Analysis of a Variant Chromosome in an Alzheimer Family

Present State of Knowledge: Alzheimer disease (AD) is a neurodegenerative disorder possibly affecting 10% of those over 65 years of age and 25% of those over 80. In some families AD appears to be genetically transmitted. The occurrence of early onset AD in a high proportion of Down syndrome (DS) patients (these individuals have 3 copies of chromosome 21 instead of the normal 21), and the finding of an excess of DS in immediate relatives of DS patients, suggested some genetic connection between AD and DS, and an involvement of chromosome 21. In one study of 4 large kindreds with familial AD, genetic linkage with chromosome 21 was established. This was subsequently confirmed in a study of 6 British families, but not in several others, suggesting that there may be more than one cause for AD. A very recent international study of 49 families suggests that the the gene for AD with onset under 65 years of age (but not with onset after 65) is l inked to chromosome 21, probably on the long arm, just underneath the centromere. The exact location of this AD gene is still not known, and the problem is still analogous to “finding the needle in the haystack.” The present proposal may lead to the precise localization and identification of an AD gene.

Background: The search for other mutant genes causing genetic diseases has been facilitated by the finding of rearranged or translocated chromosomes associated with the disease. As no abnormal chromosomes had been found in AD patients, we conducted a search for such. In a cytogenetic screening of 30 AD patients with suspected AD, we identified one affected female with an unusual chromosome 22 that had a greatly elongated short arm. A chromosome similar in appearance has been observed only 3 times in 3000 cases in the general population. The marker chromosome was also found in this person’s affected sister. An investigation of their family revealed 10 cases of late onset dementia of the Alzheimer type among 72 related individuals. Cytogenetic analysis has now revealed the presence of the marker in a total of 13 of 27 individuals who were tested. The probability that there is not some biological association between marker and disease is only 1 in 20, suggestive of genetic linkage.

The application of specialized techniques for staining chromosomes strongly suggests that the variant chromosome 22 in this family is a trans location chromosome, containing not only almost all of a normal chromosome 22, but also a large part of another chromosome (the p arm, the centromere, and a part of the long arm). In view of the staining properties of the variant, and other studies implicating an association between chromosome 21 and AD, chromosome 21 becomes a prime suspect, although other possibilities have not, and must be, excluded. The present study is designed to test the hypothesis that the variant chromosome 22 has originated from a 22/21 translocation and that altered, or extra, chromosome 21 sequences in the p arm of the variant may be causing the expression of AD in this particular family. It is therefore essential to obtain further proof that the variant chromosome 22 contains extra DNA from another chromosome, and if so, to determine which chromosome was involved, and identify the sequences which are present or missing in the variant. It is also very important to find more cases of AD associated with the variant chromosome 22 in this family to prove beyond a doubt, that it causes the disease and is not just a trait “like blue eyes” that happens to be present in this particular family. The present proposal deals with the former aspect.