The DOI matches its Crossref record; 19 of the 19 references it cites were found in a registry or an index.
Somatic and germline mosaicism in sporadic early-onset Alzheimer's disease
Abstract
Alzheimer's disease (AD) is the commonest neurodegenerative disease worldwide. Rare familial cases may be caused by mutations in one of three genes-amyloid precursor protein, presenilin-1 and presenilin-2; however, the molecular basis of >99% of AD cases is unknown. Somatic mutation has been considered to be a mechanism that may account for a proportion of sporadic cases of AD, but to date there has been no evidence for this. We now report a sporadic early-onset patient with AD, and show that this individual is a somatic mosaic for a mutation in the presenilin-1 gene, suggesting a novel molecular mechanism for AD. Quantification of the mosaicism demonstrated the degree of mosaicism at 8% in peripheral lymphocytes and 14% in cerebral cortex in the index patient; a clear gene dosage effect on age of presentation and clinical phenotypic presentation is demonstrated. This finding has important implications for the aetiology of sporadic AD, and for other apparently sporadic neurodegenerative diseases such as Parkinson's disease, motor neuron disease and Creutzfeldt-Jakob disease.
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“the finding of a sporadic AD patient who harbored a disease-causative mutation in PSEN1 only in approximately 14% of brain cells [236]”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [236]
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Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS)
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Apolipoprotein E4 allele in a population–based study of early–onset Alzheimer's disease
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Mechanisms and consequences of somatic mosaicism in humans
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Screening for PS1 mutations in a referral-based series of AD cases
Rogaeva, E. A., Fafel, K. C., Song, Y., Medeiros, H., Sato, C., Liang, Y., Richard, E., Rogaev, E. I., Frommelt, P., Sadovnick, A. D., et al. (2001) · Neurology · doi:10.1212/wnl.57.4.621 · Cited by 205
Alzheimer disease γ-secretase: a complex story of GxGD-type presenilin proteases
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Somatic mosaicism in the brain: linking development, ageing and neurodegeneration
Zhou, Z., & Walsh, C. A. (2026) · Nature Reviews Neurology · doi:10.1038/s41582-026-01268-x
Freischmidt, A., & Weishaupt, J. H. (2026) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2026.102549
Metadata
- Authors
- Beck, J. A.
- Affiliations
- MRC Prion Unit (GB)
- Corresponding author
- Beck, J. A.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-04-28
- Volume
- 13
- Issue
- 12
- Pages
- 1219-1224
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2109880206
- Cited by
- 102
- References
- 19
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 5 · 2022: 8 · 2021: 7 · 2020: 8 · 2019: 4 · 2018: 10 · 2017: 6 · 2016: 4 · 2015: 10 · 2014: 5 · 2013: 5 · 2012: 2
- FWCI
- 1.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Medical Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- Alzheimer's disease, somatic mosaicism, germline mosaicism, presenilin 1, presenilin 2, amyloid precursor protein, somatic mutations, gene dosage effect, age of onset, cerebral cortex, lymphocytes
- MeSH terms
- Adult, Alzheimer Disease, Base Sequence, Female, Humans, Male, Membrane Proteins, Middle Aged, Mosaicism, Pedigree, Age of Onset, Germ-Line Mutation, Presenilin-1
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