Evidence map›Paper›PMID 38824433›Full record

ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2024

The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated Aβ43 and atypical clinical manifestations.

Charles Arber, Christopher R S Belder, Filip Tomczuk, Rebecca Gabriele, Yazead Buhidma, Clíona Farrell, Antoinette O'Connor, Helen Rice, Tammaryn Lashley, Nick C Fox and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed.

  1. Review
  2. Article
  3. Article
  4. Article
  5. Article
  6. Article
  7. Article
  8. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Charles ArberDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.ORCID 0000-0002-9743-8134
Christopher R S BelderDementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.
Filip TomczukDepartment of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.
Rebecca GabrieleDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
Yazead BuhidmaDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
Clíona FarrellDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
Antoinette O'ConnorDementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.
Helen RiceDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
Tammaryn LashleyDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
Nick C FoxDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
Natalie S RyanDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
Selina WrayDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.

Funding

Alzheimer's Research UK ARUK-SRF2016B-2Alzheimer's Society and ARUKAlzheimer's Society fellowship AS-JF-18-008Association of Frontotemporal DementiaEMBO scientific exchange 9297Medical Research Council MR/M02492X/1National Institute for Health and Care Research University College London Hospitals Biomedical Research CentreThe Sigrid Rausing TrustUK Dementia Research Institute UKDRI-1014UK Medical Research CouncilUniversity of London Chadburn Academic Clinical Lectureship
6 · The paper itself

Abstract

introductionFamilial Alzheimer's disease (fAD) is heterogeneous in terms of age at onset and clinical presentation. A greater understanding of the pathogenicity of fAD variants and how these contribute to heterogeneity will enhance our understanding of the mechanisms of AD more widely.

methodsTo determine the pathogenicity of the unclassified PSEN1 P436S mutation, we studied an expanded kindred of eight affected individuals, with magnetic resonance imaging (MRI) (two individuals), patient-derived induced pluripotent stem cell (iPSC) models (two donors), and post-mortem histology (one donor).

resultsAn autosomal dominant pattern of inheritance of fAD was seen, with an average age at symptom onset of 46 years and atypical features. iPSC models and post-mortem tissue supported high production of amyloid beta 43 (Aβ43). PSEN1 peptide maturation was unimpaired. DISCUSSION: We confirm that the P436S mutation in PSEN1 causes atypical fAD. The location of the mutation in the critical PSEN1 proline-alanine-leucine-proline (PALP) motif may explain the early age at onset despite appropriate protein maturation. HIGHLIGHTS: PSEN1 P436S mutations cause familial Alzheimer's disease. This mutation is associated with atypical clinical presentation. Induced pluripotent stem cells (iPSCs) and post-mortem studies support increased amyloid beta (Aβ43) production. Early age at onset highlights the importance of the PALP motif in PSEN1 function.

Indexed as

Alzheimer DiseaseAmyloid beta-PeptidesInduced Pluripotent Stem CellsMutationPresenilin-1AdultAge of OnsetAmyloid beta-Protein PrecursorBrainFemaleHumansMagnetic Resonance ImagingMaleMiddle AgedPedigreeAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAPP protein, humanPresenilin-1PSEN1 protein, humanADAβfamilial Alzheimer's diseaseiPSCPALPPSEN1

Identifiers

PMID38824433
PMCPMC11247678

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.