Breakthrough genome-wide study uncovers new loci impacting apolipoprotein E levels and Alzheimer's risk

In a recent study published in the Molecular Psychiatry Journal, a team of researchers from the United States conducted a large-scale genome-wide association study to identify new genetic factors that affect the plasma apolipoprotein E levels and to test the association between baseline plasma levels of apolipoprotein E and incident dementia and cognitive function.

Study: Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk. Image Credit: vitstudio/Shutterstock.xomStudy: Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk. Image Credit: vitstudio/Shutterstock.xom

Background

Apolipoprotein E, encoded by the APOE gene, is a glycoprotein consisting of 299 amino acids that transport cholesterol and other lipids in the central nervous system and plasma.

The hepatocytes produce plasma apolipoprotein E, while the astrocytes produce apolipoprotein E in the central nervous system. The phospholipids and cholesterol essential for neurotransmission, neuronal repair, and neurodevelopment are transported to the central nervous system by apolipoprotein E.

The APOE gene is known to have three common alleles — APOE*2, APOE*4, and APOE*4 — which give rise to six genotypes based on homozygous and heterozygous combinations of these alleles. These genotypes are known to determine the variation between individuals in plasma cholesterol levels and the risk of Alzheimer's disease.

The APOE*4 allele is the risk allele, while the APOE*2 allele is believed to be protective compared to the APOE*3 allele. Genome-wide association studies have previously been used on a small scale to understand plasma apolipoprotein E-level variations.

About the study

In the present study, the researchers conducted a large-scale genome-wide association study to identify novel genetic variants that could influence the plasma apolipoprotein E levels and understand the association between baseline apolipoprotein E levels and incident dementia and cognitive function.

Apart from increasing the risk of Alzheimer's, the APOE*4 allele is also believed to result in lower apolipoprotein E levels in the plasma.

In contrast, the APOE*2 allele is believed to increase the plasma apolipoprotein E levels compared to the APOE*3 allele, with low plasma levels of apolipoprotein E believed to increase the risk of Alzheimer's disease.

The researchers used the longitudinal cohort that is part of a study called Ginkgo Evaluation of Memory, which comprised individuals between the ages of 72 and 96 years with normal cognitive abilities or mild cognitive impairments during the baseline assessments.

The subjects enrolled in the study between 2000 and 2002 and were screened for incident dementia every six months until 2008.

Plasma apolipoprotein E levels were determined at baseline, and genetic studies were conducted for those participants for whom deoxyribonucleic acid (DNA) samples were available. Since the representation of other ethnicities was very low in the cohort, only samples from European Americans were used for the genome-wide association study.

Hazard ratios were calculated for apolipoprotein E levels lower by one standard deviation to understand the association between lower plasma levels of apolipoprotein E and increased risk of dementia.

The analyses were adjusted for age, ethnicity, sex, body mass index, and education levels. A linear regression framework was also used in the single nucleotide polymorphism (SNP) analysis, with education levels, age, and sex used as covariates.

Results

The findings indicated that lower plasma levels of apolipoprotein E were associated with a decrease in cognitive function but did not show any correlation with incident dementia.

Furthermore, the genome-wide association study confirmed that the rs7412 SNP in the APOE*2 allele was associated with increased plasma apolipoprotein E levels. In contrast, the rs429358 SNP in the APOE*4 allele was responsible for decreased plasma apolipoprotein E levels.

Additionally, when the researchers examined the plasma apolipoprotein E levels across the six genotypes consisting of combinations of the three APOE alleles, they found that the apolipoprotein E levels were the highest for the genotype homozygous for APOE*2 and then decreased gradually across the genotypes in the order APOE*2/ APOE*3, APOE*2/ APOE*3, APOE*2/ APOE*4, APOE*3 homozygous, APOE*3/ APOE*4, and APOE*4 homozygous.

The analysis also revealed 42 other SNPs associated with increasing plasma apolipoprotein E levels and 15 SNPS linked to decreased plasma apolipoprotein E levels.

The genome-wide association analysis also revealed nine independent signals in the region of the APOE gene that cumulatively explained 22% of the plasma apolipoprotein E level variations.

Seven new loci were also identified on seven different chromosomes, contributing to variations in apolipoprotein E levels.

Furthermore, the independent variants associated with plasma apolipoprotein E levels were also linked to an increased risk of Alzheimer's disease and amyloid deposition, confirming the correlation between plasma apolipoprotein E levels and the risk of Alzheimer's disease.

Conclusions

To summarize, the genome-wide association study revealed nine independent signals in the region of the APOE gene and seven new loci associated with variations in the plasma apolipoprotein E levels.

These independent signals were also associated with an increase in the risk of Alzheimer's disease, indicating that the factors that influence the levels of apolipoprotein E in the plasma also play a role in determining the risk of Alzheimer's disease.

Journal reference:
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

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