Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73659471 A>G
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CAG to CGG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7


This mutation was found in a Turkish family with five individuals affected by dementia and spastic paraplegia (Uttner et al., 2010). The proband presented with memory deficits, slurred speech, social disinhibition, a lack of initiative, and emotional blunting at age 34. One year later, he had developed spastic paraparesis and dysphagia, and his cognition had severely declined. Affected family members, spanning three generations, died with similar symptoms in their late 30s or early 40s. The mutation was absent from 192 controls. 

The mutation was also reported in a French family with two affected individuals (Wallon et al., 2012). Age at onset was 31-34 years old, and disease duration was five years. As in the Turkish family, symptoms included spastic paraparesis.

The variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).


Neuropathological data from mutation carriers are unavailable, but brain biopsies from the affected mother and brother of the Turkish proband revealed cortical cotton-wool plaques and neurofibrillary tangles (Uttner et al., 2010). In addition, MRI of the proband revealed a few white matter lesions in the frontotemporal region. In the affected brother, MRI showed generalized atrophy and bilateral, frontally pronounced white matter lesions. Moreover, FDG-PET of the proband showed slightly decreased glucose metabolism in the precuneus and part of the posterior cingulate at disease onset. A year later, the reduction had progressed in both areas, and also included bilateral parietal hypometabolism.

Levels of Aβ42 were drastically decreased in the CSF of two mutation carriers (Uttner et al., 2010; Wallon et al., 2012). In the Turkish proband, the reduction was observed early in the disease, when an FDG-PET scan revealed only minor metabolic alterations and CSF tau levels were normal. In the French proband, CSF tau and phospho-tau levels were increased, consistent with the AD phenotype.

Biological Effect

Amyloid-β peptide production in 2EB2 cells transfected with PSEN1 Q223R, while stably overexpressing Swedish APP and BACE1, was altered compared with that of cells transfected with wild-type PSEN1 (Li et al., 2016). Mutant carriers produced less Aβ40, seemingly due to a reduction of Aβ43 cleavage into Aβ40, and more Aβ42, due to decreased Aβ42 cleavage into Aβ38. Consistent with these findings, a subsequent study that examined a range of Aβ peptides produced by human embryonic kidney cells expressing this mutant and lacking endogenous PSEN1 and PSEN2, revealed increased Aβ42/Aβ40 and decreased Aβ37/Aβ42, both indicators of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Of note, in this study, Aβ37/Aβ42 outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples. In addition, levels of toxic Aβ43 were dramatically increased. 

An in vitro study with purified proteins, however, reported nearly complete ablation of both Aβ40 and Aβ42 production (Sun et al., 2017). However, this assay appears to be limited in its cleavage efficiency given that 68 of 138 mutant recombinant PSEN1 enzymes tested produced less than 10 percent of the Aβ40 and Aβ42 produced by the wildtype protein (Liu et al., 2021).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).


Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.


Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.


Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.


Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.


Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 29 Nov 2022


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News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?

Paper Citations

  1. . A novel presenilin1 mutation (Q223R) associated with early onset Alzheimer's disease, dysarthria and spastic paraparesis and decreased Abeta levels in CSF. Eur J Neurol. 2010 Apr;17(4):631-3. PubMed.
  2. . The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.
  3. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  4. . Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  5. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
  6. . Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
  7. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A novel presenilin1 mutation (Q223R) associated with early onset Alzheimer's disease, dysarthria and spastic paraparesis and decreased Abeta levels in CSF. Eur J Neurol. 2010 Apr;17(4):631-3. PubMed.


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