Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS2, PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73653589 C>T
dbSNP ID: rs63750577
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TCT to TTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6


This mutation has been identified in several independent families with variable clinical phenotypes. The most consistent findings are very early onset dementia in the late 20s and cerebellar ataxia as a robust, non-cognitive symptom (Tiedt et al., 2018). It was first reported in a family with three affected individuals over three generations, all of whom experienced dementia onset in the third decade of life (Snider et al., 2005). In all three patients, the disease began with insidious memory loss at 26 or 27 years of age, and progressed rapidly, although the average duration to death was 11 years. The clinical picture was complicated by myoclonus, seizures, and extrapyramidal signs.

The proband in this family developed gradual memory loss at age 26. She then became suspicious, had difficulties finding words, suffered frequent falls, and was observed to walk on her toes. At 28 she developed generalized tonic-clonic seizures. By 30, she required an NG tube, was mute and incontinent. She died at age 43. The proband’s brother developed progressive memory loss at age 27 and was diagnosed with AD one year later. He deteriorated rapidly, becoming bedridden, mute, and unresponsive. He died at age 35, eight years after symptom onset. The father of the two siblings was similarly affected with memory impairment beginning at age 27, followed by generalized tonic-clonic seizures at age 36. He died at age 37. Of the family members who were genotyped, the mutation was detected in the proband and absent in her unaffected sibling (age 51) and in her three paternal uncles, unaffected at 72-plus years of age.

An unrelated mutation carrier was subsequently identified who presented with a different clinical and pathological phenotype, specifically dementia with cerebellar ataxia (Piccini et al., 2007). At age 28 he developed delusions and lower limb jerks accompanied by intentional myoclonus and ataxia. His cerebellar syndrome was noted to correlate with extensive Aβ deposition in the cerebellar cortex as well as a severe loss of Purkinje cells. The family history in this case was incomplete, so it is unknown if the man’s condition was familial.

In another case, the patient's parents were unaffected and there was no family history of dementia, so the mutation is thought to have arisen de novo (Golan et al., 2007). The proband was 29 years old when she began to experience cognitive disturbances, especially difficulties with short-term memory. She then developed limb myoclonus, bradykinesia, wondering, confusion, and behavioral disturbances. Her condition rapidly deteriorated. She developed seizures. She was severely demented at the time of the report, requiring ventilation via tracheostomy tube, just three years after symptom onset. Her parents were unaffected at age 56 and 58 years; neither carried the mutation. Paternity was confirmed by microsatellite genotyping. He sister (37 years) and brother (26 years) were also healthy and declined to be genotyped.

More recently a large Austrian family was reported with five affected individuals over three generations (Ehling et al., 2013). Similar to the previous reported families, disease in this kindred presented as a rapidly progressive dementia with prominent ataxia, leading to death within a few years of onset. Exome sequencing identified the S170F mutation and it was shown to segregate with disease; it was present in two affected individuals and absent in one unaffected relative. In addition, a variant in the Cathepsin D gene (CTSD) was found in three affected family members. This variant (p.A58V, rs17571) was inherited through their unaffected father, and therefore did not segregate with disease, but may have been a disease modifier in S170F carriers. Notably, this Cathepsin D variant has been linked with increased risk of AD (see meta-analysis on AlzGene) and mutations in this gene are a known cause of neuronal ceroid lipofuscinosis (NCL) type 10, which is characterized by behavioral abnormalities and dementia, often in conjunction with motor dysfunction and ataxia.

Moreover, four affected individuals spanning three generations, were identified in a German family (Tiedt et al., 2018). Two siblings, whose mother and grandmother had suffered from early onset dementia, were found to carry the mutation and studied in detail. The carriers presented with memory impairments that surfaced in their late 20s, as well as non-amnestic alterations, including disruption of visuospatial abilities, myoclonus, and cerebellar ataxia.

The mutation was also identified in a Korean man with AD and a family history of the disease (Kim et al., 2020). As in other cases, symptoms surfaced at a very early age, 28 years, and progressed rapidly. They included memory impairment, visuospatial dysfunction, anomia, acalculia, and myoclonus.

Although the mutation was reported as present in the gnomAD variant database, with an allele count of eight and a frequency of 0.0028, and was predicted to have reduced penetrance (Koriath et al., 2018), it was not found in a subsequent search of an updated version of the same database (gnomAD v2.1.1, Aug 2021). Also of note, Kim and colleagues reported the mutation was found at a very low frequency (0.0000024) in the non-neuro gnomAD cohort which excludes individuals participating in neurological studies (Kim et al., 2020). 


All three affected cases in the first family identified with this mutation were examined neuropathologically. The proband’s brain showed severe generalized atrophy except for relative sparing of the cerebellum. Knife-edge sulci were observed, as well as severe thinning of the corpus collosum. Extensive neuronal loss and abundant neuritic plaques and neurofibrillary tangles involving the entire neocortex were observed (Braak neurofibrillary and amyloid stages VI-C). Of note were classic Lewy bodies within the substantia nigra and as well as deposits of Lewy bodies and Lewy neurites throughout the brain, including in the midbrain, amygdala, hippocampus, and prefrontal and entorhinal cortices, among other regions. This pathology was sufficient to fulfill a diagnosis of neocortical dementia with Lewy bodies according to the criteria of McKeith et al. 1996. Autopsy of the proband’s brother revealed widespread cortical and hippocampal neurofibrillary tangles and neuritic plaques, sufficient to confirm the diagnosis of AD. Autopsy of the proband’s father showed severe cerebral atrophy, gliosis, and neocortical neuronal loss. The postmortem diagnosis was AD.

The neuropathology in an unrelated mutation carrier, whose clinical course was marked by severe ataxia, was notable for cerebellar pathology, including severe Aβ deposition in the cerebellar cortex and loss of Purkinje cells. Abundant amyloid plaques were noted throughout the brain, including in all neocortical areas, the hippocampus, basal ganglia, thalamus, and midbrain. Parenchymal and meningeal arteries of the cerebrum and cerebellum were affected by amyloid angiopathy. Prion deposition and α-synuclein reactivity were not observed (Piccini et al., 2007).

Neuropathological evaluation of one individual from the Austrian family revealed pathology consistent with AD (i.e., abundant amyloid plaques, dystrophic neurites, and neurofibrillary tangles). Diffuse amyloid plaques were specifically noted in the cerebellar molecular layer. Neuronal loss and spongiosis of the superficial layers in the frontal and entorhinal cortices were observed, along with reactive astrogliosis and congophilic amyloid angiopathy. In contrast to NCL patients, prominent neuronal accumulation of lipofuscin was absent (Ehling et al., 2013).

Biological Effect

Studies of the biological effect of this mutant have yielded mixed results, but an increase the Aβ42/Aβ40 ratio has been consistently reported. In neurons differentiated from induced pluripotent stem cells (iPSCs), secretion of Aβ42, but not Aβ40, was increased, and the intracellular levels of both peptides were increased (Li et al., 2020). When expressed in HEK-293T cells, it increased levels of both secreted Aβ42 and Aβ40 by approximately three-fold (Piccini et al., 2007). However, a study in human neuroblastoma (SH-SY5Y) cells reported a very large increase in the Aβ42/Aβ40 ratio due to both a large increase in secreted Aβ42 and a smaller decrease in Aβ40, compared to cells expressing wild-type PSEN1 or APP with the Swedish mutation alone (Boyle et al., 2012). Consistent with these results, when transfected into HEK293 cells stably expressing Swedish mtAPP695 and BACE1, the mutation decreased the cleavage of Aβ42 to Aβ38, and of Aβ43 to Aβ40, resulting in an increased Aβ42/Aβ40 ratio (Li et al., 2016). A study using in vitro assay to test the ability of the variant to cleave the APP-C99 substrate, also reported an increased Aβ42/Aβ40 ratio, but decreased production of both Aβ42 and Aβ40 (Sun et al. 2017).

In addition, S170F has been reported to affect cellular functions beyond APP processing. One study found reduced cell viability compared with cells expressing wild-type PSEN1 or other FAD mutations. Mitochondrial respiration was not affected, but changes in calcium homeostasis were measured (Boyle et al., 2012). In a subsequent study using iPSC-derived neurons, phopho-tau levels were reported as increased both in soma and dendrites, defects in autophagy were observed, and the expression of mictochondrial fission and fusion proteins was found to be altered (Li et al., 2020). Moreover, examination of post-mortem tissue from the frontal cortices of two S170F carriers revealed elevated levels of a complex between PSEN1 and a subunit of the NMDA glutatmate receptor, GLUN1, implicating a potential disruption of the neuroprotective interaction of trophic factor receptors with GLUN1 (Al Rahim et al., 2020). 

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).

Research Models

An iPSC cell line carrying this mutation has been generated (Li et al., 2020). The donor patient was a 33-year-old Korean man suffering from AD with a family history of early onset dementia. Neuropsychological, MRI, and FDG-PET data were collected.


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.


De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.


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.


Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. S170F: Cosegregation demonstrated in >1 family.


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: 22 Feb 2022


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Paper Citations

  1. . Phenotypic Variability in Autosomal Dominant Familial Alzheimer Disease due to the S170F Mutation of Presenilin-1. Neurodegener Dis. 2018;18(2-3):57-68. Epub 2018 Feb 22 PubMed.
  2. . Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life. Arch Neurol. 2005 Dec;62(12):1821-30. PubMed.
  3. . Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype. Arch Neurol. 2007 May;64(5):738-45. PubMed.
  4. . Early-onset Alzheimer's disease with a de novo mutation in the presenilin 1 gene. Exp Neurol. 2007 Dec;208(2):264-8. PubMed.
  5. . Cerebellar dysfunction in a family harboring the PSEN1 mutation co-segregating with a Cathepsin D variant p.A58V. J Neurol Sci. 2013 Mar 15;326(1-2):75-82. PubMed.
  6. . PSEN1 variants in Korean patients with clinically suspicious early-onset familial Alzheimer's disease. Sci Rep. 2020 Feb 26;10(1):3480. PubMed.
  7. . Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
  8. . Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. 1996 Nov;47(5):1113-24. PubMed.
  9. . Pathological manifestation of the induced pluripotent stem cell-derived cortical neurons from an early-onset Alzheimer's disease patient carrying a presenilin-1 mutation (S170F). Cell Prolif. 2020 Apr;53(4):e12798. Epub 2020 Mar 25 PubMed.
  10. . Cellular consequences of the expression of Alzheimer's disease-causing presenilin 1 mutations in human neuroblastoma (SH-SY5Y) cells. Brain Res. 2012 Mar 14;1443:75-88. PubMed.
  11. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  12. . 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.
  13. . Presenilin1 familial Alzheimer disease mutants inactivate EFNB1- and BDNF-dependent neuroprotection against excitotoxicity by affecting neuroprotective complexes of N-methyl-d-aspartate receptor. Brain Commun. 2020;2(2):fcaa100. Epub 2020 Jul 20 PubMed.
  14. . 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. AlzGene
  2. gnomAD v2.1.1

Further Reading


  1. . Highly Pathogenic Alzheimer's Disease Presenilin 1 P117R Mutation Causes a specific Increase in p53 and p21 Protein Levels and Cell Cycle Dysregulation in Human Lymphocytes. J Alzheimers Dis. 2012 Jan 1;32(2):397-415. PubMed.

Protein Diagram

Primary Papers

  1. . Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life. Arch Neurol. 2005 Dec;62(12):1821-30. PubMed.

Other mutations at this position


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