Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Myoclonus
Reference Assembly: GRCh37/hg19
Position: Chr14:73653568 A>G
dbSNP ID: rs63750590
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CAT to CGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5
Research Models: 1


H163R is a relatively frequent pathogenic mutation with numerous reports in different populations. At least 15 families have been identified worldwide, in countries including Europe, Japan, China, Canada, Turkey, Korea, and the United States.

The H163R mutation was first described in 1995 in conjunction with the cloning of the PSEN1 gene. It was detected in two families, one American (Pedigree 603) and one French-Canadian (Tor42). The mutation was shown to segregate with early onset familial Alzheimer’s disease in both families, the latter with onset around 45 years of age (Sherrington et al., 1995). This mutation was also detected in a French family, known as SAL001, with two affected family members (onset at 42 and 47 years) (Campion et al., 1995).

H163R has been detected in several Japanese families. In one large Japanese kindred, the mutation strongly segregated with disease: It was found in three affected individuals but was absent in three unaffected family members (Tanahashi et al., 1995). Two other Japanese families had familial AD with age at onset in the 40s (Kamino et al., 1996; Yagi et al., 2014). This mutation was also described in a young Japanese man with apparently sporadic AD. He experienced symptom onset at age 41 and met diagnostic criteria for AD (NINCDS-ADRDA). The mutation likely arose de novo, as his parents (82 and 76 years old) and two siblings (53 and 47 years old) were not affected by AD and were not mutation carriers. Genetic analysis confirmed paternity (Tanahashi et al., 1996). 

H163R was reported in another family, family 603, affected by early-onset AD. The clinical diagnosis was confirmed by postmortem examination in at least one family member (Boteva et al., 1996). It was also found in a Caucasian family of European descent living in Texas. This family had three siblings who met NINCDS-ADRDA criteria for AD. They developed symptoms in their 40s and were confirmed mutation carriers. They had a family history of dementia; their deceased father was also affected, but segregation with disease could not be assessed (Poduslo et al., 1996).

H163R was detected in two sisters with fairly typical clinical presentations of early-onset AD. They developed symptoms at ages 50 and 51. The older sister developed severe dementia five years after the onset of the disease. The younger was mildly demented two years after the onset of symptoms. Their mother had died of dementia after developing symptoms at age 50. Segregation with disease could not be assessed (Zekanowski et al., 2003).

A large Spanish kindred carrying the H163R mutation with an estimated 35 affected individuals over five generations has been described. Detailed clinical details are available for five affected family members. The age of onset was noted to be rather homogenous in this family, in the mid-40s (mean 46, range: 42 to 50 years). Most of the cases developed typical AD, some with neuropsychiatric symptoms such as anxiety, apathy, depression, and/or irritability. Myoclonus and/or seizures were frequently observed in advanced stages (Gómez-Tortosa et al., 2010).

A Turkish family known as AD-45 was found to carry this mutation. The proband developed memory problems at the age of 41. Her dementia progressed rapidly and within two years she was unable to care for herself and had developed visual hallucinations. Her father had also suffered from dementia and died at the age of 51. Segregation with disease could not be assessed (Lohmann et al., 2012).

Two individuals in a family from Hong Kong have also been found to carry the H163R mutation. The mutation carriers, a woman and a man, developed symptoms of AD at 42 and 41 years of age, respectively. Further details were not reported (Shea et al., 2015). This mutation was also detected in a Chinese man with a family history of dementia (Shi et al., 2015). This individual developed memory loss at age 42 and was diagnosed with probable AD according to NINCDS-ADRDA criteria. His father had dementia by age 50 and died at age 60. Segregation with disease could not be assessed in this family. The H163R mutation segregated with early-onset AD in another Chinese family with at least five affected mutation carriers (Lin et al., 2016).

The mutation was also reported in a Korean woman with a strong family history of dementia (Park et al., 2020). She began having memory problems at age 46, and also developed parkinsonism, delusion, and compulsive behavior.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, June 2021).


Data are limited, but neuropathology consistent with AD has been observed in at least one case (Boteva et al., 1996) and MRI showing diffuse brain atorphy was observed in another case (Park et al., 2020).

Biological Effect

In vitro, COS-1 cells expressing mutant PSEN1 had an increased Aβ42/Aβ total ratio (Murayama et al., 1999). This mutation has also been shown to affect γ-secretase-dependent neurexin processing (Saura et al., 2011). In experiments with isolated proteins, the mutation was reported to reduce Aβ40 and Aβ42 production to undetectable levels (Sun et al., 2017). Although some in silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Yagi et al., 2014Sala Frigerio et al., 2015; Park et al., 2020, Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).

Research Models

This mutation has been introduced into at least one mouse model of disease. See PSEN1-YAC (line G9).

Last Updated: 21 Sep 2021


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Research Models Citations

  1. PSEN1-YAC (line G9)

Paper Citations

  1. . Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.
  2. . Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.
  3. . Missense mutation of S182 gene in Japanese familial Alzheimer's disease. Lancet. 1995 Aug 12;346(8972):440. PubMed.
  4. . Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families. Neurosci Lett. 1996 Apr 26;208(3):195-8. PubMed.
  5. . Detecting gene mutations in Japanese Alzheimer's patients by semiconductor sequencing. Neurobiol Aging. 2014 Jul;35(7):1780.e1-5. Epub 2014 Jan 25 PubMed.
  6. . Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patients. Neurosci Lett. 1996 Nov 1;218(2):139-41. PubMed.
  7. . Mutation analysis of presenillin 1 gene in Alzheimer's disease. Lancet. 1996 Jan 13;347(8994):130-1. PubMed.
  8. . A presenilin 1 mutation in an early onset Alzheimer's family: no association with presenilin 2. Neuroreport. 1996 Aug 12;7(12):2018-20. PubMed.
  9. . Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland. Exp Neurol. 2003 Dec;184(2):991-6. PubMed.
  10. . Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. PubMed.
  11. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
  12. . A systematic review of familial Alzheimer's disease: Differences in presentation of clinical features among three mutated genes and potential ethnic differences. J Formos Med Assoc. 2016 Feb;115(2):67-75. Epub 2015 Aug 31 PubMed.
  13. . Clinical and neuroimaging characterization of Chinese dementia patients with PSEN1 and PSEN2 mutations. Dement Geriatr Cogn Disord. 2015;39(1-2):32-40. Epub 2014 Oct 15 PubMed.
  14. . [Mutation analysis of presenilin 1 gene in a Chinese family affected with early-onset familial Alzheimer's disease]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2016 Jun;33(3):324-7. PubMed.
  15. . Analysis of dementia-related gene variants in APOE ε4 noncarrying Korean patients with early-onset Alzheimer's disease. Neurobiol Aging. 2020 Jan;85:155.e5-155.e8. Epub 2019 May 22 PubMed.
  16. . Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.
  17. . Presenilin/γ-secretase regulates neurexin processing at synapses. PLoS One. 2011;6(4):e19430. PubMed.
  18. . 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.
  19. . 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.

Other Citations

  1. Sala Frigerio et al., 2015

External Citations

  1. gnomAD v2.1.1
  2. CADD v.1.6

Further Reading


  1. . Cerebrospinal fluid levels of phosphorylated tau and Aβ1-38/Aβ1-40/Aβ1-42 in Alzheimer's disease with PS1 mutations. Amyloid. 2013 Jun;20(2):107-12. PubMed.
  2. . Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene. Hum Mutat. 1998;11(3):216-21. PubMed.
  3. . Familial Alzheimer's disease genes in Japanese. J Neurol Sci. 1998 Sep 18;160(1):76-81. PubMed.
  4. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
  5. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  6. . Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain. Arch Neurol. 2002 Nov;59(11):1759-63. PubMed.
  7. . Somatic mutation analysis of the APP and Presenilin 1 and 2 genes in Alzheimer's disease brains. J Neurogenet. 1998 Jan;12(1):55-65. PubMed.
  8. . Identification of presenilin-1 gene point mutations in early-onset Alzheimer's disease families. Am J Hum Genet. 1996;59(Suppl):A252
  9. . Familial Alzheimer's Disease Lymphocytes Respond Differently Than Sporadic Cells to Oxidative Stress: Upregulated p53-p21 Signaling Linked with Presenilin 1 Mutants. Mol Neurobiol. 2016 Sep 19; PubMed.
  10. . On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients. Alzheimers Dement. 2015 Apr 29; PubMed.

Protein Diagram

Primary Papers

  1. . Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.
  2. . Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.
  3. . Missense mutation of S182 gene in Japanese familial Alzheimer's disease. Lancet. 1995 Aug 12;346(8972):440. PubMed.

Other mutations at this position


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