Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Reference Assembly: GRCh37 (105)
Position: Chr14:73678584 C>T
dbSNP ID: rs376433615
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CCT to TCT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 10


This rare variant was found in a 60-year-old woman from Italy who suffered from dementia with pseudo-psychotic symptoms similar to those associated with frontotemporal dementia (Monacelli et al., 2019). The authors described the condition as a frontal variant form of AD. None of the patient’s known family members had developed similar symptoms; only her mother had dementia, but it was late-onset. The patient presented with abulia, apathy, loss of initiative, poor self-care, social withdrawal, and hyporexia. In addition, she had delusions, blunted emotions, and obsessive thinking. Cognitive impairment initially included short-term memory loss, temporal disorientation, and impaired visuospatial organization, and later involved language and executive functions. She also developed limb rigidity and postural instability.

The authors reported a minor allele frequency of 0.000024, as found in the ExAC variant database.

The variant was also identified in a Belgian AD patient who also carried a mutation in the APP gene: G625_S628del (Perrone et al., 2020).

Neuropathology data are unavailable, but a brain MRI scan revealed microbleeds in the cortex, basal ganglia, and subcortical white matter suggestive of amyloid angiopathy. FDG-PET showed bilateral frontotemporal hypometabolism. The authors suspected Lewy body pathology.

Biological Effect
The biological effect of this mutation is unknown, but the authors hypothesize it perturbs the catalytic activity of PSEN1 by disrupting hybrid β-sheet formation between PSEN1 and its APP substrate. The hypothesis is based on a cryo-electron microscopy study which revealed the atomic structure of human γ-secretase in complex with a transmembrane APP fragment (Zhou et al., 2019).

Last Updated: 29 Oct 2020


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Paper Citations

  1. . Frontal Variant of Alzheimer's Disease: A Report of a Novel PSEN1 Mutation. J Alzheimers Dis. 2019;70(1):11-15. PubMed.
  2. . Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. PubMed.
  3. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Frontal Variant of Alzheimer's Disease: A Report of a Novel PSEN1 Mutation. J Alzheimers Dis. 2019;70(1):11-15. PubMed.

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