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Researchers Publish Data on Gene Variant Associated with Late-Onset Alzheimer's Disease

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By Turna Ray

Newly published data on a gene variant associated with late onset of Alzheimer's disease serves as an open invitation to research institutes to independently validate this link and may provide the basis for a new diagnostic test.

In the Dec. 22 issue of The Pharmacogenomics Journal, a team led by Allen Roses, director of Duke University's Deane Drug Discovery Institute, published data from two independent study populations linking longer lengths of a polymorphic poly-T variant, rs10524523, with a higher risk of late-onset Alzheimer's disease. "This paper provides the data and the first opportunity for other research laboratories to test and validate the data," the study authors note.

Roses' team, which initially presented this finding at the International Conference on Alzheimer's Disease in Vienna last year, discovered the link through deep sequencing and phylogenetic analysis of the linkage disequilibrium region encompassing three genes associated with LOAD — APOE, translocase of outer mitochondrial membrane 40 homolog (TOMM40), and APOC1 [see PGx Reporter 07-15-2009]. At ICAD, the researchers presented data showing that long, repeated sequences of the TOMM40 gene linked to APOE3 and APOE4 polymorphisms are predictors of whether a person over 60 years old will develop Alzheimer's disease within a five- to seven-year window.

The study published in The Pharmacogenomics Journal showed that for APOE ε3/4 patients who developed LOAD after 60 years of age, those harboring long poly-T repeats linked to APOE ε3 develop LOAD an average of seven years earlier than individuals with shorter poly-T repeats linked to APOE ε3.

"Independent mutation events at rs10524523 that occurred during Caucasian evolution have given rise to multiple categories of poly-T length variants at this locus. On replication, these results will have clinical utility for predictive risk estimates for LOAD and for enabling clinical disease prevention studies," the researchers wrote in the paper. "In addition, these results show the effective use of a phylogenetic approach for analysis of haplotypes of polymorphisms, including structural polymorphisms, which contribute to complex diseases."

At this time, the data on the '523 allele is specific to Caucasians, but the frequencies of these alleles will be measured in other ethnic groups, Roses said. "The '523 data will be transferable to other ethnicities, but the estimated risk prediction algorithms may change," he wrote on the Alzheimer's Research Forum (www.alzforum.org).

Shortly after ICAD last year, Roses told Pharmacogenomics Reporter that based on this new data, diagnostic development plans were in the works. Since then, Roses has written commentary that sheds more light on the commercialization and ongoing research plans associated with this discovery.

According to a posting by Roses on Alzforum.org, he and his colleagues are planning to conduct a prospective validation study of the '523 genetic marker to confirm its association with delay of Alzheimer's onset and test the marker's ability to predict response to an investigational Alzheimer's drug. The researchers are discussing the design of this study with the US Food and Drug Administration, under the Voluntary Exploratory Data Submissions program, which allows sponsors to discuss genomic, proteomic, and metabolomic data with the agency without any regulatory impact.

While conducting this prospective study, which Roses expects to take more than five years to complete, researchers will develop an assay to measure the polyT variation. The assay "may be used for patient stratification of planned and ongoing clinical trials of Alzheimer's disease interventions or preventatives," Roses wrote in his post on Alzforum.org. Until the assay is validated and patents on the marker are filed by the Deane Drug Discovery Institute, the test will be available for research use only, at "low cost."

Over the next six months to a year, Roses' company Zinfandel Pharmaceuticals will review potential pharmaceutical partners with investigational drugs for delaying Alzheimer's disease onset in their pipelines that might be paired with the test.

In the recently published paper, the authors note that Alzheimer's cases are estimated to quadruple globally by 2050 to more than 107 million. "It has been estimated that delaying Alzheimer's disease onset by one or two years could decrease the disease burden in 2050 by 9.5 million or 23 million cases, respectively," researchers wrote in the paper.

Late-onset Alzheimer's disease, which develops after 60 to 65 years of age, is the most common form of Alzheimer's and accounts for more than 95 percent of cases. Researchers estimate that between 58 percent and 79 percent of people's predisposition to LOAD is attributable to genetic factors.

Anticipating ethical, legal, and social issues associated with the development of a test that would predict Alzheimer's risk, the researchers have established a team of ELSI experts who are providing advice on the appropriate use of the test currently under development.

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