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GWAS Unearths Variants with Ties to Alzheimer's Biomarker

NEW YORK (GenomeWeb News) – Common genetic variants at three newly detected loci appear to be linked to elevated Alzheimer's disease risk, according to a study out today in the journal Neuron.

A large, Washington University-led team that included representatives from the GERAD Consortium, the Alzheimer's Disease Neuroimaging Initiative, and the Alzheimer Disease Genetic Consortium genotyped nearly 1,300 individuals whose cerebrospinal fluid had been tested for tau and phosphorylated tau protein, well-studied biomarkers for Alzheimer's disease.

The search led not only to an associated region near the APOE gene on chromosome 19, but also to previously unidentified sites on chromosomes 3, 6, and 9. A series of follow-up experiments indicated that the new loci were also associated with Alzheimer's disease risk and with the presence of other Alzheimer's-related symptoms.

"We have identified several genes that influence the levels of soluble tau in the cerebrospinal fluid, and we show that one of these genes also influences risk for Alzheimer's disease, rate of cognitive decline in Alzheimer's disease, and density of tangle pathology in the brain," Washington University genetics and neurology researcher Alison Goate, the study's senior author, said in a statement.

By delving further into functional impact of variants at these loci — which may themselves serve to aid Alzheimer's genetic risk prediction in the future — researchers hope to learn more about some of the biological processes that go awry during Alzheimer's disease development.

"In the longer term, we anticipate that knowledge about the role of these genes in Alzheimer's disease may lead to the identification of new targets from therapies or new animal or cellular models of the disease," Goate noted.

Past studies have shown that higher-than-usual CSF levels of tau protein that has been phosphorylated at a specific threonine residue correspond to a range of Alzheimer's disease-related features — from risk of the disease itself to neuron loss, cognitive dips, and the presence of neurofibrillary tangles in the brain, Goate and her co-authors said.

As such, they argued that "CSF tau levels may be a useful marker to identify genetic variants implicated not only with risk for Alzheimer's disease but also age at onset or rate of progression."

To explore that possibility — and expand on smaller association studies done previously — the researchers conducted a genome-wide association study involving 1,269 individuals whose CSF had been tested for tau and phosphorylated tau proteins.

The participants included nearly 600 individuals who had been diagnosed with Alzheimer's disease and an even larger group of elderly individuals who did not show signs of dementia.

Using information at more than 5.8 million directly tested or imputed SNPs, study authors narrowed in on a set of SNPs showing significant ties to tau and phosphorylated tau levels in individuals' CSF.

Several of these SNPs fell in a chromosome 19 region in and around the known Alzheimer's disease-related gene APOE — a relationship that the researchers explored further in an effort to better understand APOE-associated Alzheimer's pathogenesis.

But variants coinciding with tau and phosphorylated tau levels in the CSF turned up on other chromosomes, too.

In particular, the team highlighted three new loci that were significantly associated with the protein markers: a chromosome 3 locus falling in the region between the GEMC1 and OSTN genes, a site in the TREM gene cluster on chromosome 6, which contains rare variants linked to Alzheimer's disease in the past, and a chromosome 9 region within a gene called GLIS3.

Through their subsequent analyses, which included data on additional Alzheimer's disease cases and controls, the investigators found evidence suggesting that at least some of the tau/ptau level-linked SNPs also correspond with overall Alzheimer's risk, cognitive decline, and the extent to which neurofibrillary tangles appear in individuals' brain samples at autopsy.

"[A]ll of these associations are in the direction predicted by the CSF tau and ptau associations," the researchers wrote. "The alleles associated with lower tau and ptau levels (which would be considered protective) are associated with lower risk for [Alzheimer's disease], lower tangle counts, and slower memory decline."

Preliminary findings from the study suggested that the SNPs may impact CSF levels of tau and phosphorylated tau via post-transcriptional interactions, they noted, though future studies will be needed to further characterize the variants and identify additional SNPs involved in Alzheimer's disease features.