Genetic Studies of Alzheimer Disease

The observation that some cases of Alzheimer Disease (AD) show familial  aggregation and a pattern of transmission compatible with autosomal dominant inheritance, suggests that molecular genetic techniques can be applied to isolate and characterize these disease genes. Isolation of one or more Familial Alzheimer Disease (FAD) genes would provide a means to nosologically classify AD according to etiology, would permit the construction of a presymptomatic test for carriers of that defective gene, and would serve as a basis for subsequent attempts to discover the biochemical cascade which ultimately leads to the death of neurons in AD. The latter could in turn permit the construction of effective diagnostic and therapeutic tools based upon a rational knowledge of the pathophysiology of this disorder. In independent studies, we have previously shown that one FAD susceptibility locus maps to chromosome 21, but that mutations at this locus do not cause all forms of FAD. The latter observation implies that AD is etiologically heterogeneous and that other FAD susceptibility loci may exist on other chromosomes. This grant application seeks funds to permit an intensive search of the remainder of the human genome for these additional FAD susceptibility genes.

To accomplish this goal we will collect new pedigrees segregating FAD and expand existing pedigrees using a national FAD registry. We will examine the inheritance of highly informative genetic markers from the other autosomal chromosomes. Particular attention will be paid to a new class of genetic markers which can be assayed by the Polymerase Chain Reaction (PCR). We will initially begin our search on chromosomes 14, 15, and 22 because structural abnormalities in these chromosomes have been reported in association with AD, suggesting that these structural changes may have disrupted an FAD susceptibility locus.

Successful identification of the chromosomal locations of additional FAD genes will provide three advantages to AD research. First, identification of additional sites will allow pedigrees to be grouped into more homogeneous groups based upon the posterior probability of linkage at each putative locus, or based upon phenotypic similarities. Analysis of homogeneous groups of pedigrees will be necessary in order to achieve very precise localization of these genes between close flanking markers (within 1-2 Million nucleotides) prior to the initiation of attempts to clone these genes using traditional chromosome walking or jumping strategies. Second, knowledge of the chromosomal location of additional FAD loci provides a potential means to directly clone these genes using strategies such as those based upon sequence homologies between members of “gene families.” Third, in an etiologically heterogeneous disorder like AD, the conventional approach of working backward from universal clinical or pathological events (eg. ß-APP deposition) may be intractably complex since the pathways backward to the diverse etiologies are likely to be divergent. However, the latter studies would be facilitated if etiologically homogeneous groups were examined. The ability to achieve such a homogeneous subgrouping could arise from this current proposal, particularly if phenotypic features could be discovered which correlated with the molecular genetic data to be generated here.