Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Myoclonus
Genome Build: 105
Position: Chr14:73653568 A>G
dbSNP ID: rs63750590
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: CAT to CGT
Research Models: 1


H163R is a relatively frequent pathogenic mutation with numerous reports in different populations. At least 15 families have been identified worldwide, including from Europe, Japan, Canada, 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 family having an age of onset of about 45 years (Sherrington et al., 1995).

H163R was detected in a French family with early onset autosomal-dominant AD, known as SAL001, with two affected family members with symptom onset at ages 42 and 47 (Campion et al., 1995).

H163R has been detected in several Japanese families, starting with three individuals in a large Japanese kindred identified as having familial AD. The mutation was found to segregate with disease in this family; it was absent in three unaffected family members (Tanahashi et al., 1995). In 1996 it was detected in a Japanese family, known as TK-2, with familial AD. The mean age at onset in this family was 47 ± 4 (range: 43 to 50) (Kamino et al., 1996). It was also described in a Japanese individual known as AD-K, a 44-year-old man diagnosed with AD according to NINCDS-ADRDA criteria who had experienced symptom onset at the age of 41. The mutation is thought to have arisen de novo in this patient, 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).

Also in 1996, H163R was reported in another family, family 603, with a clinical history of early onset AD and postmortem confirmation of the diagnosis in at least one affected member (Boteva et al., 1996).

H163R was reported in a Caucasian family of European descent living in Texas at the time of their enrollment in a genetic study. 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 of the two sisters 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 similarly 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 of the disease. The authors noted that the phenotype in this family was quite similar to what had been previously reported for affected carriers of this mutation (Gómez-Tortosa et al., 2010).

More recently, 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. By age 49 she was bedridden. Her father also suffered from dementia and died at the age of 51. Segregation of the mutation with the disease could not be assessed in this family (Lohmann et al., 2012).


Data are limited, but neuropathology consistent with AD has been observed in at least one case (Boteva et al., 1996).

Biological Effect

In contrast to the strong genetic data supporting pathogenicity, in silico, this mutation was predicted probably benign by PolyPhen2 (Lohmann et al., 2012). 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).

Research Models

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


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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. . Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patients. Neurosci Lett. 1996 Nov 1;218(2):139-41. PubMed.
  6. . Mutation analysis of presenillin 1 gene in Alzheimer's disease. Lancet. 1996 Jan 13;347(8994):130-1. PubMed.
  7. . 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.
  8. . 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.
  9. . Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. PubMed.
  10. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
  11. . 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.
  12. . Presenilin/γ-secretase regulates neurexin processing at synapses. PLoS One. 2011;6(4):e19430. PubMed.

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. American Journal of Human Genetics 59 Supp: A252, 1996.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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.

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