Pathogenicity: Alzheimer's Disease : Pathogenic, Cerebral Amyloid Angiopathy : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Myoclonus
Reference Assembly: GRCh37 (105)
Position: Chr14:73664775 G>A
dbSNP ID: rs63750900
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CGT to CAT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8


This mutation has been described in at least five families worldwide. The age at onset has been described as particularly variable for carriers of this mutation, ranging from mid-40s to late 60s.

This mutation was first described in a Caucasian American man who developed memory impairment at the age of 46. He died after a nine-year course of progressive dementia and met CERAD criteria for AD. His clinical phenotype included visual and auditory hallucinations and myoclonus He did not have seizures or extrapyramidal signs. His APOE genotype was ε4/ε4. The patient’s father died at the age of 61 after a five-year history of dementia. There was no further family history of dementia and segregation with disease could not be assessed (Gómez-Isla et al., 1997).

Two members of a Japanese family (Mat-1) were found to carry this mutation. They met NINCDS-ADRDA criteria for AD and had an average age at onset of 50 years. Further clinical details were not reported (Kamimura et al., 1998).

A U.K. family (Family 226) was identified with four affected individuals over three generations. The mean age of onset in this family was 53 years of age (range: 50 to 56). At least one member of this family had autopsy-confirmed AD (Janssen et al., 2003).

A second U.K. family has been reported with nine affected individuals over three generations in a pattern consistent with autosomal-dominant transmission. The proband presented with forgetfulness at the age of 66 and was diagnosed with probable AD. He later developed prominent visual agnosia. His mother had been diagnosed with AD at the age of 67 and died two years later. She was one of seven sisters, five of whom were reported to have had AD, as had the maternal grandfather. At the age of 69, the proband’s sister also developed memory impairment consistent with AD. The proband was determined to carry the R269H mutation, but segregation with disease could not be assessed due to lack of DNA from family members (Larner et al., 2007).

The mutation was also identified in a 59-year-old man in a longitudinal study of familial AD at the Dementia Research Centre, University College London (Ryan et al., 2012). Cognitive decline started at 58 years of age. The man presented with a pronounced dysexecutive syndrome, mild episodic memory impairment, and relative preservation of parietal lobe function. Finger myoclonus was also reported. The family history of disease was unknown.

The mutation was also found in a screen involving whole-exome sequencing of 15 unrelated Chinese patients with familial AD (Jiang et al., 2019). The proband presented with cognitive deficits typical of AD, without any atypical neurological features.


Postmortem analysis in the first mutation carrier showed a high burden of Aβ and neurofibrillary tangles in cortical areas compared with other cases of similar age and APOE genotype (Gómez-Isla et al., 1997). In another case, MRI revealed prominent cerebellar, parieto-occipital and temporal lobar microbleeds sufficient to fulfill criteria for probable cerebral amyloid angiopathy (Ryan et al., 2012). The authors hypothesized that the patient’s atypical phenotype, with early dysexecutive syndrome, could be related to this pathology. In addition, mild generalized volume loss, without predominance of medial temporal lobe atrophy, and moderate white matter disease were observed. MRI in another patient showed global brain atrophy and white-matter changes thought to be associated with the patient’s visual agnosia (Larner et al., 2007).

Biological Effect

The biological effect of this mutation is unknown, but it was classified as deleterious and most likely fully penetrant, with an allele count of one and a frequency of 0.000004 in the gnomAD variant database (Koriath et al., 2018).

Last Updated: 30 Jul 2019


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Paper Citations

  1. . A novel presenilin-1 mutation: increased beta-amyloid and neurofibrillary changes. Ann Neurol. 1997 Jun;41(6):809-13. PubMed.
  2. . Familial Alzheimer's disease genes in Japanese. J Neurol Sci. 1998 Sep 18;160(1):76-81. PubMed.
  3. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  4. . The R269H mutation in presenilin-1 presenting as late-onset autosomal dominant Alzheimer's disease. J Neurol Sci. 2007 Jan 31;252(2):173-6. Epub 2006 Dec 26 PubMed.
  5. . Cerebral microbleeds in familial Alzheimer's disease. Brain. 2011 Jun 17; PubMed.
  6. . Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing. Neurobiol Aging. 2019 Apr;76:215.e15-215.e21. Epub 2018 Dec 6 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.

Further Reading


  1. . The R269H mutation in presenilin-1 presenting as late-onset autosomal dominant Alzheimer's disease. J Neurol Sci. 2007 Jan 31;252(2):173-6. Epub 2006 Dec 26 PubMed.
  2. . The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors. Brain. 1999 Sep;122 ( Pt 9):1709-19. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . A novel presenilin-1 mutation: increased beta-amyloid and neurofibrillary changes. Ann Neurol. 1997 Jun;41(6):809-13. PubMed.

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