Overview

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
Position: (GRCh38/hg38):Chr14:732192012_732192014 ACC>---
Position: (GRCh37/hg19):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

Findings

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).

Neuropathology

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

Transgenic mice expressing this variant developed several phenotypes consistent with AD-like pathology, including age-dependent memory impairment, reductions in synaptic strength and paired-pulse facilitation, hippocampal and cortical loss of neurons, and astrogliosis (Fuller et al., 2024).

In an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate Aβ40 production was abrogated and Aβ42 production, as well as PSEN1 autoproteolysis, were greatly reduced (Sun et al., 2017). However, note that this assay's ability to recapitulate physiological cleavage efficiency appears to be limited; in some cases yielding results that are inconsistent with cell-based assays (Liu et al., 2021).

Also of note, transcriptomic analysis of brains from zebrafish carrying the homologous mutation, T428del, suggested early disruptions in energy metabolism (Barthelson et al., 2022, Lardelli et al., 2024). This model system also suggested a potential increase in γ-secretase activity based on analyses of Notch signaling targets (Barthelson et al., 2021)

Several in silico algorithms predicted this variant is damaging (Xiao et al., 2021).

Pathogenicity

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.

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References

Paper Citations

1. Ishikawa A, Piao YS, Miyashita A, Kuwano R, Onodera O, Ohtake H, Suzuki M, Nishizawa M, Takahashi H. A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease. Ann Neurol. 2005 Mar;57(3):429-34. PubMed.
2. McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, Salmon DP, Lowe J, Mirra SS, Byrne EJ, Lennox G, Quinn NP, Edwardson JA, Ince PG, Bergeron C, Burns A, Miller BL, Lovestone S, Collerton D, Jansen EN, Ballard C, de Vos RA, Wilcock GK, Jellinger KA, Perry RH. 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. Fuller PE, Collis VL, Sharma P, Burkett AM, Wang S, Brown KA, Weir N, Goulbourne CN, Nixon RA, Longden TA, Gould TD, Monteiro MJ. Pathophysiologic abnormalities in transgenic mice carrying the Alzheimer disease PSEN1 Δ440 mutation. Hum Mol Genet. 2024 Sep 26; PubMed.
4. Sun L, Zhou R, Yang G, Shi Y. 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.
5. Liu L, Lauro BM, Wolfe MS, Selkoe DJ. Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
6. Barthelson K, Newman M, Lardelli M. Brain transcriptomes of zebrafish and mouse Alzheimer's disease knock-in models imply early disrupted energy metabolism. Dis Model Mech. 2022 Jan 1;15(1) Epub 2022 Jan 26 PubMed.
7. Lardelli M, Baer L, Hin N, Allen A, Pederson SM, Barthelson K. The Use of Zebrafish in Transcriptome Analysis of the Early Effects of Mutations Causing Early Onset Familial Alzheimer's Disease and Other Inherited Neurodegenerative Conditions. J Alzheimers Dis. 2024;99(s2):S367-S381. PubMed.
8. Barthelson K, Dong Y, Newman M, Lardelli M. PRESENILIN 1 Mutations Causing Early-Onset Familial Alzheimer's Disease or Familial Acne Inversa Differ in Their Effects on Genes Facilitating Energy Metabolism and Signal Transduction. J Alzheimers Dis. 2021;82(1):327-347. PubMed.
9. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. 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