Just What the Doctor Ordered? Polygenic Test Gauges Your Alzheimer’s Risk

As ever-larger genome-wide association studies make clear, a person’s genetic risk for Alzheimer’s disease is driven by the cumulative effects of myriad variations in their genes. The public will now have access to a test that sums up that risk from a few drops of spit. The genoSCORETM-LAB, a polygenic test developed by Cytox Ltd. in Manchester, England, U.K., uses a custom chip to tally genotypes at thousands of genomic positions. According to the company’s CEO, Richard Pither, the test is already being marketed in the U.K. and other European countries, and he hopes it will be available in the U.S. within the next two months. The test will not be sold directly to consumers, but requires a physician’s prescription. Cytox also aims to deploy the test as a screening tool for clinical trials.  

  • GenoScore estimates AD risk by weighing thousands of polymorphisms.
  • It has been approved for use in the U.K. and Europe, with the U.S. close behind.
  • The spit test will be used by practicing physicians, and in clinical trials.

Several iterations of polygenic risk score have been developed over the years. While some gauge genetic risk by weighing the contributions of variants that rose to genome-wide significance in GWAS, others take the broader approach of incorporating thousands of variants scattered across the genome even if they didn’t reach that statistical threshold (Escott-Price et al., 2015; Jul 2016 news; Feb 2019 news). Cytox’s Genoscore does the latter, adding up the risk, no matter how small, imparted by genotypes at each of 114,000 single-nucleotide polymorphisms. Developed with guidance from AD geneticists, including Valentina Escott-Price and Julie Williams at Cardiff University, and John Hardy of University College London, Genoscore uses a proprietary genotyping chip to survey SNPs.

Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Cytox recently reported that its polygenic risk score predicted subsequent cognitive decline in people who were cognitively normal or who had mild cognitive impairment (Daunt et al., 2021). The genetic test rivaled, but did not outperform, the CSF p-tau/Aβ42 ratio in predicting cognitive decline over four years in people with MCI. It trended toward predicting decline in people who were cognitively normal, but there were too few participants in this category to reach statistical significance. The test, which includes APOE genotype, was predictive regardless of whether a person carried an ApoE4 allele. However, unlike the CSF test—which requires a lumbar puncture and stringent sample handling procedures—the genetic risk score can be gleaned from a saliva sample donated by the participant at home, noted Pither. He added that GenoScore is not intended to replace fluid biomarkers, but to be used in conjunction with them, or as the initial part of a screening pipeline. Plasma biomarkers—in particular p-tau-181, 217, and 231—are rapidly becoming the tests of choice over CSF. Pither said his company has not directly compared plasma p-tau markers to Genoscore for their ability to predict cognitive decline.

Genoscore has received the CE mark of approval that is required for marketing tests in Europe, and the company expects to receive a CLIA designation as a laboratory developed test (LDT) in the United States before May, Pither told Alzforum. These approvals recognize that products meet manufacturing, technical, and health standards, i.e., that Genoscore accurately and reliably genotypes samples. Even so, Pither said, further testing will need to validate that the polygenic score predicts AD risk in the general population, and to show that knowing one’s genetic AD risk has health benefits.

On the latter point, Pither believes that if a person learns they are at a high genetic risk for AD, this could motivate them to adopt a healthier lifestyle to offset that risk. This knowledge might also steer them toward clinical trials, or to a disease-modifying treatment once one becomes available. The company hopes eventually to make the case that the test will cut healthcare costs, warranting insurance reimbursement.

As of now, GenoScore is validated for use in people of European descent only, because the genetic studies used to define risk associated with each polymorphism were conducted in overwhelmingly white populations, Pither said. He said Cytox is working to validate its test in people with other genetic backgrounds, but could not say when that would be done.

Initially, the test will be offered to specialists, such as geriatricians and neurologists, who see people with cognitive complaints or who are concerned because they have a family history of dementia. Later, the tests could be rolled out to primary-care physicians, Pither said.

The company is currently negotiating with pharmaceutical companies in hopes of incorporating GenoScore into the screening pipeline of their clinical trials. As AD trials attempt to recruit participants in preclinical stages of the disease, the saliva test could be a non-invasive tool to help select cognitively normal participants who are nonetheless on the precipice of decline.

Unlike fluid biomarkers that reflect an ongoing disease process, change over time, and can be used to track progression or drug response, polygenic risk scores are one-time static measures of the genome. So how can they estimate the coming onset of age-related neurodegenerative disease in a person? Pither told Alzforum that much as a child’s weight is charted in quartiles superimposed on an age-based population growth chart, a person’s polygenic AD risk score is projected onto age-based population trajectories of AD risk. In this way, GenoScore places people of a given age into different levels of risk.

Separately, Cytox hopes to partner with pharmaceutical companies to identify genetic pathways that predict responsiveness to treatment. For example, if only a group of participants with a certain combination of genetic risk factors—say, variants in microglial genes— respond to a drug, then subsequent trials could enroll participants most likely to benefit from that treatment, Pither said.

As GWAS continue to burgeon in size, they are still identifying new variants. A recent mega-GWAS identified 42 new AD risk loci (Feb 2021 news). Will Cytox need to constantly update the GenoScore test to keep up? Pither doesn’t think so. New loci may well rise to genome-wide significance as GWAS grow larger, but these “newbies” are likely already included in the GenoScore chip, along with thousands of other loci with subthreshold significance. Tweaking the test to reflect the increased significance of some loci would be unlikely to alter scores, he said.—Jessica Shugart

Comments

  1. “…. [F]urther testing will need …. to show that knowing one’s genetic AD risk has a health benefit. If a person learns they are at a high genetic risk for AD, this could motivate them to adopt a healthier lifestyle to offset that risk.” In my view, knowing this risk has potentially devastating consequences, and healthier lifestyles are both unlikely and ineffective preventive interventions. Learning that one has a high genetic risk for AD seems just as likely to cause years of anxiety, desperate adherence to fake remedies, or depression, sometimes without any cognitive decline. Genetic tests lack the longitudinal accuracy that is provided by current, brief computerized neuropsychological screens. (Disclosure: I developed the CANS-MCI specifically to track the onset and progression of pre-AD symptoms.) Patients may benefit from knowing when they are starting to decline and, then, how rapidly, as well as the likelihood of AD.

    View all comments by Emory Hill

  2. A polygenic test for measurement of Alzheimer's risk will be valuable when a disease-modifying therapy is available. At the current moment I am skeptical of its value. Healthy lifestyle behaviors are advisable for all people regardless of genetic risk for Alzheimer's disease! These lifestyle behaviors are protective against cardiovascular disease as well as dementia.

    In addition, people with a low polygenic risk score do not have a zero risk of developing Alzheimer's disease. Because of the relatively late age of onset of Alzheimer's, many people with a high genetic risk may not live long enough to develop the disease. In many cases, a high score may cause decades of unnecessary anxiety. In the absence of disease-modifying therapy, I do not see how a genetic risk assessment will lower healthcare costs.

    View all comments by Robert Friedland

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References

News Citations

  1. Are Early Harbingers of Alzheimer’s Scattered Across the Genome?
  2. Multi-Gene Score Predicts Cognitive Decline Independently of Brain Imaging
  3. Massive GWAS Meta-Analysis Digs Up Trove of Alzheimer’s Genes

Paper Citations

  1. Escott-Price V, Sims R, Bannister C, Harold D, Vronskaya M, Majounie E, Badarinarayan N, GERAD/PERADES, IGAP consortia, Morgan K, Passmore P, Holmes C, Powell J, Brayne C, Gill M, Mead S, Goate A, Cruchaga C, Lambert JC, van Duijn C, Maier W, Ramirez A, Holmans P, Jones L, Hardy J, Seshadri S, Schellenberg GD, Amouyel P, Williams J. Common polygenic variation enhances risk prediction for Alzheimer's disease. Brain. 2015 Dec;138(Pt 12):3673-84. Epub 2015 Oct 21 PubMed.
  2. Daunt P, Ballard CG, Creese B, Davidson G, Hardy J, Oshota O, Pither RJ, Gibson AM. Polygenic Risk Scoring is an Effective Approach to Predict Those Individuals Most Likely to Decline Cognitively Due to Alzheimer's Disease. J Prev Alzheimers Dis. 2021;8(1):78-83. PubMed.

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