NEW YORK (GenomeWeb) – Researchers are beginning to tie genetic variants associated with Alzheimer's disease and Parkinson's disease risk to symptoms of the disease or its progression.
Genome-wide association studies have linked dozens of SNPs to neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. Two studies appearing in JAMA Neurology today have begun to tease out how these genetic risk variants contribute to disease.
In one, researchers from Indiana University and the University of California, Los Angeles, found that a number of Alzheimer's disease-associated risk variants were associated with the accumulation of amyloid protein in the brain, while a separate team from UCLA and the University of Lübeck has found that Parkinson's disease risk variants are cumulatively linked to motor and cognitive decline.
"[I]mproved understanding of the polygenetic risk factors for [Alzheimer's disease] could enable personalized risk assessment, whereas an in-depth characterization of disease-associated mechanisms could lead to new therapeutic avenues," Indiana's Andrew Saykin and his colleagues wrote in their study.
For that first study, the researchers drew upon 977 participants from the Alzheimer's Disease Neuroimaging Initiative studies who had undergone both genotyping and PET scans. They examined whether 36 variants — including 20 risk genes uncovered through a large GWAS and 16 others variants associated with brain amyloidiosis — were linked to amyloid deposition levels as gauged by the brain scans.
Overall, Saykin and his colleagues found that a number of the risk variants were indeed linked to levels of amyloid in the brain. They reported that, after the well-known Alzheimer's APOE ε4 risk allele, ABCA7 exhibited the strongest association with amyloid levels.
ABCA7 encodes an ABC family transporter that helps move molecules, often lipids, across cell membranes and is expressed in nervous tissue, especially microglia. Different mutations within ABCA7 have previously been shown to lead to either higher amyloid beta levels or protect against Alzheimer's disease.
Other risk variants associated with amyloid levels included CLU, DSG2, and EPHAI.
Another variant, in FERMT2, had a stage-dependent association with amyloid levels, the researchers noted. FERMT2 encodes a scaffolding extracellular matrix that is involved in cell adhesions that is expressed in the brain. Its association was most pronounced among participants with mild cognitive impairment.
"This study found an association of several AD risk variants with brain amyloidosis," Saykin and his colleagues wrote. "The data also suggest that AD genes might differentially regulate AD pathologic findings across the disease stages."
In a separate study, UCLA and Lübeck researchers created a polygenic risk score based on 23 loci that were linked to Parkinson's disease risk through GWAS. In about 200 people from the population-based Parkinson Environment and Gene study, they then tested whether that score was linked to cognitive decline, motor decline, or survival.
GWAS have linked 26 SNPs with Parkinson's disease, which the researchers genotyped among their cohort. Three SNPs had to be left out due to assay failure or low genotyping efficiency. They then developed the score based on the number of risk alleles an individual has, weighted for their estimated effect size.
This risk score, UCLA's Beate Ritz and her colleagues reported, is associated with both motor symptom progression and cognitive decline, as gauged by the Unified Parkinson's Disease Rating Scale part III and the Mini-Mental State Examination, respectively. It was not, though, linked to survival.
When the researchers dropped GBA, a key Parkinson's risk gene, from the score, the risk score remained associated with symptom progression.
"Our findings support a polygenic architecture contributing to PD progression, as has been suggested for PD susceptibility, and suggest that progression in PD may, at least in part, be driven by an accumulation of many common genetic variants, each individually having a relatively small effect size," the researchers wrote.