MONTREAL - Algene Biotechnologies Corp., one of Canada's premier genomics research companies, has revealed a new genetic locus which is likely to harbor a gene associated with early-onset Alzheimer's disease.

Denis Gauvreau, president and CEO of Algene, said this locus, for which the statistical significance is compelling, has never been linked to this disease before.

He attributed the discovery to application of new versions of genetic analysis tools that Algene has developed and refined for gene mapping of individuals suffering from Alzheimer's disease.

The technology enables Algene to identify causal, susceptibility and protective genes in complex human disorders such as Alzheimer's, using powerful haplotype sharing and positional-cloning methods in founder populations.

Founder populations are ideal for sorting out the genetics of complex disorders because of their relative genetic homogeneity. The goal is to use founder population genetics to identify and characterize mutations that give rise to specific disease phenotypes.

“Our four-phase approach to gene discovery uses a combination of genetic and physical methods to zoom into the relevant genes by progressively eliminating large non-relevant regions of the genome, Gauvreau said.

Quebec's French Canadian population is one of the better-known founder population models that Algene uses in its research. This is because of the relative genetic homogeneity stemming from the group's uniquely French Catholic ancestry and its cultural isolation up until the 1950s.

This large population base of 6 million individuals arose through rapid expansion (large families) from relatively few founding families and is composed of several very large extended families. The geneological records of the population are intact and were recorded by parish officials.

Linkage disequilibrium (LD) studies such as those traditionally performed within families can be effectively scaled up in founder populations. In relatively young founder populations, haplotype segments shared between individuals are still relatively large even after 12 generations. The large population base also ensures the number of meiotic steps between two “unrelated“ individuals is large enough for fine-mapping studies in a relatively homogenous genetic background.

In young founder populations, relatively large chromosomal segments are inherited through identity-by-descent (IBD). Algene's haplotype-sharing algorithms have been specifically developed to search for IBD sequences. “Hot“ loci are identified in a genome-wide screen. The assumption is that relatively large chromosomal segments still will be associated with disease in a young founder population.

Highly significant loci obtained in the genome-wide search are refined with genetic algorithms by saturating the region with known microsatellite markers.

While not revealing where the locus is at this time, the company said the gene associated with early-onset Alzheimer's disease is on a different chromosome from presenilin-1 and presenilin-2, the two genes identified as related to the early-onset form of this disorder.

Algene Expands Alzheimer's-Related Genes

Many cases of autosomal dominant inherited forms of early-onset Alzheimer's disease are thought to be caused by mutations in the genes encoding presenilin-1 (chromosome 14) and presenilin-2 (chromosome 1).

Presenilin-1 and presenilin-2 explain only 35 to 45 percent of cases suffering from this form of Alzheimer's disease; the locus identified by Algene may contain other elements that elucidate the causes of this disorder and its development. In addition, the study of early-onset Alzheimer's disease could shed additional light on the late-onset form of this same disorder, Gauvreau said.

In the genetic study of Alzheimer's disease, Algene's research is focused on both the early-onset and late-onset forms.

In October 1996, Algene disclosed the identification of five candidate loci obtained from an association-type analysis on a first selected sample of neuropathologically confirmed late-onset Alzheimer's cases. Physical mapping of these loci was undertaken and in June 1997, Algene reported identification - in two of these loci - of two candidate genes whose products are in a common biochemical pathway. Sequencing studies to identify disease-related polymorphisms currently are under way. *