Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659500 A>G
dbSNP ID: rs63751287
Coding/Non-Coding: Coding
Genomic Region: Exon 7
Mutation Type: Point, Missense
Codon Change: ATG to GTG


This mutation was detected in a woman with very early onset Alzheimer’s disease (at age 28) whose pedigree showed five affected family members over four generations (Houlden et al., 2001). Disease in the proband progressed rapidly, and she died at age 34. Her clinical presentation involved extrapyramidal features and early seizures. The clinical course in the proband was typical of her family, with affected members experiencing onset between the ages of 28 and 34 years, followed by rapid deterioration leading to death between 34 and 37. The clinical and neuropathological characteristics of this pedigree were described prior to the identification of the mutation (Revesz et al., 1997).

Although lack of DNA from family members precluded segregation analysis, the inheritance pattern is consistent with an autosomal-dominant trait. The mutation was not present in 150 control chromosomes.


Neuropathological examination of the proband showed abundant neurofibrillary tangles and amyloid plaques throughout the cerebral cortex. Occasional plaques in the spinal cord were also noted. Lewy bodies were observed in the substantia nigra and cortex. Moderate to severe amyloid angiopathy was also present in leptomeningeal, cerebral, and cerebellar vessels (Revesz et al., 1997; Houlden et al., 2001).

Biological Effect

When transfected into HEK293 cells stably expressing Swedish mtAPP 695 and BACE1, this mutation impaired the carboxypeptidase-like γ-cleavage, but spared the endoproteolytic ε-cleavage activity of PSEN1. This resulted in reduced secreted Aβ40, increased Aβ42, and an increased Aβ42/Aβ40 ratio (Li et al., 2016).


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Paper Citations

  1. . A novel presenilin mutation (M233V) causing very early onset Alzheimer's disease with Lewy bodies. Neurosci Lett. 2001 Nov 2;313(1-2):93-5. PubMed.
  2. . Pathology of familial Alzheimer's disease with Lewy bodies. J Neural Transm Suppl. 1997;51:121-35. PubMed.
  3. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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Primary Papers

  1. . A novel presenilin mutation (M233V) causing very early onset Alzheimer's disease with Lewy bodies. Neurosci Lett. 2001 Nov 2;313(1-2):93-5. PubMed.

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