New Alzheimer’s Genetic Markers Unearthed


Summary: Researchers unearthed fresh gene variations related to Alzheimer’s disease risk, potentially paving the way for predictive blood tests. The study, targeting the APOE gene, identified 15 new variations linked to Alzheimer’s likelihood.

These findings delve deeper into the intricate web of factors contributing to this ailment. This new knowledge could significantly aid in diagnosing Alzheimer’s even before symptoms emerge.

Key Facts:

  1. The study identified 15 new variations in the APOE gene regions and other parts of the genome connected to Alzheimer’s disease risk.
  2. The APOE-4 variant of the ApoE molecule is among the highest genetic risks for Alzheimer’s, whereas the APOE-2 variant appears protective.
  3. Low plasma ApoE levels have been linked to increased risks of Alzheimer’s, cognitive impairment, and dementia.

Source: University of Pittsburgh

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. 

This shows an older man and DNA.
Further analysis found seven new variations in non-APOE regions of the genome that explained additional changes in plasma ApoE levels. Credit: Neuroscience News

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, 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. 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.”

Other authors of the study are M. Muaaz Aslam, Ph.D., Kang-Hsien Fan, Ph.D., Elizabeth Lawrence, B.S., Margaret Anne Bedison, B.S., Beth Snitz, Ph.D., Oscar Lopez, M.D., Eleanor Feingold, Ph.D., all of Pitt; and Steven DeKosky, M.D., of the University of Florida.

About this genetics and Alzheimer’s disease research news

Author: Anastasia Gorelova
Source: University of Pittsburgh
Contact: Anastasia Gorelova – University of Pittsburgh
Image: The image is credited to Neuroscience News

Original Research: Open access.
“Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk” by Ilyas Kamboh et al. Molecular Psychiatry


Abstract

Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk

The APOE 2/3/4 polymorphism is the greatest genetic risk factor for Alzheimer’s disease (AD). This polymorphism is also associated with variation in plasma ApoE level; while APOE*4 lowers, APOE*2 increases ApoE level. Lower plasma ApoE level has also been suggested to be a risk factor for incident dementia.

To our knowledge, no large genome-wide association study (GWAS) has been reported on plasma ApoE level.

This study aimed to identify new genetic variants affecting plasma ApoE level as well as to test if baseline ApoE level is associated with cognitive function and incident dementia in a longitudinally followed cohort of the Ginkgo Evaluation of Memory (GEM) study.

Baseline plasma ApoE concentration was measured in 3031 participants (95.4% European Americans (EAs)). GWAS analysis was performed on 2580 self-identified EAs where both genotype and plasma ApoE data were available.

Lower ApoE concentration was associated with worse cognitive function, but not with incident dementia. As expected, the risk for AD increased from E2/2 through to E4/4 genotypes (P for trend = 4.8E-75). In addition to confirming the expected and opposite associations of APOE*2 (P = 4.73E-79) and APOE*4 (P = 8.73E-12) with ApoE level, GWAS analysis revealed nine additional independent signals in the APOE region, and together they explained about 22% of the variance in plasma ApoE level.

We also identified seven new loci on chromosomes 1, 4, 5, 7, 11, 12 and 20 (P range = 5.49E-08 to 5.36E-10) that explained about 9% of the variance in ApoE level.

Plasma ApoE level-associated independent variants, especially in the APOE region, were also associated with AD risk and amyloid deposition in the brain, indicating that genetically determined ApoE level variation may be a risk factor for developing AD.

These results improve our understanding of the genetic determinants of plasma ApoE level and their potential value in affecting AD risk.



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