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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.
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In this manuscript, Le Guen and colleagues report that two missense variants in APOE were associated with a twofold to threefold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95 percent CI, 0.33-0.59; P = 4.7 × 10−8) and APOE ε3 (V236E) (odds ratio, 0.37; 95 percent CI, 0.25-0.56; P = 1.9 × 10−6). While the allele frequencies of these variants are less than 0.1 percent, given the number of cohorts and number of individuals examined, it definitely appears that these coding changes are playing an important role in decreasing AD risk. The R251G mutation appears to be the first variant that protects against the increased risk caused by the APOE4 allele. The V236E mutation has been reported previously by the lab of Guojun Bu (the so-called Jacksonville variant).
A key question is why do these variants, or, for that matter, other variants in APOE, lead to altered AD risk? While APOE has pleiotropic effects biologically, several of which may be relevant to influencing AD risk or clinical progression, it seems most likely that the variants in APOE sequence that affect AD risk are due to APOE’s ability to alter Aβ aggregation/clearance to influence to age of onset of Aβ accumulation in the brain. If one effect of APOE is to influence Aβ accumulation, then it would be critical to understand the molecular structure of APOE in its physiological state.
In the brain, APOE is present in HDL-like lipoprotein particles. In amyloid plaques, APOE is found bound to plaques and, in this state, there is evidence that its conformation is different than in its physiological state (Liao et al., 2018). Factors that allow APOE to change its structure from its physiological form in lipidated particles to a non-lipidated form may be important in amyloid deposition.
In assessing the structure of the V236E form of APOE, switching a nonpolar valine for an acidic glutamic acid might be predicted to reduce the hydrophobicity of this region, and reduce its tendency to oligomerize. This was tested by the Bu lab, where it was found that there were fewer Aβ aggregates and fewer ApoE aggregates in the brains of V236E carriers versus noncarriers. This APOE variant also resulted in less amyloid deposition in a mouse model (Liu et al., 2021). What structure in the C-terminal domain of ApoE in its physiological form explains these properties remains unclear.
In regard to the fact that R251G appears to be directly in the lipid-binding C-terminal region of APOE (Dong et al., 1994), it is also possible that R251G confers a protective effect by influencing APOE’s ability to aggregate/form oligomers. Weisgraber, Agard, Mahley and colleagues originally proposed that an interaction between the N-terminal α-helical bundle and C-terminal α-helix of E4 with a salt bridge across Arg at position 61 and position Glu 255 is important in ApoE structure and DMPC binding (Hatters et al., 2005).
Given that residue 251 sits directly above the E255 on the α-helix (3.6 A.A. per turn) that may interact with D65/E66 above the R61, the loss of positive charge in the R251G variant may impact a chain of salt bridges led by R61-E255. If so, the R251G may be altering this N- and C-terminal interaction in APOE to alter its stability in its lipidated state, making it more likely to aggregate as well. The ApoE4_R251G could also potentially become a key mutant to study the molecular characteristics in the N- and C-terminal interactions with biochemical assays.
However, there are several structural models of APOE that have been more recently proposed by different groups (reviewed in Chen et al., 2021) when APOE is in its native, lipidated state. 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 such interactions are key in determining how ApoE alters AD risk.
It has been difficult to determine the structure of apolipoproteins in their native lipidated state. 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.
References:
Liao F, Li A, Xiong M, Bien-Ly N, Jiang H, Zhang Y, Finn MB, Hoyle R, Keyser J, Lefton KB, Robinson GO, Serrano JR, Silverman AP, Guo JL, Getz J, Henne K, Leyns CE, Gallardo G, Ulrich JD, Sullivan PM, Lerner EP, Hudry E, Sweeney ZK, Dennis MS, Hyman BT, Watts RJ, Holtzman DM. Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation. J Clin Invest. 2018 May 1;128(5):2144-2155. Epub 2018 Mar 30 PubMed.
Liu CC, Murray ME, Li X, Zhao N, Wang N, Heckman MG, Shue F, Martens Y, Li Y, Raulin AC, Rosenberg CL, Doss SV, Zhao J, Wren MC, Jia L, Ren Y, Ikezu TC, Lu W, Fu Y, Caulfield T, Trottier ZA, Knight J, Chen Y, Linares C, Wang X, Kurti A, Asmann YW, Wszolek ZK, Smith GE, Vemuri P, Kantarci K, Knopman DS, Lowe VJ, Jack CR Jr, Parisi JE, Ferman TJ, Boeve BF, Graff-Radford NR, Petersen RC, Younkin SG, Fryer JD, Wang H, Han X, Frieden C, Dickson DW, Ross OA, Bu G. APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia. Sci Transl Med. 2021 Sep 29;13(613):eabc9375. PubMed.
Dong LM, Wilson C, Wardell MR, Simmons T, Mahley RW, Weisgraber KH, Agard DA. Human apolipoprotein E. Role of arginine 61 in mediating the lipoprotein preferences of the E3 and E4 isoforms. J Biol Chem. 1994 Sep 2;269(35):22358-65. PubMed.
Hatters DM, Budamagunta MS, Voss JC, Weisgraber KH. Modulation of apolipoprotein E structure by domain interaction: differences in lipid-bound and lipid-free forms. J Biol Chem. 2005 Oct 7;280(40):34288-95. PubMed.
Chen Y, Strickland MR, Soranno A, Holtzman DM. Apolipoprotein E: Structural Insights and Links to Alzheimer Disease Pathogenesis. Neuron. 2021 Jan 20;109(2):205-221. Epub 2020 Nov 10 PubMed.
View all comments by David HoltzmanHong Kong University of Science & Technology
APOE is one of the most well-accepted genetic risk factors for Alzheimer’s disease, represented by the common coding variant APOE-ε4, which is known to modify Aβ metabolism. Along with APOE-ε4, recent studies have also identified coding and noncoding variants in this locus that modify disease risk. Specifically, indications are that some rare coding mutations, including APOE3-Jac (V236E) (Oct 2021 news) and Christchurch (R136S) (Nov 2019 news), alleviate disease risk by altering the function of the ApoE protein.
In this study, the authors assembled a large group of participants (n = 544,384; who are predominantly European and admixed European individuals) to investigate APOE coding variants associated with the disease. The authors showed an AD protective effect of the V236E (APOE3-Jac, or rs199768005) mutation, which was co-inherited with the APOE-ε3 allele and exhibited a fourfold decrease in AD risk in the general population. Notably, the authors also identified another AD protective missense mutation, R251G (rs267606661), which was co-inherited with the APOE-ε4 allele and associated with a decreased chance of developing AD.
It is interesting to note that all the identified AD protective missense mutations (Christchurch, APOE3-Jac, and R251G) are in the carboxyl-terminal of ApoE, which functions as the lipid-binding region. In particular, previous studies on V236E (APOE3-JAC) indicated that V236E can modify ApoE structure, reduce ApoE aggregation, and enhance its lipid-binding properties (Nov 2019 news; Liu et al., 2021). Further biochemical study is warranted to determine whether R251G would alter the structure and function of ApoE in a similar, or different, way, thereby helping us better understand the roles of APOE in health and disease.
In addition, it would also be interesting to conduct similar analysis in populations of non-European descent, given that the local ancestry at the APOE locus, and its surrounding regions, can also influence the AD risk effect of APOE-ε4 (Zhou et al., 2021).
References:
Liu CC, Murray ME, Li X, Zhao N, Wang N, Heckman MG, Shue F, Martens Y, Li Y, Raulin AC, Rosenberg CL, Doss SV, Zhao J, Wren MC, Jia L, Ren Y, Ikezu TC, Lu W, Fu Y, Caulfield T, Trottier ZA, Knight J, Chen Y, Linares C, Wang X, Kurti A, Asmann YW, Wszolek ZK, Smith GE, Vemuri P, Kantarci K, Knopman DS, Lowe VJ, Jack CR Jr, Parisi JE, Ferman TJ, Boeve BF, Graff-Radford NR, Petersen RC, Younkin SG, Fryer JD, Wang H, Han X, Frieden C, Dickson DW, Ross OA, Bu G. APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia. Sci Transl Med. 2021 Sep 29;13(613):eabc9375. PubMed.
Zhou X, Fu AK, Ip NY. APOE signaling in neurodegenerative diseases: an integrative approach targeting APOE coding and noncoding variants for disease intervention. Curr Opin Neurobiol. 2021 Aug;69:58-67. Epub 2021 Feb 26 PubMed.
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