Taub Institute: Genomics Core
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Drs. Joseph Lee, Richard Mayeux, and colleagues are attempting to identify genes that influence risk for late onset Alzheimer's disease. They are studying more than one hundred extended families containing two or more affected individuals using a method called "linkage analysis," in which genes evenly spaced over the twenty-three human chromosomes ("genetic markers") are examined systematically to determine whether any are inherited with the disease more often than expected by chance. The co-inheritance of a genetic marker with disease would indicate that a risk-influencing gene is likely to be located within the same chromosomal region as the genetic marker. Using this method, they found strong evidence that a gene on chromosome 18 influences risk for late onset Alzheimer's disease. They also confirmed evidence for genes on chromosomes 10 and 12 that had been previously reported by other research groups. When they followed up the initial findings with additional analyses to zoom in on the locations on chromosomes 18 and 10, the evidence strengthened. Additional work is ongoing to identify which specific genes in these chromosomal regions could influence risk for Alzheimer's disease; several genes in the regions are expressed in the brain and appear to be good candidates. In other work, Lee and Mayeux studied several genetic variant(s)—variations in DNA sequence found commonly in human populations—previously found to be associated with late onset Alzheimer's disease. They found that some variants were associated with both Alzheimer's disease and verbal memory, while others were associated with nonverbal memory alone. This approach of studying the relations of a gene to several related traits may enable them to further disentangle the causes of Alzheimer's disease.

Also see: http://www.cumc.columbia.edu/dept/sergievsky/is.html

Genetics of Alzheimer's Disease in the Dominican Republic and Puerto Rico

Over the last two decades variant alleles in four genes have been firmly implicated in the cause of this disease. These genes appear to be involved in the production, processing or clearance of amyloid, a beta pleated sheet polypeptide. These genes: amyloid precuror protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2), are found in families with an autosomal dominant pattern of disease inheritance beginning as early as the third decade of life, but have also been observed in families without a distinct Mendelian pattern of inheritance. Studies of mutant genes from early-onset families indicate that many lead to enhanced generation or aggregation of amyloid Ăź peptide that is subsequently deposited in brain in the form of neuritic plaques implicating this peptide as a critical factor in the cause of this disease.

APOE has been called a "susceptibility" gene because possession of the ε4 allele does not always lead to Alzheimer's disease. One APOE-ε4 allele is associated with a two- to three-fold increased risk, while having two copies is associated with a five-fold increase and each APOE-ε4 allele lowers the age-at-onset in a dose dependent fashion. Approximately 20% of all late-onset or more typical Alzheimer's disease can be attributed to this variant form of APOE.

Continued studies of families with Alzheimer's disease, here and elsewhere, have shown at least four additional loci with possible association to the disease on chromosomes 9q, 10q, 12p, 20q and 18q. However, though several putative loci have been linked to familial Alzheimer's disease, no specific variation in a gene has yet been reported but the linkages has been confirmed.

While Hispanics currently represent 4% to 5% of population over age 65, but they are the most rapidly increasing ethnic group in this age category in the United States. The elderly Hispanic population is expected to double by the year 2010 and increase 11-fold by 2050, especially in the northeast where a majority of the Hispanic population is from the Caribbean Islands. Thus, the Hispanic elderly will face many of the diseases associated with advanced age, such as Alzheimer's disease, but there are few investigations of age-related diseases in this population.

At Columbia University's Taub Institute and Sergievsky Center, we focused our efforts on the Caribbean Hispanic population in the Dominican Republic, Puerto Rico and New York City for several scientific and practical reasons: 1) the effect of APOE-ε4 on disease risk is less than that observed in whites of European descent; 2) the cumulative risk of disease is 3 times higher for Hispanics than Caucasians suggesting additional genetic or environmental factors; 3) Caribbean Hispanics generally had larger surviving families than either whites or African-American elderly; 4) family members of Caribbean Hispanic patients tend to be either in our community or in the Dominican Republic; 5) and several of our medical and research staff are from the Dominican Republic which has facilitated work in that country.

We have already identified, examined and collected blood samples from 2500 individuals from 450 families of Caribbean Hispanic origin with familial Alzheimer disease. We have completed two genome-wide scans consisting of microsatellite markers and have begun fine mapping of four major regions in the genome that we believe harbor variant genes that increase the susceptibility to Alzheimer's disease. The ultimate goal of this project is to realize a more complete molecular picture of Alzheimer's disease by identifying proteins or enzymes that are altered by variant genes. In doing so, we will uncover new targets for the development of therapeutic agents that we hope will some day cure or prevent this disease.

This study has been supported by NIH and was recently designated as a MERIT Award (R37 AG15473).


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