Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Reference Assembly: GRCh37/hg19
Position: Chr14:73659407 A>T
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATC to TTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7


This mutation was identified in a Welsh kindred affected by familial Alzheimer’s disease (Church et al., 2011). The average age of onset in this family was 53 years (range: 49 to 59 years). The proband developed progressive forgetfulness at the age of 49. By 53, she was disoriented, with a jerky, myoclonic postural tremor as well as a tremor at rest. The reported pedigree shows seven affected family members over two generations. One of the proband’s six siblings developed memory impairment at the age of 53 and died at the age of 59. The proband’s father was one of nine siblings, of whom four developed dementia. Overall, the clinical phenotype in this family consisted of an amnestic syndrome with some members also exhibiting language deficits, visuo-spatial difficulties, and/or myoclonus. This mutation was confirmed present in three affected family members.

A subsequent report described a woman from the same kindred whose episodic memory started gradually declining at age 48 (Ryan et al., 2015). At age 53, she had significant impairment of immediate and delayed recall memory, as well as finger myoclonus. Her condition steadily declined, with a sub-acute period of cognitive and behavioral deterioration at age 57. She was homozygous for the APOE 4 allele. Similar symptoms were experienced by her father, at age 67, and two of her sisters in their early 50s.

Moreover, this variant was also identified in a woman from a large cohort study in South China in which 14 genes associated with neurodegenerative dementias were sequenced in 1795 patients (Jiao et al., 2021). She was diagnosed with AD and had a family history of the disease. Her age at onset was 46 years, and her symptoms included memory decline and language impairment. Her APOE genotype was E3/E4. 

The variant was found at a frequency of 0.000003976, with an allele count of one in the gnomAD variant database (gnomAD v2.1.1, Sep 2021), and at a frequency of 0.000004805 and an allele count of one in the non-neuro subdivision of the gnomAD database (gnomAD v2.1.1 (non-neuro), July 2021).


In the case reported by Ryan et al., neuropathology was consistent with end-stage AD with severe cerebral amyloid angiopathy (Ryan et al., 2015). The amyloid angiopathy included chronic inflammatory infiltrate surrounding some of the cortical and leptomeningeal blood vessels. Lewy pathology was reported predominantly in the amygdala. Two years prior, an MRI scan revealed white matter hyperintensities, particularly in a parieto-occipital distribution, associated with marked focal loss of sulcal spaces, suggesting edema. These alterations were similar to those known as ARIA (amyloid-related imaging abnormalities) observed in some patients participating in amyloid-modifying therapy trials. A follow-up MRI nine months later revealed some degree of spontaneous improvement in the severity of white matter change and edema.

Biological Effect

Multiple assays have yielded varied results but, together, the data indicate this variant impairs the carboxypeptidase-like digestion of Aβ into shorter peptides. In vitro assays using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed decreased production of Aβ42 and Aβ40, with the Aβ42/Aβ40 ratio reported as approximately three-fold greater than that generated by wild-type PSEN1 in one study (Bai et al., 2015), and similar to wild-type in another (Sun et al., 2017). In assays using membrane samples isolated from the brain of a mutation carrier, the Aβ42/Aβ40 ratio was found to be elevated, although changes in de novo production of Aβ40 and Aβ42 compared with samples from healthy brains failed to reach significance (Szaruga et al., 2015). Aβ38 production, however, was reduced relative to controls, as was the Aβ38/Aβ42 ratio. These findings suggested impairment of the fourth catalytic cleavage in the carboxypeptidase-like processing of Aβ. Consistent with these results, another study using human embryonic kidney cells lacking endogenous PSEN1 and PSEN2 and expressing this variant, revealed a slight elevation of the Aβ42/Aβ40 ratio and a decrease in the Aβ37/Aβ42 ratio (Liu et al., 2022; Apr 2022 news). Of note, the Aβ37/Aβ42 ratio outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples.

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 (gnomAD v2.1.1 (non-neuro), July 2021; 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. I202F: Functional observations are mixed, but most suggest damaging effect.


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: 14 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 presenilin 1 mutation, I202F occurring at a previously predicted pathogenic site causing autosomal dominant Alzheimer's disease. Neurobiol Aging. 2011 Mar;32(3):556.e1-2. Epub 2010 Dec 7 PubMed.
  2. . Spontaneous ARIA (amyloid-related imaging abnormalities) and cerebral amyloid angiopathy related inflammation in presenilin 1-associated familial Alzheimer's disease. J Alzheimers Dis. 2015;44(4):1069-74. PubMed.
  3. . The role of genetics in neurodegenerative dementia: a large cohort study in South China. NPJ Genom Med. 2021 Aug 13;6(1):69. PubMed.
  4. . An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-7. Epub 2015 Aug 17 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. . Qualitative changes in human γ-secretase underlie familial Alzheimer's disease. J Exp Med. 2015 Nov 16;212(12):2003-13. Epub 2015 Oct 19 PubMed.
  7. . Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  8. . 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
  2. gnomAD v2.1.1 (non-neuro)

Further Reading


  1. . Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014 Jul 15;83(3):253-60. Epub 2014 Jun 13 PubMed.

Protein Diagram

Primary Papers

  1. . A novel presenilin 1 mutation, I202F occurring at a previously predicted pathogenic site causing autosomal dominant Alzheimer's disease. Neurobiol Aging. 2011 Mar;32(3):556.e1-2. Epub 2010 Dec 7 PubMed.


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