ApoE just got a little more interesting—if that’s possible. While scientists may debate how this apolipoprotein contributes to Alzheimer’s disease pathology, nobody disputes that one of its isoforms, ApoE4, increases a person’s risk for developing the disease. Now, a twist. In the May 31 JAMA Neurology, researchers led by Yann Le Guen, Stanford University, California, report that two rare variants decrease risk for the disease. Both lie in the C-terminal, lipid-binding domain of the protein—and wouldn’t you know, one co-inherits with, and seems to neutralize, the E4 isoform. ApoE4 carriers who also inherit this R251G variant are at no more risk for AD than are ApoE2/3 carriers. The finding might prompt scientists to look for new ways to temper ApoE4 and protect against AD.
- Large case-control study identified two rare ApoE variants.
- V236E, which was known, co-inherits with ApoE3.
- A novel variant, R251G, co-inherits with ApoE4, neutralizing it.
“While the allele frequencies of these variants are less than 0.1 percent, … it definitely appears that these coding changes are playing an important role in decreasing AD risk,” David Holtzman, Washington University, St. Louis, wrote to Alzforum. Guojun Bu, Mayo Clinic, Jacksonville, Florida, agreed. “… [T]he genetic data are in general convincing, despite the typical difficulties in genetic association studies on rare variants,” he wrote.
Protective Variants. The V236E and R251G variants in APOE reduced a person’s chances of getting AD to about that of an APOE2/3 carrier. Risks shown are relative to ApoE3/3 carriers whose odds ratios 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 relevance to AD unknown. The R136S Christchurch mutation in the N-terminal appears to be protective, but is based on only one person who also carried a pathogenic AD mutation in her presenilin 1 gene and whose disease onset was delayed by decades (see Nov 2019 news on Arboleda-Velasquez et al., 2019). Bu and colleagues at the Mayo Clinic, Jacksonville, discovered the V236E “Jac” mutation, which also seemed protective, based on data from a small cohort of 9,000 people (Oct 2021 news). Le Guen and colleagues, including senior author Michael Greicius at Stanford, wanted to look for variants in a much larger dataset.
The authors first analyzed whole-genome and whole-exome data from the Alzheimer’s Disease Sequencing Project, looking for associations between APOE variants and AD risk. Among 11,868 cases and 11, 934 controls of European ancestry, people who carried the V236E or R251G variants were four- and fivefold less likely to have AD. Next, the authors expanded the analysis in two more stages to almost 3.5 million volunteers across eight other cohorts. They were the UK Biobank, the European Alzheimer’s Disease DNA Biobank; the European Alzheimer’s Disease Initiative, the Genetic and Environmental Risk in Alzheimer’s Disease Consortium, the Norwegian Dementia Genetics Network, Genome Research at Fundació Alzheimer Center Barcelona/Dementia Genetics Spanish Consortium, the Copenhagen City Heart Study, and the Copenhagen General Population Study. All told, 544,384 people passed inclusion criteria, and their risk association was assessed.
This larger analysis confirmed that the two variants are protective. The odds ratio of having AD were 0.44 and O.37, for R251G and V236E, respectively, indicating two- and threefold lower risk. When stratified by ApoE2/3/4 genotype, the results were similar. In short, compared to ApoE3/3 carriers, risk for AD among ApoE3/3 V236E carriers was similar to that for ApoE2/3 carriers. Remarkably, the same held for R251G. That variant reduced risk for AD among ApoE3/4 carriers to that of ApoE2/3 carriers (see image above). This is the first variant ever found to mitigate the effect of ApoE4. One copy of APOE4 triples risk for AD and two copies increases it about 15-fold.
How these variants protect is unclear. Previously, Bu had reported that V236E reduces the tendency of the protein to aggregate. Whether the same goes for R251G remains to be seen, but evidence suggests the amino acid forms a salt bridge with glutamine 98, which would be abolished by swapping arginine with glycine (Chen et al., 2011). There are other salt bridges between the C-terminal and N-terminal ends of the protein that might also be disrupted. “Depending on the actual structure of ApoE in its native state, how the N- and C-terminals interact to influence ApoE structure will be critical to resolve, because it is likely that such interactions are key in determining how ApoE alters AD risk,” wrote Holtzman.
Alternatively, R251G might enhance ApoE binding with lipids, making it more like ApoE2/3. Scientists have found it challenging to study the structure of native proteins in their lipidated state, including ApoE. “New technologies such as cryoEM as well as small molecule FRET may be key in unlocking the high-resolution structure of lipidated APOE to get at some of these key issues,” Holtzman wrote.
Protective missense variations in APOE are very rare, but the magnitude of their observed effects is large and thus will further our understanding of the biological pathways through which APOE profoundly modifies the risk of AD,” wrote Gil Rabinovici and Dena Dubal, University of California, San Francisco, in a JAMA Neurology editorial. “A better understanding of these pathways will likely identify novel therapeutic targets that can delay or possibly prevent disease even in individuals at high genetic risk owing to APOE ε4 or autosomal dominant pathogenic gene variants, or even individuals with late-onset AD,” they wrote.
One caveat is that the study was limited to people of European ancestry. “It would also be interesting to conduct similar analyses in non-European populations given that the local ancestry at the APOE locus, and its surrounding regions, can also influence the AD risk effect of APOE-ε4,” noted Nancy Ip, Honk Kong University of Science and Technology. She has reported two genes, PVRL2 and APOC1, that associate with AD and are inherited as haplotypes with APOE and modulate its risk (Aug 2019 news on Zhou et al., 2019).
Le Guen found that the results held when limiting the analysis to people with at most 55 per cent non-European ancestry. The authors note that the variants have been found in African American’s and Latinos based on gnomAD data, but they had insufficient number in their datasets to analyze the effects of these rare variants in non-Europeans.—Tom Fagan
- Can an ApoE Mutation Halt Alzheimer’s Disease?
- Protective APOE3 Variant Binds More Lipids, Self-Aggregates Less
- Geneticists Seek Out Rare Contributors to Alzheimer’s
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No Available Further Reading
- Le Guen Y, Belloy ME, Grenier-Boley B, de Rojas I, Castillo-Morales A, Jansen I, Nicolas A, Bellenguez C, Dalmasso C, Küçükali F, Eger SJ, Rasmussen KL, Thomassen JQ, Deleuze JF, He Z, Napolioni V, Amouyel P, Jessen F, Kehoe PG, van Duijn C, Tsolaki M, Sánchez-Juan P, Sleegers K, Ingelsson M, Rossi G, Hiltunen M, Sims R, van der Flier WM, Ramirez A, Andreassen OA, Frikke-Schmidt R, Williams J, Ruiz A, Lambert JC, Greicius MD, Members of the EADB, GR@ACE, DEGESCO, DemGene, GERAD, and EADI Groups, Arosio B, Benussi L, Boland A, Borroni B, Caffarra P, Daian D, Daniele A, Debette S, Dufouil C, Düzel E, Galimberti D, Giedraitis V, Grimmer T, Graff C, Grünblatt E, Hanon O, Hausner L, Heilmann-Heimbach S, Holstege H, Hort J, Jürgen D, Kuulasmaa T, van der Lugt A, Masullo C, Mecocci P, Mehrabian S, de Mendonça A, Moebus S, Nacmias B, Nicolas G, Olaso R, Papenberg G, Parnetti L, Pasquier F, Peters O, Pijnenburg YA, Popp J, Rainero I, Ramakers I, Riedel-Heller S, Scarmeas N, Scheltens P, Scherbaum N, Schneider A, Seripa D, Soininen H, Solfrizzi V, Spalletta G, Squassina A, van Swieten J, Tegos TJ, Tremolizzo L, Verhey F, Vyhnalek M, Wiltfang J, Boada M, García-González P, Puerta R, Real LM, Álvarez V, Bullido MJ, Clarimon J, García-Alberca JM, Mir P, Moreno F, Pastor P, Piñol-Ripoll G, Molina-Porcel L, Pérez-Tur J, Rodríguez-Rodríguez E, Royo JL, Sánchez-Valle R, Dichgans M, Rujescu D. Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease. JAMA Neurol. 2022 Jul 1;79(7):652-663. PubMed.
- Rabinovici GD, Dubal DB. Rare APOE Missense Variants-Can We Overcome APOE ε4 and Alzheimer Disease Risk?. JAMA Neurol. 2022 Jul 1;79(7):649-651. PubMed.