Alzheimer's disease (AD) is a progressive neurological disease in which there is gradual loss of the nerve cells in the cerebral cortex of the brain causing serious mental deterioration. It is the most common form of dementia, with an average lifetime risk of about 10-12%. The genetic basis of Alzheimer’s has been extensively investigated, based on rare familial forms of the disease, although the vast majority of AD cases are sporadic and not inherited. Mutations in three genes have been found associated with the familial forms of early onset AD: the amyloid precursor protein (APP), pre-senilin 1 (PSEN1) and pre-senilin 2 (PSEN2) genes; the common polymorphic APOE4 allele has also been associated with a modestly increased risk of Alzheimer’s. However, no genes have been associated with sporadic cases of early onset (or the more common late-onset) forms of AD. A paper in this month’s edition of Human Molecular Genetics reports on a case of somatic and germline mosaicism in a patient with sporadic early-onset AD [Beck JA et al. (2004) Hum Mol Genet. 2004 13, 1219-1224]. Mosaicism refers to a phenomenon whereby an individual has two or more different cell lines within their body with different genetic content. It has previously been suggested that mosaicism for trisomy of chromosome 21 might cause AD, because of the known association between Trisomy 21 (Down’s Syndrome) and early onset AD. Patches of cells in the brain with additional copies of chromosome 21 might cause these changes in individuals who do not have Down’s.
The paper reports a woman who presented with a neurodegenerative disorder, confirmed as early onset AD by autopsy after her death age 58. The woman’s daughter then presented at age 27 with very different neurodegenerative symptoms. Analysis of DNA from the daughter’s blood identified a P436Q mutation in the PSEN1 gene, but the mutation was not present in DNA from the mother’s blood. However, when DNA from the mother’s cerebral tissue was sequenced, the P436Q mutation was identified. A subsequent, more sensitive analysis of blood cell DNA found low levels of the mutation were present after all. Further investigations revealed the existence of three different alleles in the original patient, two wild-type and one mutant, indicating the existence of somatic (non-reproductive cell) mosaicism. Haplotype analysis of three of her children showed that the two unaffected children had inherited wild-type alleles whereas the affected daughter had inherited the mutant allele, meaning that the original patient showed mosaicism in both somatic and germ cells.
The authors claim this to be an important finding on the basis that patients with sporadic AD may have somatic cell mutations that are expressed in their neural tissue, causing the disease, that are undetectable by normal analysis of DNA from the blood. The frequency of cases of sporadic AD that may be caused by somatic mosaicism affecting brain cells is not known; to estimate this it would be necessary to detect mutations in post-mortem cerebral tissue. In the original patient, the degree of mosaicism for the mutant allele was calculated to be 14% in the cerebral cortex. It is presumed by the authors that this relatively low degree of expression of the mutant allele accounts for the later onset and different symptoms of disease compared with those of the affected daughter, who died at age 39. They suggest that even very low levels of mosaicism could cause clinical disease within the expected lifetime of a patient, and hence account for a proportion of not only early-onset sporadic AD cases, but also of the much more common late-onset AD, and possibly other late-onset neurodegenerative disorders too.
Comment: This paper raises the possibility of a new genetic factor involved in the pathology of a common disease that represents a significant public health burden in developed countries such as the UK. Further research into the incidence of somatic cell mosaicism in post-mortem cerebral tissue from patients with AD and similar diseases is strongly indicated, to determine the extent of this phenomenon. If it is found to account for a significant proportion of cases, this may influence research into potential new therapies for these diseases.
For more information on the genetics of Alzheimer's Disease, see the disease profile from our information resource pages.