Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh37/hg19):Chr14:73653588_73653590 TCT>---
Position: (GRCh38/hg38):Chr14:73186880_73186882 TCT>---
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Deletion
Codon Change: TCT to ---
Genomic Region: Exon 6

Findings

Detailed information on carriers of this variant is unavailable. However, it was classified as “Likely Pathogenic” for Alzheimer’s disease (AD) and eligible for inclusion in clinical trials organized by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) to test disease-modifying treatments for AD. Data used to determine DIAN-TU eligibility include family history suggesting an autosomal dominant pattern of inheritance, documentation of amnestic-predominant, progressive cognitive impairment leading to AD dementia (preferably with AD biomarkers and/or neuropathological confirmation of AD in at least one family member), low frequency of the variant in a large population database such as the gnomAD, evidence of co-segregation with disease within a family, and assessment of Aβ42 and Aβ40 levels in a cell-based assay. Additional supportive criteria include conservation of the affected amino acid between PSEN1 and PSEN2, presence of other AD pathogenic variants at the same amino acid site, and in silico prediction of damaging effects.

This variant was absent from the gnomAD variant database (gnomAD v4.1.0, March 2025).

Neuropathology
Neuropathological data are unavailable.

Biological Effect
Experiments in transfected cells revealed the mutant increased the Aβ42/40 ratio and decreased the Aβ37/40 ratio, both being predictive of pathogenicity, with the latter outperforming the former in its ability to distinguish between AD and control samples (Liu et al., 2022, Apr 2022 news). An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate also showed an increased Aβ42/40 ratio (Sun et al., 2017). Of note, while the cell-based experiments found increased production of Aβ42 and Aβ40 (Liu et al., 2022), the in vitro study showed a reduction of both (Sun et al., 2017). This may be due to deficient cleavage efficiency in this assay—68 of the 138 mutant PSEN1 enzymes tested produced less than 10 percent of the Aβ40 and Aβ42 produced by the wildtype protein (Liu et al., 2021).

Cryo-electron microscopy studies indicate that, in wild-type PSEN1, S169 helps anchor the interface between PSEN1and APP with its hydroxyl group forming H-bonds with the substrate (Zhou et al., 2019; Jan 2019 news; Odorčić et al., 2024; Guo et al., 2024; Jun 2024 news). Moreover, molecular dynamics simulations have implicated S169 in the formation of an internal docking site that stabilizes substrate binding (Chen and Zacharias, 2022). Of note, although S169del was reported to leave Notch 1 cleavage and Notch signaling intact both in vitro and in vivo (Zhang et al., 2018), a cryo-EM study suggests S169 interacts with Notch as it does with APP (Yang et al., 2019).

In silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Not Classified*

*Carriers of this variant are eligible for inclusion in clinical trials organized by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) to test disease-modifying treatments for Alzheimer’s disease (Liu et al., 2025). Alzforum has not yet classified this variant because carrier data are not yet published.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

No Available References

Further Reading

No Available Further Reading