Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653589 C>T
dbSNP ID: rs63750577
Coding/Non-Coding: Coding
Genomic Region: Exon 6
Mutation Type: Point, Missense
Codon Change: TCT to TTT


This mutation has been identified in four independent families, one of which is thought to be a de novo mutation.

The S170F mutation was first reported in a family with three affected individuals over three generations, all of whom experienced very early onset dementia 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.

A third individual with this mutation has been described (Golan et al., 2007). Both parents were unaffected and there was no family history of dementia, so the mutation is thought to have arisen de novo in this case. 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.


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

When expressed in HEK-293T cells, this mutation increased levels of both secreted Aβ42 and Aβ40 to an equal extent, resulting in an overall 2.8-fold increase compared with cells expressing wild-type PSEN1 (Piccini et al., 2007).

However, a study in human neuroblastoma (SH-SY5Y) cells observed 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. In addition, S170F was found to reduce 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).


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Paper Citations

  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.
  2. . Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype. Arch Neurol. 2007 May;64(5):738-45. PubMed.
  3. . Early-onset Alzheimer's disease with a de novo mutation in the presenilin 1 gene. Exp Neurol. 2007 Dec;208(2):264-8. PubMed.
  4. . 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.
  5. . 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.
  6. . 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.

External Citations

  1. AlzGene

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.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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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.