ApoE just got more interesting – if that’s even possible. While scientists may debate how this lipoprotein contributes to the pathology of Alzheimer’s disease, no one is arguing that one of its isoforms, ApoE4, increases a person’s risk of developing the disease. Now, evolution. In the May 31 JAMA Neurology, researchers led by Yann Le Guen, Stanford University, California, reported that two rare variants reduce the risk of developing the disease. Both are located at the C terminus, the lipid-binding domain of the protein – and you don’t know, one inherits with the E4 isoform and seems to neutralize it. ApoE4 carriers who also inherit this R251G variant are no more likely to develop Alzheimer’s disease than ApoE2/3 carriers. This finding may prompt scientists to search for new ways to moderate ApoE4 and protect against Alzheimer’s.
- A large case-control study identified two rare ApoE variants.
- V236E, which was known, shares genetics with ApoE3.
- A new variant, R251G, is inherited in combination with ApoE4, neutralizing it.
“While the allele frequencies for these variants are less than 0.1 percent, … these coding changes certainly appear to play an important role in reducing Alzheimer’s risk,” David Holtzman, of Washington University, St. Louis, wrote to Alzforum. Guojun Bu, Mayo Clinic, Jacksonville, Florida approved. “… [T]The genetic data are generally compelling, despite the typical difficulties of genetic association studies on rare variants,” he wrote.
protective variables. The V236E and R251G variants in the APOE reduced a person’s chances of getting AD to approximately an APOE2/3 carrier. The risks shown pertain to ApoE3/3 carriers whose ORs are 1. [Courtesy of Le Guen et al., JAMA Neurol 2022]
Beyond ApoE2, ApoE3, and ApoE4, the three major isoforms, gnomAD lists about 300 others, but most of them are rare and their link to Alzheimer’s disease is unknown. The R136S mutation in Christchurch at the N-terminus appears to protect, but is based on only one individual who also carries a pathogenic mutation in the presnillin 1 gene and delayed disease onset by decades (see November 2019 news on Arboleda-Velasquez et al., 2019). Bu and colleagues at the Mayo Clinic, Jacksonville discovered the V236E “Jac” mutation, which also appeared to be protective, based on data from a small group of 9,000 people (News October 2021). Le Guen and colleagues, including lead author Michael Greicius at Stanford, wanted to search for variants in a much larger data set.
The authors first analyzed whole-genome and whole-exome data from the Alzheimer’s Disease Sequencing Project, looking for associations between APOE variants and Alzheimer’s risk. Among 11,868 cases and 11,934 controls of European ancestry, subjects who carried either the V236E or R251G variants had a four- and five-fold lower risk of developing Alzheimer’s disease. Then, the authors expanded the analysis in two further phases to approximately 3.5 million volunteers across eight other groups. They were the UK Biobank, the European DNA Biobank for Alzheimer’s Disease; European Alzheimer’s Disease Initiative, Genetic and Environmental Risks in the Alzheimer’s Disease Consortium, Norwegian Dementia Genetics Network, Genomic Research in Fundació Alzheimer Center Barcelona/Dementia Genetics Spanish Consortium, Copenhagen Cardiac Study, and Copenhagen General Population Study. Finally, 544,384 subjects passed the inclusion criteria, and their association with risk was assessed.
This larger analysis confirmed that the two variables are protective. The odds ratio for getting AD was 0.44 and O.37, for R251G and V236E, respectively, indicating two and three times lower risk. When stratified by ApoE2/3/4 genetic makeup, the results were similar. In summary, compared to ApoE3/3 carriers, the risk of AD disease among ApoE3/3 V236E carriers was similar to that of ApoE2/3 carriers. Notably, the same was kept for R251G. This variant reduced the risk of Alzheimer’s disease among ApoE3/4 carriers compared to ApoE2/3 carriers (see image above). This is the first variant ever discovered to mitigate the effect of ApoE4. One copy of APOE4 triples the risk of developing Alzheimer’s disease, and two copies of it increase it nearly 15-fold.
How to protect these variables is not clear. Previously, Poe reported that V236E reduces the protein’s tendency to aggregate. It remains to be seen if the same is true for R251G, but the evidence suggests that the amino acid forms a salt bridge with glutamine 98, which would be abolished by swapping arginine for glycine (Chen et al., 2011). There are other salt bridges between the C terminus and the N terminus of the protein that may also be disrupted. “Depending on the actual structure of the ApoE in its native state, how the N and C-terminals interact to influence the structure of the ApoE will be critical to resolving it, because these interactions are likely to be key in determining how ApoE alters AD risk,” Holtzmann wrote.
Alternatively, R251G may enhance ApoE’s binding to lipids, making it more similar to ApoE2/3. The scientists found it difficult to study the structure of native proteins in their lipid state, including ApoE. “New technologies such as cryoEM as well as the small molecule FRET may be key in unlocking the high-resolution structure of lipid APOE to access some of these key issues,” Holtzmann wrote.
Error-protective differences in APOE are very rare, but the magnitude of their observed effects is large, and will therefore increase our understanding of the biological pathways through which APOE profoundly modulates Alzheimer’s disease risk,” writes Gil Rabinovici and Dina Dobal, University of California, San Francisco, in a JAMA editorial. Neurology, they wrote, “A better understanding of these pathways is likely to lead to the identification of novel therapeutic targets that can delay or prevent disease even in individuals at high genetic risk due to APOE-4 or dominant disease-causing genetic variants, or even individuals with Alzheimer’s disease.” belated.”
One caveat is that the study was limited to people of European descent. “It would also be interesting to perform similar analyzes in non-European populations given that local strain at the site of the APOE, and surrounding areas, could also influence the effect of AD risk for APOE-ε4,” noted Nancy Ip, Hong Kong University of Science and Technology. I have reported two genes, PVRL2 and APOC1, that are associated with AD disease and are inherited as haplotypes with APOE and its risk modulation (August 2019 news on Zhou et al., 2019).
Le Guen found that the results held up when the analysis was restricted to people of non-European ancestry of 55 percent at most. The authors note that variants were found in African Americans and Hispanics based on gnomAD data, but that they did not have enough numbers in their datasets to analyze the effects of these rare variants in non-Europeans. – Tom Fagan
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