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Researchers at the University of Pittsburgh analyzed thousands of human genomes to find new gene variations responsible for controlling the levels of blood plasma molecules linked to Alzheimer’s disease risk. The findings, published recently in Molecular Psychiatry, could contribute to the future development of simple blood tests for the disease.

Led by Ilyas Kamboh, Ph.D., professor of human genetics and epidemiology at Pitt Public Health, the group found that, in addition to known gene variants associated with disease risk, there are at least 15 more variations in the APOE, or Apolipoprotein E, gene and other genome areas that may influence the likelihood of Alzheimer’s, hydrochlorothiazide buy online though more research is needed to draw definitive conclusions.

Alzheimer’s disease is one of many ailments that have thousands of factors influencing it. In addition to the typical signs of Alzheimer’s disease, such as amyloid plaques and tau tangles, dozens of other factors contribute to whether a person will develop the disease at some point in their life.

One of the most fascinating aspects of human DNA is how it is at once very stable and very variable. Some genes encoded in the DNA have two or more variant forms, called polymorphisms, that often differ by only a few letters of the DNA alphabet. While some of these gene variants are benign and don’t influence gene function, others may be predictive of a disease risk.

Polymorphisms in the APOE gene are one such example. Among the genetic traits that confer the highest risk of Alzheimer’s disease is APOE-4, a variant of a gene encoding the ApoE molecule. APOE-2 variant, on the other hand, seems to be protective.

In the brain tissue, ApoE supports neurons by supplying them with fat-soluble factors, including cholesterol and fat-soluble vitamins, required for neurodevelopment and repair. And ApoE is also abundant in the blood, where it transports cholesterol and other factors to different parts of the body. Low plasma ApoE seems to correlate with a higher risk of Alzheimer’s disease, cognitive impairment and dementia.

In a study that looked at genomes of more than 2,500 elderly individuals, Kamboh and his team found that, in addition to already described APOE variants, eight more previously unknown variations in the APOE gene regions are associated with differences in the plasma ApoE levels, risk of Alzheimer’s disease and deposition of toxic amyloid in the brain. Further analysis found seven new variations in non-APOE regions of the genome that explained additional changes in plasma ApoE levels.

While additional animal studies are needed to draw definitive conclusions about the link between genetic determinants of plasma ApoE and possible mechanistic connection to Alzheimer’s disease, the researchers are optimistic that their insights can help inform the development of future blood biomarkers of Alzheimer’s disease.

“The field has made significant advances in developing diagnostic methods that detect Alzheimer’s risk in a blood sample of individuals who have not developed disease symptoms yet,” said Kamboh. “Someday, plasma ApoE can be a great addition to the panel of biomarkers that will be used to inform clinicians about their patients’ disease prognosis.”

More information:
M. Muaaz Aslam et al, Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk, Molecular Psychiatry (2023). DOI: 10.1038/s41380-023-02170-4

Journal information:
Molecular Psychiatry

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