Pathogenicity: Alzheimer's Disease : Pathogenic, Dementia with Lewy Bodies : Pathogenic, Primary Progressive Aphasia : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659355 A>C
dbSNP ID: rs63750311
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GAA to GAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7


This mutation was first discovered in a family of Japanese origin with early onset AD affecting four individuals across three generations (Yasuda et al., 1997). The mutation was found in the proband and his affected mother, but not in the proband’s three healthy sisters, 64 patients with early onset AD, 100 unrelated patients with probable AD, nor 100 healthy volunteers (Yasuda et al., 1997; Yokota et al., 2002). All affected members developed dementia, with symptoms emerging in their early 40s, and a mean duration of disease of nine years. Symptoms in the proband included memory loss, disorientation, mild extrapyramidal signs, and seizures in the advanced stages of disease. In three cases, the first symptom was memory impairment, and in one, personality change. Two members experienced myoclonus, while the other two developed parkinsonism.

The mutation has also been associated with dementia with Lewy bodies (DLB) and primary progressive aphasia (PPA). In the Japanese pedigree, one case developed symptoms consistent with DLB, including hallucinations, delusions, and parkinsonism in the middle stages of disease (Yokota et al., 2002). Moreover, a 44-year-old Czech woman who carried the mutation and had a family history of early onset dementia, presented with the logopenic variant of PPA, including a severe difficulty finding words, but preserved language comprehension (Picková et al., 2017). This patient developed episodic memory impairment, progressing to dementia with behavioral changes including irritability and compulsiveness.

The mutation was also found in the U.K. in a family with five individuals affected by AD spanning three generations (Janssen et al., 2003). Mean age at onset was 42 years.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).


In three cases, neuropathology was consistent with AD (Yasuda et al., 1997; Yokota et al., 2002; Picková et al., 2017). However, unique features were also reported. In one case, there were heavy amyloid deposits in the walls of small meningeal arteries, as well as around small vessels within the brain parenchyma (Yasuda et al., 1997). Immunostaining showed that Aβ42 was predominant over Aβ40 in neuritic plaques of the temporal cortex, whereas Aβ40 was predominant in cerebral amyloid angiopathy lesions in the hippocampus (Yasuda 2000). In the patient who developed DLB symptoms, there was, additionally, robust α-synuclein pathology, including Lewy bodies and accumulation of the non-Aβ component of AD amyloid (NAC) in plaques and astrocytes (Yokota et al., 2002). Lewy body pathology was also found in the patient who developed PPA, meeting the diagnostic criteria for diffuse neocortical Lewy body disease (Picková et al., 2017).

In the original proband, MRI demonstrated mild atrophy of the left medial temporal lobe and moderate atrophy of the bilateral parietal lobes, whereas PET revealed mild temporoparietal and moderate parietal hypoperfusion bilaterally (Yasuda et al., 1997). In the patient diagnosed with PPA, MRI showed early left perisylvian and bitemporal atrophy (Picková et al., 2017).

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed decreased Aβ40 and Aβ42 production, and an elevated Aβ42/Aβ40 ratio (Sun et al., 2017).

Last Updated: 02 Jul 2021


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Paper Citations

  1. . A novel missense mutation in the presenilin-1 gene in a familial Alzheimer's disease pedigree with abundant amyloid angiopathy. Neurosci Lett. 1997 Aug 22;232(1):29-32. PubMed.
  2. . NACP/alpha-synuclein, NAC, and beta-amyloid pathology of familial Alzheimer's disease with the E184D presenilin-1 mutation: a clinicopathological study of two autopsy cases. Acta Neuropathol. 2002 Dec;104(6):637-48. PubMed.
  3. . Genetic Alzheimer Disease and Sporadic Dementia With Lewy Bodies: A Comorbidity Presenting as Primary Progressive Aphasia. Cogn Behav Neurol. 2017 Mar;30(1):23-29. PubMed.
  4. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  5. . Novel presenilin-1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy. J Neurol Neurosurg Psychiatry. 2000 Feb;68(2):220-3. PubMed.
  6. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

Learn More

  1. Japanese Familial Alzheimer's Disease Database

Protein Diagram

Primary Papers

  1. . A novel missense mutation in the presenilin-1 gene in a familial Alzheimer's disease pedigree with abundant amyloid angiopathy. Neurosci Lett. 1997 Aug 22;232(1):29-32. PubMed.

Other mutations at this position


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