Pathogenicity: Alzheimer's Disease : Not Pathogenic
Clinical Phenotype: Alzheimer's Disease, None, Parkinson's Disease Dementia
Genome Build: 105
Position: Chr1:227071475 C>T
dbSNP ID: rs140501902
Coding/Non-Coding: Coding
Genomic Region: Exon 4
Mutation Type: Point, Missense
Codon Change: CGG to TGG


This PSEN2 variant has been reported in a handful of individuals diagnosed with Alzheimer's disease, including those with early onset as well as those with late-onset disease. Although some of these variant carriers have a family history of dementia, the variant does not appear to segregate with disease. It has been shown not to segregate in at least one family. Although not thought to be a causative mutation, R71W may be a disease modifier.

The R71W variant was first identified in a Caucasian patient with late-onset Alzheimer's disease. In the same study, it was also found in one of 283 healthy controls (Sleegers et al., 2004). The R71W variant was subsequently reported in two more patients with late-onset AD (Brouwers et al., 2008; Guerreiro et al., 2010).

The R71W variant was also found in a woman from Macedonia who developed apparently sporadic AD at the age of 64. Her symptoms were described as fairly typical of AD, with the addition of a hand tremor. She had no known family history of dementia, but her mother had died at age 20 from tuberculosis, and information relating to the maternal line was unknown (Lohmann et al., 2012).

This variant was also found in a large French study reporting 56 families with a putative familial form of Alzheimer disease (Wallon et al., 2012). The R71W variant was detected in two families, EXT 075 and EXT 179. Both probands met NINCDS-ADRDA criteria for probable AD. In the EXT 075 family, both affected family members screened were mutation carriers, suggesting possible segregation with disease. Ages at onset were 63 and 64 years, with a disease duration of six to nine years. In the EXT 179 family, only the proband was a known carrier of R71W; DNA was not available from family members, including three affected relatives, so segregation with disease could not be determined. Onset in this family was 55 to 56 years of age, with a disease duration of seven to 16 years.

Another recent study detected the R71W variant in six families with a history of familial late-onset AD, but the mutation did not segregate with disease. Specifically, it was found in six affected individuals and three healthy individuals. In addition, it was absent in eight affected family members, arguing against pathogenicity. The authors noted that the R71W mutation was associated with an earlier age at onset, 70.2 years versus 76.7 years in non-carriers, suggesting that R71W may be a disease modifier (Cruchaga et al., 2012).

This variant was also reported in an individual with idiopathic Parkinson’s disease with dementia (Schulte et al., 2015). This individual developed symptoms at age 65, starting with resting tremor. Later symptoms included bradykinesia, rigidity, postural instability, and dementia over a 10–year disease course. It was unclear what role, if any, the R71W variant played in disease pathogenesis.

In a recent study using whole-exome sequencing, this variant was identified in two of 424 French people with early onset AD (Nicolas et al., 2015). Associated clinical data were sparse for these individuals. One had apparently sporadic AD, with onset at age 60 and an APOE genotype of E3/E3. The other individual had a family history of AD, although segregation of the R71W variant could not be assessed. Onset in this individual occurred at age 65 and APOE genotype was E3/E4.


Unknown. Neuroimaging data were available for one mutation carrier with late-onset AD. The patient was described as having leukoencephalopathy with periventricular white-matter lacunar infarctions (Guerreiro et al., 2010).

Biological Effect

This variant does not affect the ratio of Aβ42/Aβ40 when co-expressed in HEK293 cells with APP. It has been shown to reduce the stability of the presenilin-2 protein and to impair Notch signaling (To et al., 2006). In silico, this variant is predicted to be probably damaging by Poly-Phen2 (Cruchaga et al., 2012).


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Paper Citations

  1. . Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. Brain. 2004 Jul;127(Pt 7):1641-9. Epub 2004 May 6 PubMed.
  2. . Molecular genetics of Alzheimer's disease: an update. Ann Med. 2008;40(8):562-83. PubMed.
  3. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
  4. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
  5. . The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.
  6. . Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One. 2012;7(2):e31039. PubMed.
  7. . Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. Eur J Hum Genet. 2015 Jan 21; PubMed.
  8. . Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.
  9. . Functional characterization of novel presenilin-2 variants identified in human breast cancers. Oncogene. 2006 Jun 15;25(25):3557-64. PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. Brain. 2004 Jul;127(Pt 7):1641-9. Epub 2004 May 6 PubMed.