespread cotton wool plaques.

Unknown, but multiple in silico algorithms predicted it is damaging.

Miravalle et al., 2005
L262V
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 8

Unknown.

Unknown; predicted probably damaging in silico.

Wallon et al., 2012;
Lohmann et al., 2012
L262S
AD : Not Classified Substitution Substitution | Missense Coding Exon 8

Unknown

Predicted to be damaging by four different algorithms, with a PHRED-CADD score of 32.

Wang et al., 2019
L262F
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 8

A brain biopsy from one case "confirmed the diagnosis of AD".

Increased Aβ42/Aβ40 ratio in vitro, exhibiting a moderate increase in Aβ42 production, and a decrease in Aβ40 production.

Forsell et al., 1997
C263R
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Neuropathology consistent with AD.

Decreased Aβ40 and Aβ42 production and increased Aβ42/Aβ40 ratio in vitro.

Wasco et al., 1995
C263F
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Unknown. AD-like CSF levels of Aβ40, Aβ42, Aβ43, tau, and phospho-tau in 3 of 4 carriers.

Increased Aβ43 and the Aβ42/Aβ40 ratio; decreased Aβ38, Aβ40, and Aβ42.

Janssen et al., 2003
C263W
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Unknown, but in one case, CSF biomarkers were consistent with AD and brain imaging revealed cortical atrophy in three cases.

Unknown, but 3D modeling suggested conformational effects and the PHRED-scaled CADD score was above 20 suggesting a deleterious effect.

Tortelli et al., 2021
P264S
AD : Not Classified Substitution Substitution | Missense Coding Exon 8

Unknown.

Aβ42/Aβ40 ratio increased, but production of both peptides decreased, in a cell-based assay.

Takada et al., 2022
P264L
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Variable: Neuropathology frequently consistent with a diagnosis of AD, but also significant white-matter abnormalities and severe cerebral amyloid angiopathy with numerous small cortical infarcts. Abundant cotton-wool plaques composed of Aβ42 have also been reported.

Increased Aβ42/Aβ40 and decreased Aβ38/Aβ42 ratios; increased Aβ42, and decreased Aβ40 and Aβ38 production; Deposition of PSEN-1 in the endoplasmic reticulum; impaired mitochondrial activity and ATP production.

Campion et al., 1995;
Wasco et al., 1995
G266S
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

In one case, cotton-wool plaques; cerebral amyloid angiopathy; temporal and frontal lobe atrophy; widespread NFTs; reactive gliosis in white matter. MRI in another case revealed parietal lobe atrophy, frontal lobe deep white matter abnormalities. SPECT showed hypoperfusion of parietal and occipital areas.

Marked increase in Aβ42/Aβ40 ratio; reduced production of Aβ42, and particularly Aβ40, in vitro. 

Matsubara-Tsutsui et al., 2002;
Akatsu et al., 2008
P267A
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Frequent neuritic plaques, including in the neocortex (Braak stage VI); Severe cerebral amyloid angiopathy.

Decreased Aβ37/Aβ42, increased Aβ42/Aβ40, and increased Aβ43 in cultured cells.

Ringman et al., 2016
P267S
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Neuropathology consistent with Alzheimer's disease.

Reduced γ-secretase activity; Increased cell cycle arrest.

Alzheimer's Disease Collaborative Group, 1995;
Hutton et al., 1996
P267L
AD : Not Classified Substitution Substitution | Missense Coding Exon 8

Unknown.

Unknown, but predicted damaging by multiple in silico algorithms.

Kowalska et al., 2003
R269G
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 8

Unknown, but in one patient, MRI showed mild, non-specific cortical atrophy and EEG revealed a moderate, bilateral excess of slow wave activity. SPECT imaging showed non-specific, moderate hypoperfusion of the posterior parietal cortex.

 

Decreased Aβ40 and Aβ42 production; increased Aβ42/Aβ40 ratio. 

Perez-Tur et al., 1996
R269H
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 8

Neuropathology consistent with Alzheimer's disease; a high burden of Aβ and neurofibrillary tangles in cortical areas. Prominent microbleeds in the cerebellum, parieto-occipital region, and temporal lobe revealed by MRI in one patient. MRI in two cases showed white matter alterations.

Decreased the Aβ (37 + 38 + 40) / (42 + 43) ratio in cells; decreased γ-secretase activity (53% of wildtype).

Gómez-Isla et al., 1997
L271V
AD : Pathogenic Substitution Splicing Alteration | Deletion; Missense Coding Exon 8

Considerable atrophy of the temporal and posterior white matter with enlargement of the lateral ventricles. Variant plaques: large, non-cored, reminiscent of cotton-wool plaques. Depigmented locus coeruleus.

 

Affects splicing of exon 8 such that more transcripts are produced which lack exon 8. Causes amino acid replacement (D257A) at the splice junction of exons 7 and 9. In vitro, Aβ40 and Aβ42 production were abrogated, but in cells, increased Aβ42 secretion was reported, with no change in Aβ production.

 

Kwok et al., 2003
V272D
AD : Not Classified Substitution Substitution | Missense Coding Exon 8

Unknown, but MRI in one case revealed frontotemporal atrophy.

Increased Aβ42/Aβ40 ratio in cultured cells. 

Mengel et al., 2020
V272A
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Neuropathology consistent with AD, but also Lewy bodies in cortex and substantia nigra, and widespread subcortical neuritic lesions. MRI and PET abnormalities in subcortical-frontal areas in later stages of disease.

Increased plasma Aβ42. In vitro, increased Aβ42 production and Aβ42/Aβ40.

Jimenez-Escrig et al., 2004
E273A
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Unknown

Increased Aβ43 and decreased Aβ38 in cells; increased Aβ42 and Aβ42/Aβ40 ratio in vitro; disrupted calcium flow in ER.

Kamimura et al., 1998
E273G
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 8

Unknown.

Unknown, but multiple in silico algorithms predicted it is damaging.

Wallon et al., 2012
T274R
AD : Not Classified Substitution Substitution | Missense Coding Exon 8

Unknown

In vitro, Aβ40 and Aβ42 production was undetectable.

Rogaeva et al., 2001
T274K
AD : Not Classified Substitution Substitution | Missense Coding Exon 8

Unknown, but MRI imaging revealed alterations consistent with AD in one case.

Unknown, but in silico algorithms predicted the substitution is damaging, disrupting PSEN1 structure and function.

A275S
Dementia : Not Classified Substitution Substitution | Missense Coding Exon 8

Unknown, but in one case, MRI showed mild generalized atrophy sparing the hippocampus, and florbetaben-PET showed cortical amyloid accumulation. Dopamine transporter status was normal.

Unknown, but in silico algorithms predicted damaging (CADD score >20).

Joshi et al., 2021
A275T
AD : Not Classified Substitution Substitution | Missense Coding Exon 8

Unkown but brain MRI of one carrier showed hippocampal and temporoparietal atrophy and SPECT revealed hypoperfusion of the right posterior parietal cortex.

Aβ42/Aβ40 ratio was unchanged, but production of both peptides increased in cell-based assay.

Takada et al., 2022
A275V
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Neuropathology consistent with AD.

Increased the Aβ42/Aβ40 ratio and decreased the Aβ (37 + 38 + 40) / (42 + 43) ratio.

Luedecke et al., 2014
R278T
AD : Not Classified Substitution Substitution | Missense Coding Exon 8

Neuropathology consistent with AD was detected in one brain biopsy.

Increased Aβ42/Aβ40 ratio and decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios in cells. Also, increased Aβ43 levels 10-fold.

Kwok et al., 1997
R278K
AD : Not Classified, SP : Not Classified Substitution Substitution | Missense Coding Exon 8

Unknown; MRI and CT scans reported as normal in one individual

Increased Aβ42 production in patient fibroblasts; but reduced Aβ42 and Aβ40 production in assay with purified proteins. In both cases, increased Aβ42/Aβ40.

Assini et al., 2003
R278I
AD : Pathogenic, Progressive Nonfluent Aphasia : Not Classified Substitution Substitution | Missense Coding Exon 8

Neuropathology consistent with AD in two cases; with more Aβ deposition in the APOE3/4 carrier than the APOE2/3 carrier. Also, in the amygdala, α-synuclein pathology in both cases, and, in one case, TDP-43 pathology. 

Deficient maturation of mutant protein in iPSC-derived neurons. Selective increase in secreted Aβ43; impaired endoproteolysis of PSEN1. Increased Aβ42/Aβ40, Aβ42/Aβ38, and particularly Aβ43/Aβ40 ratios. Aβ38/Aβ40 ratio similar to wild-type.  Impaired processing of the ApoER2 LDL receptor. 

 

Godbolt et al., 2004
R278S
AD : Not Classified Substitution Substitution | Missense Coding Exon 8

Unknown

Unknown, but multiple in silico algorithms predicted it is damaging.

Raman et al., 2007
E280K
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Unknown; MRI showed generalized brain atrophy, including atrophy of the hippocampus.

Unknown; predicted probably damaging in silico.

Ch'ng et al., 2015
E280A
(Paisa)
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Neuropathology consistent with AD. Aβ42 abundant in the cerebral cortex, hippocampus, cerebellum, midbrain, and basal ganglia. Frequent CAA and cerebellar damage including ubiquitin–positive plaques, reactive astrocytes, and dystrophic neurites. Lewy body disease and TDP-43 pathology. Also, small vessel disease, disrupted gliovascular units, hyper-reactive astrocytes, and olfactory system alterations.

In cells, increased the Aβ42/Aβ40 ratio and decreased the Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios. Activation of chaperone-mediated autophagy. Deleterious effects on stress vulnerability with increased tau phosphorylation, and impairment of sodium channels, calcium homeostasis, mitochondrial function, AChE activity.

Alzheimer's Disease Collaborative Group, 1995;
Lopera et al., 1997;
Lemere et al., 1996
E280G
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Frequent cotton-wool plaques and vascular amyloid deposits; Some cases with white-matter abnormalities and degeneration of the corticospinal tract.

Increased Aβ42/Aβ40 ratio in cells and in vitro. Aβ42 secretion was increased in cells, but production of both Aβ42 and Aβ40 was reduced in vitro, as was endoproteolytic processing of PSEN1.

Alzheimer's Disease Collaborative Group, 1995;
O'Riordan et al., 2002
T281T
AD : Likely Benign Substitution Substitution | Silent Coding Exon 8

Unknown.

Unkown, but in silico algorithm predicted low deleteriousness (PHRED-scaled CADD < 20).

Jia et al., 2020
L282V
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Extensive neurofibrillary tangles and amyloid deposits including both dense-cored plaques and diffuse plaques. Severe cerebral amyloid angiopathy (CAA) in the neocortex, hippocampus, and cerebellum. CAA deposits associated with dystrophic neurites and inflammatory gliosis. Severe white-matter loss. Cerebellar amyloid pathology associated with severe CAA and loss of Purkinje cells.

Increased Aβ42/Aβ40 ratio and decreased Aβ37/Aβ42 ratio in cells. In vitro, Aβ42 and Aβ40 production, as well as Aβ42/Aβ40 ratio, similar to wild-type. Impairs trafficking of the APOE receptor apoER2.

Dermaut et al., 2001
L282F
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Unknown; MRI showed mild medial temporal atrophy. FDG-PET showed glucose hypometabolism in the bilateral parietal cortices and posterior cingulate gyri.

Although Aβ42/Aβ40 was similar to controls, Aβ37/Aβ42 was decreased and Aβ43 levels were increased in a cell-based assay.

Hamaguchi et al., 2009
L282R
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Neuropathology consistent with Alzheimer's disease.

Decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios and increased Aβ43. The Aβ42/Aβ40 ratio was increased or unchanged.

Aldudo et al., 1998
L282P
AD : Not Classified Substitution Substitution | Missense Coding Exon 8

Unknown, but in one patient, MRI revealed mild, diffuse cortical atrophy, and FDG-PET showed severe, bilateral hypometabolism in parietal and temporal cortices.

Unknown, but multiple in silico algorithms predicted damaging

Kim et al., 2020
F283L
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Neuropathology consistent with AD; absence of CBD pathology (2 cases in 1 family). MRI showed severe parietal, perirolandic, and temporal atrophy with relative sparing of frontal and ipsilateral hippocampal regions.

Unknown, but predicted to have a damaging effect according to SIFT, Polyphen, and Mutation Taster.

Scahill et al., 2013;
Ryan et al., 2016
P284S
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 8

Unknown, but in 4 family members, MRI revealed widespread white-matter lesions, with lobar microbleeds in two. In an unrelated carrier, PET showed Aβ deposition in cortex, cerebellum, and putamen and CSF biomarkers consistent with AD.

Aβ40 and Aβ42 production was similar to wild-type PSEN1 in vitro.

Marrosu et al., 2006
P284L
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 8

Prominent cotton-wool plaques in the cerebral cortex, basal ganglia, brainstem, and spinal cord. Some dense core plaques, primarily in the hippocampus and cerebral cortex. Vacuolar changes. Amyloid angiopathy. Neurofibrillary tangles. Mild neuritic changes and gliosis.

Unknown, but several in silico algorithms predict it is damaging.

Tabira et al., 2002
A285S
AD : Not Classified Substitution Substitution | Missense Coding Exon 8

Unknown, but in one case, PiB-PET was positive, MRI revealed bilateral hippocampal atrophy, and FDG-PET showed bilateral hypometabolism in the temporal cortex.

Unknown, but most in silico algorithms predicted probably damaging. 

Kim et al., 2020
A285V
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 8

Unknown, but MRI from 2 patients showed atrophy of the temporo-parietal cortex and hippocampus, and abnormalities in the deep white matter of the pariteo-occipital lobes. SPECT revealed hypoperfusion in parietal and occipital areas.

Aβ40 and Aβ42 levels similar to controls in CSF of one patient. In cells, Aβ42 production elevated compared to Aβ40 and Aβ38 production. In vitro, both Aβ40 and Aβ42 production modestly reduced; Aβ42/Aβ40 similar to wild-type PSEN1.

Ikeda et al., 1996
L286V
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Neuropathology consistent with AD.

Increased Aβ42/Aβ total ratio, unchanged Aβ42/Aβ40 ratio, and increased Aβ43, Aβ42, and Aβ40 levels, with decreased non-amylodiogenic processing of APP in cells. In vitro, decreased ε-cleavage. Disrupts intracellular calcium dynamics and cellular redox status.

Sherrington et al., 1995
L286P
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Cotton wool plaques and severe amyloid angiopathy (2 cases); brain hematoma at early age (3 cases).

Decreased Aβ37, Aβ38, Aβ39, and Aβ42 in patient CSF; increased Aβ15 and Aβ20. Increased Aβ42/43 amyloid production in cultured cells; reduced production rates of Aβ38 and Aβ40 in isolated brain membranes, and decreased Aβ38/Aβ42 ratio.

Sánchez-Valle et al., 2007
Y288H
AD : Not Classified Substitution Substitution | Missense Coding Exon 8

Unknown, but increased levels of Aβ42 and an elevated Aβ42/Aβ40 ratio in serum. Also, high incidence of cerebral microhemorrhages in multiple carriers.

Unknown, but CADD score (>20) suggests damaging effect.

Wicklund et al.,
c.856+3089_943+467del (ΔE9)
AD : Not Classified, SP : Not Classified Deletion Deletion | Deletion Both Exon 9, Introns 8 and 9

Unknown but, in one carrier, MRI showed slight brain atrophy and SPECT showed hypoperfusion of the parietal lobes, precuneus, and posterior cingulate cortex.

Unknown, but other Δ9 mutations result in increased Aβ42/Aβ40 ratio and decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios. They also disrupt multiple cellular functions.

Fukuda et al., 2023
S290_S319delinsC
(ΔE9, Δ9)
AD : Pathogenic Deletion Deletion | Deletion-Insertion Both Intron 8, Exon 9, Intron 9

Variable: lesions observed include cotton-wool plaques, cored plaques, and tangles. Corticospinal tract degeneration, cortical atrophy, and congophilic amyloid angiopathy also variably observed.

5.9 kb deletion including entire exon 9 and extending into flanking intronic sequences; results in skipping of exon 9 and S290C substitution at the splice junction of exons 8 and 10. Δ9 mutations generally result in increased Aβ42/Aβ40 ratio and decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios. They also disrupt multiple cellular functions.

Smith et al., 2001
S290_S319delinsC
(ΔE9Finn, Δ9Finn, Δ9)
AD : Pathogenic Deletion Deletion | Deletion-Insertion Both Intron 8, Exon 9, Intron 9

Variable across two families: One family had unusual plaques described as “reminiscent of loosely packed cotton-wool balls” which were large (100-150 μM in diameter) and not congophilic, suggesting a lack of amyloid at the core, in addition to more typical AD plaques and tangles. The other family had more typical AD pathology.

4.6 kb deletion including entire exon 9 and extending into flanking intronic sequences; results in skipping of exon 9 and S290C substitution at the splice junction of exons 8 and 10. Δ9 mutations generally result in increased Aβ42/Aβ40 ratio and decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios. They also disrupt multiple cellular functions.

Crook et al., 1998;
Prihar et al., 1999
S290_R377delinsW (Δ9-10)
(Δ9-10, Delta9-10, p.Ser290_Arg377delinsTrp, g.73671948_73682054del)
AD : Not Classified Deletion Deletion | Deletion-Insertion Both Introns 8-10, Exons 9-10

No data.

This mutation involves the deletion of 10.1 kilobases including exons 9 and 10. Severe deficits in endopeptidase and carboxypeptidase activity; decreased production of Aβ42, Aβ40, and Aβ38, with increased Aβ43.

Le Guennec et al., 2017;
Lanoiselée et al., 2017
c.869-22_869-23ins18
(ΔE9, Δ9, deltaE9)
AD : Not Classified Insertion Splicing Alteration | Deletion Both Intron 8, Exon 9

Cotton-wool plaques in addition to widespread neurofibrillary tangles and neuritic plaques more typical of AD. Marked cerebral amyloid angiopathy.

Insertion of 18 nucleotides in intron 8 upstream of exon 9, resulting in exon 9 skipping. Δ9 mutations generally result in increased Aβ42/Aβ40 ratio and decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios. They also disrupt multiple cellular functions.

Dumanchin et al., 2006
S290_S319delinsC A>G
(ΔE9, Δ9, c.869-2A>G)
AD : Pathogenic Substitution Splicing Alteration | Deletion-Insertion Both Intron 8, Exon 9

Unknown; in one patient, MRI showed supratentorial atrophy, particularly of parietal and occipital cortex. Also, reduced Aβ42 in CSF.

Point mutation in splice acceptor site in intron 8 resulting in skipping of exon 9 and S290C change at the splice junction of exons 8 and 10. Δ9 mutations generally result in increased Aβ42/Aβ40 ratio and decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios. They also disrupt multiple cellular functions.

Rovelet-Lecrux et al., 2015
S290_S319delinsC G>A
(ΔE9, Δ9, c.869-1G>A)
AD : Pathogenic Substitution Splicing Alteration | Deletion-Insertion Both Intron 8, Exon 9

Cotton-wool plaques are common, in addition to classic neuritic, amyloid plaques. Tangles, neuronal loss, atrophy typical of AD.

Point mutation in splice acceptor site in intron 8 resulting in skipping of exon 9 and S290C change at the splice junction of exons 8 and 10. Δ9 mutations generally result in increased Aβ42/Aβ40 ratio and decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios. They also disrupt multiple cellular functions.

Sato et al., 1998
S290_S319delinsC G>T
(ΔE9, Δ9)
AD : Pathogenic Substitution Splicing Alteration | Deletion-Insertion Both Intron 8, Exon 9

Cotton-wool plaques throughout the neocortex. Less frequent cored plaques. Neurofibrillary tangles, some neuronal loss, gliosis, and cerebral amyloid angiopathy.

Point mutation in a splice acceptor site in intron 8 resulting in in-frame skipping of exon 9 and S290C change at the splice junction of exon 8 and 10. Δ9 mutations generally result in increased Aβ42/Aβ40 ratio and decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios. They also disrupt multiple cellular functions.

Perez-Tur et al., 1995;
Hutton et al., 1996
T291A
AD : Benign, Parkinsonism : Not Classified Substitution Substitution | Missense Coding Exon 9

Unknown, patient with 2 PSEN1 mutations (A434T, T291A) had AD pathology with cotton wool plaques, diffuse deposits, and severe amyloid angiopathy

Unknown, in silico analyses predicted a damaging effect (PHRED-scaled CADD = 22.8).

Ryan et al., 2016
T291P
AD : Likely Pathogenic Substitution Splicing Alteration | Missense; Deletion Coding Exon 9

Unknown; MRI showed marked diffuse atrophy and a signal in the right temporal lobe, compatible with previous bleeding.

In cells, this mutation increased both Aβ40 and Aβ42, causing an overall increase in the Aβ42/Aβ40 ratio. However, in an in vitro assay, it dramatically decreased Aβ42 and abolished Aβ40 production. Also affects exon 9 splicing.

Dumanchin et al., 2006
W294Ter
Retinitis Pigmentosa : Not Classified Substitution Substitution | Nonsense Coding Exon 9

Unknown, but MRI of two carriers showed white matter and subcortical lesions, and a third carrier had lesions in the occipital and parietal cortices. All 3 carriers had abnormal EEG recordings.

Unknown, but 3D in silico modeling predicted pronounced structural effects.

You et al., 2020
P303L
FTD : Not Classified Substitution Substitution | Missense Coding Exon 9

Unknown.

Unknown. In silico algorithms yielded conflicting results.

Koriath et al., 2018
K311R
AD : Uncertain Significance Substitution Substitution | Missense Coding Exon 9

Unknown

Increased Aβ42 and reduced Aβ40 levels in conditioned media of cultured cells, resulting in increased Aβ42:Aβ40. Also increased phosphorylated tau levels in cell lysates.

Dong et al., 2017
E318G
AD : Benign Substitution Substitution | Missense Coding Exon 9

Mixed results. Some carriers have AD neuropatholgy, but some do not.

Most data indicate no effect on Aβ42/Aβ40, Aβ (37 + 38 + 40) / (42 + 43), and Aβ37/Aβ42 ratios.

Sandbrink et al., 1996;
Cruts et al., 1998;
Aldudo et al., 1998
D333G
AD : Benign, Dilated Cardiomyopathy : Not Classified Substitution Substitution | Missense Coding Exon 10

Unknown

Aβ42 production slightly reduced in vitro. Altered calcium signaling in fibroblasts.

Li et al., 2006
R352C
AD : Likely Benign Substitution Substitution | Missense Coding Exon 10

Unknown; imaging showed cerebral global atrophy.

Aβ42/Aβ40 ratio similar to wildtype as assessed in cellular and in vitro assays.

Jiang et al., 2015
R352dup
FTD : Not Classified Duplication Duplication | Duplication Coding Exon 10

Unknown, single case with confirmed mutation had FTD symptoms and pathology, but was subsequently found to also have a progranulin mutation

In-frame insertion of 3 nucleotides in exon 10 resulting in insertion of an arginine between amino acids R352 and S353. Aβ CSF and plasma levels in proband are roughly normal. In cultured cells, expression of the mutant increased the Aβ42:Aβ40 ratio, but markedly reduced the levels of both secreted Aβ40 and Aβ42. In vitro, production of Aβ42 was markedly decreased and production of Aβ40 was abolished.

Rogaeva et al., 2001;
Tang-Wai et al., 2002;
Amtul et al., 2002
T354I
AD : Uncertain Significance Substitution Substitution | Missense Coding Exon 10

Unknown, but brain imaging showed generalized atrophy in one case and cortical parieto-temporal hypometabolism in another. CSF levels of Aβ42, total tau, and phospho-tau were consistent with AD in the latter case. 

Decreased Aβ42 and Aβ40 production, and decreased Aβ42/Aβ40 ratio in vitro. Decreased Aβ42 in CSF of one case.

Rogaeva et al., 2001;
Lee et al., 2006
P355S
AD : Likely Benign Substitution Substitution | Missense Coding Exon 10

Unknown, but MRI revealed microbleeds in cortex, basal ganglia, and subcortical white matter suggestive of amyloid angiopathy. FDG-PET showed bilateral frontotemporal hypometabolism. Lewy body pathology suspected.

Unknown, but cryo-EM data suggest perturbation of γ-secretase catalytic activity. In silico algorithms yielded conflicting predictions.

Monacelli et al., 2019
S357Ter
MCI-VaD : Not Classified Substitution Substitution | Nonsense Coding Exon 10

Unknown, but MRI in one case revealed multifocal subcortical microhemorrhages mainly in the left posterior hemisphere.

Unknown, but in silico algorithms predict deleterious (PHRED-scaled CADD score > 20).

Palmieri et al., 2021
R358Q
AD : Likely Benign Substitution Substitution | Missense Coding Exon 10

Unknown

Decreased Aβ40 and Aβ42 production and increased Aβ42/Aβ40 ratio in vitro. in cells, increased Aβ40 and Aβ42 secretion, with no significant change in the Aβ42/Aβ40 ratio.

Rogaeva et al., 2001
A360T
AD : Likely Benign Substitution Substitution | Missense Coding Exon 10

Unknown. In one carrier, CSF Aβ42 was reduced, but tau and phospho-tau levels were normal. In another, CSF phospho-tau was increased, but Aβ42 and tau were normal. MRI in latter carrier showed hippocampal and posterior cortical atrophy. 

Unknown

Lanoiselée et al., 2017
L364P
AD : Not Classified Substitution Substitution | Missense Coding Exon 10

Unknown, but but an MRI scan showed atrophy consistent with AD in one case.

Unknown. In silico algorithms provided mixed predictions, with the integrative CADD score (> 20) suggesting a damaging effect.

Eryilmaz et al., 2021
S365A
AD : Uncertain Significance Substitution Substitution | Missense Coding Exon10

Unknown

In vitro production of Aβ38, Aβ40, Aβ42, and Aβ43 similar to wildtype in one study; in another Aβ40 and Aβ42 production moderately increased, with Aβ42/Aβ40 ratio unchanged. Another study reported the phosphorylation status of this site appears to modulate a PSEN1 calcium-triggered conformational change linked to increased Aβ42/Aβ40.

Clarimón et al., 2008;
Guerreiro et al., 2010
S365Y
AD : Not Classified Substitution Substitution | Missense Coding Exon 10

Unknown.

Unknown. In silico algorithms yielded conflicting results, with integrative CADD score (>20) suggesting damaging effects.

Rogaeva et al., 2001
G371C
AD : Not Classified Substitution Substitution | Missense Coding Exon 10

Unknown

Unknown. In silico algorithms yielded conflicting results.

Perrone et al., 2020
R377W
AD : Likely Pathogenic Substitution Splicing Alteration | Deletion; Missense Coding Exon 10

Unknown; in one case, imaging showed amyloid deposition in the precuneus and frontal and parietal areas, with mild parietal atrophy and hypometabolism in precuneus, posterior cingulum, inferior parietal lobes, temporal, and frontal lobes. Frontotemporal atrophy and hypometabolism seen in another case.

 

In vitro, decreased Aβ42 production and abrogated Aβ40 production.

Wallon et al., 2012;
Borroni et al., 2011
R377M
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 11

Unknown

Unknown, but in silico algorithm predicted it is deleterious (PHRED-scaled CADD = 32).

Janssen et al., 2003
G378R
AD : Not Classified Substitution Substitution | Missense Coding Exon 11

Unknown, but MRI of one patient showed fronto-temporo-parietal atrophy and CSF biomarkers consistent with AD.

Unknown, but predicted deleterious in silico and two other pathogenic mutations in same residue.

Ramos-Campoy et al., 2020
G378E
AD : Pathogenic Substitution Substitution | Missense Coding Exon 11

Neuropathology consistent with AD. One case also had notable cerebral amyloid angiopathy.

Increased Aβ42/Aβ40 ratio; increased Aβ42.

Besançon et al., 1998
G378V
AD : Pathogenic Substitution Substitution | Missense Coding Exon 11

Neuropathology consistent with AD.

Decreased Aβ42 and abrogation of Aβ40 production in vitro. Predicted to have a damaging effect by SIFT, Polyphen, and Mutation Taster.

Janssen et al., 2003
G378fs
AD : Not Classified Insertion Insertion | Frame Shift Coding Exon 11

Unknown; MRI showed hippocampal and parahippocampal atrophy.

The insertion of one nucleotide in exon 11 is predicted to cause a frameshift. In cells, Aβ40 and Aβ42 production decreased and Aβ42/Aβ40 ratio increased. 

El Kadmiri et al., 2014
K380R
AD : Not Classified Substitution Substitution | Missense Coding Exon 11

Unknown

Unknown, but in silico predictions suggest damaging effect (PHRED-scaled CADD score > 20).

Jiao et al., 2021
L381V
AD : Pathogenic Substitution Substitution | Missense Coding Exon 11

Unknown, but in one carrier, PET revealed widespread amyloid and tau pathology, atrophy, hypometabolism, and reduced dopamine transporter in the putamen. In another, Aβ38 and Aβ40 in CSF were proportionately reduced while Aβ43 was relatively high resulting in an elevated Aβ43/Aβ42 ratio.

Increased Aβ42/Aβ40 ratio; increased Aβ42 and Aβ43; Reduced PSEN1 N-terminal fragment (NTF), suggesting impaired endoproteolysis of PSEN1.

Dintchov Traykov et al., 2009;
Mehrabian et al., 2004
L381F
AD : Pathogenic Substitution Substitution | Missense Coding Exon 11

Neuropathology consistent with AD, including neuritic amyoid plaques and neurofibrillary tangles. Hirano bodies and granulovacuolar degeneration in the hippocampus.

In silico analysis suggests that the mutation affects the folding free energy and flexibility of the protein.

Dolzhanskaya et al., 2014
G384A
AD : Pathogenic Substitution Substitution | Missense Coding Exon 11

Neuropathology consistent with AD.

Increased Aβ42/Aβ40 ratio; increased relative amounts of longer vs. shorter Aβ peptides; decreased Aβ40, Aβ38, Aβ38/Aβ42, and Aβ40/Aβ43. Abolished ER calcium leak channel activity and reduced ApoE secretion. Altered subcellular localization of PSEN1 and its interaction with GLT-1.

Cruts et al., 1995;
Tanahashi et al., 1996
F386I
AD : Pathogenic Substitution Substitution | Missense Coding Exon 11

Unknown; MRI showed atrophy of hippocampus.

 

Increased Aβ42/Aβ40 and Aβ43; decreased Aβ37/Aβ42 in cells.

Shea et al., 2017
F386S
AD : Pathogenic Substitution Substitution | Missense Coding Exon 11

Unknown

Decreased Aβ37/Aβ42 ratio and dramatically increased Aβ43 in cells. Increased Aβ42/Aβ40 ratio in 3 assays.

Raux et al., 2005
F386L
AD : Pathogenic Substitution Substitution | Missense Coding Exon 11

Unknown.

Unknown, but predicted to be pathogenic by multiple in silico analyses.

Yagi et al., 2014
F388S
AD : Pathogenic Substitution Substitution | Missense Coding Exon 11

Unknown, but MRI revealed brainstem atrophy, and DTI showed corticospinal tract abnormalities typical of spastic paraparesis.

Unknown, but cryo-EM data and in silico algorithms suggest it is damaging.

Ringman et al.,
F388L
AD : Pathogenic Substitution Substitution | Missense Coding Exon 11

Unknown.

Increased Aβ42 and Aβ42/Aβ40 ratio.

Zhan et al., 2017
Y389H
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 11

Unknown, but in two cases, amyloid-PET was positive. MRI revealed mild, diffuse cortical atrophy in one case, and severe frontotemporal atrophy in another. FDG-PET showed bilateral hypometabolism in parietal and temporal cortices in one case. 

Unknown, but in silico algorithms predicted probably damaging (Polyphen2) and not tolerable/damaging (SIFT). CADD score = 26.9.

Park et al., 2020;
Kim et al., 2020
Y389S
AD : Not Classified Substitution Substitution | Missense Coding Exon 11

Unknown, but one case had Aβ accumulation (PiB-PET+), with mild, diffuse cortical atrophy (MRI), and bilateral hypometabolism in the parieto-temporal cortex (FDG-PET).

Unknown, but predicted probably damaging by in silico algorithms Polyphen2 and SIFT. CADD score = 26.8.

Kim et al., 2020
S390N
AD : Not Classified Substitution Substitution | Missense Coding Exon 11

Unknown; MRI showed cerebral amyloid angiopathy.

Unknown.

Nicolas et al., 2015
S390I
AD : Not Classified Substitution Substitution | Missense Coding Exon 11

Unknown

Drastic decrease in production of both Aβ40 and Aβ42 in vitro.

Campion et al., 1999
V391F
AD : Pathogenic Substitution Substitution | Missense Coding Exon 11

Unknown

Increased Aβ42/Aβ40 ratio; reduced Aβ40 production in vitro.

Raux et al., 2005
V391G
AD : Pathogenic, Parkinsonism : Not Classified Substitution Substitution | Missense Coding Exon 11

Unknown; in single case MRI showed generalized mild cortical and subcortical atrophy, thinner hippocampus, and enlarged ventricles.

Unknown, probable damaging as predicted by multiple in silico algorithms. Phenotype complicated by family history of extrapyramidal disease with several associated recessive mutations (PANK2, SYNE1, ZNF592)

Lou et al., 2017
L392V
AD : Pathogenic Substitution Substitution | Missense Coding Exon 11

Neuropathology consistent with AD, including cortical atrophy, amyloid plaques, and neurofibrillary tangles.

Increased Aβ42:Aβ40 ratio; increased Aβ48-39 production line, including Aβ42, in cells; decreased Aβ40 production in vitro. Impaired Notch cleavage. 

Campion et al., 1995;
Campion et al., 1995;
Rogaev et al., 1995;
Campion et al., 1999
L392P
AD : Not Classified Substitution Substitution | Missense Coding Exon 11

Unknown

Unknown

Tedde et al., 2000
V393F
AD : Not Classified Substitution Substitution | Missense Coding Exon 11

Unknown

Unknown, but predicted deleterious by in silico analysis (CADD Phred score= 35).

Koriath et al., 2018
G394V
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 11

Unknown

In vitro, Aβ40 production undetectable; Aβ42 drastically reduced; autoproteolysis abrogated. Four algorithms predicted the mutation to be damaging, with a PHRED-CADD score of 31. In patient cells with additional mutation (E318G), no change in Aβ40 or Aβ42 levels.

Rogaeva et al., 2001
K395I
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 11

Neuropathological data are unavailable. No abnormalities were detected in an early MRI scan of the proband’s brain, nor in an EEG.

Increased Aβ42/Aβ40 ratio and decreased both Aβ42 and Aβ40 levels.

Takada et al., 2022
A396T
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 11

Neuropathology was consistent with AD, plus widespread α-synuclein inclusions characteristic of Lewy body disease, in one case. MRI of another case showed atrophy of the frontal lobes.

Increased Aβ40 and Aβ42 production with Aβ42/Aβ40 ratio unchanged in cells; reduced Aβ40 production and increased Aβ42/Aβ40 ratio in vitro. 

Lohmann et al., 2012
N405S
AD : Not Classified Substitution Substitution | Missense Coding Exon 11

Neuropathology consistent with AD.

Decreased Aβ40 and Aβ42 production, and decreased Aβ42/Aβ40 ratio in vitro.

Yasuda et al., 2000
I408T
AD : Not Classified, DLB : Not Classified Substitution Substitution | Missense Coding Exon 11

Unknown; MRI of two carriers showed termporal and hippocampal atrophy consistent with AD. CSF biomarkers consistent with AD and deficit in dopamine uptake in one case, but additional mutation present. 

Unknown; predicted damaging in silico.

Tedde et al., 2016
A409T
AD : Not Classified Substitution Substitution | Missense Coding Exon 11

Unknown

In cells, increased Aβ43 production and the Aβ42/Aβ40 ratio; decreased total Aβ, Aβ38, Aβ40, and Aβ42. In vitro, decreased Aβ40, Aβ42, and the Aβ42/Aβ40 ratio.

Aldudo et al., 1999
C410Y
AD : Pathogenic Substitution Substitution | Missense Coding Exon 11

Neuropathology consistent with AD.

Increased Aβ42/Aβ total ratio and decreased Aβ (37 + 38 + 40) / (42 + 43) ratio in cells. Dominant-negative inhibition of wild-type PSEN1. Partial loss of γ-secretase cleavage of Notch and β-neurexin.

Sherrington et al., 1995;
Campion et al., 1995
V412I
FTD : Not Classified Substitution Substitution | Missense Coding Exon 11

Unknown; in one case, 18FDG-PET showed hypometabolism in the parietal and frontal cortices, as well as in the putamen and caudate. In another case, SPECT showed widespread cortical hypoperfusion. 

Severe decrease in Aβ42 and undetectable Aβ40 levels in in vitro assay using isolated proteins.

Bernardi et al., 2009
I414T
Dementia : Not Classified Substitution Substitution | Missense Coding Exon 11

Unknown.

Did not alter Aβ42/Aβ40 ratio, reduced both Aβ40 and Aβ42 production.

Takada et al., 2022
I416T
AD : Pathogenic Substitution Substitution | Missense Coding Exon 11

Unknown, but two cognitively normal mutation carriers had preclinical amyloid plaques and tau accumulation, as assessed by PET, similar to those of individuals at-risk for late-onset AD or individuals carrying other AD-causing PSEN1 mutations.

Unknown, but mutation results in the substitution of a highly conserved, transmembrane, hydrophobic amino acid with a polar amino acid near a splice site. CADD score >20.

Ramirez Aguilar et al., 2019
G417S
AD : Not Classified, SP : , Parkinsonism : Substitution Substitution | Missense Coding Exon 12

Cotton wool plaques throughout cortex, abundant Aβ deposits in cerebellum and spinal gray matter (one patient). Also, CAA, extensive neuronal loss, astrocytic and microglial markers, and extensive distribution of neocortical Lewy bodies. TDP-43 inclusions in limbic region and temporal cortex.

Increased Aβ42 and the Aβ42/Aβ40 ratio in cultured cells.

Miki et al., 2019
G417A
AD : Not Classified Substitution Substitution | Missense Coding Exon 12

Unknown, but MRI and PET are consistent with AD in one case. PiB-PET showed diffuse amyloid in the cerebellum, and the frontal, parietal, and temporal cortices.

Unknown, but in silico analyses predict mutation is damaging (PolyPhen2, SIFT, Provean). Changes in amino acid bulkiness, polarity, and hydrophobicity, together with 3D modeling, suggest reduced flexibility in transmembrane helix. Splicing may also be affected.

Giau et al., 2018
L418W
AD : Not Classified Substitution Substitution | Missense Coding Exon 12

Unknown, but in 2 carriers imaging showed symmetrical hyperintensities in the posterior-dominant white matter and the splenium of corpus. SPECT imaging showed hypoperfusion in the posterior cingulate gyrus and parietal lobe. In one carrier, DAT imaging revealed decreased dopamine uptake in the putamen bilaterally.

Unknown, but in silico analysis predicted damaging effects (PHRED-scaled CADD > 20).

Takahashi et al., 2018
L418F
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 12

Unknown

Decreased Aβ40 and Aβ42 production, and elevated Aβ42/Aβ40 ratio, in vitro.

Rogaeva et al., 2001
L420R
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 12

Extensive amyloid pathology, primarily in the form of cotton-wool plaques, although some rare dense core plaques. Some amyloid angiopathy.

Decreased Aβ40 and Aβ42 production; increased Aβ42/Aβ40 ratio in vitro.

Shrimpton et al., 2007
L424V
AD : Not Classified, Atypical Dementia : Not Classified Substitution Substitution | Missense Coding Exon 12

Unknown; CT and SPECT imaging showed diffuse cortical and subcortical atrophy and hypoperfusion affecting the frontal, temporal, and parietal lobes in one patient. In another, fronto-temporal atrophy was predominant, as revelaed by CT and MRI. 

Increased Aβ40, Aβ42, and Aβ42/Aβ40 in vitro.

Robles et al., 2009
L424F
AD : Pathogenic Substitution Substitution | Missense Coding Exon 12

Unknown, but neuroimaging in two patients revealed brain atrophy with white-matter changes.

Increased Aβ42/Aβ40 and decreased Aβ37/Aβ42 in cultured cells.

 

 

Mehrabian et al., 2006
L424R
AD : Pathogenic Substitution Substitution | Missense Coding Exon 12

Unknown; MRI showed cortical and subcortical atrophy with a thin corpus callosum.

Increased Aβ42/Aβ40 and Aβ43 levels, and decreased Aβ37/Aβ42.

Kowalska et al., 1999
L424P
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 12

Unknown, but in proband, MRI showed medial temporal lobe atrophy and global cortical atrophy; PET showed hypometabolism in parietal areas, the precuneus, and the posterior cingulate cortex. Also, reduced CSF Aβ42.

Unknown, but predicted pathogenic by multiple in silico algorithms. 3D in silico analysis predicted shortening of two intramembrane α-helices and creation of a new one.

Guven et al., 2019
L424H
AD : Pathogenic Substitution Substitution | Missense Coding Exon 12

Unknown; generalized cerebral atrophy by MRI; diffuse cerebral hypoperfusion by SPECT.

Increased Aβ42/Aβ40 and Aβ43; decreased Aβ37/Aβ42.

Raux et al., 2005;
Zekanowski et al., 2006
A426P
AD : Pathogenic Substitution Substitution | Missense Coding Exon 12

Unknown, but PiB-PET revealed robust amyloid deposition in the striatum. PiB retention was also found in the neocortex and thalamus. Compared to sporadic AD, amyloid accumulation in frontal, temporoparietal, and precuneus cortices was lower.

Aβ42/Aβ40 ratio increased, Aβ (37 + 38 + 40) / (42 + 43) ratio decreased in cells. γ-secretase composite score (% relative to wildtype) = 52.86 

 

Poorkaj et al., 1998
I427V
AD : Uncertain Significance Substitution Substitution | Missense Coding Exon 12

Unknown.

Unknown, but predicted in silico to be damaging (PHRED-scaled CADD score = 20.3).

Wang et al., 2023
A431E
AD : Pathogenic, SP : Pathogenic Substitution Substitution | Missense Coding Exon 12

Neuropathology consistent with AD. Widespread white-matter abnormalities in several patients with motor impairments, high incidence of cerebral microhemorrhages. In one case, Lewy body pathology.

Aβ42/Aβ40 ratio increased in vitro and Aβ (37 + 38 + 40) / (42 + 43) decreased in cultured cells. Toxic peptide Aβ43 was particularly elevated. Increased expression of cell cycle genes and activation of REST in iPSC-neurons. Enhanced MAO-A activity in HT-22 cells.

Rogaeva et al., 2001;
Yescas et al., 2006
A431V
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 12

Unknown, but in one case FDG-PET at MCI-AD stage showed low metabolic rates in posterior cingulate gyrus, posterior and lateral parietal cortices, and medial temporal regions; elevated tau and phospho-tau in CSF.

Unknown. Multiple in silico algorithms predicted damaging.

Matsushita et al., 2002
P433S
AD : Pathogenic Substitution Substitution | Missense Coding Exon 12

Unknown

Increased Aβ42, Aβ43, and Aβ42/Aβ40 ratio in transfected cells. Reduced PSEN1 endoproteolysis.

Koriath et al., 2018
A434T
AD : Pathogenic Substitution Substitution | Missense Coding Exon 12

Unknown.

Unknown; predicted damaging in silico.

Jiao et al., 2014
A434C
AD : Pathogenic Deletion-Insertion Deletion-Insertion | Missense Coding Exon 12

Numerous diffuse plaques and neuritic plaques with dense amyloid cores throughout the neocortex; Abundant neurofibrillary tangles and Hirano bodies; Moderate cell loss and gliosis in the hippocampus, amygdala, and nucleus basalis.

Increased Aβ42 and decreased Aβ40 production in vitro, resulting in an increased Aβ42/Aβ40 ratio.

Devi et al., 2000
A434V
AD : Not Classified Substitution Substitution | Missense Coding Exon 12

Unknown, but predicted deleterious (PHRED-scaled CADD score = 28.7)

Roveta et al., 2023
L435F
AD : Pathogenic Substitution Substitution | Missense Coding Exon 12

Widespread cotton-wool plaques in the neocortex, hippocampus, and deep cerebral nuclei contain substantially more Aβ43 than typical plaques. Abundant neurofibrillary tangles in the entorhinal cortex and hippocampus. Mild cerebral amyloid angiopathy. Neuronal loss, depigmentation, and gliosis in the substantia nigra.

Elevated Aβ43 in cells, inluding iPSC-derived neurons, knockin rats, and human brain tissue (although decreased Aβ43 in knockin mice). Decreased total Aβ, Aβ42, Aβ40, APP-CTF. Decreased ε-cleavage, autoproteolysis, and Aβ46→Aβ43 and Aβ43→Aβ40 trimming. Altered Notch function. Impaired wildtype PSEN1 γ-secretase activity. Increased seeding and propagation of tau aggregates.

Rogaeva et al., 2001
P436S
AD : Not Classified Substitution Substitution | Missense Coding Exon 12

Unknown

Increased Aβ42/Aβ40 ratio in cells and in vitro. In cells, decreased production of Aβ40, Aβ42, AICD, Notch. In vitro, decreased Aβ40, with no effect on Aβ42 production.

Palmer et al., 1999
P436Q
AD : Pathogenic Substitution Substitution | Missense Coding Exon 12

Neuropathology consistent with AD in at least one mutation carrier, including frequent Aβ plaques, many of the cotton-wool type, and severe neurofibrillary tangle pathology (Braak and Braak stage VI).

Unknown, but multiple in silico algorithms predicted it is damaging.

Taddei et al., 1998
I437V
AD : Likely Pathogenic Substitution Substitution | Missense Coding Exon 12

Unknown.

Decreased Aβ40 and Aβ42 production, and increased Aβ42/Aβ40 ratio in vitro.

Nicolas et al., 2015
I439V
AD : Uncertain Significance Substitution Substitution | Missense Coding Exon 12

Unknown.

In vitro, moderately increased Aβ40 and Aβ42 production; Aβ42/Aβ40 ratio unchanged. In cells, increased Aβ42 secretion; Aβ42/Aβ40 unchanged.

 

Rogaeva et al., 2001
I439S
AD : Not Classified Substitution Substitution | Missense Coding Exon 12

Unknown, but MRI showed diffuse cortical atrophy in one case.

Unknown, but PolyPhen analysis predicted the mutation is possibly damaging.

Gómez-Tortosa et al., 2010
T440del
PDD : Not Classified, AD : Not Classified Deletion Deletion | Deletion Coding Exon 12

Cotton-wool plaques, Lewy bodies, CAA, neuronal loss in cortex and substantia nigra, corticospinal tract degeneration in one case.

Abrogation of Aβ40 production and dramatic reduction of Aβ42 production in vitro. Near abrogation of autoproteolysis.

Ishikawa et al., 2005
M457V
AD : Not Classified Substitution Substitution | Missense Coding Exon 12

Unknown

Unknown, but in silico data predicted a damaging effect (PHRED-scaled CADD score > 20).

Jiao et al., 2021
c.*9C>T
AD : Uncertain Significance Substitution Substitution | Non-Coding Exon 12, 3' UTR

Unknown.

Unknown, but in silico algorithm predicted low deleteriousness (PHRED-CADD < 20). 

Jia et al., 2020
c.*947G>A
AD : Benign Substitution Substitution | Non-Coding Exon 12, 3' UTR

Unknown, associated with increased thickness in the inferior frontal and orbitofrontal cortices, and basal ganglia

Unknown

Seo et al., 2020