Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640351 T>C
dbSNP ID: rs63751106
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: ATG to ACG


This mutation has been reported in at least three European families.

A French family known as CAE 010 was found to carry this mutation and to have a history of early onset Alzheimer’s disease. The proband and one affected first-degree relative were both mutation carriers. They experienced symptom onset at age 48 and 50 (Campion et al., 1995; Campion et al., 1999).

This mutation was also detected in two Spanish sisters who began to experience cognitive symptoms at ages 47 and 48. Depression and anxiety were also present, with later behavioral disturbances. Both were diagnosed with probable AD. The sisters did not have a family history of dementia; however, their parents had died early, at age 35 and 65, from an accident and cancer, respectively. Neither parent had shown signs of cognitive decline at the time of their death (Queralt et al., 2001).

A second Spanish family with familial AD has been reported (Lleó et al., 2002). The mean age of onset in this family was 45.2 (range: 39 to 51 years). The mean age at death was reported as 54.1 (range: 45 to 64 years). The clinical presentation was noted as fairly typical for AD, and family members met NINCDS-ADRDA criteria (McKhann et al., 1984), but additional clinical details were not reported.

Another individual of Spanish descent was also found to carry this mutation (Jin et al., 2012). This individual was described as having early onset sporadic AD with onset at age 47.5. Further clinical details were not reported.

Follow-up studies have looked for changes in brain and fluid biomarkers in presymptomatic mutation carriers. Although the number of subjects is small, one study showed that preclinical carriers had relatively high levels of Aβ1-42 in the cerebral spinal fluid, suggesting that this mutation may be associated with a relative overproduction of Aβ early in life (Portelius et al., 2012). An imaging study showed that asymptomatic PSEN1 mutation carriers, including those carrying the M139T mutation, had increased cortical thickness in the precuneus and parietotemporal areas and increased caudate volumes approximately 10 years before predicted symptom onset. Although the reasons for this paradoxical increase in brain volume are not clear, one hypothesis postulates reactive neuronal hypertrophy early in the disease process (Fortea et al., 2010).



Biological Effect

In vitro, this mutation was associated with an increased Aβ42/Aβ total ratio in COS-1 cells co-transfected with APP695 (Murayama et al., 1999).


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Paper Citations

  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. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
  3. . Detection of the presenilin 1 gene mutation (M139T) in early-onset familial Alzheimer disease in Spain. Neurosci Lett. 2001 Feb 23;299(3):239-41. PubMed.
  4. . 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.
  5. . Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939-44. PubMed.
  6. . Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer's disease Ibero-American cohort. Alzheimers Res Ther. 2012 Aug 20;4(4):34. PubMed.
  7. . The amyloid-β isoform pattern in cerebrospinal fluid in familial PSEN1 M139T- and L286P-associated Alzheimer's disease. Mol Med Report. 2012 Apr;5(4):1111-5. PubMed.
  8. . Increased cortical thickness and caudate volume precede atrophy in PSEN1 mutation carriers. J Alzheimers Dis. 2010;22(3):909-22. PubMed.
  9. . 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.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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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.

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