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Human Molecular Genetics Advance Access published online on April 28, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh134
© 2004 by Oxford University Press
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Article

Somatic and germline mosaicism in sporadic early-onset Alzheimer's disease

Jonathan A Beck 1, Mark Poulter 1, Tracy A Campbell 1, James B Uphill 1, Gary Adamson 1, Jennian F Geddes 2, Tamas Revesz 3, Mary B Davis 3, Nicholas W Wood 3, John Collinge 1*, Sarah J Tabrizi 1

1 MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology UCL, Queen Square, London WC1N 3BG
2 Department of Histopathology and Morbid Anatomy, Royal London Hospital, Whitechapel, London
3 Department of Molecular Neuroscience, Institute of Neurology UCL, Queen Square, London WC1N 3BG

* To whom correspondence should be addressed. E-mail: j.collinge{at}prion.ucl.ac.uk.


  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 (1-3); however the molecular basis of more than 99% of AD cases is unknown. Somatic mutation has been considered a mechanism that may account for a proportion of sporadic cases of AD (4,5), 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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