PSEN1 T440del


Pathogenicity: Parkinson's Disease Dementia : Not Classified, Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM4, PP3
Clinical Phenotype: Alzheimer's Disease, Dementia with Lewy Bodies
Reference Assembly: GRCh37/hg19
Position: Chr14:73685910_73685912 ACC>---
dbSNP ID: rs63750470
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Deletion
Codon Change: ACC to ---
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12


This mutation was discovered in a Japanese man with a family history of parkinsonism and dementia (Ishikawa et al., 2005). The proband first developed parkinsonism, which was responsive to L-dopa, at age 34. At age 41, cognitive decline and generalized dystonia set in. Dementia, diagnosed as variant Alzheimer's disease, progressed rapidly. At age 52, the patient died of respiratory infection. The father and grandfather of the proband also suffered from parkinsonism and died in their late 40s. Of note, the father developed dementia first, followed by parkinsonism nine years later. The proband was the only family member genotyped. No additional mutations were found in the coding regions and exon-intron junctions of APP, PSEN1, PSEN2, nor in those of α-, β-, and γ-synuclein. Moreover, the T441 deletion was absent from eight patients with familial dementia with Lewy bodies, 50 patients with sporadic AD, and 94 healthy Japanese controls. 

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


Neuropathological examination of the proband's brain revealed neuronal loss in several brain regions, including the substantia nigra and cerebral cortex. In addition, the authors reported widespread Lewy bodies and cotton wool plaques, as well as corticospinal tract degeneration and cerebral amyloid angiopathy. 

Based on guidelines for the clinical and pathological diagnosis of dementia with Lewy bodies (McKeith et al., 1996), the patient was classified as having Parkinson's disease with dementia of the neocortical subtype. He was also described as meeting the pathological criteria for variant AD.

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed abrogation of Aβ40 production and a dramatic reduction of Aβ42 production. In addition, autoproteolysis of PSEN1 was nearly abolished (Sun et al., 2017). Several in silico algorithms predicted this variant is damaging (Xiao et al., 2021).


Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

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


Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. T440del: Aβ42/Aβ40 ratio increased, but production of both peptides decreased.


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. T440del: Variant located at edge of mutational hot spot.


Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.


Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. T440del: Single amino acid deletion.


Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 22 Feb 2022


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Paper Citations

  1. . A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease. Ann Neurol. 2005 Mar;57(3):429-34. PubMed.
  2. . Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. 1996 Nov;47(5):1113-24. PubMed.
  3. . 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.
  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.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease. Ann Neurol. 2005 Mar;57(3):429-34. PubMed.


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