Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637680 C>T
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CCT to CTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4


This mutation was found in two sisters clinically diagnosed with early onset Alzheimer’s disease (Liu et al., 2017). The proband began exhibiting symptoms of myoclonus in her 20s and of memory difficulties at age 41. Her cognition declined rapidly, and by age 45 she was severely demented. Additional clinical features included Parkinsonism, spasticity, ataxia, apraxia, and dystonia. MRI showed generalized cortical atrophy, FDG-PET showed hypometabolism in putamina and temporo-parietal regions, and CSF biomarkers (low Aβ42 and elevated total- and phospho-tau) were consistent with the diagnosis of AD.

The proband’s younger sister, who also carried the P88L mutation, exhibited myoclonus followed by cognitive decline.

The mother of the two affected sisters was cognitively normal at age 63, and she did not carry this mutation. The mutation was not found in the 1000 Genomes, Exome Variant Server, ExAC, or AD&FTD databases.


Unknown. However, MRI of the proband revealed generalized cortical atrophy.

Biological Effect

This mutation occurs in the first transmembrane domain of PSEN1. It was predicted to be "tolerated" by SIFT and "probably damaging" by PolyPhen-2 (Liu et al., 2017).

The effect of the PSEN1 P88L mutation on Aβ generation was studied in stably transfected fibroblasts from double-knockout Psen1/Psen2 mice (Ohki et al., 2014). PSEN1 P88L resulted in an increased ratio of Aβ42,43/Aβ40, compared with cells transfected with wild-type PSEN1. In addition, cells expressing the P88L mutant secreted Aβ45 and Aβ46, two species not generated by cells expressing wild-type PSEN1 (these studies were performed prior to the identification of P88L as a causal mutation in early onset AD, and the nucleotide change giving rise to the proline-to-leucine substitution was not specified). Moreover, assays using purified PSEN1 complexes and a tagged APPC99 substrate revealed P88L is more sensitive to elevated temperatures than the wild-type protein (Szaruga et al., 2017). This suggests the mutation consistently destabilizes the interaction required for proteolysis of APPC99 and newly produced Aβn substrates, resulting in the release of longer Aβ peptides.

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021)

Last Updated: 30 Jul 2021


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Paper Citations

  1. . Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer's Disease. J Alzheimers Dis. 2017;58(4):1035-1041. PubMed.
  2. . Binding of longer Aβ to transmembrane domain 1 of presenilin 1 impacts on Aβ42 generation. Mol Neurodegener. 2014 Jan 13;9:7. PubMed.
  3. . Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions. Cell. 2017 Jul 27;170(3):443-456.e14. PubMed.
  4. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer's Disease. J Alzheimers Dis. 2017;58(4):1035-1041. PubMed.

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