Oligonucleotide, oligonucleotide conjugate, composition, and use

Abstract

Provided is a single-stranded oligonucleotide having a length of 16-30 nucleotides. The single-stranded oligonucleotide and APOE4 mRNA have complementarity sufficient to mediate an RNAi effect; and each nucleotide in the single-stranded oligonucleotide is a modified or unmodified nucleotide. Also provided are a double-stranded oligonucleotide comprising the single-stranded oligonucleotide as an antisense strand, an oligonucleotide conjugate, and a pharmaceutical composition.

Description

Oligonucleotides, oligonucleotide conjugates, and compositions and uses TECHNICAL FIELD The present disclosure relates to a single-stranded oligonucleotide, and also relates to a double-stranded oligonucleotide comprising the single-stranded oligonucleotide as an antisense strand, an oligonucleotide conjugate, a composition, uses thereof and a method of preparation. The present disclosure provides a double-stranded oligonucleotide for inhibiting APOE4 mRNA expression and applications in treating, preventing or ameliorating diseases related to APOE4 mRNA expression. BACKGROUND APOE4 (Apolipoprotein E4) is a variant allele of the human APOE gene, which is strongly associated with increased risk of various neurological diseases, particularly Alzheimer's disease (AD). Apolipoprotein E, encoded by the APOE gene, is a protein that plays an important role in cholesterol and lipid metabolism. There are three major alleles of APOE: APOE2, APOE3 and APOE4, among which APOE4 is considered the strongest risk factor for Alzheimer's disease. Alzheimer's disease patients carrying APOE4 have an earlier onset of symptoms than Alzheimer's disease patients not carrying the APOE4 mutant gene. In siRNA drugs, the antisense strand is the most important part that determines the performance of double-stranded oligonucleotides, which can specifically pair with the messenger RNA (mRNA) of the target gene, leading to degradation or inactivation of the mRNA, thereby inhibiting or blocking the expression of the gene. Given this unique mechanism, siRNA drugs show great potential and are expected to become an effective means of treating APOE4 gene-related diseases. SUMMARY The present disclosure provides a single-stranded oligonucleotide, a double-stranded oligonucleotide comprising the single-stranded oligonucleotide of the present disclosure as an antisense strand and an oligonucleotide conjugate, all of which exhibit good pharmaceutical activity and stability when targeting APOE4 mRNA. In one aspect, the present disclosure provides a single-stranded oligonucleotide having a length of 16-30 nucleotides, the single-stranded oligonucleotide having complementarity with an APOE4 mRNA sufficient to mediate an RNAi effect; each nucleotide in the single-stranded oligonucleotide is a modified or unmodified nucleotide, wherein at least one nucleotide in the single-stranded oligonucleotide is a nucleotide X, at least one nucleotide is a fluorinated modified nucleotide; and, in the direction from the 5' end to the 3' end, at least 1 nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide and is spaced 4-7 nucleotides from the 8th nucleotide; and, in the direction from the 5' end to the 3' end, if the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X, and all nucleotides from the 15th nucleotide and onwards of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide, and a BNA; each nucleotide X is a deoxynucleotide or an unmodified nucleotide. In another aspect, the present disclosure provides a double-stranded oligonucleotide containing a sense strand and an antisense strand, each nucleotide in the sense strand being a modified or unmodified nucleotide, the sense strand and the antisense strand being at least partially reverse-complementary to form a double-stranded region, wherein the antisense strand is the single-stranded oligonucleotide as described in the present disclosure. In yet another aspect, the present disclosure also provides an oligonucleotide conjugate containing at least one oligonucleotide group and a delivery group conjugated to the oligonucleotide group, the oligonucleotide group being independently a group formed by removing one or more atoms or atom groups from the single-stranded oligonucleotide or the double-stranded oligonucleotide as described in the present disclosure. In yet another aspect, the present disclosure also provides a pharmaceutically acceptable salt of the single-stranded oligonucleotide of the present disclosure, the double-stranded oligonucleotide as described in the present disclosure, or the oligonucleotide conjugate. In yet another aspect, the present disclosure also provides a pharmaceutical composition containing one or more of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate, and the pharmaceutically acceptable salt of the present disclosure, and a pharmaceutically acceptable excipient. In yet another aspect, the present disclosure also provides a use of one or more of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate, the pharmaceutically acceptable salt, and the pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating and / or preventing a disease or a symptom associated with an expression level of an APOE4 mRNA. In yet another aspect, the present disclosure also provides a method of treating and / or preventing a disease or a symptom associated with APOE4 mRNA expression level, the method comprising administering to a subject in need thereof an effective amount of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure. In yet another aspect, the present disclosure also provides a method of modulating APOE4 mRNA expression level in a cell in vitro or in vivo, the method comprising contacting an effective amount of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure with the cell in vitro or in vivo. In yet another aspect, the present disclosure also provides a kit comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure. In yet another aspect, the present disclosure also provides one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure for use as a medicament. In addition, the present disclosure also provides a cell expressing APOE4 mRNA, the cell comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure. All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually incorporated by reference. All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually incorporated by reference. Advantages One or more of the single-stranded oligonucleotides, double-stranded oligonucleotides comprising the single-stranded oligonucleotides of the present disclosure as antisense strand, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure have higher activity of modulating APOE4 mRNA, for example, good stability and inhibitory activity of APOE4 mRNA in vivo in a subject, and have long-acting property. For example, the double-stranded oligonucleotides (e.g., siRNA) containing the single-stranded oligonucleotide of the present disclosure as the antisense strand, the oligonucleotide conjugate of the present disclosure and / or the pharmaceutical composition of the present disclosure show excellent mRNA inhibition effect on APOE4 gene expression in in vitro experiments. For example, compared with the blank control group, the siRNA conjugates of the present disclosure all exhibit better inhibition effect in in vitro HepG2 human hepatoma cells at a concentration of 50 nM, and the APOE4 mRNA inhibition rate is at least 56%, and the APOE4 mRNA inhibition rate of some conjugates is greater than 90%, and even can reach 96.1%, which reflects the better inhibition effect of the siRNA conjugates of the present disclosure on APOE4 mRNA expression in in vitro HepG2 cells. For another example, in monkey liver primary cells, the siRNA conjugates provided by the present disclosure all have a certain inhibition rate on APOE4 mRNA at a concentration of 50 nM, and the APOE4 mRNA inhibition rate can reach more than 65%, and even can reach 98%, indicating that the conjugates of the present disclosure have excellent in vitro inhibition activity on APOE4 mRNA in in vitro monkey liver primary cells. For another example, in mouse liver primary cells, the siRNA conjugates of the present disclosure all have an APOE4 mRNA inhibition rate of more than 77% at a concentration of 50 nM, and the APOE4 mRNA inhibition rate of some conjugates is as high as 97.9%, showing good APOE4 mRNA inhibition activity in in vitro mouse liver primary cells, and the above results show that the conjugates of the present disclosure can effectively inhibit APOE4 mRNA in in vitro cell experiments. On the other hand, the siRNA containing the single-stranded oligonucleotide of the present disclosure as the antisense strand, the oligonucleotide conjugate of the present disclosure and / or the pharmaceutical composition of the present disclosure can still show excellent inhibitory effect on the mRNA of APOE4 gene expression and APOE4 protein in the in vivo experiment. For example, the double-stranded oligonucleotide provided by the present disclosure can continuously inhibit the expression of APOE4 protein in the cerebrospinal fluid of cynomolgus monkeys during the experimental period of 36 days, and the inhibition rate can be as high as 46%, indicating that the siRNA provided by the present disclosure has excellent long-acting APOE4 protein inhibition capacity. For another example, the double-stranded oligonucleotide provided by the present disclosure shows very high inhibition rate on the mRNA of APOE4 gene expression in different regions of the brain, lumbar segment of the spinal cord, cervical segment of the spinal cord and thoracic segment of the spinal cord of cynomolgus monkeys, wherein the inhibition rate on APOE4 mRNA in the spinal cord is maintained at more than 92%, and the inhibition rate on APOE4 mRNA in the thoracic segment of the spinal cord is as high as 96.3%; the inhibition on APOE4 mRNA in the brain tissue is also maintained, and the inhibition rate on APOE4 mRNA in the cortex is maintained at more than 86%, and the inhibition rate on APOE4 mRNA in the occipital lobe region of the left brain is as high as 93.5%, indicating that the double-stranded oligonucleotide provided by the present disclosure can specifically target the central nervous system of cynomolgus monkeys and has excellent APOE4 mRNA inhibition effect. Therefore, the double-stranded oligonucleotide and conjugate of the present disclosure have excellent development prospects in the preparation of drugs for the treatment and / or prevention of diseases or symptoms related to APOE4 mRNA expression. DETAILED DESCRIPTION The detailed description of the present disclosure is described in detail below. It should be understood that the detailed description described herein is only used to illustrate and explain the present disclosure, and is not used to limit the present disclosure. In the present disclosure, APOE4 mRNA refers to the mRNA of the sequence shown in Genbank registration number NM_000041.4. Further, unless otherwise specified, the term "APOE4 gene" used in the present disclosure refers to the gene transcribing the above-mentioned APOE4 mRNA. DEFINITIONS In the context of this document, the expressions "complementary" or "reverse complementary" are used interchangeably and have the meaning well known to those skilled in the art, i.e. in a double-stranded nucleic acid structure, the bases of one strand each form a hydrogen bond between base pairs in a complementary manner with the bases on the other strand, effecting base pairing, forming Watson-Crick base pairs. A "base pair" refers to two bases that form a base pair. In DNA, the purine base adenine (A) always pairs with the pyrimidine base thymine (T) (or in RNA with uracil (U)); the purine base guanine (G) always pairs with the pyrimidine base cytosine (C). Each base pair comprises one purine and one pyrimidine. When adenine on one strand always pairs with thymine (or uracil) on the other strand and guanine always pairs with cytosine, the two strands are considered to be complementary to each other and the sequence of one strand can be deduced from the sequence of its complementary strand. When the bases are modified, as long as the purine-pyrimidine pairing relationship described above is not affected (including but not limited to the number and strength of hydrogen bonds between the bases), the modified bases are also considered to be able to form complementary pairs. Accordingly, "mismatch" or "base mismatch" in the art means that the bases at the corresponding positions between the two single-stranded nucleic acids involved do not pair in a complementary manner; when the corresponding position includes an abasic nucleotide, it is also considered to form a mismatch with the base on the other strand. In the above and below, "nucleotide sequence A is substantially reverse complementary, substantially reverse complementary or completely reverse complementary to nucleotide sequence B over a span of X nucleotides" means that there is a continuous nucleotide sequence A' of length X in nucleotide sequence A which is substantially reverse complementary, substantially reverse complementary or completely reverse complementary to a continuous nucleotide sequence B' of the same length X in nucleotide sequence B. Unless specifically stated, in the context of this document, a reference to an oligonucleotide and / or oligonucleotide conjugate described in the applications or methods provided by the present disclosure, including but not limited to an oligonucleotide and / or oligonucleotide conjugate represented by any of the structural formulae described in the applications or methods provided by the present disclosure, also refers to a pharmaceutically acceptable salt of the oligonucleotide and / or the conjugate, depending on the context. In the foregoing and hereinafter, particularly in describing the preparation of a single-stranded oligonucleotide, double-stranded oligonucleotide, pharmaceutical composition, or oligonucleotide conjugate of the disclosure, unless otherwise specified, the nucleoside monomer refers to modified or unmodified nucleoside phosphoramidite monomers (unmodified or modified RNA phosphoramidites, sometimes also referred to as Nucleoside phosphoramidites) used in the phosphoramidite solid phase synthesis according to the kind and order of nucleotides in the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate to be prepared. The phosphoramidite solid phase synthesis is a method commonly known to those skilled in the art for use in RNA synthesis. All nucleoside monomers used in the present disclosure are commercially available. As used herein, "alkyl" refers to saturated straight-chain and / or branched-chain hydrocarbon groups having the specified number of carbon atoms, typically from 1 to 20 carbon atoms, for example, from 1 to 10 carbon atoms, such as from 1 to 8 or from 1 to 6 carbon atoms. For example, C1-C6 alkyl includes straight- chain and branched-chain alkyl groups of from 1 to 6 carbon atoms. When reference is made to an alkyl group having a specific number of carbons, it is intended to encompass all possible branched and straight-chain forms having that number of carbons; thus, for example, "butyl" is intended to include n-butyl, sec-butyl, iso-butyl, and t-butyl; "propyl" includes n-propyl and iso-propyl. Alkylene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment. As used herein, "alkoxy" refers to an alkyl group of the specified number of carbon atoms attached via an oxygen bridge, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. Alkoxy groups typically have from 1 to 10, from 1 to 8, from 1 to 6, or from 1 to 4 carbon atoms attached via an oxygen bridge. As used herein, "alkoxy-modified alkyl" refers to a group formed upon substitution of one or more hydrogen atoms in an alkyl group with an alkoxy group, for example, methoxymethyl (CH3OCH2-), ethoxymethyl (CH3CH2OCH2-), methoxyethyl (CH3OCH2CH2-), and the like. As used herein, "alkenyl" refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon double bond, obtained by removing one molecule of hydrogen from adjacent carbon atoms of a parent alkyl group. The group can be in the cis- or trans- configuration with respect to the double bond. Typical alkenyl groups include, but are not limited to, ethenyl; propenyl, such as prop-1 -en-1 -yl, prop-1 -en-2-yl, prop-2-en-1 -yl (allyl), prop-2-en-2-yl; butenyl, for example, but-1 -en-1 -yl, but-1 -en-2-yl, 2-methylprop-1 -en-1 -yl, but-2-en-1 -yl, but-2-en-2-yl, but-1,3-dien-1 -yl, but-1,3-dien-2-yl, and the like. In certain embodiments, alkenyl groups have 2 to 20 carbon atoms, while in other embodiments, 2 to 10, 2 to 8, or 2 to 6 carbon atoms. Alkenylene is a subset of alkenyl, referring to the same groups as alkenyl, but with two points of attachment. As used herein, "alkynyl" refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon triple bond, obtained by removing two molecules of hydrogen from adjacent carbon atoms of a parent alkyl group. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl, such as prop-1 -yn-1 -yl, prop-2-yn-1 -yl; butynyl, for example, but-1 -yn-1 -yl, but-1 -yn-3-yl, but-3-yn-1 -yl, and the like. In certain embodiments, alkynyl groups have 2 to 20 carbon atoms, while in other embodiments, 2 to 10, 2 to 8, or 2 to 6 carbon atoms. Alkynylene is a subset of alkynyl, referring to the same groups as alkynyl, but with two points of attachment. As used herein, "aryl" refers to a radical derived by removing a hydrogen atom from a carbon atom of an aromatic monocyclic or polycyclic hydrocarbon ring system. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only carbon and hydrogen atoms with 6 to 18 carbon atoms in the ring system, wherein at least one ring in the ring system is completely unsaturated, i.e., contains a cyclic, delocalized (4n+2) pi-electron system, according to Hückel theory. Aryl includes, but is not limited to, phenyl, fluorenyl, and naphthyl groups, and the like. Arylene is a subset of aryl, referring to the same groups as aryl, but with two points of attachment. As used herein, "heterocyclyl" refers to a radical derived from a monocyclic saturated or partially unsaturated, non-aromatic ring or bicyclic saturated or partially unsaturated heterocyclic hydrocarbon radical, wherein the bicyclic ring system is non-aromatic, the monocyclic or bicyclic ring has, for example, 3 to 10 members or 5 to 10 members, wherein at least 1 member and up to 5 members, particularly 1, 2, or 3 ring members are a heteroatom selected from N, O, and S, and the remaining ring atoms are carbon atoms, in stable combinations known to those skilled in the art. Among these, the heterocyclic nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. As used herein, the heterocycle can form a bicyclic ring with another ring system, i.e., one or two of the atoms making up the heterocycle are shared with another ring system. The heterocyclyl group can be attached to the rest of the molecule by a carbon or heteroatom; and, in the case where the heterocyclyl group is a bicyclic radical, the aforementioned attachment can be via a heteroatom-containing ring or a fused ring. Examples of heterocyclyl groups include, but are not limited to: azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dioxolanyl, morpholinyl, oxazolidinyl, oxazinanyl, indolinyl, isoindolinyl, piperazinyl, tetrahydrofuranyl, thiomorpholinyl, dihydropyranyl (e.g., 3,4-dihydropyranyl, 3,6-dihydropyranyl), homopiperazinyl, dioxanyl, hexahydropyrimidinyl, pyrazolinyl, pyrazolidinyl, 4H-quinolizinyl, quinuclidinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, thiazolidinyl, benzopyranyl, tetrahydroquinolinyl, dihydropyrrolopyridinyl, dihydrobenzoxazinyl, pyrrolopyridinyl, dihydronaphthridinyl, dihydroisoquinolinyl, and tetrahydroisoquinolinyl. Heterocyclylenyl is a subset of heterocyclyl, referring to the same residues as heterocyclyl, but with two points of attachment. As used herein, "heteroaryl" refers to a radical derived by the removal of one hydrogen atom from a 3- to 18-membered aromatic ring radical, containing 2 to 17 carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in the ring system is completely unsaturated, i.e., contains a cyclic delocalized (4n+2) p-electron system according to Hückel theory. Heteroaryl groups include fused or bridged ring systems. In some embodiments, a heteroatom in a heteroaryl group is an oxidized heteroatom. In some embodiments, a heteroaryl group contains one or more nitrogen atoms. In some embodiments, one or more of the nitrogen atoms in a heteroaryl group is a quaternized nitrogen atom. A heteroaryl group is attached to the rest of the molecule through any ring atom. Examples of heteroaryl groups include, but are not limited to: azepinyl, acridinyl, benzimidazolyl, benzoindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl, benzo-thieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, diphenfuranyl, diphenylthiophenyl, furanyl, furanonyl, furopyrido[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, dihydroindolyl, isoindolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]oxazinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]dioxepinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]dioxinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]oxazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiadiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]cinnolinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyridazinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyridinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyranyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyranonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]furanyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]furanonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thienyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiophenyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyrimidinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiadiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]oxazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]cinnolinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyridazinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyridinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyranyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyranonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]furanyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]furanonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thienyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiophenyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyrimidinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiadiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]oxazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]cinnolinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyridazinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyridinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyranyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyranonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]furanyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]furanonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thienyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiophenyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyrimidinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiadiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]oxazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]cinnolinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyridaz8-tetrahydroquinazolinyl), naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[H]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl / thienyl. Heteroarylenyl is a subset of heteroaryl, referring to the same residues as heteroaryl, but with two points of attachment. In the foregoing or hereinafter, a “substituted” or “substituted” group, such as a substituted amino, substituted alkyl, or substituted aryl. Where no indication is given, a “substituted” or “substituted” group refers to a group in which one or more hydrogen atoms are replaced with one or more substituents. For example, a “substituted alkyl” refers to a group in which one or more hydrogen atoms of an alkyl group are replaced with a substituent. Those skilled in the art will appreciate that various substituents can be included in the compounds useful in the present disclosure, as long as the introduction of the substituent does not affect the function of the present disclosure, as long as the purpose of the present disclosure can be achieved, it can be used in the present disclosure. In some embodiments, the substituents are selected from the group consisting of C1-C 10 alkyl, C6-C 10 aryl, C5-C 10 heteroaryl, C1-C 10 haloalkyl, -OC1-C 10 alkyl, OC1-C 10 alkylphenyl, -C1-C 10 alkyl-OH, -OC1-C 10haloalkyl, -SC1-C 10 alkyl, -SC1-C 10 alkyl, -SC1-C 10 alkyl-SH, -SC1-C 10 haloalkyl, halo substituent, -OH, -SH, -NH2, -C1-C 10 alkyl-NH2, -N(C1-C 10 alkyl)(C1-C 10 alkyl), -NH(C1-C 10 alkyl), N(C1-C 10 alkyl)(C1-C 10 alkyl), N(C1-C 10 alkyl), -CN, -NO2, -CO2H, -C(O)O(C1-C 10 alkyl), -CON(C1-C 10 alkyl)(C1-C 10 alkyl), -CONH(C1-C 10 alkyl), -CONH2, -NHC(O)(C1-C 10 alkyl), -NHC(O)(phenyl), -N(C1-C 10 alkyl)C(O)(C1-C 10 alkyl), -N(C1-C 10 alkyl)C(O)(phenyl), C(O)C1-C 10 alkyl, C(O)C1-C 10 alkyl, C(O)C1-C 10 haloalkyl, -OC(O)C1-C 10 alkyl, -SO2(C1-C 10 alkyl), -SO2(phenyl), -SO2(C1-C 10 haloalkyl), -SO2NH2, -SO2NH(C1-C 10 alkyl), -SO2NH(phenyl), -NHSO2(C1-C 10 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C 10 haloalkyl). In some embodiments, the substituent is one of -C1-C3alkyl, -C6-C8aryl, -O-C1-C3alkyl, O-(C1-C3alkyl)phenyl, halo, -OH, -NH2, -CN, or -NO2. It will be understood by one skilled in the art that for any group containing one or more substituents, the group is not intended to introduce any substitution or substitution pattern that is not physically or synthetically realistic. Various protecting groups, such as hydroxyl protecting groups, can be used in the present disclosure. Generally, protecting groups render a chemical functional group insensitive to particular reaction conditions, and can be added to and removed from that functional group in a molecule without substantially damaging the rest of the molecule. Representative hydroxyl protecting groups are disclosed in Beaucage et al., Tetrahedron 1992, 48, 2223-2311, and Peter G. M. Wuts, GREENE’s Protective Groups in Organic Synthesis, Chapter 2, 5th edition, John Wiley & Sons, Inc., New Jersey, 2014, each of which is incorporated by reference herein in its entirety. In some embodiments, the protecting group is stable under basic conditions, but can be removed under acidic conditions. In some embodiments, nonexclusive examples of hydroxyl protecting groups that can be used herein include dimethoxytrityl (DMT), monomethoxytrityl, 9-phenylxanthyl (Pixyl), and 9-(p- methoxyphenyl)xanthyl (Mox). In some embodiments, nonexclusive examples of hydroxyl protecting groups that can be used herein include Tr (trityl), MMTr (4-methoxytrityl), DMTr (4,4'-dimethoxytrityl), and TMTr (4,4',4"-trimethoxytrityl). The term "subject," as used herein, refers to any animal, such as a mammal or a marsupial. Subjects of the present disclosure include, but are not limited to, humans, non-human primates (e.g., rhesus or other types of macaques), mice, pigs, horses, donkeys, cows, rabbits, sheep, rats, and any species of poultry. As used herein, "treatment" refers to an approach for obtaining beneficial or desired results, including but not limited to therapeutic benefit. "Therapeutic benefit" means eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the observation of improvement in a subject, even though the subject can still be afflicted with the underlying disorder, by eradicating or ameliorating one or more of the signs or symptoms of the underlying disorder. As used herein, "prevent" refers to an approach that results in a beneficial or desired result, including but not limited to prophylactic benefit. To obtain "prophylactic benefit", the single-stranded oligonucleotide, double-stranded oligonucleotide, pharmaceutical composition or oligonucleotide conjugate of the present disclosure can be administered to a subject at risk of developing an APOE4 mRNA related disease, or to a subject reporting one or more physiological symptoms of the disease, even though a diagnosis of the disease can not have been made. In some embodiments, "prevention" includes reducing or eliminating the risk of an APOE4 mRNA related disease by administering the single-stranded oligonucleotide, double-stranded oligonucleotide, pharmaceutical composition or oligonucleotide conjugate of the present disclosure to a subject at risk of developing the disease before the risk progresses to an overt disease process, intervening in the level of APOE4 mRNA or APOE4 protein. Single-stranded oligonucleotide of the present disclosure In one aspect, the present disclosure provides a single-stranded oligonucleotide having a length of 16-30 nucleotides, the single-stranded oligonucleotide having a complementarity with an APOE4 mRNA sufficient to mediate an RNAi effect; each nucleotide in the single-stranded oligonucleotide is a modified or unmodified nucleotide, wherein at least one nucleotide in the single-stranded oligonucleotide is a nucleotide X, and at least one nucleotide is a fluorine-modified nucleotide; and, in the direction from the 5' end to the 3' end, at least 1 nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide and is spaced 4-7 nucleotides from the 8th nucleotide; and, in the direction from the 5' end to the 3' end, if the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X, and all nucleotides from the 15th nucleotide and thereafter of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide and a BNA; each nucleotide X is a deoxynucleotide or an unmodified nucleotide. In the present disclosure, diseases related to the level of APOE4 mRNA and / or the level of APOE4 protein are treated or prevented by modulating the level of APOE4 mRNA and / or changing the level of the corresponding protein. The inventors have surprisingly found that the single-stranded oligonucleotide, the double-stranded oligonucleotide comprising the single-stranded oligonucleotide of the present disclosure as the antisense strand and the oligonucleotide conjugate of the present disclosure have good stability and APOE4 mRNA inhibitory activity in cells and / or in subjects, and thus have good application prospects. To exert the RNAi effect, the single-stranded oligonucleotide of the present disclosure has a length of 16 to 30 nucleotides. In some embodiments, the single-stranded oligonucleotide of the present disclosure has a length of 17 to 28, 19 to 26, or 20 to 24 nucleotides. In some embodiments, the single-stranded oligonucleotide of the present disclosure has a length of 19, 21, or 23 nucleotides. In this case, the single-stranded oligonucleotide of the present disclosure, the double-stranded oligonucleotide comprising the single-stranded oligonucleotide as an antisense strand, and the oligonucleotide conjugate have a better balance between stability and RNAi activity. In the single-stranded oligonucleotide of the present disclosure, at least one nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide and is spaced apart from the 8th nucleotide of the single-stranded oligonucleotide by 4 to 7 nucleotides; and, in the direction from the 5' end to the 3' end, if the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X, and all the nucleotides from the 15th nucleotide and thereafter of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide, and a BNA. The inventors have particularly found that the single-stranded oligonucleotide of the present disclosure can effectively maintain high inhibitory activity of the single-stranded oligonucleotide, the double-stranded oligonucleotide, and the oligonucleotide conjugate against APOE4 mRNA, while maintaining stability, by comprising a fluorine-modified nucleotide and a nucleotide X. In some embodiments, the number of nucleotides X in the single-stranded oligonucleotide is 1 to 3, for example, 1, 2, or 3. In some embodiments, in the direction from the 5' end to the 3' end, each nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide, and each nucleotide X is spaced apart from the 8th nucleotide of the single-stranded oligonucleotide by 3, 5, 7, or 10 nucleotides. In some embodiments, each nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide, and one of the nucleotides X is spaced apart from the 8th nucleotide by 5 nucleotides, i.e., in the direction from the 5' end to the 3' end, the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X. In some embodiments, there is only one nucleotide X in the single-stranded oligonucleotide, which is spaced 5 nucleotides from the 8th nucleotide in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, there are 2 nucleotides X in the single-stranded oligonucleotide, in the 5' end to 3' end direction, one of which is spaced 5 nucleotides from the 8th nucleotide in the single-stranded oligonucleotide, and the other of which is spaced 3, 7, or 10 nucleotides from the 8th nucleotide in the single-stranded oligonucleotide. In some embodiments, the 12th and 14th nucleotides, or the 14th and 16th nucleotides, or the 14th and 19th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction are nucleotides X. Each nucleotide X is independently selected from a deoxynucleotide or an unmodified nucleotide. In the present context, an "unmodified nucleotide" refers to a ribonucleotide (RNA) whose base and ribose are unmodified, i.e., the nucleotide base is a natural ribose base (one of A, U, C, G, T), and the nucleotide ribose 2' position is an unprotected hydroxyl group (2'-OH). Correspondingly, a "modified nucleotide" refers to a nucleotide whose base is modified, a nucleotide whose nucleotide ribose 2' position is substituted with an atom or a group other than a hydroxyl group, or a nucleotide analog. In some embodiments, the 14th nucleotide or the 12th and 14th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction are deoxynucleotides, and the other nucleotide X is an unmodified nucleotide. In some embodiments, the 14th nucleotide in the single-stranded oligonucleotide in the 5' end to 3' end direction is a deoxynucleotide, and the other nucleotides are modified nucleotides. In some embodiments, the number of modified nucleotides in the single-stranded oligonucleotide of the present disclosure is more than 50%, more than 70%, or more than 85% of the total number of nucleotides in the single-stranded oligonucleotide; or, the number of unmodified nucleotides in the single-stranded oligonucleotide is no more than 5, no more than 4, or no more than 3. In some embodiments, the number of unmodified nucleotides in the single-stranded oligonucleotide is 2 or 1. In some embodiments, each of the total number of nucleotides in the single-stranded oligonucleotide is independently a modified nucleotide. As previously described, the single-stranded oligonucleotide described herein can include fluorine-modified nucleotides in addition to nucleotide X. In some embodiments, the number of fluorine-modified nucleotides is 2-7. In some embodiments, the fluorine-modified nucleotides refer to 1 or 2 of the 2nd and 12th, 1 or 2 of the 5th-7th, and 0-2 of the 16th-19th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to 2-5 of the 2nd, 5th, 6th, 7th, 12th, 16th, 18th, and 19th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to the 2nd and 6th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to the 2nd, 6th, and 16th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to the 2nd, 5th, 7th, 12th, and 16th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to the 2nd, 7th, 12th, 16th, and 19th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to the 2nd, 6th, 12th, 16th, and 19th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, each modified nucleotide in the single-stranded oligonucleotide other than nucleotide X and the fluorine-modified nucleotide is independently selected from one of an alkoxy-modified nucleotide, a substituted alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide, and a BNA. In some embodiments, the number of substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide is no more than 3. In some embodiments, the number of substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide is no more than 2. In some embodiments, the number of substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide is 1. In some embodiments, there is no substituted alkoxy-modified nucleotide in the single-stranded oligonucleotide. In some embodiments, each modified nucleotide in the single-stranded oligonucleotide, except for the nucleotide X and the fluorine-modified nucleotide, is selected from an alkoxy-modified nucleotide, a substituted alkoxy-modified nucleotide, or a thermally unstable nucleotide. In some embodiments, the number of thermally unstable nucleotides in the single-stranded oligonucleotide is 0-2. In some embodiments, there is no thermally unstable nucleotide in the single-stranded oligonucleotide. In some embodiments, the number of thermally unstable nucleotides in the single-stranded oligonucleotide is no more than 2; or the number of thermally unstable nucleotides is 1 or 2; the single-stranded oligonucleotide contains only 1 thermally unstable nucleotide; or, each modified nucleotide in the single-stranded oligonucleotide, except for the nucleotide X and the fluorine-modified nucleotide and the thermally unstable nucleotide, is selected from an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide. In the above context, “thermally unstable nucleotide” refers to a nucleotide with a thermally unstable modification, which is a modification that reduces the thermal dissociation temperature of a double-stranded oligonucleotide with the modification at least 0.5 °C compared to a double-stranded oligonucleotide with an unmodified nucleotide at the corresponding position. Exemplary thermally unstable modifications can be found in the specification of PCT Publication No. WO2018 / 098328A1

[0236] -

[0251] The thermally unstable modification described in the paragraph. In some embodiments, the thermally unstable nucleotide is one of an acyclic nucleotide or an isonucleotide. An acyclic nucleotide is a class of nucleotides in which the sugar ring of the nucleotide is opened. In some embodiments, the acyclic nucleotide can be an unlocked nucleic acid (UNA) or a glycerol nucleic acid (GNA), wherein the UNA is shown in formula (15) and the GNA is shown in formula (16): In the above formula (15) and formula (16), R is selected from H, OH, or alkoxy (O-alkyl), and Base represents a nucleic acid base, such as A, U, G, C, or T. An isonucleotide refers to a compound in which the position of the base on the ribose ring of the nucleotide is changed. In some embodiments, the isonucleotide can be a compound in which the base is moved from the 1'-position to the 2'-position or the 3'-position of the ribose ring, as shown in formula (17) or (18). In the above formula (17)-(18) compounds, Base represents a nucleic acid base, such as A, U, G, C, or T; and R is selected from H, OH, F, or a non-fluorine group as described above. In some embodiments, the thermally unstable nucleotides are selected from one of GNA as shown in formula (27A), 2'-OMe abasic nucleotide as shown in formula (27B), 3'-OMe modified nucleotide as shown in formula (27C), 5'-Me modified nucleotide as shown in formula (27D), SNA as shown in formula (27E), hGNA as shown in formula (27F), hhGNA as shown in formula (27G), mGNA as shown in formula (27H), TNA as shown in formula (27I), and h'GNA as shown in formula (27J), UNA as shown in formula (27K), and Hyp-spacer as shown in formula (27L): In the above compounds of formula (27A)-(27L), Base represents a nucleic acid base, such as A, U, G, C, or T; R 27 represents H, OH, F, alkoxy, alkyl, or alkoxy-substituted alkyl. The * indicates that the carbon atom has chirality, and the compound can be in the R configuration, the S configuration, or a racemic mixture of the R and S configurations. In some embodiments, each thermally unstable nucleotide is independently a GNA as shown in formula (27A). In the above context, BNA refers to a constrained or inaccessible nucleotide. A BNA can contain a five-, six-, or seven-membered ring bridged structure with a "fixed" C3'-endo sugar conformation. The bridge is typically incorporated at the 2'-, 4'-position of the ribose to provide a 2',4'-BNA nucleotide. In some embodiments, the BNA can be a LNA, ENA, or cET BNA, etc., where the LNA is shown in formula (12), the ENA is shown in formula (13), and the cET BNA is shown in formula (14): In the above compounds of formula (12)-(14), Base represents a nucleic acid base, such as A, U, G, C, or T. In some embodiments, for ease of synthesis, each alkoxy-modified nucleotide is a 2'-methoxy-modified nucleotide (2'-OMe). A 2'-methoxy-modified nucleotide is shown in formula (8). In some embodiments, a 2'-amino-modified nucleotide (2'-NH2) is shown in formula (9). In some embodiments, a 2'-deoxy nucleotide (DNA) is shown in formula (10): In the above compounds of formula (7)-(10), Base represents a nucleic acid base, such as A, U, G, C, or T. In the foregoing and hereinafter, "fluoro-modified nucleotide", "2'-fluoro-modified nucleotide", "nucleotide whose 2'-hydroxyl of the ribose group is replaced by fluorine" and "nucleotide having 2'-fluoro-ribosyl" have the same meaning, and all refer to a nucleotide whose 2'-hydroxyl is replaced by fluorine to form a compound having a structure as shown in Formula (7); "methoxy-modified nucleotide", "2'-methoxy-modified nucleotide", "nucleotide whose 2'-hydroxyl of the ribose group is replaced by methoxy" and "nucleotide having 2'-methoxy-ribosyl" have the same meaning, and all refer to a nucleotide whose 2'-hydroxyl of the ribose group is replaced by methoxy to form a compound having a structure as shown in Formula (8). In some embodiments, the single stranded oligonucleotide of the present disclosure is 19-23 nucleotides in length and, in the 5' end to 3' end direction, the 14th nucleotide is a nucleotide X, 2 of the 5th-7th nucleotides and the 19th nucleotide and the 2nd, 12th and 16th nucleotides are fluorinated nucleotides, the 3rd nucleotide is an alkoxy modified nucleotide or a substituted alkoxy modified nucleotide, the 5th nucleotide is an alkoxy modified nucleotide or a substituted alkoxy modified nucleotide when it is not a fluorinated nucleotide, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 19-23 nucleotides in length and, in the 5' end to 3' end direction, the 12th and 14th nucleotides are nucleotide X, the 2nd, 7th and 16th nucleotides are fluorinated nucleotides, the 3rd or 5th nucleotide is an alkoxy modified nucleotide or a substituted alkoxy modified nucleotide, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 19-23 nucleotides in length and, in the 5' end to 3' end direction, the 14th and 16th nucleotides are nucleotide X, the 2nd and 6th nucleotides are fluorinated nucleotides, the 13th nucleotide is a substituted alkoxy modified nucleotide or a BNA, the 3rd or 5th nucleotide is an alkoxy modified nucleotide or a substituted alkoxy modified nucleotide; in the 3' end to 5' end direction, 1 of the 1st-2nd nucleotides of the single stranded oligonucleotide is a thermally unstable nucleotide, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 19-23 nucleotides in length and, in the 5' end to 3' end direction, 1 of the 16th-19th nucleotides and the 14th nucleotide is nucleotide X, the 2nd and 6th nucleotides are fluorinated nucleotides, the 16th nucleotide is a fluorinated nucleotide when it is not nucleotide X, the 13th nucleotide is a substituted alkoxy modified nucleotide or a BNA, the 3rd or 5th nucleotide is an alkoxy modified nucleotide or a substituted alkoxy modified nucleotide, the 20th nucleotide is an alkoxy modified nucleotide or a thermally unstable nucleotide, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy modified nucleotide. In some embodiments, the single stranded oligonucleotide is 21 nucleotides in length, in the 5' end to 3' end direction, wherein the 16th or 19th nucleotide and the 14th nucleotide is nucleotide X, and wherein the 14th nucleotide is a deoxynucleotide or an unmodified nucleotide, and the 16th or 19th nucleotide is an unmodified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 14thnucleotide is a deoxy nucleotide, the 2nd, 5th, 7th, 12th, and 16thnucleotides are fluoro-modified nucleotides, the 3rdnucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 14thnucleotide is a deoxy nucleotide, the 2nd, 7th, 12th, 16th, and 19thnucleotides are fluoro-modified nucleotides, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 14thnucleotide is a deoxy nucleotide, the 2nd, 6th, 12th, 16th, and 19thnucleotides are fluoro-modified nucleotides, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 12thand 14thnucleotides are deoxy nucleotides, the 2nd, 7th, and 16thnucleotides are fluoro-modified nucleotides, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 14thnucleotide is a deoxy nucleotide, the 16thnucleotide is an unmodified nucleotide, the 2ndand 6thnucleotides are fluoro-modified nucleotides, the 13thnucleotide is a substituted alkoxy-modified nucleotide, the 2ndnucleotide of the single stranded oligonucleotide is a thermally unstable nucleotide in the 3' end to 5' end direction, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 14thnucleotide is a deoxy nucleotide, the 19thnucleotide is an unmodified nucleotide, the 2nd, 6th, and 16thnucleotides are fluoro-modified nucleotides, the 13thnucleotide is a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, each alkoxyl-modified nucleotide in the single stranded oligonucleotide of the present disclosure is a methoxyl-modified nucleotide. In some embodiments, each substituted alkoxyl-modified nucleotide in the single stranded oligonucleotide of the present disclosure is a 2'-0-methoxyethyl-modified nucleotide. In some embodiments, each BNA in the single stranded oligonucleotide of the present disclosure is a LNA or a cET BNA. In some embodiments, each thermally unstable nucleotide in the single stranded oligonucleotide of the present disclosure is a GNA. In some embodiments, each of at least 2 of the linking groups between adjacent nucleotides in the single stranded oligonucleotide of the present disclosure is independently a phosphorothioate group with a modification group. In some embodiments, 1-4 of the linking groups between adjacent nucleotides in the first 5 nucleotides at the 5' end in the single stranded oligonucleotide of the present disclosure is each independently a phosphorothioate group with a modification group. In some embodiments, 1-4 of the linking groups between adjacent nucleotides in the first 5 nucleotides at the 3' end in the single stranded oligonucleotide of the present disclosure is each independently a phosphorothioate group with a modification group. In some embodiments, 2 of the linking groups between adjacent nucleotides in the first 3 nucleotides at the 5' end or 4 of the linking groups between adjacent nucleotides in the first 5 nucleotides at the 5' end in the single stranded oligonucleotide of the present disclosure is each independently a phosphorothioate group with a modification group. In some embodiments, 2 of the linking groups between adjacent nucleotides in the first 3 nucleotides at the 3' end or 4 of the linking groups between adjacent nucleotides in the first 5 nucleotides at the 3' end in the single stranded oligonucleotide of the present disclosure is each independently a phosphorothioate group with a modification group. In some embodiments, if there is an unmodified nucleotide in the single stranded oligonucleotide of the present disclosure, each of 1 or 2 of the 2 linking groups between the unmodified nucleotide and the adjacent nucleotides is independently a phosphorothioate group with a modification group. The modified phosphorothioate group can make the single stranded oligonucleotide of the present disclosure better resistant to exonuclease, enhancing the stability of the oligonucleotide in a subject. In some embodiments, at least 2, or each of 2-6, of the linking groups between adjacent nucleotides in the single stranded oligonucleotide of the present disclosure is independently a phosphorothioate group with a modification group. In some embodiments, each of 2-6 of the linking groups between adjacent nucleotides in the single stranded oligonucleotide is independently a phosphorothioate group with a modification group. In some embodiments, each of 3 or 4 of the linking groups between adjacent nucleotides in the single stranded oligonucleotide is independently a phosphorothioate group with a modification group. In some embodiments, each of the linking groups between adjacent nucleotides in the first 1-3 nucleotides at the 5' end, and the linking groups between adjacent nucleotides in the first 1-3 nucleotides at the 3' end of the single stranded oligonucleotide is independently a phosphorothioate group with a modification group. In some embodiments, if there is an unmodified nucleotide in the single stranded oligonucleotide, each of the 1 or 2 of the 2 linking groups between the unmodified nucleotide and the adjacent nucleotides is independently a phosphorothioate group with a modification group. In some embodiments, the phosphorothioate group with a modification group is a phosphorothioate group with a structure as shown in formula (28): In some embodiments, the 5' terminal nucleotide of the single stranded oligonucleotide is a 5'-hydroxyl nucleotide with a structure as shown in formula (29); a 5'-phosphate nucleotide with a structure as shown in formula (30); or a 5'-phosphate analog modified nucleotide with a structure selected from one of formula (31) - formula (34): wherein R is selected from one of H, OH, OCH3, and F; Base represents a nucleic acid base selected from A, U, C, G, or T. In some embodiments, the 5'-phosphonate nucleotide is a 5'-phosphate containing nucleotide of Formula (30), the 5'-phosphonate analog modified nucleotide is a 5'- (E)-vinylphosphonate (E-VP) modified nucleotide of Formula (31), or a phosphorothioate modified nucleotide of Formula (33). In some embodiments, the 5' terminal nucleotide of the single stranded oligonucleotide is a 5'-hydroxyl nucleotide or a 5'- (E)-vinylphosphonate (E-VP) modified nucleotide. In some embodiments, the 5' terminal nucleotide is a 5'- (E)-vinylphosphonate (E-VP) modified nucleotide, which can further increase one or more of the stability, the pharmacodynamic activity in a subject, and the long-acting property of the single stranded oligonucleotide, the double stranded oligonucleotide comprising the same, and the oligonucleotide conjugate of the present disclosure. In some embodiments, the single stranded oligonucleotide has a length of 21 nucleotides, and in a 5' end to 3' end direction, the 14thnucleotide is a deoxy nucleotide, the 2nd, 5th, 7th, 12th, and 16thnucleotides are fluorine-modified nucleotides, the 3rdnucleotide is a methoxy-modified nucleotide, and each of the remaining nucleotides in the single stranded oligonucleotide is a methoxy-modified nucleotide; or the 14thnucleotide is a deoxy nucleotide, the 2nd, 5th, 7th, 11th, and 16thnucleotides are fluorine-modified nucleotides, the 3rdnucleotide is a methoxy-modified nucleotide, and each of the remaining nucleotides in the single stranded oligonucleotide is a methoxy-modified nucleotide; the linking group between any two adjacent nucleotides of the 1stto 3rdnucleotides at the 5' end and the linking group between any two adjacent nucleotides of the 1stto 3rdnucleotides at the 3' end are phosphorothioate groups; the 5' terminal nucleotide is a 5'-hydroxyl nucleotide of Formula (29), a 5'-phosphate containing nucleotide of Formula (30), or a 5'- (E)-vinylphosphonate modified nucleotide of Formula (31). As previously described, the single-stranded oligonucleotides of the present disclosure have sufficient complementarity to APOE4 mRNA to mediate an RNAi effect. In some embodiments, the single-stranded oligonucleotides of the present disclosure are sufficiently complementary to APOE4 mRNA. In the context of the present disclosure, “sufficiently complementary” means that the complementarity between the single-stranded oligonucleotides of the present disclosure and APOE4 mRNA is sufficient to cause the single-stranded oligonucleotides to reduce or eliminate the production of a protein encoded by the APOE4 mRNA through an RNAi effect. In some embodiments, “sufficiently complementary” means that the single-stranded oligonucleotides of the present disclosure are substantially reverse complementary, substantially reverse complementary, or completely reverse complementary to APOE4 mRNA over a length of at least 16 nucleotides, e.g., over a length of 16-25 nucleotides, over a length of 18-23 nucleotides, or over a length of 19-21 nucleotides. In some embodiments, the single-stranded oligonucleotides of the present disclosure are completely reverse complementary to APOE4 mRNA. In the foregoing and hereinafter, “at least partially reverse complementary,” “substantially reverse complementary,” “substantially reverse complementary,” “completely reverse complementary” can be used to refer to the base pairing between two nucleotide sequences of single-stranded oligonucleotides and APOE4 mRNA, between the sense and antisense strands of double-stranded oligonucleotides, and between the antisense strand of double-stranded oligonucleotides and APOE4 mRNA. Unless otherwise specified, “at least partially reverse complementary” means that there are no more than 50% base mismatches between two nucleotide sequences over a given length of nucleotide sequence; “substantially reverse complementary” means that there are no more than 3 base mismatches between two nucleotide sequences over a given length of nucleotide sequence; “substantially reverse complementary” means that there is 1 base mismatch between two nucleotide sequences over a given length of nucleotide sequence; “completely reverse complementary” means that there are no base mismatches between two nucleotide sequences over a given length of nucleotide sequence. When two nucleotide sequences are completely reverse complementary over a given length of nucleotide sequence, the two nucleotide sequences are capable of annealing to form a double-stranded hybrid consisting solely of Watson-Crick base pairs over the given length of nucleotide sequence. Unless otherwise specified, when referring to a shorter nucleotide sequence being “completely reverse complementary” to a longer nucleotide sequence, it is meant that the two nucleotide sequences are completely reverse complementary over the entire length of the shorter nucleotide sequence. For example, a single-stranded oligonucleotide of the present disclosure being completely reverse complementary to APOE4 mRNA means that it is completely reverse complementary over the entire length of the single-stranded oligonucleotide; in other words, the single-stranded oligonucleotide is capable of forming a double-stranded hybrid with APOE4 mRNA in which each nucleotide of the single-stranded oligonucleotide forms a Watson-Crick base pair with a nucleotide of APOE4 mRNA. In some embodiments, two nucleotide sequences that are "substantially complementary" can include an internal region that is completely reverse complementary (e.g., completely reverse complementary over a length of at least 6, 8, or 10 nucleotides). In some embodiments, the single-stranded oligonucleotide described in the present disclosure is completely reverse complementary to the APOE4 mRNA at least within the seed region. The "seed region" refers to a region within the 2nd-8th nucleotide of the single-stranded oligonucleotide described in the present disclosure, at which the single-stranded oligonucleotide described in the present disclosure can better mediate the RNAi effect to inhibit the level of the APOE4 mRNA. In some embodiments, the single-stranded oligonucleotide is substantially reverse complementary or completely reverse complementary to the APOE4 mRNA over a length of at least 16 nucleotides. In some embodiments, the nucleotide sequence of the 2nd-19th nucleotide of the single-stranded oligonucleotide is completely reverse complementary to the APOE4 mRNA in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence of the 5' end 1st nucleotide and beyond of the single-stranded oligonucleotide is completely reverse complementary to the APOE4 mRNA in the direction from the 5' end to the 3' end. In some embodiments, all the nucleotides of the single-stranded oligonucleotide are completely reverse complementary to the APOE4 mRNA. In some embodiments, the single-stranded oligonucleotide of the present disclosure can be the first, second, third, fourth, fifth, or sixth single-stranded oligonucleotide described below, each of which is described below. The first single-stranded oligonucleotide In some embodiments, the present disclosure provides the first single-stranded oligonucleotide. The single-stranded oligonucleotide contains a nucleotide sequence II, which is equal in length to the nucleotide sequence set forth in SEQ ID NO: 2, and has no more than 3 base differences: 5'-Z2GAAACUUGGUGAAUCUUU-3' (SEQ ID NO: 2), wherein Z2 is U or A, the nucleotide sequence II contains a nucleotide Z'2 at a position corresponding to Z2, and Z'2 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In the foregoing and hereinafter of the present disclosure, "corresponding to a position" means being at the same position in a nucleotide sequence, counting from the same end of the nucleotide sequence, e.g., the first nucleotide at the 5' end of the nucleotide sequence II is the nucleotide corresponding to the 1st nucleotide of SEQ ID NO: 2. In some embodiments, each U in the nucleotide sequence of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate of the present disclosure can be optionally replaced by T. These base differences do not significantly reduce the APOC3 mRNA inhibitory ability or increase the off-target effect of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate. While these single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate containing base differences are also within the scope of the present disclosure. In some embodiments, the nucleotide sequence II has no more than 1 base difference from the nucleotide sequence set forth in SEQ ID NO: 2. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 can include a base difference at position Z'2 and / or a base difference at any other nucleotide position in the nucleotide sequence II. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 can include a base difference at position Z'2 and / or a base difference at a nucleotide position adjacent to Z'2. In some embodiments, there is no base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 includes a base difference at position Z'2, and Z'2 is selected from C, A, or G. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 is a base difference at position Z'2, and Z'2 is selected from C, A, or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV linked to the 3' end of the nucleotide sequence II, the nucleotide sequence IV having a length of 1, 2, 3, or 4 nucleotides, each nucleotide in the nucleotide sequence IV being independently one of a non-fluoro-modified nucleotide, the nucleotide sequence IV being substantially reverse-complementary or fully reverse-complementary to APOE4 mRNA, each of the non-fluoro-modified nucleotide being independently selected from one of a 2'-methoxy-modified nucleotide, a 2'-alkyl-modified nucleotide having an alkyl group having a carbon number of 1-3, a 2'-amino-modified nucleotide, a 2'-substituted amino-modified nucleotide, and a thermally unstable nucleotide. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is A; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is AU from 5' end to 3' end; or, the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is AUU from 5' end to 3' end; or, the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is AUUA from 5' end to 3' end. In some embodiments, the single-stranded oligonucleotide of the present disclosure further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, and is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the sense strand, the nucleotide sequence V constitutes the 3' overhang end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V of the present disclosure has a length of 2 nucleotides, and from 5' end to 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or is fully reverse complementary to the APOE4 mRNA. In some embodiments, the nucleotide sequence V in the present disclosure is linked to the 3' end of the nucleotide sequence II, and from 5' end to 3' end, the base composition of the nucleotide sequence V is AU or AT, the A is a methoxy-modified nucleotide or GNA, and the T or U is a methoxy-modified nucleotide. In some embodiments, the single-stranded oligonucleotide comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 2, and the base composition of the nucleotide sequence V is AU. Second single-stranded oligonucleotide In some embodiments, the present disclosure provides a second single-stranded oligonucleotide. The single-stranded oligonucleotide comprises a nucleotide sequence II, the nucleotide sequence II has a length equal to the nucleotide sequence shown in SEQ ID NO: 4, and has no more than 3 base differences: 5'-Z4AAACUUGGUGAAUCUUUA-3' (SEQ ID NO: 4), wherein Z4 is G, A or U, the nucleotide sequence II comprises a nucleotide Z'4 at a position corresponding to Z4, and Z'4 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In some embodiments, the nucleotide sequence II has no more than 1 base difference from the nucleotide sequence set forth in SEQ ID NO: 4. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 can include a base difference at the Z'4 position and / or a base difference at any other nucleotide position in the nucleotide sequence II. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 can include a base difference at the Z'4 position and / or a base difference at a nucleotide position adjacent to Z'4. In some embodiments, there is no base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 includes a base difference at the Z'4 position, and Z'4 is selected from C, U, or A. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 is a base difference at the Z'4 position, and Z'4 is selected from C, U, or A. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is linked to the 3' end of the nucleotide sequence II, has a length of 1, 2, 3, or 4 nucleotides, each nucleotide in the nucleotide sequence IV is independently one of non-fluoro-modified nucleotides, the nucleotide sequence IV is substantially reverse-complementary or fully reverse-complementary to the APOE4 mRNA, and each of the non-fluoro-modified nucleotides is independently selected from one of 2'-methoxy-modified nucleotides, 2'-alkyl-modified nucleotides having an alkyl group of 1-3 carbon atoms, 2'-amino-modified nucleotides, 2'-substituted amino-modified nucleotides, and heat unstable nucleotides. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is U; or the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is UU in the direction from the 5' end to the 3' end; or the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is UUA in the direction from the 5' end to the 3' end; or the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is UUAA in the direction from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide of the present disclosure further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the sense strand, the nucleotide sequence V constitutes a 3' overhang end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V of the present disclosure has a length of 2 nucleotides, and in the direction from the 5' end to the 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or is fully reverse complementary to the APOE4 mRNA. In some embodiments, the nucleotide sequence V in the present disclosure is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is UU or TT, the T or U is a methoxy-modified nucleotide or GNA. In some embodiments, the single-stranded oligonucleotide only comprises the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 4, and the base composition of the nucleotide sequence V is UU. A third single-stranded oligonucleotide In some embodiments, the present disclosure provides a third single-stranded oligonucleotide. Wherein the single-stranded oligonucleotide comprises a nucleotide sequence II, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 6, and has no more than 3 base differences from the nucleotide sequence set forth in SEQ ID NO: 6: 5'-Z6GGCGUUCAGUGAUUGUCG-3' (SEQ ID NO: 6), Wherein Z6 is C, A or U, the nucleotide sequence II comprises a nucleotide Z'6 at the position corresponding to Z6, Z'6 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In some embodiments, the nucleotide sequence II has no more than 1 base difference from the nucleotide sequence set forth in SEQ ID NO: 6. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6 can include a base difference at the Z'6 position and / or a base difference at any other nucleotide position in the nucleotide sequence II. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6 can include a base difference at the Z'6 position and / or a base difference at the nucleotide position adjacent to Z'6. In some embodiments, there is no base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6 comprises a base difference at the Z'6 position, and Z'6 is selected from A, U, or G. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6 is a base difference at the Z'6 position, and Z'6 is selected from A, U, or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is linked to the 3' end of the nucleotide sequence II, has a length of 1, 2, 3, or 4 nucleotides, each nucleotide in the nucleotide sequence IV is independently one of the non-fluoro-modified nucleotides, the nucleotide sequence IV is substantially reverse-complementary or fully reverse-complementary to the APOE4 mRNA, and each of the non-fluoro-modified nucleotides is independently selected from one of 2'-methoxy-modified nucleotide, 2'-alkyl-modified nucleotide with carbon number of 1-3, 2'-amino-modified nucleotide, 2'-substituted amino-modified nucleotide, and heat unstable nucleotide. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is C; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is CU in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is CUG in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is CUGG in the direction from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide of the present disclosure further comprises a nucleotide sequence V, each nucleotide in the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V has a length of 1-3 nucleotides, and is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the positive strand, the nucleotide sequence V constitutes the 3' overhang end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V of the present disclosure has a length of 2 nucleotides, and in the direction from the 5' end to the 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or is fully reverse-complementary to the APOE4 mRNA. In some embodiments, the nucleotide sequence V in the present disclosure is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is CU or CT, the C is a methoxy-modified nucleotide or GNA, and the T or U is a methoxy-modified nucleotide. In some embodiments, the single-stranded oligonucleotide comprises only nucleotide sequence II and nucleotide sequence V, nucleotide sequence II consists of SEQ ID NO: 6, and nucleotide sequence V has a base composition of CU. A fourth single-stranded oligonucleotide In some embodiments, the present disclosure provides a fourth single-stranded oligonucleotide. Wherein the single-stranded oligonucleotide contains a nucleotide sequence II, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 8, and differs by no more than 3 bases from the nucleotide sequence set forth in SEQ ID NO: 8: 5'-Z8GAAUCUUUAUUAAACUAG-3' (SEQ ID NO: 8), wherein Z8 is U or A, the nucleotide sequence II comprises a nucleotide Z'8 at the position corresponding to Z8, and Z'8 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In some embodiments, the nucleotide sequence II differs by no more than 1 base from the nucleotide sequence set forth in SEQ ID NO: 8. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 8 can include a base difference at the Z'8 position and / or a base difference at any other nucleotide position in the nucleotide sequence II. In some embodiments, wherein the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 8 can include a base difference at the Z'8 position and / or a base difference at a nucleotide position adjacent to Z'8. In some embodiments, there is no base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 8. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 8 includes a base difference at the Z'8 position, and Z'8 is selected from C, A, or G. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 8 is a base difference at the Z'8 position, and Z'8 is selected from C, A, or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is 1, 2, 3, or 4 nucleotides in length, each nucleotide in the nucleotide sequence IV is independently one of the non-fluoro-modified nucleotides, the nucleotide sequence IV is substantially reverse-complementary or fully reverse-complementary to the APOE4 mRNA, each of the non-fluoro-modified nucleotides is independently selected from one of 2'-methoxy-modified nucleotide, 2'-alkyl-modified nucleotide with carbon number of 1-3, 2'-amino-modified nucleotide, 2'-substituted amino-modified nucleotide, and heat unstable nucleotide. In some embodiments, the nucleotide sequence IV is 2 nucleotides in length. In some embodiments, the nucleotide sequence IV is 1 nucleotide in length, the base is G; or, the nucleotide sequence IV is 2 nucleotides in length, the base composition is GG from 5' end to 3' end; or, the nucleotide sequence IV is 3 nucleotides in length, the base composition is GGU from 5' end to 3' end; or, the nucleotide sequence IV is 4 nucleotides in length, the base composition is GGUC from 5' end to 3' end. In some embodiments, the single-stranded oligonucleotide of the present disclosure further comprises a nucleotide sequence V, each nucleotide in the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V is 1-3 nucleotides in length, and is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the positive strand, the nucleotide sequence V constitutes the 3' overhang end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V of the present disclosure is 2 nucleotides in length, and is consecutive 2 thymine deoxynucleotides, consecutive 2 uracil nucleotides, or fully reverse-complementary to the APOE4 mRNA from 5' end to 3' end. In some embodiments, the nucleotide sequence V in the present disclosure is linked to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V is UU or GG from 5' end to 3' end, each of the G and U is independently a methoxy-modified nucleotide or GNA. In some embodiments, the single-stranded oligonucleotide comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 8, and the base composition of the nucleotide sequence V is GG. Fifth single-stranded oligonucleotide In some embodiments, the present disclosure provides a fifth single-stranded oligonucleotide. Wherein the single-stranded oligonucleotide contains a nucleotide sequence II, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 44, and differs by no more than 3 bases from the nucleotide sequence set forth in SEQ ID NO: 44: 5'-Z 10 AUUUGUAGGCCUUCAACU-3' (SEQ ID NO: 44), wherein Z 10 is G, A, or U, the nucleotide sequence II comprises a nucleotide Z' 10 corresponding to the position of Z 10 in the single-stranded oligonucleotide sequence 5' end. 10 Z' In some embodiments, the nucleotide sequence II differs by no more than 1 base from the nucleotide sequence set forth in SEQ ID NO: 44. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 44 can include a base difference at the position of Z' 10 and / or a base difference at any other nucleotide position in the nucleotide sequence II. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 44 can include a base difference at the position of Z' 10 and / or a base difference at the adjacent nucleotide position of Z' 10 . In some embodiments, there is no base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 44. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 44 includes a base difference at the position of Z' 10 , and Z' 10 is selected from A, U, or C. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 44 is a base difference at the position of Z' 10 , and Z' 10 is selected from A, U, or C. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is linked to the 3' end of the nucleotide sequence II, has a length of 1, 2, 3, or 4 nucleotides, each nucleotide in the nucleotide sequence IV is independently one of the non-fluoro-modified nucleotides, the nucleotide sequence IV is substantially reverse-complementary or fully reverse-complementary to the APOE4 mRNA, and each of the non-fluoro-modified nucleotides is independently selected from one of 2'-methoxy-modified nucleotide, 2'-alkyl-modified nucleotide with carbon number of 1-3, 2'-amino-modified nucleotide, 2'-substituted amino-modified nucleotide, and heat-unstable nucleotide. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is C; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is CC from 5' end to 3' end; or, the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is CCU from 5' end to 3' end; or, the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is CCUU from 5' end to 3' end. In some embodiments, the single-stranded oligonucleotide of the present disclosure further comprises a nucleotide sequence V, each nucleotide in the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V has a length of 1-3 nucleotides, and is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the positive strand, the nucleotide sequence V constitutes the 3' overhang end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V of the present disclosure has a length of 2 nucleotides, and from 5' end to 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or is fully reverse-complementary to the APOE4 mRNA. In some embodiments, the nucleotide sequence V in the present disclosure is linked to the 3' end of the nucleotide sequence II, and from 5' end to 3' end, the base composition of the nucleotide sequence V is CC or UU, each of the C and U is independently a methoxy-modified nucleotide or GNA. In some embodiments, the single-stranded oligonucleotide comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 44, and the base composition of the nucleotide sequence V is CC. Sixth single-stranded oligonucleotide In some embodiments, the present disclosure provides a sixth single stranded oligonucleotide. Wherein the single stranded oligonucleotide contains a nucleotide sequence II, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 46, and differs by no more than 3 bases from the nucleotide sequence set forth in SEQ ID NO: 46: 5'-Z 12 GCUUCUGCAGGUCAUCGG-3' (SEQ ID NO: 46), wherein Z 12 is C, A, or U, the nucleotide sequence II comprises a nucleotide Z' 12 at a position corresponding to Z 12 , the Z' 12 is the first nucleotide at the 5' end of the single stranded oligonucleotide sequence. In some embodiments, the nucleotide sequence II differs by no more than 1 base from the nucleotide sequence set forth in SEQ ID NO: 46. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 46 can include a base difference at the Z' 12 position and / or a base difference at any other nucleotide position in the nucleotide sequence II. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 46 can include a base difference at the Z' 12 position and / or a base difference at an adjacent nucleotide position to Z' 12 . In some embodiments, the nucleotide sequence II is identical to the nucleotide sequence set forth in SEQ ID NO: 46. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 46 includes a base difference at the Z' 12 position, and Z' 12 is selected from A, U, or G. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 46 is a base difference at the Z' 12 position, and Z' 12 is selected from A, U, or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is linked to the 3' end of the nucleotide sequence II, has a length of 1, 2, 3, or 4 nucleotides, each nucleotide in the nucleotide sequence IV is independently one of the non-fluoro-modified nucleotides, the nucleotide sequence IV is substantially reverse-complementary or fully reverse-complementary to the APOE4 mRNA, each of the non-fluoro-modified nucleotides is independently selected from one of 2'-methoxy-modified nucleotide, 2'-alkyl-modified nucleotide with carbon number of 1-3, 2'-amino-modified nucleotide, 2'-substituted amino-modified nucleotide, and heat-unstable nucleotide. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is C; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is CA from 5' end to 3' end; or, the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is CAU from 5' end to 3' end; or, the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is CAUC from 5' end to 3' end. In some embodiments, the single-stranded oligonucleotide of the present disclosure further comprises a nucleotide sequence V, each nucleotide in the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V has a length of 1-3 nucleotides, and is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the positive strand, the nucleotide sequence V constitutes the 3' overhang end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V of the present disclosure has a length of 2 nucleotides, and from 5' end to 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or is fully reverse-complementary to the APOE4 mRNA. In some embodiments, the nucleotide sequence V in the present disclosure is linked to the 3' end of the nucleotide sequence II, and from 5' end to 3' end, the base composition of the nucleotide sequence V is CA or UU, each of the U, C, and A is independently a methoxy-modified nucleotide or GNA. In some embodiments, the single-stranded oligonucleotide comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 46, and the base composition of the nucleotide sequence V is CA. In some embodiments, the single-stranded oligonucleotide is the antisense strand of any one of siRNAa1-siRNAf1 listed in Table 1; Alternatively, the single stranded oligonucleotide is the antisense strand of siRNA 1 listed in Table 2A; Alternatively, the single stranded oligonucleotide is the antisense strand of any one of conjugate 1-conjugate 9 and conjugate 11-conjugate 27 listed in Table 2A. In some embodiments, the single stranded oligonucleotide of the present disclosure can independently exert a pharmacodynamic activity. In some embodiments, the single stranded oligonucleotide of the present disclosure is an antisense oligonucleotide (ASO). In some embodiments, the single stranded oligonucleotide of the present disclosure is a single stranded RNAi (ssRNAi) compound. In some embodiments, the single stranded oligonucleotide of the present disclosure exerts a pharmacodynamic activity as one single strand (e.g., antisense strand) of a double stranded oligonucleotide. The double stranded oligonucleotide of the present disclosure In another aspect, the present disclosure also provides a double stranded oligonucleotide comprising a sense strand and an antisense strand, each nucleotide in the sense strand being a modified or unmodified nucleotide, the sense strand and the antisense strand being at least partially reverse complementary to form a double stranded region, wherein the antisense strand is a single stranded oligonucleotide as described in the present disclosure above. In the double stranded oligonucleotide of the present disclosure, the length of the sense strand and the antisense strand is 19-26 nucleotides. In some embodiments, the length of the antisense strand is no less than the length of the sense strand. In some embodiments, the length of the sense strand is 19-23 nucleotides. Thus, the ratio of the length of the sense strand and the antisense strand of the double stranded oligonucleotide of the present disclosure can be 19 / 19, 19 / 20, 19 / 21, 19 / 22, 19 / 23, 19 / 24, 20 / 20, 20 / 21, 20 / 22, 20 / 23, 20 / 24, 21 / 21, 21 / 22, 21 / 23, 21 / 24, 22 / 22, 22 / 23, 22 / 24, 22 / 25, 23 / 23, 23 / 24, 23 / 25, or 23 / 26. In some embodiments, for the sake of simplicity in synthesis, the length of the sense strand is 19-21 nucleotides, and the length of the antisense strand is 19-23 nucleotides. In some embodiments, the length of the sense strand and the antisense strand is the same, both being 19, 20, or 21 nucleotides. In some embodiments, the length of the sense strand is 19 nucleotides, and the length of the antisense strand is 20-24 nucleotides. In some embodiments, the length of the sense strand is 20 nucleotides, and the length of the antisense strand is 21-24 nucleotides. In some embodiments, the length of the sense strand is 21 nucleotides, and the length of the antisense strand is 22-24 nucleotides. In some embodiments, the length of the sense strand is 19 nucleotides, and the length of the antisense strand is 21 nucleotides. In some embodiments, the length of the sense strand is 21 nucleotides, and the length of the antisense strand is 23 nucleotides. In some embodiments, in the sense strand of the double stranded oligonucleotide of the present disclosure, 2-3 of the 11th-13thnucleotides from the 3' end to the 5' end are fluorinated nucleotides, the 1stnucleotide is an alkoxy-modified nucleotide or an inverted abasic deoxyribonucleotide (abbreviated as invab or ia, having a structure as shown in formula (35)), and the nucleotides at the remaining positions are non-fluorinated nucleotides, each of which is independently selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, an amine-modified nucleotide, and a thermally unstable nucleotide. In some embodiments, in the sense strand of the double stranded oligonucleotide of the present disclosure, the 11thand 13thnucleotides, or the 11th-13thnucleotides from the 3' end to the 5' end are fluorinated nucleotides, the 1stnucleotide is an inverted abasic deoxyribonucleotide, and the nucleotides at the remaining positions are all alkoxy-modified nucleotides. In some embodiments, each of the alkoxy-modified nucleotides is a methoxy-modified nucleotide. In some embodiments, in the sense strand, at least one of the linking groups connecting adjacent two nucleotides is a phosphate group with a modification group, which is present between adjacent nucleotides in the 1st-5thnucleotides at the 5' end and / or between adjacent nucleotides in the 1st-5thnucleotides at the 3' end. In some embodiments, 1-4 of the linking groups between adjacent nucleotides in the 1st-5thnucleotides at the 5' end, and / or 1-4 of the linking groups between adjacent nucleotides in the 1st-5thnucleotides at the 3' end are phosphate groups with a modification group. In some embodiments, the linking groups connecting adjacent nucleotides in the 1st-3rd, 1st-4th, or 1st-5thnucleotides at the 5' end and / or 3' end of the sense strand are phosphate groups with a modification group. The phosphate group with a modification group is defined and selected from the same range as described above for the phosphate group with a modification group in the antisense strand of the present disclosure. In some embodiments, each of the phosphate groups with a modification group is a phosphorothioate group having a structure as shown in formula (28). In some embodiments, the sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; in the sense strand, the 11thand 13thnucleotides, or the 11th-13thnucleotides from the 3' end to the 5' end are fluorinated nucleotides, the 1stnucleotide is a methoxy-modified nucleotide or an inverted abasic deoxyribonucleotide, and the nucleotides at the remaining positions are all methoxy-modified nucleotides. In some embodiments, 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides from the 5' end of the sense strand, and / or 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides from the 3' end of the sense strand are phosphorothioate groups. In some embodiments, the linking group between every two adjacent nucleotides in the 1st-2nd, 1st-3rd, 1st-4th or 1st-5th nucleotides from the 5' and / or 3' end of the sense strand is a phosphorothioate group, and the remaining adjacent nucleotides in the sense strand are linked by phosphate groups. In some embodiments, the linking group between every two adjacent nucleotides in the 1st-3rd, 1st-4th or 1st-5th nucleotides from the 5' end of the sense strand is a phosphorothioate group, and the remaining adjacent nucleotides in the sense strand are linked by phosphate groups. In some embodiments, the linking group between every two adjacent nucleotides in the 1st-2nd, 1st-3rd, 1st-4th or 1st-5th nucleotides from the 3' end of the sense strand is a phosphorothioate group, and the remaining adjacent nucleotides in the sense strand are linked by phosphate groups. In some embodiments, all adjacent nucleotides in the sense strand are linked by phosphate groups. In some embodiments, in the double-stranded oligonucleotide of the present disclosure, the sense strand comprises 19 nucleotides, and the antisense strand comprises 21 nucleotides; in the sense strand, the 11th and 13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide is an inverted deoxy-ribonucleotide, and the nucleotides at the remaining positions are methoxy-modified nucleotides; 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides from the 5' end of the sense strand, and / or 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides from the 3' end of the sense strand are phosphorothioate groups. In some embodiments, in the antisense strand, the 14th nucleotide is a deoxy nucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluoro-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide, in the 5' to 3' direction. In some embodiments, in the antisense strand, the 14th nucleotide is a deoxy nucleotide, the 2nd, 7th, 12th, 16th and 19th nucleotides are fluoro-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide, in the 5' to 3' direction. In some embodiments, in the antisense strand, the 14th nucleotide is a deoxy nucleotide, the 2nd, 6th, 12th, 16th and 19th nucleotides are fluoro-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide, in the 5' to 3' direction. In some embodiments, in the antisense strand, the 12th and 14th nucleotides are deoxy nucleotides, the 2nd, 7th and 16th nucleotides are fluoro-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide, in the 5' to 3' direction. In some embodiments, in the antisense strand, the 14th nucleotide is a deoxy nucleotide, the 16th nucleotide is an unmodified nucleotide, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 2nd and 6th nucleotides are fluoro-modified nucleotides, the 2nd nucleotide in the 5' to 3' direction is a thermally destabilizing nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide. In some embodiments, in the antisense strand, the 14th nucleotide is a deoxy nucleotide, the 19th nucleotide is an unmodified nucleotide, the 2nd, 6th and 16th nucleotides are fluoro-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide. In some embodiments, in the antisense strand, each of the linking groups between adjacent nucleotides in the 1st to 3rd nucleotides at the 5' end and in the 1st to 3rd nucleotides at the 3' end of the antisense strand is a phosphate group with a modification group, and if there is an unmodified nucleotide, 1-2 of the 2 linking groups between each of the unmodified nucleotide and the adjacent nucleotides is a phosphate group with a modification group. In some embodiments, the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide of formula (29), a 5'-phosphate nucleotide of formula (30), or a 5'-vinylphosphate modified nucleotide of formula (31). The double-stranded oligonucleotide of the present disclosure is capable of achieving a good balance between gene expression modulating activity and in vivo stability by having the above-mentioned modification scheme. In the context of the present disclosure, the “modification scheme” refers to a combination of different numbers, positions, and types of nucleotide ribose modifications, phosphate modifications, 5’-end modifications, and / or base modifications that are not or weakly related to a specific sequence. In some embodiments, the double-stranded oligonucleotide of the present disclosure is capable of achieving a good balance between gene expression modulating activity and in vivo stability by having the above-mentioned modification scheme, while maintaining excellent stability without significantly reducing the original pharmaceutical activity of the double-stranded oligonucleotide. In some embodiments, the double-stranded oligonucleotide of the present disclosure is siRNA, and the double-stranded oligonucleotide of the present disclosure is capable of achieving a good balance between APOE4 mRNA inhibitory activity and in vivo stability by having the above-mentioned modification scheme, while maintaining excellent stability without significantly reducing the original RNAi activity of the siRNA. In some embodiments, the double-stranded oligonucleotide of the present disclosure consists of a double-stranded region that is substantially reverse-complementary or fully reverse-complementary, and one or two overhanging ends of the sense strand and / or one or two overhanging ends of the antisense strand. In some embodiments, the double-stranded oligonucleotide of the present disclosure consists of a double-stranded region that is substantially reverse-complementary or fully reverse-complementary and one overhanging end of the antisense strand. In the context of the present disclosure, the “double-stranded region” is a double-stranded structure formed between the shortest nucleotide sequences including all base pairs and all base mismatches located between the base pairs on each single strand in a double-stranded nucleic acid structure. Thus, the double-stranded region consists of all base pairs and all base mismatches located between the base pairs in a double-stranded nucleic acid structure. In some embodiments, the number of base mismatches is not more than 20%, 15%, 10%, or 5% of the total number of base pairs forming the double-stranded region. In some embodiments, the number of base mismatches in the double-stranded region is not more than 3, not more than 2, or not more than 1. In some embodiments, the double-stranded nucleic acid structure includes the double-stranded region and one or more overhanging ends composed of nucleotides that do not form base pairs on one or both single strands. In some embodiments, the double-stranded nucleic acid structure includes only the double-stranded region. In some embodiments, the sense strand and the antisense strand form a double-stranded region spanning at least 16 nucleotide positions, i.e., the sense strand and the antisense strand form a double-stranded region comprising at least 16 base pairs. In the context of the present disclosure, each base pair forming the double-stranded region is independently complementary or mismatched. In some embodiments, the sense strand and the antisense strand form a double-stranded region spanning 16-23 nucleotide positions, i.e., the sense strand and the antisense strand form a double-stranded region comprising 16-23 base pairs. In some embodiments, the sense strand and the antisense strand form a double-stranded region spanning 18, 19, 20, or 21 nucleotide positions, i.e., the sense strand and the antisense strand form a double-stranded region comprising 18, 19, 20, or 21 base pairs. In some embodiments, the sense strand and the antisense strand are substantially reverse complementary or fully reverse complementary within the double-stranded region. In some embodiments, the sense strand and the antisense strand of the double-stranded oligonucleotide of the present disclosure are substantially reverse complementary or fully reverse complementary over the entire nucleotide length. In some embodiments, the number of base differences between the sense strand and the APOE4 mRNA is no more than 3, no more than 2, or no more than 1. In some embodiments, there is no base difference between the sense strand and the APOE4 mRNA. In the foregoing and hereinafter, a nucleotide sequence and another nucleotide sequence have “base differences” if the base type of a nucleotide at a same position in the former is different from that in the latter, e.g., if a nucleotide base in the latter is A, and the corresponding nucleotide base at the same position in the former is U, C, G, or T, it is recognized that there is a base difference between the two nucleotide sequences at the position. When a base is modified, as long as the modification does not affect the purine-pyrimidine pairing relationship when forming the double-stranded nucleic acid structure described above, it is also recognized that there is no base difference between the modified base and the original base. In some embodiments, it is recognized that there is no base difference between U and T. In some embodiments, it is recognized that there is no base difference between C and 5-methylcytosine (5mC). In some embodiments, when a nucleotide at a position is replaced with an abasic nucleotide or an equivalent thereof, it is also recognized that a base difference is generated at the position. When aligning two nucleotide sequences to determine the number of base differences, the alignment is performed in a manner that has the least number of base differences among all possible alignments, and the base differences are determined based on the alignment. At this time, the “same position” refers to the corresponding position between the two nucleotide sequences in the alignment. For example, when nucleotide sequence A positions 1-5 are aligned with nucleotide sequence B positions 2-6 in the same direction, and the number of base differences is the least compared to other alignments, the “same position” refers to the alignment of nucleotide sequence A position 1 with nucleotide sequence B position 2, nucleotide sequence A position 2 with nucleotide sequence B position 3, and so on. In some embodiments, the number of base differences between two nucleotide sequences of different lengths is the total number of base differences between the first nucleotide to the last nucleotide of the shorter nucleotide sequence and each corresponding nucleotide of the other nucleotide sequence, in the same orientation. In some embodiments, the number of base differences between two nucleotide sequences of the same length is the total number of base differences between the first nucleotide to the last nucleotide of either nucleotide sequence and the first nucleotide to the last nucleotide of the other nucleotide sequence, in the same orientation. In some embodiments, the absence of base differences between two nucleotide sequences of different lengths is the absence of base differences between the first nucleotide to the last nucleotide of the shorter nucleotide sequence and each corresponding nucleotide of the other nucleotide sequence, in the same orientation. In some embodiments, the absence of base differences between two nucleotide sequences of the same length is the absence of base differences between the first nucleotide to the last nucleotide of one nucleotide sequence and the first nucleotide to the last nucleotide of the other nucleotide sequence, in the same orientation. The double-stranded oligonucleotide of the present disclosure can be various double-stranded oligonucleotides that modulate the level of APOE4 mRNA. In some embodiments, it can be a double-stranded oligonucleotide that inhibits or down-regulates the level of APOE4 mRNA, such as siRNA; in some embodiments, it can be a double-stranded oligonucleotide that activates or up-regulates the level of APOE4 mRNA, such as saRNA. In some embodiments, the double-stranded oligonucleotide is siRNA. In some embodiments, the siRNA of the present disclosure can be the first to sixth siRNAs described below, each of which is described below. The first siRNA In some embodiments, the present disclosure provides the first siRNA. The first siRNA contains a sense strand and an antisense strand, the sense strand contains a nucleotide sequence I consisting of 19 nucleotides, the nucleotide sequence I is equal in length to the nucleotide sequence shown in SEQ ID NO: 1, and no more than 3 base differences, the nucleotide sequence II is equal in length to the nucleotide sequence shown in SEQ ID NO: 2, and no more than 3 base differences: 5'-AAAGAUUCACCAAGUUUCZ1-3' (SEQ ID NO: 1) 5'-Z2GAAACUUGGUGAAUCUUU-3' (SEQ ID NO: 2); wherein Z1 is A or an inverted abasic deoxy nucleotide (ia), Z2 is U or A, the nucleotide sequence I comprises a nucleotide Z'1 at a position corresponding to Z1, the nucleotide sequence II comprises a nucleotide Z'2 at a position corresponding to Z2, and Z'2 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand comprises only the nucleotide sequence I, and the antisense strand comprises only the nucleotide sequence II. In some embodiments, there is no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 1, and / or there is no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 1 can include a base difference at the Z'1 position and / or a base difference at any other nucleotide position in the nucleotide sequence I. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 1 can include a base difference at the Z'1 position and / or a base difference at a nucleotide position adjacent to Z'1. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 1 is a base difference at the Z'1 position, preferably, Z'1 is an inverted abasic deoxy nucleotide. In some embodiments, there is no base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 1. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 includes a base difference at the Z'2 position, and Z'2 is selected from C, A or G. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 is a base difference at the Z'2 position, and Z'2 is selected from C, A or G. In some embodiments, there is no base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2. In some embodiments, the 2nd-19th nucleotides of the nucleotide sequence II are fully reverse-complementary to the 1st-17th nucleotides of the nucleotide sequence I in the direction from 5' end to 3' end. In some embodiments, the nucleotide sequence II is fully reverse-complementary to the nucleotide sequence I. In some embodiments, the 2nd nucleotide in the nucleotide sequence II is base-mismatched to the 2nd nucleotide in the nucleotide sequence I in the direction from 3' end to 5' end. By including the base-mismatch, one can have a higher siRNA target gene expression inhibition activity while maintaining a low off-target effect. In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3, or 4 nucleotides, the nucleotide sequence IV and the nucleotide sequence III have equal length, and the nucleotide sequence IV and the nucleotide sequence III are substantially reverse complementary or fully reverse complementary, the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 1 nucleotide, the nucleotide sequence III has a base of U, and the nucleotide sequence IV has a base of A, in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 2 nucleotides, the nucleotide sequence III has a base composition of AU, and the nucleotide sequence IV has a base composition of AU, in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 3 nucleotides, the nucleotide sequence III has a base composition of AAU, and the nucleotide sequence IV has a base composition of AUU, in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 4 nucleotides, the nucleotide sequence III has a base composition of UAAU, and the nucleotide sequence IV has a base composition of AUUA, in the direction from the 5' end to the 3' end. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the antisense strand after forming the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and in the direction from the 5' end to the 3' end, the nucleotide sequence V is two consecutive thymine deoxyribonucleotides, two consecutive uracil ribonucleotides, or fully reverse complementary to the APOE4 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is selected from AU or UU. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 2, the nucleotide sequence I consists of SEQ ID NO: 1, the nucleotide sequence V is linked at the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V is AU in the direction from the 5' end to the 3' end. The second siRNA In some embodiments, the present disclosure provides a second siRNA. The second siRNA comprises a sense strand and an antisense strand, the sense strand comprises a nucleotide sequence I, the nucleotide sequence I consists of 19 nucleotides, the nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 3, and no more than 3 base differences, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 4, and no more than 3 base differences: 5'-UAAAGAUUCACCAAGUUUZ3-3' (SEQ ID NO: 3) 5'-Z4AAACUUGGUGAAUCUUUA-3' (SEQ ID NO: 4); wherein Z3 is C, A or inverted abasic deoxynucleotide (ia), Z4 is G, A or U, the nucleotide sequence I comprises a nucleotide Z'3 at a position corresponding to Z3, the nucleotide sequence II comprises a nucleotide Z'4 at a position corresponding to Z4, and the Z'4 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand comprises only the nucleotide sequence I, and the antisense strand comprises only the nucleotide sequence II. In some embodiments, there is no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 3, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 3 can include a base difference at position Z'3 and / or a base difference at any other nucleotide position in the nucleotide sequence I. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 3 can include a base difference at position Z'3 and / or a base difference at a nucleotide position adjacent to Z'3. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 3 is a base difference at position Z'3. In some embodiments, Z'3 is an inverted dealkylated deoxynucleotide. In some embodiments, there is no base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 3. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 includes a base difference at position Z'4, and Z'4 is selected from C, U or A. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 is a base difference at position Z'4, and Z'4 is selected from C, U or A. In some embodiments, there is no base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4. In some embodiments, the 2nd to 19th nucleotides of the nucleotide sequence II are fully reverse-complementary to the 1st to 17th nucleotides of the nucleotide sequence I in the 5' end to 3' end direction. In some embodiments, the nucleotide sequence II is fully reverse-complementary to the nucleotide sequence I. In some embodiments, there is a base mismatch between the 2nd nucleotide in the nucleotide sequence II and the 2nd nucleotide in the nucleotide sequence I in the 5' end to 3' end direction and in the 3' end to 5' end direction, respectively. By including the base mismatch, a higher siRNA target gene expression inhibition activity can be achieved while maintaining a low off-target effect. In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3 or 4 nucleotides, the nucleotide sequence IV and the nucleotide sequence III have an equal length, and the nucleotide sequence IV and the nucleotide sequence III are substantially reverse-complementary or fully reverse-complementary, and the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the length of the nucleotide sequence III and the nucleotide sequence IV is 1 nucleotide, the base of the nucleotide sequence III is A, and the base of the nucleotide sequence IV is U, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand and the antisense strand is 20 / 20. In some embodiments, the length of the nucleotide sequence III and the nucleotide sequence IV is 2 nucleotides, the base composition of the nucleotide sequence III is AA, and the base composition of the nucleotide sequence IV is UU, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand and the antisense strand is 21 / 21. In some embodiments, the length of the nucleotide sequence III and the nucleotide sequence IV is 3 nucleotides, the base composition of the nucleotide sequence III is UAA, and the base composition of the nucleotide sequence IV is UUA, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand and the antisense strand is 22 / 22. In some embodiments, the length of the nucleotide sequence III and the nucleotide sequence IV is 4 nucleotides, the base composition of the nucleotide sequence III is UUAA, and the base composition of the nucleotide sequence IV is UUAA, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand and the antisense strand is 23 / 23. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the length of the nucleotide sequence V is 1 to 3 nucleotides, the nucleotide sequence V is connected to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the antisense strand after forming the double-stranded oligonucleotide. In some embodiments, the length of the nucleotide sequence V is 2 nucleotides, and the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the APOE4 mRNA, in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence V is connected to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V is UU, in the direction from the 5' end to the 3' end. In some embodiments, the sense strand only comprises the nucleotide sequence I, the antisense strand only comprises the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 4, the nucleotide sequence I consists of SEQ ID NO: 3, the nucleotide sequence V is connected to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V is UU, in the direction from the 5' end to the 3' end. The third siRNA In some embodiments, the present disclosure also provides a third siRNA. The third siRNA comprises a sense strand and an antisense strand, the sense strand comprises a nucleotide sequence I consisting of 19 nucleotides, the nucleotide sequence I is identical to the nucleotide sequence set forth in SEQ ID NO: 5 except for no more than 3 base differences, the nucleotide sequence II is identical to the nucleotide sequence set forth in SEQ ID NO: 6 except for no more than 3 base differences: 5'-CGACAAUCACUGAACGCCZ5-3' (SEQ ID NO: 5) 5'-Z6GGCGUUCAGUGAUUGUCG-3' (SEQ ID NO: 6); wherein Z5 is G, A or inverted deoxyabasic nucleotide (ia), Z6 is C, A or U, the nucleotide sequence I comprises a nucleotide Z'5 at a position corresponding to Z5, the nucleotide sequence II comprises a nucleotide Z'6 at a position corresponding to Z6, the Z'6 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand comprises only the nucleotide sequence I, and the antisense strand comprises only the nucleotide sequence II. In some embodiments, there are no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 5, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 5 can include a base difference at the Z'5 position and / or a base difference at any other nucleotide position in the nucleotide sequence I. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 5 can include a base difference at the Z'5 position and / or a base difference at a nucleotide position adjacent to Z'5. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 5 is a base difference at the Z'5 position, preferably, Z'5 is an inverted deoxyabasic nucleotide. In some embodiments, there is no base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 5. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6 comprises a base difference at position Z'6, and Z'6 is selected from A, U, or G. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6 is a base difference at position Z'6, and Z'6 is selected from A, U, or G. In some embodiments, there is no base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6. In some embodiments, the nucleotide at position 2-19 of the nucleotide sequence II is fully complementary to the nucleotide at position 1-17 of the nucleotide sequence I in the direction from 5' end to 3' end. In some embodiments, the nucleotide sequence II is fully complementary to the nucleotide sequence I. In some embodiments, there is a base mismatch between the 2nd nucleotide in the nucleotide sequence II and the 2nd nucleotide in the nucleotide sequence I in the direction from 5' end to 3' end. By including this base mismatch, one can have a higher siRNA target gene expression inhibitory activity while maintaining a low off-target effect. In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3, or 4 nucleotides, the nucleotide sequence IV and the nucleotide sequence III have an equal length, and the nucleotide sequence IV and the nucleotide sequence III are substantially or fully complementary, the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 1 nucleotide, the base of the nucleotide sequence III is G, and the base of the nucleotide sequence IV is C, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 20 / 20. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 2 nucleotides, the base composition of the nucleotide sequence III is AG, and the base composition of the nucleotide sequence IV is CU, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 3 nucleotides, the base composition of the nucleotide sequence III is CAG, and the base composition of the nucleotide sequence IV is CUG, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 22 / 22. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 4 nucleotides, the base composition of the nucleotide sequence III is CCAG, and the base composition of the nucleotide sequence IV is CUGG, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 23 / 23. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the length of the nucleotide sequence V is 1 to 3 nucleotides, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the antisense strand after the double-stranded oligonucleotide is formed. In some embodiments, the length of the nucleotide sequence V is 2 nucleotides, and the nucleotide sequence V is, in the direction from the 5' end to the 3' end, 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the APOE4 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V, in the direction from the 5' end to the 3' end, is selected from CU or UU. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 6, the nucleotide sequence I consists of SEQ ID NO: 5, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V, in the direction from the 5' end to the 3' end, is CU. The fourth siRNA In some embodiments, the present disclosure also provides a fourth siRNA. The fourth siRNA comprises a sense strand and an antisense strand, the sense strand comprises a nucleotide sequence I consisting of 19 nucleotides, the nucleotide sequence I is identical to the nucleotide sequence set forth in SEQ ID NO: 7 except for no more than 3 base differences, the nucleotide sequence II is identical to the nucleotide sequence set forth in SEQ ID NO: 8 except for no more than 3 base differences: 5'-CUAGUUUAAUAAAGAUUCZ7-3' (SEQ ID NO: 7) 5'-Z8GAAUCUUUAUUAAACUAG-3' (SEQ ID NO: 8); wherein Z7 is A or inverted deoxyabasic nucleotide (ia), Z8 is U or A, the nucleotide sequence I comprises a nucleotide Z'7 at a position corresponding to Z7, the nucleotide sequence II comprises a nucleotide Z'8 at a position corresponding to Z8, the Z'8 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand comprises only the nucleotide sequence I, and the antisense strand comprises only the nucleotide sequence II. In some embodiments, there are no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 7, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 8. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 7 can include a base difference at Z'5 position and / or any other nucleotide position in the nucleotide sequence I. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 7 can include a base difference at Z'7 position and / or at a nucleotide position adjacent to Z'7. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 7 is a base difference at Z'7 position, preferably Z'7 is an inverted deoxyabasic nucleotide. In some embodiments, there is no base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 7. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 8 comprises a base difference at position Z'8, wherein Z'8 is selected from C, A, or G. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 8 is a base difference at position Z'8, and Z'8 is selected from C, A, or G. In some embodiments, there is no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 8. In some embodiments, the nucleotide at position 2-19 of the nucleotide sequence II is fully complementary to the nucleotide at position 1-17 of the first nucleotide sequence, in the 5' end to 3' end direction. In some embodiments, the nucleotide sequence II is fully complementary to the nucleotide sequence I. In some embodiments, the 2nd nucleotide in the nucleotide sequence II is base mismatched with the 2nd nucleotide in the nucleotide sequence I, in the 5' end to 3' end direction and the 3' end to 5' end direction, respectively. By including the base mismatch, one can have a higher siRNA target gene expression inhibitory activity while maintaining a low off-target effect. In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3, or 4 nucleotides, the nucleotide sequence IV and the nucleotide sequence III have an equal length, and the nucleotide sequence IV and the nucleotide sequence III are substantially or fully complementary, the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 1 nucleotide, the base of the nucleotide sequence III is C, and the base of the nucleotide sequence IV is G, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 20 / 20. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 2 nucleotides, the base composition of the nucleotide sequence III is CC, and the base composition of the nucleotide sequence IV is GG, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 3 nucleotides, the base composition of the nucleotide sequence III is ACC, and the base composition of the nucleotide sequence IV is GGU, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 22 / 22. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 4 nucleotides, the base composition of the nucleotide sequence III is GACC, and the base composition of the nucleotide sequence IV is GGUC, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 23 / 23. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the length of the nucleotide sequence V is 1 to 3 nucleotides, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the antisense strand after the double-stranded oligonucleotide is formed. In some embodiments, the length of the nucleotide sequence V is 2 nucleotides, and the nucleotide sequence V is, in the direction from the 5' end to the 3' end, 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the APOE4 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V, in the direction from the 5' end to the 3' end, is selected from GG or UU. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 8, the nucleotide sequence I consists of SEQ ID NO: 7, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V, in the direction from the 5' end to the 3' end, is GG. The fifth siRNA In some embodiments, this disclosure provides a fifth siRNA. This fifth siRNA contains a sense strand and an antisense strand, wherein the sense strand contains nucleotide sequence I, which consists of 19 nucleotides, and nucleotide sequence I is of the same length as the nucleotide sequence shown in SEQ ID NO:43, and differs from it by no more than 3 bases; nucleotide sequence II is of the same length as the nucleotide sequence shown in SEQ ID NO:44, and differs from it by no more than 3 bases. 5'-AGUUGAAGGCCUACAAAUZ9-3'(SEQ ID NO:43) 5'-Z 10 AUUUGUAGGCCUUCAACU-3' (SEQ ID NO:44), Where Z9 is a C or reverse debased deoxynucleotide (ia), Z 10 The nucleotide sequence is G, A, or U, wherein nucleotide sequence I contains a nucleotide Z'9 at position Z9, and nucleotide sequence II contains a nucleotide at position Z... 10 nucleotide Z' 10 The Z' 10 It is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand contains only nucleotide sequence I, and the antisense strand contains only nucleotide sequence II. In some embodiments, the nucleotide sequence I differs from the nucleotide sequence shown in SEQ ID NO:43 by no more than one base, and / or the nucleotide sequence II differs from the nucleotide sequence shown in SEQ ID NO:44 by no more than one base. The base difference between the nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:43 may include a base difference at the Z'9 position and / or a base difference at any other nucleotide position in nucleotide sequence I. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:43 may include a base difference at the Z'9 position and / or a base difference at a nucleotide position adjacent to Z'9. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:43 is a base difference at the Z'9 position, preferably, Z'9 is a reverse debased deoxynucleotide. In some embodiments, there is no base difference between the nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:43. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:44 includes Z' 10 The base difference at the position, and Z' 10selected from C, A, or U. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 44 is Z 10 a base difference at the position, and Z 10 selected from C, A, or U. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 44 is Z In some embodiments, the nucleotide at position 2-19 of the nucleotide sequence II is fully complementary to the nucleotide at position 1-17 of the nucleotide sequence I in the direction from 5' end to 3' end. In some embodiments, the nucleotide sequence II is fully complementary to the nucleotide sequence I. In some embodiments, there is a base mismatch between the 2ndnucleotide in the nucleotide sequence II and the 2ndnucleotide in the nucleotide sequence I in the direction from 5' end to 3' end. By including this base mismatch, one can have a higher siRNA target gene expression inhibition activity while maintaining a low off-target effect. In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3, or 4 nucleotides, the nucleotide sequence IV and the nucleotide sequence III have an equal length, and the nucleotide sequence IV and the nucleotide sequence III are substantially complementary or fully complementary, and the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each have a length of 1 nucleotide in the direction from 5' end to 3' end, the nucleotide sequence III has a base of G, and the nucleotide sequence IV has a base of C; in this case, the length ratio of the sense strand and the antisense strand is 20 / 20. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each have a length of 2 nucleotides, the nucleotide sequence III has a base composition of GG in the direction from 5' end to 3' end, and the nucleotide sequence IV has a base composition of CC; in this case, the length ratio of the sense strand and the antisense strand is 21 / 21. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each have a length of 3 nucleotides, the nucleotide sequence III has a base composition of AGG in the direction from 5' end to 3' end, and the nucleotide sequence IV has a base composition of CCU; in this case, the length ratio of the sense strand and the antisense strand is 22 / 22. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each have a length of 4 nucleotides, the nucleotide sequence III has a base composition of AAGG in the direction from 5' end to 3' end, and the nucleotide sequence IV has a base composition of CCUU; in this case, the length ratio of the sense strand and the antisense strand is 23 / 23. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, is linked to the 3’-end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3’-overhang end of the antisense strand after forming the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and in the direction from the 5’-end to the 3’-end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse-complementary to the APOE4 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3’-end of the nucleotide sequence II, and in the direction from the 5’-end to the 3’-end, the base composition of the nucleotide sequence V is selected from CC or UU. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 44, the nucleotide sequence I consists of SEQ ID NO: 43, the nucleotide sequence V is linked to the 3’-end of the nucleotide sequence II, and in the direction from the 5’-end to the 3’-end, the base composition of the nucleotide sequence V is CC. Sixth siRNA In some embodiments, the disclosure provides a sixth siRNA. The sixth siRNA comprises a sense strand and an antisense strand, the sense strand comprises a nucleotide sequence I, the nucleotide sequence I consists of 19 nucleotides, the nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 45, and differs by no more than 3 bases, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 46, and differs by no more than 3 bases: 5'-CCGAUGACCUGCAGAAGCZ 11 -3'(SEQ ID NO: 45) 5'-Z 12 GCUUCUGCAGGUCAUCGG-3'(SEQ ID NO: 46), wherein Z 11 is G or an inverted abasic deoxynucleotide (ia), Z 12 is C, A or U, the nucleotide sequence I comprises a nucleotide Z' 11 corresponding to the position of Z 11 , and the nucleotide sequence II comprises a nucleotide Z' 12 corresponding to the position of Z 12 , the Z' 12is the first nucleotide of the 5' terminus of the antisense strand. In some embodiments, the sense strand comprises only the nucleotide sequence I, and the antisense strand comprises only the nucleotide sequence II. In some embodiments, there is no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 45, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 46. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 45 can comprise a base difference at position Z 11 and / or a base difference at any other nucleotide position in the nucleotide sequence I. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 45 can comprise a base difference at position Z 11 and / or a base difference at a nucleotide position adjacent to Z 11 In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 45 is a base difference at position Z 11 , preferably Z 11 is an inverted abasic deoxynucleotide. In some embodiments, there is no base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 45. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 46 comprises a base difference at position Z 12 , and Z 12 is selected from G, A, or U. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 46 is a base difference at position Z 12 , and Z 12 is selected from G, A, or U. In some embodiments, there is no base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 46. In some embodiments, the nucleotides at positions 2-19 of the nucleotide sequence II are fully reverse-complementary to the nucleotides at positions 1-17 of the nucleotide sequence I, in the 5' end to 3' end direction. In some embodiments, the nucleotide sequence II is fully reverse-complementary to the nucleotide sequence I. In some embodiments, there is a base mismatch between the 2nd nucleotide in the nucleotide sequence II and the 2nd nucleotide in the nucleotide sequence I, in the 5' end to 3' end direction and in the 3' end to 5' end direction, respectively. By including this base mismatch, one can have a higher siRNA target gene expression inhibitory activity while maintaining a low off-target effect. In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3, or 4 nucleotides, the nucleotide sequence IV has the same length as the nucleotide sequence III, and the nucleotide sequence IV and the nucleotide sequence III are substantially reverse-complementary or fully reverse-complementary to each other, and the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 1 nucleotide, the nucleotide sequence III has a base of G, and the nucleotide sequence IV has a base of C, in the 5' end to 3' end direction; in this case, the length ratio of the sense strand to the antisense strand is 20 / 20. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 2 nucleotides, the nucleotide sequence III has a base composition of UG, and the nucleotide sequence IV has a base composition of CA, in the 5' end to 3' end direction; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 3 nucleotides, the nucleotide sequence III has a base composition of AUG, and the nucleotide sequence IV has a base composition of CAU, in the 5' end to 3' end direction; in this case, the length ratio of the sense strand to the antisense strand is 22 / 22. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 4 nucleotides, the nucleotide sequence III has a base composition of GAUG, and the nucleotide sequence IV has a base composition of CAUC, in the 5' end to 3' end direction; in this case, the length ratio of the sense strand to the antisense strand is 23 / 23. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, and the nucleotide sequence V is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the antisense strand after the double-stranded oligonucleotide is formed. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and in the 5' end to 3' end direction, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the APOE4 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the 5' end to 3' end direction, the base composition of the nucleotide sequence V is selected from CA or UU. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 46, the nucleotide sequence I consists of SEQ ID NO: 45, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the 5' end to 3' end direction, the base composition of the nucleotide sequence V is CA. In some embodiments, the double-stranded oligonucleotide is one of siRNAa1, siRNAb1, siRNAc1, siRNAd1, siRNAe1, or siRNAf1 as shown in Table 1 below: Table 1 siRNA sequences of the disclosure wherein, capital letters C, G, U, A, and T represent the base composition of a nucleotide; capital letter N represents a nucleotide of C, G, U, or A; lower case letter o indicates that the nucleotide represented by the immediately left capital letter of the letter o is an alkoxy-modified nucleotide; lower case letter f indicates that the nucleotide represented by the immediately left capital letter of the letter f is a fluoro-modified nucleotide; each Z is independently U or T; lower case letter s indicates that the linkage between the two nucleotides represented by the two immediately left and right capital letters of the letter s is a phosphorothioate linkage; lower case letter x indicates that the linkage between the two nucleotides represented by the two immediately left and right capital letters of the letter x is a phosphodiester linkage or a phosphorothioate linkage, and at least two lower case letters x in the same nucleotide sequence represent a phosphorothioate linkage; lower case letter d indicates that the nucleotide represented by the immediately right capital letter of the letter d is a deoxynucleotide; letter combination P1 indicates that the nucleotide represented by the immediately right capital letter of the letter combination P1 is a 5'-hydroxyl nucleotide or a 5'-vinylphosphonate-modified nucleotide; ia represents an inverted abasic deoxynucleotide. In some embodiments, all lower case letters x in the same sense strand represent a phosphorothioate linkage. In some embodiments, each Z is independently T. In some embodiments, each alkoxy-modified nucleotide is a 2'-methoxy-modified nucleotide; each P1 is independently a 5'-hydroxyl nucleotide or a 5'-vinylphosphonate (E-VP) modified nucleotide. The single-stranded oligonucleotides and / or double-stranded oligonucleotides provided by the present disclosure can be obtained by conventional oligonucleotide preparation methods in the art, such as solid-phase synthesis and liquid-phase synthesis methods. Among them, solid-phase synthesis has been commercialized as a subscription service. The methods of preparing nucleoside monomers with corresponding modifications and introducing modified nucleotide groups into the single-stranded oligonucleotides and / or double-stranded oligonucleotides described by the present disclosure by using nucleoside monomers with corresponding modifications are also well known to those skilled in the art. All modified nucleoside monomers can be commercially available or prepared by known methods. The single-stranded oligonucleotides, double-stranded oligonucleotides provided by the present disclosure can be used alone, or form a pharmaceutical composition with a pharmaceutically acceptable carrier, or form an oligonucleotide conjugate with a delivery group, or in any other suitable form. An effective amount of the single-stranded oligonucleotides, the double-stranded oligonucleotides, the pharmaceutical composition or the oligonucleotide conjugate is contacted with cells to regulate the expression of the target gene, or an effective amount of the single-stranded oligonucleotides, the double-stranded oligonucleotides, the oligonucleotide conjugate or the pharmaceutical composition is administered to a subject to regulate the expression of the target gene, so as to treat pathological conditions or diseases related to the expression level of the target gene. Oligonucleotide conjugate In another aspect, the present disclosure provides an oligonucleotide conjugate containing an oligonucleotide group and a delivery group conjugated to the oligonucleotide group, wherein the oligonucleotide group is independently a group formed by removing one or more atoms or atom groups from the single-stranded oligonucleotide or the double-stranded oligonucleotide provided by the present disclosure. In the context of the present disclosure, unless otherwise specified, "conjugation" refers to the connection between two or more chemical moieties each having a specific function in a covalent manner; accordingly, "conjugate" refers to a compound formed by the covalent connection between the respective chemical moieties. Further, "oligonucleotide conjugate" means a compound formed by the covalent connection of one or more chemical moieties having a specific function to an oligonucleotide. Oligonucleotide conjugate should be understood in the context of the present disclosure as a general term for a plurality of oligonucleotide conjugates or an oligonucleotide conjugate represented by a certain chemical formula. In the context of the present disclosure, "conjugation molecule" should be understood as a specific compound that can be conjugated to an oligonucleotide by a reaction to ultimately form an oligonucleotide conjugate of the present disclosure. The delivery moiety is a moiety for delivering the single-stranded oligonucleotide moiety or the double-stranded oligonucleotide moiety into a cell expressing APOE4 mRNA. In some embodiments, the delivery moiety comprises a linking moiety and a pharmaceutically acceptable targeting moiety, and the single-stranded oligonucleotide moiety or the double-stranded oligonucleotide moiety, the linking moiety, and the targeting moiety are covalently or non-covalently linked in sequence, each of the targeting moieties is selected from a ligand capable of binding to a surface receptor of a cell or a moiety capable of increasing compatibility with a tissue. In some embodiments, each of the targeting moieties independently targets one or more of the central nervous system, the liver, the kidney, the lung, the muscle, and the eye. In some embodiments, each of the targeting moieties independently targets the central nervous system. In some embodiments, each of the targeting moieties is independently selected from a ligand capable of binding to a surface receptor of a cell in the central nervous system or a moiety capable of increasing compatibility with a tissue in the central nervous system. In some embodiments, the targeting moieties are 1-6. In one embodiment, the targeting moieties are 2-4. The oligonucleotide moiety can be non-covalently or covalently conjugated to the delivery moiety, for example, can be covalently conjugated to the delivery moiety. In some embodiments, the oligonucleotide moiety is a single-stranded oligonucleotide moiety, and the conjugation site to the delivery moiety can be at the 3' end or 5' end of the single-stranded oligonucleotide, or in an internal sequence of the single-stranded oligonucleotide. In some embodiments, the double-stranded oligonucleotide moiety is a double-stranded oligonucleotide moiety, and the conjugation site to the delivery moiety can be at the 3' end or 5' end of the sense strand of the double-stranded oligonucleotide, or at the 5' end of the antisense strand, or in an internal sequence of the double-stranded oligonucleotide. In some embodiments, the conjugation site of the double-stranded oligonucleotide moiety to the delivery moiety is at the 3' end of the sense strand of the double-stranded oligonucleotide. In some embodiments, the delivery group can be attached at any position of the nucleotides, such as the phosphate group, the 2'-, 3'- or 5'-position hydroxyl of the ribose, or the base. When the delivery group is attached at the 3'- or 5'-terminal of the single-stranded oligonucleotide or the double-stranded oligonucleotide, the delivery group is usually attached to the oxygen atom formed after the removal of the hydrogen atom from the 3'- or 5'-hydroxyl of the nucleotide; when the delivery group is attached to the internal sequence of the single-stranded oligonucleotide or the double-stranded oligonucleotide, the delivery group is usually attached to the phosphate group, the ribose sugar ring, or the base. In some embodiments, the delivery group can be attached to the 3'-position hydroxyl of the nucleotide in the internal sequence of the single-stranded oligonucleotide or the double-stranded oligonucleotide, in which case the nucleotides are connected by 2'-5' phosphodiester bonds. Various attachment methods can be referred to in the following non-patent literature: Muthiah Manoharan et. al. siRNA conjugates carrying sequentially assembled trivalent N-acetylgalactosamine linked through nucleosides elicit robust gene silencing in vivo in hepatocytes. ACS Chemical biology, 2015, 10(5): 1181-7. The disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the oligonucleotide and the delivery group can be connected by acid-labile or reducible chemical bonds, which can be degraded in the acidic environment of the intracellular endosome, thereby converting the oligonucleotide group into a free oligonucleotide. For non-degradable conjugation, the delivery group can be connected to the sense strand of the single-stranded oligonucleotide or the double-stranded oligonucleotide group, so as to minimize the impact of conjugation on the activity of the oligonucleotide group. The targeting group can be connected to the oligonucleotide group via a suitable linker, which can be selected by a person skilled in the art according to the specific type of the targeting group. The types of these linkers, targeting groups, and the connection methods to the oligonucleotide can be referred to in the disclosure of WO2015006740A2, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the targeting group can be a ligand commonly used in the field of oligonucleotide administration, such as various ligands described in WO2009082607A2, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, at least one or each of the targeting groups is selected from a ligand capable of binding to a cell surface receptor that expresses APOE4 mRNA. In some embodiments, at least one or each of the targeting groups is selected from any group capable of targeting the central nervous system, such as a small molecule ligand group or a targeting peptide group capable of binding to a surface receptor of a cell in the central nervous system, or a group capable of increasing compatibility with tissue in the central nervous system, such as a lipophilic group. In some embodiments, the double-stranded oligonucleotide group is capable of modulating the expression level of APOE4 mRNA in the central nervous system. In some embodiments, at least one or each of the targeting groups is selected from a ligand capable of binding to a mammalian liver parenchymal cell surface receptor. In some embodiments, each of the targeting groups is independently a ligand that has affinity for an asialoglycoprotein receptor on the surface of a mammalian liver cell. In some embodiments, at least one or each of the targeting groups is galactose or N-acetylgalactosamine. The delivery group in the oligonucleotide conjugate of the present disclosure can be various delivery groups known to those skilled in the art of oligonucleotide drugs. In some embodiments, the linking group in the oligonucleotide conjugate of the present disclosure has a structure as shown in formula (301): wherein k is an integer from 1 to 5, denotes the site of covalent attachment of the group; all L A are connected to the same atom in L C ; or, each L A is independently connected to a different atom in L C . In some embodiments, L C has a structure as shown in -NH-C(H) n301 (CH2O-) k wherein k is an integer from 1 to 3, n301=3-k; L B has a length of 5 to 20 atoms. In some embodiments, each L A is independently a straight chain alkylene having a length of 5 to 20 carbon atoms, wherein one or more methylene groups are optionally replaced by any one or more selected from the group consisting of C(O), NH, O, S, 1,2,3-triazolylene, butylenediamineylene. In some embodiments, L A has a structure comprising an amide bond as shown in formula (302), L B has a structure as shown in formula (303): wherein n 302 , q 302and p 302 each independently is an integer from 2 to 6, optionally, n 302 , q 302 and p 302 each independently is 2 or 3; n 303 is an integer from 4 to 16, optionally, n 303 is an integer from 8 to 12, denotes the site of covalent attachment of a group. In some embodiments, the linking group has a structure as shown in formula (304) or formula (305): each L A is attached to one of the targeting groups through an ether linkage, and is attached to the oligonucleotide group through the oxygen atom of the hydroxyl group of the moiety C is attached to one of the targeting groups through an ether linkage, and is attached to the oligonucleotide group through the nitrogen atom of the amino group of the moiety C is attached to one of the targeting groups through an ether linkage, and is attached to the oligonucleotide group through the oxygen atom of the moiety B is attached to one of the targeting groups through an amide linkage formed between the carbonyl group of formula (303) and the nitrogen atom of the amino group of the moiety C is attached to the oligonucleotide group through an oxygen atom of formula (303) and a phosphodiester linkage or a phosphorothioate linkage. In some embodiments, the oligonucleotide conjugate provided by the present disclosure has a structure as shown in formula (305A): wherein Nu represents an oligonucleotide group formed by a single-stranded oligonucleotide or a double-stranded oligonucleotide provided by the present disclosure. In some embodiments, the linking group in the oligonucleotide conjugate of the present disclosure has a structure as shown in formula (306): wherein n 306 is an integer from 0 to 3, each p 306 independently is an integer from 1 to 6, denotes the site of covalent attachment of a group; the linking group is attached to the targeting group through an ether linkage via the oxygen atom marked by *; the linking group is attached to the oligonucleotide through at least one of the oxygen atoms marked by # to form a phosphodiester linkage or a phosphorothioate linkage, and the remaining oxygen atoms marked by # are attached to hydrogen atoms to form hydroxyl groups, or to C1-C3 alkyl groups to form C1-C3 alkoxy groups; In some embodiments, the oligonucleotide conjugate of the present disclosure has a structure as shown in formula (307): wherein Nu represents an oligonucleotide group formed by a single-stranded oligonucleotide or a double-stranded oligonucleotide provided by the present disclosure. In some embodiments, the oligonucleotide conjugate of the present disclosure has a structure represented by Formula (308): wherein, n 308 is an integer selected from 2-4; each m 308 is independently an integer selected from 2-5; each R 308 is independently a hydrogen atom, a methyl group, or an ethyl group, or 2 R 308 groups attached to the same carbon atom together form a carbonyl group; one of the groups represented by A0, each independently, is an oligonucleotide group which is a single-stranded oligonucleotide or a double-stranded oligonucleotide described in the present disclosure minus one atom or group of atoms; all the remaining A0are targeting groups, each targeting group being the same or different, and the definition and selection range thereof are as previously described. In some embodiments, each targeting group is independently selected from a group capable of targeting the central nervous system or targeting the liver. each L1is independently a divalent linking group having a length of 3-25 atoms; denotes the site of covalent attachment of the groups. In some embodiments, each L1is independently a straight-chain alkylene having a length of 1-20 carbon atoms, wherein one or more carbon atoms are optionally replaced by any one or more selected from the group consisting of C(O), NH, O, S, CH=N, S(O)2, OP(O)2, OP(O)(S), C2-C 10 alkenylene, C2-C 10 alkynylene, C6-C 10 arylene, C3-C 18 heterocyclylene, and C5-C 10 heteroarylene; and the straight-chain alkylene can optionally have substituents of any one or more selected from the group consisting of C1-C 10 alkyl, C6-C 10 aryl, C5-C 10 heteroaryl, C1-C 10 haloalkyl, -OC1-C 10 alkyl, OC1-C 10 alkylphenyl, -C1-C 10 alkyl-OH, -OC1-C 10 haloalkyl, -SC1-C 10 alkyl, -SC1-C 10 alkylphenyl, -C1-C 10 alkyl-SH, -SC1-C10 haloalkyl, halogen substituent, -OH, -SH, -NH2, -C1-C 10 alkyl-NH2, -N(C1-C 10 alkyl)(C1-C 10 alkyl), -NH(C1-C 10 alkyl), N(C1-C 10 alkyl)(C1-C 10 alkyl), NH(C1-C 10 alkyl), cyano, nitro, -CO2H, -C(O)O(C1-C 10 alkyl), -CON(C1-C 10 alkyl)(C1-C 10 alkyl), -CONH(C1-C 10 alkyl), -CONH2, -NHC(O)(C1-C 10 alkyl), -NHC(O)(phenyl), -N(C1-C 10 alkyl)C(O)(C1-C 10 alkyl), -N(C1-C 10 alkyl)C(O)(phenyl), C(O)C1-C 10 alkyl, C(O)C1-C 10 alkyl), C(O)C1-C 10 haloalkyl, -OC(O)C1-C 10 alkyl, -SO2(C1-C 10 alkyl), -SO2(phenyl), -SO2(C1-C 10 haloalkyl), -SO2NH2, -SO2NH(C1-C 10 alkyl), -SO2NH(phenyl), -NHSO2(C1-C 10 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C 10 haloalkyl). A skilled artisan will appreciate that, although L1is defined for convenience as being a linker group formed by the initial replacement or substitution of a linear alkylene, it can not be a linear group or the name different, e.g., an amine or alkenyl group resulting from the above-mentioned replacement and / or substitution. Unless otherwise indicated, the "length" of any group in a chemical structure depicted in the present disclosure refers to the number of atoms in the longest chain of atoms in the group, not counting hydrogen atoms; in the case of groups in which there are multiple ways of connecting two atoms (e.g., two atoms belong to the same cyclic group, such that there are at least 2 chains of atoms that include the two atoms), the length is calculated as the shortest chain of atoms between the two atoms. For example, 1,4-cyclohexanediyl, 1,4-piperidinediyl, 1,4-phenylene, 1,4-piperazinediyl are each calculated as 4 atoms in length, while 1,2-cyclopentanediyl is calculated as only 2 atoms in length. The role of L1covalently linked to A0representing the oligonucleotide group is to enable covalent linkage of the oligonucleotide group to the targeting group, to enable entry of the oligonucleotide conjugate comprising the oligonucleotide group into a cell expressing APOE4 mRNA via the targeting effect of the targeting group, and not to affect the APOE4 mRNA level modulating effect of the oligonucleotide group after entry into a cell expressing APOE4 mRNA. Thus, in some embodiments, L1covalently linked to A0representing the oligonucleotide group has a length of 3-20 atoms, or 4-15 atoms, or 5-12 atoms. In some embodiments, L1covalently linked to A0representing the oligonucleotide group is selected from one or more of the following combinations of A1, A2, A4, A5, A10, A16, A18, and A19with a phosphate group or a modified phosphate group: wherein j1is an integer from 2 to 10; denotes the site of covalent linkage of groups. In some embodiments, R2is selected from at least 2 combinations of A1, A2, A4, A10, and A16with a phosphate group or a modified phosphate group; in some embodiments, R2is selected from at least 2 combinations of A1, A2, A10with a phosphate group or a modified phosphate group. In some embodiments, L1covalently linked to A0representing the double-stranded oligonucleotide group has a structure as shown in formula (B1), (B2), (B3), or (B4): wherein, denotes the site of covalent linkage of groups, L B1 and L B2 are the same or different, independently selected from one or any combination of the following groups: -(CH2)q1 -CH(OH)-, -CH(CH2OH)-, -NH-, -O-, -S-, 1,4-cyclohexanediyl, 1,4-piperidinediyl, 1,4- phenylenediyl, 1,4-piperazinediyl, pyrrolidinediyl, wherein q1 is an integer from 1 to 6, L B1 and L B2 each independently have a length of 1 to 20 atoms. In some embodiments, L B1 and L B2 each independently have a length of 1 to 10 atoms. In some embodiments, L B1 and L B2 each independently have a length of 1 to 6 atoms. L B3 is selected from one of a phosphonate group, a thiophosphonate group, a dithiophosphonate group, and is covalently attached to the oxygen atom remaining after removal of a hydrogen atom from the ribose 5' position hydroxyl group of the 5' terminal nucleotide, or the ribose 3' position hydroxyl group of the 3' terminal nucleotide of the sense strand or the antisense strand of the double-stranded oligonucleotide group. In some embodiments, L B3 is a phosphonate group, and is covalently attached to the oxygen atom remaining after removal of a hydrogen atom from the ribose 5' position hydroxyl group of the 5' terminal nucleotide, or the ribose 3' position hydroxyl group of the 3' terminal nucleotide of the sense strand of the double-stranded oligonucleotide group. In some embodiments, where the oligonucleotide conjugate of the disclosure is prepared by a process of solid phase synthesis, L1covalently attached to A0representing the oligonucleotide group needs to contain simultaneously a linking site to N on the nitrogen-containing backbone, a linking site to the oligonucleotide group, and a functional group capable of linking to a solid support. In some embodiments, the site linked to N on the nitrogen-containing backbone in L1covalently attached to A0representing the oligonucleotide group forms an amide bond with N, the oligonucleotide group is covalently attached through a phosphonate bond, and the functional group capable of linking to a solid support is a hydroxyl group or an amino group. In some embodiments, R2is B5, B6, B5', or B6': wherein, represents the site of covalent bond linkage of the group. q2may have a value in the range of an integer from 1 to 10, and in some embodiments, q2is an integer from 1 to 5. The role of L1 covalently linked to A0 representing the targeting group is to place the targeting group in a suitable spatial position for better binding to the receptor, thus specifically targeting and entering the liver. Thus, L1 covalently linked to A0 representing the targeting group can be used in the present disclosure as long as it has a suitable length and the chemical properties do not significantly affect the delivery. In some embodiments, each L1 covalently linked to A0 representing the targeting group is independently a divalent linking group of 3-25 atoms in length. In some embodiments, each L1 covalently linked to A0 representing the targeting group is 4-15 atoms in length. In some embodiments, each L1 covalently linked to A0 representing the targeting group is 5-10 atoms in length. In some embodiments, each L1 covalently linked to A0 representing the targeting group is the same. In some embodiments, each L1 covalently linked to A0 representing the targeting group is the same or different, and is independently selected from the group consisting of the groups represented by formulae (L3)-(L18) and any combination of connections thereof: wherein each j1 is an integer from 2 to 10; each R’ is independently a hydrogen atom or a C1-C3 alkyl group, the site to which the group is covalently linked. For ease of synthesis and / or chemical stability, in some embodiments, each L1 covalently linked to A0 representing the targeting group is independently a combination of connections of at least 2 connection units, each connection unit independently having a structure represented by any one of formulae (L3)-(L7). In some embodiments, each connection unit independently has a structure represented by any one of formulae (L3), (L4), and (L7). For ease of synthesis, in some embodiments, each L1 covalently linked to A0 representing the targeting group includes a carbonyl group connected to the nitrogen atom represented in formula (308). In some embodiments, each L1 covalently linked to A0 representing the targeting group independently has a structure represented by formula (L20) or (L21): wherein j2 is an integer from 4 to 9, and j3 is 1 or 2. In some embodiments, j2 is 5, 6, or 7, and j3 is 1. In some embodiments, each L1 covalently linked to A0 representing the targeting group is the same. In the conjugate of the present disclosure, the number of targeting groups and the spacing between the targeting groups are the number and spacing that can provide a proper spatial configuration of multiple targeting groups. To this end, n308and each m308are independently an integer selected from 2-4. In some embodiments, n308is 3 or 4, so that the number of targeting groups in the conjugate of the present disclosure is 3 or 4, which can better bind to the surface receptors of liver cells. In some embodiments, n308is 3, and each m308is independently 3 or 4. As understood by those skilled in the art, each R 308 When each R 308 is a hydrogen atom, a methyl group or an ethyl group, it does not affect the delivery effect of the oligonucleotide conjugate, and the purpose of the present disclosure can be achieved. In some embodiments, for the convenience of synthesis, each R 308 is a hydrogen atom. In the conjugate of the present disclosure, each targeting group is the same or different, and is independently selected from a ligand capable of binding to a cell surface receptor or a group capable of increasing compatibility with a tissue. In some embodiments, at least one or each targeting group is a group capable of targeting the liver. In some embodiments, at least one or each targeting group is a group capable of targeting the central nervous system. In some embodiments, the targeting group is a small molecule peptide group. In some embodiments, the oligonucleotide conjugate of the present disclosure has a structure represented by formula (403): wherein Nu represents an oligonucleotide group, such as a single-stranded oligonucleotide group or a double-stranded oligonucleotide group formed by a single-stranded oligonucleotide or a double-stranded oligonucleotide provided by the present disclosure. In some embodiments, the oligonucleotide group is a double-stranded oligonucleotide group, and the P atom shown in the above structural formula is covalently connected to the 3' terminal nucleotide of the sense strand of the double-stranded oligonucleotide group. In some embodiments, the 3' terminal nucleotide of the sense strand of the double-stranded oligonucleotide group is a reverse deoxy-dealkyl nucleotide, and the P atom shown in the above structural formula is covalently connected to the double-stranded oligonucleotide group by replacing the hydrogen atom in the hydroxyl group of the ribose ring connected to the 3' terminal reverse deoxy-dealkyl nucleotide of the sense strand of the double-stranded oligonucleotide group represented by Nu with a methylene group. In some embodiments, the P atom shown in formula (403)-formula (422) is covalently connected to the oxygen atom remaining after removing one hydrogen atom from the 3' position hydroxyl group of the ribose of the 3' terminal nucleotide of the sense strand of the double-stranded oligonucleotide group represented by Nu. In some embodiments, the P atom shown in formula (403)-formula (422) is covalently connected to the oxygen atom of the reverse deoxy-dealkyl nucleotide (ia) shown in formula (35) connected to the ribose ring by a methylene group at the 3' terminal of the sense strand of the siRNA represented by Nu, so as to be covalently connected to the sense strand of the siRNA. In some embodiments, the oligonucleotide group comprised by the oligonucleotide conjugate of the present disclosure can be an siRNA group formed by removing one atom or group of atoms from an siRNA, in which case the oligonucleotide conjugate of the present disclosure is also referred to as an siRNA conjugate. In some embodiments, the double-stranded oligonucleotide group comprised by the oligonucleotide conjugate of the present disclosure can be an siRNA group formed by, for example, the siRNAs listed in Table 1. The siRNA conjugates comprising these siRNA groups exhibit excellent stability and high APOE4 mRNA inhibitory activity. In some embodiments, the oligonucleotide conjugate of the present disclosure is any one of Conjugate 1-Conjugate 9 and Conjugate 11-Conjugate 27 listed in Table 2A. Preparation of the oligonucleotide conjugate of the present disclosure The oligonucleotide conjugate of the present disclosure can be prepared by various suitable methods by those skilled in the art. For example, the oligonucleotide conjugate of the present disclosure can be synthesized by introducing the delivery group by methods that have been described in detail in the prior art when the nucleoside monomers are linked one by one according to the sequence and modification scheme of the single-stranded oligonucleotide or the sense strand and the antisense strand of the double-stranded oligonucleotide of the present disclosure by the solid-phase synthesis method. For example, the preparation of various siRNA conjugates is described in detail in WO2015006740A2. In the case of siRNA as the double-stranded oligonucleotide, the oligonucleotide conjugate of the present disclosure can also be obtained by methods well known to those skilled in the art. For example, the preparation of the structure represented by Formula (305A) is described in WO2014025805A1, and the preparation of the structure represented by Formula (307) is described in Rajeev et al., ChemBioChem 2015, 16, 903-908. The preparation of the oligonucleotide conjugate represented by Formula (308) is also described in detail in Chinese Patent Application CN110959011A. The contents of the above documents are incorporated herein by reference in their entirety. Pharmaceutically acceptable salts In yet another aspect, the present disclosure also provides a pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate described in the present disclosure. Pharmaceutically acceptable salts are known to those skilled in the art. By forming a salt form, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate described in the present disclosure can exhibit better solubility, bioavailability, or stability than the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate per se. In the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate described in the present disclosure, each adjacent nucleotide is connected by a phosphodiester bond or a phosphorothioate bond, and the non-bridging oxygen atom or the sulfur atom in the phosphodiester bond or the phosphorothioate bond carries a negative charge, which can exist in the form of a hydroxyl group or a thiol group, and the hydrogen ion in the hydroxyl group or the thiol group can also be partially or completely replaced by a cation. The cation can be any cation, such as a metal cation, an ammonium ion NH4 + Further, there can also be a group capable of forming a salt in the delivery group. For the purpose of improving solubility and / or improving bioavailability, in some embodiments, the pharmaceutically acceptable salt is a water-soluble salt of part or all of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate. In some embodiments, the water-soluble salt can be an amine salt, an alkali metal salt, or an alkaline earth metal salt, in some embodiments, the amine salt is selected from one or more of an ammonium salt, a methylamine salt, a tertiary amine salt, a quaternary ammonium salt, the alkali metal salt is selected from a potassium salt or a sodium salt, and the alkaline earth metal salt is selected from a calcium salt or a magnesium salt. In some embodiments, the tertiary amine salt is a triethylamine salt, a triisopropylamine salt, or an N,N-diisopropylethylamine salt. In some embodiments, the pharmaceutically acceptable salt is a salt or a partial salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate, and the salt is one or more of a methylamine salt, a triethylamine salt, a sodium salt, or a calcium salt. In some embodiments, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate is a sodium salt or a partial sodium salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate. In some embodiments, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate is a calcium salt or a partial calcium salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate. In some embodiments, the pharmaceutically acceptable salt of the double-stranded oligonucleotide or the oligonucleotide conjugate is a mixture of a methylamine salt and an ammonium salt of the double-stranded oligonucleotide or the oligonucleotide conjugate. Pharmaceutical composition In another aspect, the present disclosure also provides a pharmaceutical composition comprising one or more of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate, and the pharmaceutically acceptable salt provided in the present disclosure, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is one or more of various ingredients conventionally used in the art, such as one or more of a solvent, a protective agent, an osmotic pressure adjusting agent, and a pharmaceutically acceptable other carrier. For example, when the pharmaceutical composition is an injection solution, the pharmaceutically acceptable excipient is a solvent, such as one or more of deionized water, water for injection, a pH buffer, physiological saline, ethanol, an ethanol aqueous solution. The pH buffer can be a tris-hydroxymethyl aminomethane hydrochloride buffer having a pH of 7.5 to 8.5 and / or a phosphate buffer having a pH of 5.5 to 8.5, such as a phosphate buffer having a pH of 5.5 to 8.5. In some embodiments, the solvent is artificial cerebrospinal fluid. In some embodiments, the solvent is artificial cerebrospinal fluid having an increased calcium ion content. The amount of the solvent is adjusted according to the desired concentration of the solution, and the concentration of the oligonucleotide conjugate in the injection solution can be 0.01 mg / mL to 20 mg / mL, 0.1 mg / mL to 10 mg / mL, or 0.5 mg / mL to 5 mg / mL, based on the oligonucleotide group in the double-stranded oligonucleotide. The protective agent can be at least one of myo-inositol, sorbitol, sucrose, trehalose, mannose, maltose, lactose, and glucose. The content of the protective agent can be 0.01 to 30% by weight, based on the total weight of the pharmaceutical composition. The osmotic pressure adjusting agent can be sodium chloride and / or potassium chloride. The content of the osmotic pressure adjusting agent is such that the osmotic pressure of the pharmaceutical composition is 200 to 700 milliosmoles per kilogram (mOsm / kg). The content of the osmotic pressure adjusting agent can be easily determined by one skilled in the art according to the desired osmotic pressure. In some embodiments, the dose of the pharmaceutical composition prepared as a formulation is adjusted according to the administration method during administration. In some embodiments, the pharmaceutical composition can be a liquid formulation, such as an injection solution, or a lyophilized powder for injection, which is mixed with a liquid excipient to prepare a liquid formulation for administration. The liquid formulation can be, but is not limited to, used for subcutaneous, intramuscular, or intravenous injection administration, and can be, but is not limited to, delivered to the lung by spraying, or to other organ tissues (e.g., the liver) by spraying through the lung, or by oral administration, etc. In some embodiments, the pharmaceutical composition is administered by subcutaneous injection. The pharmaceutically acceptable carrier can be one or more of the carriers conventionally used in the field of double-stranded oligonucleotide administration, such as, but not limited to, magnetic nanoparticles (e.g., nanoparticles based on Fe3O4or Fe2O3), carbon nanotubes, mesoporous silicon, calcium phosphate nanoparticles, polyethylenimine (PEI), polyamidoamine (PAMAM) dendrimer, poly(L-lysine) (PLL), chitosan, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), poly(D&L-lactic / glycolic acid) copolymer (PLGA), poly(2-aminoethyl ethylene phosphate) (PPEEA), and poly(2-dimethylaminoethyl methacrylate) (PDMAEMA), and derivatives thereof. In some embodiments, the content of the double-stranded oligonucleotide and the pharmaceutically acceptable carrier in the pharmaceutical composition is not particularly limited, and in some embodiments, the weight ratio of the double-stranded oligonucleotide to the pharmaceutically acceptable carrier can be 1: (1-500), and in some embodiments, the weight ratio is 1: (1-50). In some embodiments, the pharmaceutical composition can be in the form of a liposome preparation. In some embodiments, the pharmaceutically acceptable carrier used in the liposome preparation comprises an amine-containing transfection compound (hereinafter also referred to as an organic amine), a helper lipid, and / or a pegylated lipid. The organic amine, the helper lipid, and the pegylated lipid can be selected from one or more of the amine-containing transfection compounds or pharmaceutically acceptable salts or derivatives thereof, the helper lipids, and the pegylated lipids described in Chinese Patent Application CN103380113A (herein incorporated by reference in its entirety). In some embodiments, the organic amine can be a compound represented by formula (201) or a pharmaceutically acceptable salt thereof as described in Chinese Patent Application CN103380113A: wherein: X 101 and X 102 each independently is O, S, N-A, or C-A, wherein A is hydrogen or C1-C 20 hydrocarbon chain; Y 101 and Z 101 each independently is C=0, C=S, S=0, CH-OH, or S02; R 101 , R 102 , R 103 , R 104 , R 105 , R 106 and R 107 each independently is hydrogen, a cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic group, a cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic group, a substituted or unsubstituted, branched or unbranched acyl group, a substituted or unsubstituted, branched or unbranched aryl group, a substituted or unsubstituted, branched or unbranched heteroaryl group; x is an integer from 1 to 10; n is an integer from 1 to 3, m is an integer from 0 to 20, and p is 0 or 1; wherein, if m=p=0, R 102 is hydrogen; and, if at least one of n or m is 2, then R 103 and the nitrogen in formula (201) forms a structure as shown in formula (202) or formula (203): wherein g, e, and f are each independently an integer from 1 to 6, "HCC" represents a hydrocarbon chain, and each *N represents a nitrogen atom in formula (201). In some embodiments, R 103 is a polyamine. In other embodiments, R 103 is a ketal. In some embodiments, each of R 101 and R 102 in formula (201) is independently an optionally substituted or unsubstituted, branched or unbranched alkyl or alkenyl group having from 3 to about 20 carbon atoms, such as from 8 to about 18 carbon atoms, and from 0 to 4 double bonds, such as from 0 to 2 double bonds. In some embodiments, if each of n and m independently has a value of 1 or 3, then R 103 may be any one of the following formulas (204)-(213): wherein, in formula (204) - formula (213), g, e, and f are each independently an integer from 1 to 6, each "HCC" represents a hydrocarbon chain, and each * shows R 103 possible points of attachment to the nitrogen atom in formula (201), wherein each H at any * position can be replaced to achieve attachment to the nitrogen atom in formula (201). One skilled in the art can obtain the compound shown in formula (201) by any reasonable method. In some embodiments, the compound shown in formula (201) can be prepared according to the description in Chinese patent application CN103380113A. In some embodiments, the organic amine is an organic amine as shown in formula (214) and / or an organic amine as shown in formula (215): The helper lipid is cholesterol, an analog of cholesterol, and / or a derivative of cholesterol; The PEGylated lipid is l,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine-N- [methoxy(polyethylene glycol)]-2000. In some embodiments, the molar ratio among the organic amine, the helper lipid, and the PEGylated lipid in the pharmaceutical composition is (19.7-80):(19.7-80):(0.3-50), for example, can be (50-70):(20-40):(3-20). In some embodiments, the pharmaceutical composition particles formed by the double-stranded oligonucleotide of the present disclosure and the above-mentioned amine-containing transfection reagent have an average diameter of about 30 nm to about 200 nm, typically about 40 nm to about 135 nm, more typically, the average diameter of the liposome particles is about 50 nm to about 120 nm, about 50 nm to about 100 nm, about 60 nm to about 90 nm, or about 70 nm to about 90 nm, for example, the average diameter of the liposome particles is about 30, 40, 50, 60, 70, 75, 80, 85, 90, 100, 110, 120, 130, 140, 150, or 160 nm. In some embodiments, the pharmaceutical composition formed by the double-stranded oligonucleotide of the present disclosure and the above-mentioned amine-containing transfection reagent, the weight ratio (weight / weight ratio) of the double-stranded oligonucleotide to the total lipid (e.g., organic amine, helper lipid, and / or PEGylated lipid) is in the range of from about 1:1 to about 1:50, from about 1:1 to about 1:30, from about 1:3 to about 1:20, from about 1:4 to about 1:18, from about 1:5 to about 1:17, from about 1:5 to about 1:15, from about 1:5 to about 1:12, from about 1:6 to about 1:12, or from about 1:6 to about 1:10, for example, the weight ratio of the double-stranded oligonucleotide of the present disclosure to the total lipid is about 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, or 1:18. In some embodiments, the components of the pharmaceutical composition can exist independently at the time of sale and in the form of a liquid preparation at the time of use. In some embodiments, the pharmaceutical composition formed by the double-stranded oligonucleotide of the present disclosure and the above-mentioned pharmaceutically acceptable carrier can be prepared according to various known methods, except that the double-stranded oligonucleotide of the present disclosure is used instead of the existing double-stranded oligonucleotide; in some embodiments, it can be prepared according to the following method: The organic amine, helper lipid, and PEGylated lipid are suspended in alcohol according to the above-mentioned molar ratio and mixed uniformly to obtain a lipid solution; the amount of alcohol is such that the total mass concentration of the obtained lipid solution is 2-25 mg / mL, for example, it can be 8-18 mg / mL. The alcohol is selected from pharmaceutically acceptable alcohols, such as alcohols that are liquid near room temperature, for example, one or more of ethanol, propylene glycol, benzyl alcohol, glycerol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, for example, it can be ethanol. The double-stranded oligonucleotide of the present disclosure is dissolved in a buffered salt solution to obtain an aqueous double-stranded oligonucleotide solution. The concentration of the buffered salt solution is 0.05-0.5 M, for example, it can be 0.1-0.2 M, the pH of the buffered salt solution is adjusted to 4.0-5.5, for example, it can be 5.0-5.2, the amount of the buffered salt solution is such that the concentration of the double-stranded oligonucleotide does not exceed 0.6 mg / mL, for example, it can be 0.2-0.4 mg / mL. The buffered salt is selected from one or more of soluble acetate, soluble citrate, for example, it can be sodium acetate and / or potassium acetate. The lipid solution and the aqueous double-stranded oligonucleotide solution are mixed, and the product obtained after mixing is incubated at 40-60°C for at least 2 minutes, for example, it can be 5-30 minutes, to obtain the incubated liposome preparation. The volume ratio of the lipid solution to the aqueous double-stranded oligonucleotide solution is 1:(2-5), for example, it can be 1:4. The incubated liposome preparation is concentrated or diluted, impurities are removed, and sterilization is performed to obtain the pharmaceutical composition provided by the present disclosure, which has physical and chemical parameters of pH 6.5-8, an encapsulation efficiency of not less than 80%, a particle size of 40-200 nm, a polydispersity index of not higher than 0.30, and an osmotic pressure of 250-400 mOsm / kg; for example, the physical and chemical parameters can be pH 7.2-7.6, an encapsulation efficiency of not less than 90%, a particle size of 60-100 nm, a polydispersity index of not higher than 0.20, and an osmotic pressure of 300-400 mOsm / kg. The concentration or dilution can be performed before, after or simultaneously with the removal of impurities. The method for removing impurities can use various existing methods, for example, a tangential flow system, a hollow fiber column, ultrafiltration under the condition of 100 KDa, and the ultrafiltration exchange solution is a phosphate buffer solution (PBS) with pH 7.4. The method for sterilization can use various existing methods, for example, sterilization can be performed by filtering through a 0.22 μm filter. Use of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate, the pharmaceutically acceptable salt and the pharmaceutical composition of the present disclosure The present disclosure also provides the use of one or more of the single-stranded oligonucleotide of the present disclosure, the double-stranded oligonucleotide of the present disclosure, the oligonucleotide conjugate of the present disclosure, the pharmaceutically acceptable salt of the present disclosure and the pharmaceutical composition of the present disclosure in a medicament for treating and / or preventing a disease or a symptom associated with the level of APOE4 mRNA. In some embodiments, the disease or symptom associated with the level of APOE4 mRNA expression is a neurodegenerative disease. In some embodiments, the disease or symptom associated with the level of APOE4 mRNA expression is selected from one or more of Alzheimer's disease (AD), Down's syndrome and cerebral amyloid angiopathy. The present disclosure also provides a method for treating and / or preventing a disease or a symptom associated with the level of APOE4 mRNA expression, which comprises administering to a subject in need an effective amount of the single-stranded oligonucleotide and / or the double-stranded oligonucleotide and / or the oligonucleotide conjugate and / or the pharmaceutically acceptable salt of the present disclosure and / or the pharmaceutical composition of the present disclosure. In addition, the present disclosure also provides a method for modulating the level of APOE4 mRNA expression in a cell in vivo or in vitro, which comprises contacting an effective amount of the single-stranded oligonucleotide and / or the double-stranded oligonucleotide and / or the oligonucleotide conjugate and / or the pharmaceutically acceptable salt and / or the pharmaceutical composition of the present disclosure with the cell in vivo or in vitro. The term "administering" as used herein refers to the placement of a single-stranded oligonucleotide, double-stranded oligonucleotide, pharmaceutical composition, pharmaceutically acceptable salt, and / or oligonucleotide conjugate into the body of a subject by a method or route that results, at least in part, in localization of the single-stranded oligonucleotide, double-stranded oligonucleotide, pharmaceutical composition, pharmaceutically acceptable salt, and / or oligonucleotide conjugate to a desired site to produce a desired effect. Suitable routes of administration for the methods of the disclosure include local and systemic administration. In general, local administration results in delivery of more of the single-stranded oligonucleotide, double-stranded oligonucleotide, pharmaceutical composition, pharmaceutically acceptable salt, and / or oligonucleotide conjugate to a particular site as compared to the entire body of the subject, while systemic administration results in delivery of the single-stranded oligonucleotide, double-stranded oligonucleotide, pharmaceutical composition, pharmaceutically acceptable salt, and / or oligonucleotide conjugate to substantially the entire body of the subject. The subject can be administered by any suitable route known in the art, including but not limited to oral or parenteral routes, such as intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, airway administration (aerosol), pulmonary administration, nasal administration, rectal administration, and topical administration (including buccal administration and sublingual administration). The frequency of administration can be one or more times per day, per week, per two weeks, per three weeks, per month, or per year. The dosage of the single-stranded oligonucleotide, double-stranded oligonucleotide, and / or oligonucleotide conjugate, pharmaceutically acceptable salt, and / or pharmaceutical composition of the disclosure used can be a conventional dosage in the art, which can be determined according to various parameters, especially the age, weight, and sex of the subject. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for human use. In administering the siRNAs, pharmaceutical compositions, and / or siRNA conjugates of the present disclosure, for example, to a male or female, 6-12 week old, 18-25 g body weight C57BL / 6J or C3H / HeNCrlVr mouse, the amount of siRNA in the siRNAs, pharmaceutical compositions, and / or siRNA conjugates can be 0.001-100 mg / kg body weight, in some embodiments 0.01-50 mg / kg body weight, in further embodiments 0.05-20 mg / kg body weight, in still further embodiments 0.1-15 mg / kg body weight, and in yet further embodiments 0.1-10 mg / kg body weight, of siRNA for siRNA conjugates formed with a pharmaceutically acceptable conjugate molecule. The foregoing amounts can be preferred in administering the siRNAs, pharmaceutical compositions, and / or siRNA conjugates of the present disclosure. The amount of double-stranded oligonucleotide in the single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions, pharmaceutically acceptable salts, and / or oligonucleotide conjugates provided to inhibit the expression of APOE4 mRNA in a cell according to the methods provided herein is readily determined by one of skill in the art depending on the desired effect to be obtained. For example, in some embodiments, the oligonucleotide conjugate is an siRNA conjugate, and the amount of siRNA in the siRNA conjugate provided is an amount sufficient to reduce the level of APOE4 mRNA and result in an extracellular concentration of 1 pM to 1 mM, or 0.01 nM to 100 nM, or 0.05 nM to 50 nM, or to about 5 nM at the surface of the target cell. The amount required to achieve this local concentration will vary depending on various factors including the method of delivery, the site of delivery, the number of cell layers between the site of delivery and the target cell or tissue, whether the delivery is local or systemic, etc. The concentration at the site of delivery can be significantly higher than the concentration at the surface of the target cell or tissue. Kits The present disclosure provides a kit comprising the single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions, pharmaceutically acceptable salts, and / or oligonucleotide conjugates provided herein. In some embodiments, the kits described herein can provide the single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions, pharmaceutically acceptable salts, and / or oligonucleotide conjugates in one container. In some embodiments, the kits described herein can comprise a container providing a pharmaceutically acceptable excipient. In some embodiments, the kits can further comprise other ingredients, such as stabilizers or preservatives, etc. In some embodiments, the kits described herein can comprise at least one other therapeutic agent in a container different from the container providing the single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions, pharmaceutically acceptable salts, and / or conjugates described herein. In some embodiments, the kit can comprise instructions for mixing the single-stranded oligonucleotide, double-stranded oligonucleotide, pharmaceutical composition, and / or oligonucleotide conjugate with a pharmaceutically acceptable carrier and / or excipient or other ingredients, if any. In the kit of the present disclosure, the single-stranded oligonucleotide, double-stranded oligonucleotide, and pharmaceutically acceptable carrier and / or excipient, and the pharmaceutical composition, pharmaceutically acceptable salt, and / or oligonucleotide conjugate, and / or pharmaceutically acceptable excipient can be provided in any form, for example, in a liquid form, a dry form, or a lyophilized form. In some embodiments, the single-stranded oligonucleotide, double-stranded oligonucleotide, and pharmaceutically acceptable carrier and / or excipient, and the pharmaceutical composition, and / or pharmaceutically acceptable salt, and / or oligonucleotide conjugate, and optional pharmaceutically acceptable excipient are substantially pure and / or sterile. In some embodiments, sterile water can be provided in the kit of the present disclosure. The present disclosure will be further described by way of examples below, but the present disclosure is not intended to be limited by any of them. Without wishing to be limited, the present disclosure is further described in detail in the following embodiments and examples of exemplary embodiments of double-stranded oligonucleotides in the pharmaceutical composition and / or oligonucleotide conjugate of the present disclosure, which are small interfering RNA (siRNA). In this case, the double-stranded oligonucleotide, pharmaceutical composition, and oligonucleotide conjugate of the present disclosure are siRNA, pharmaceutical composition comprising siRNA, and siRNA conjugate, respectively. In the context of the present disclosure, for ease of description, the siRNA, pharmaceutical composition comprising siRNA, and siRNA conjugate in these embodiments are also referred to as siRNA of the present disclosure, pharmaceutical composition of the present disclosure, and siRNA conjugate of the present disclosure. This does not mean that the double-stranded oligonucleotide of the present disclosure can only be siRNA, on the contrary, the double-stranded oligonucleotide can be other variants disclosed herein or known to those skilled in the art, such as small activating RNA (saRNA), etc. It is envisaged that, based on the detailed description of siRNA, pharmaceutical composition comprising siRNA, and siRNA conjugate, other double-stranded oligonucleotides will similarly function when used alone, or form the pharmaceutical composition and / or oligonucleotide conjugate described in the present disclosure. Examples Unless otherwise specified, the reagents, media used in the following examples are commercially available, and the operations such as nucleic acid electrophoresis, real-time PCR, etc. are performed according to the methods described in Molecular Cloning (Cold Spring Harbor Laboratory Press (1989)). Preparation of conjugates 1-9 and 11-24 of the present disclosure According to the preparation method described in CN110959011A Preparation Example 13, the following conjugates 1-9 and 11-24 in Table 2A were prepared, the only difference being that the sense strand and the antisense strand of the siRNA contained in the siRNA conjugate are as shown in Table 2A; for the nucleic acid sequence with the sense strand and the antisense strand sequence of the siRNA in the conjugates 1-9 and 11-24 in the following Table 2A, the sense strand and the antisense strand of the siRNA conjugate were synthesized by connecting the nucleoside phosphoramidite monomers one by one, respectively. After the synthesis was completed, the desalting purification was carried out by centrifugal ultrafiltration using a 3K (MWCO) ultrafiltration tube. The conjugates 1-9 and 11-24 are a mixture of methylamine salt and ammonium salt of a compound having a structure shown in formula (403), wherein the P atom shown in formula (403) is covalently linked to the oxygen atom in the reverse dealkylated deoxynucleotide (ia) shown in formula (35) connected to the ribose ring by a methylene group at the 3' end of the sense strand of the siRNA represented by Nu, thereby covalently linked to the sense strand of the siRNA. And the siRNA contained in the siRNA conjugate has the siRNA sequence corresponding to the conjugates 1-9 and 11-24 in Table 2A. After each siRNA conjugate was diluted to a concentration of 0.2 mg / mL (calculated as siRNA) using ultrapure water (Milli-Q ultrapure water instrument, resistivity 18.2 MΩ*cm (25℃)), the molecular weight was detected by liquid chromatography-mass spectrometry (LC-MS, Liquid Chromatography-Mass Spectrometry, purchased from Waters Company, model: LCT Premier). Conjugate 1, sense strand theoretical value: 7373.392, measured value: 7372.63, antisense strand theoretical value: 6928.592, measured value: 6927.83; Conjugate 3, sense strand theoretical value: 7386.438, antisense strand theoretical value: 6964.622, measured value: 6963.63; Conjugate 8, sense strand theoretical value: 7410.464, measured value: 7410.25, antisense strand theoretical value: 6990.620; Conjugate 23, sense strand theoretical value: 7442.459, measured value: 7441.13, antisense strand theoretical value: 6933.613, measured value: 6932.38; Conjugate 12, sense strand theoretical value: 7386.435, measured value: 7385.14, antisense strand theoretical value: 6988.649, measured value: 6987.32. The measured value is consistent with the theoretical value, indicating that the synthesized conjugate contains the target designed double-stranded nucleic acid sequence. Table 2A siRNA sequences in siRNA conjugates wherein, capital letters C, G, U, A and T represent the base composition of the nucleotides; lower case letter m represents that the nucleotide represented by the capital letter adjacent to the left of the letter m is a 2'-methoxy modified nucleotide; lower case letter f represents that the nucleotide represented by the capital letter adjacent to the left of the letter f is a 2'-fluoro modified nucleotide; letter combination VP represents that the nucleotide represented by the capital letter adjacent to the right of the letter combination is a 5'-vinylphosphonate modified nucleotide; lower case letter s represents that the linkage between the nucleotides represented by the two capital letters adjacent to the left and right of the letter s is a phosphorothioate linkage; lower case letter d represents that the nucleotide represented by the capital letter adjacent to the right of the letter d is a deoxynucleotide; ia represents an inverted abasic deoxynucleotide. Preparation Example 10 Preparation of siRNA1 of the disclosure The siRNA1 shown in Table 2A was obtained using a solid phase synthesis method according to the method described in Preparation Example 1 of US11492620B2, with the only difference being that the sense strand and the antisense strand of the siRNA1 were as shown in siRNA1 of Table 2A; for the nucleic acid sequences having the sense strand and the antisense strand sequences of siRNA1 as shown in Table 2A, the nucleoside phosphoramidite monomers were connected one by one, respectively, to synthesize the sense strand and the antisense strand of siRNA1. After the synthesis was completed, the synthesized product was first purified by ion exchange using a strong anion exchange filler self-packed column, and then desalted by HiPrep 26 / 13 Desalting desalting pre-packed column to obtain siRNA1 as a sodium salt of a double-stranded oligonucleotide as shown in Table 2A. After the siRNA was diluted to a concentration of 0.2 mg / mL (calculated as siRNA) using ultrapure water (Milli-Q ultrapure water instrument, resistivity 18.2 MΩ*cm (25℃)), the molecular weight of the sense strand and the antisense strand of siRNA1 were detected by liquid chromatography-mass spectrometry (LC-MS, Liquid Chromatography-Mass Spectrometry, purchased from Waters company, model: LCT Premier). The theoretical molecular weight of the sense strand of siRNA1 was 6159.2005, the actual molecular weight of the sense strand was 6157.03, the theoretical molecular weight of the antisense strand was 7027.62601, and the actual molecular weight of the antisense strand was 7025.10. The actual value was consistent with the theoretical value, indicating that the synthesized siRNA1 contained the double-stranded nucleic acid sequence designed as the target. Preparation Examples 25-28 Preparation of conjugates 25-28 of the disclosure According to the preparation method described in CN110959011A Preparation Example 13, conjugates 25-28 in Table 2A were prepared, the only difference being that the sense strand and the antisense strand of the siRNA contained in the siRNA conjugate are as shown in Table 2A; for the nucleic acid sequences having the sense strand and the antisense strand sequences of the siRNA in conjugates 25-28 according to Table 2A, the nucleoside phosphoramidite monomers were sequentially connected one by one to synthesize the sense strand and the antisense strand of the siRNA conjugate. After the synthesis was completed, the synthesized product was first purified by ion exchange using a strong anion exchange packing self-packed column, and then desalted by HiPrep 26 / 13 Desalting desalting pre-packed column to obtain the conjugates 25-28 which are sodium salts of compounds having the structure shown in formula (403). Synthesis of Comparative Preparation Example 1 Reference Conjugate NC According to the same method as in Preparation Example 1, reference conjugate NC in Table 2A was prepared by solid phase synthesis. Reference conjugate NC is a mixture of methylamine salt and ammonium salt of a compound having the structure shown in formula (403), wherein the conjugate group is connected to the ribose 3' position of the 3' terminal nucleotide of the sense strand of siRNA represented by Nu. And the siRNA sequence contained in this reference conjugate NC has the siRNA sequence corresponding to reference conjugate NC in Table 2A, which is a negative control sequence that is not identical to the mRNA of humans, rats, mice and non-human primates for 15 or more consecutive nucleotides. Experimental Example 1 Inhibition activity of conjugates in vitro This experimental example investigates the inhibition activity of conjugates 1-9, conjugates 11-24 and reference conjugate NC on APOE4 mRNA in HepG2 human hepatoma cells in vitro. The specific steps are as follows: [1] Cell culture HepG2 human hepatoma cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) were cultured at 37°C in a culture box containing 5% CO2 / 95% air using H-DMEM medium (M&G Gene Co., Ltd.) added with 10% fetal bovine serum (FBS, GIBCO Co.). HepG2 cells were seeded at 5x10 4 The cells were seeded in a 24-well plate at 5x10 [2] Transfection For each siRNA conjugate to be tested, each siRNA conjugate to be tested was prepared into an siRNA conjugate working solution of 20 μM (calculated by the amount of siRNA in the conjugate) using PBS. The siRNA conjugates to be tested used were conjugates 1-9, conjugates 11-24 and reference conjugate NC, respectively. For each siRNA conjugate to be tested, prepare a solution 1A, each solution 1A containing 3 μL of siRNA conjugate working solution and 97 μL of cell maintenance medium. For each siRNA conjugate to be tested, prepare a solution 1B, each solution 1B containing 3 μL of Lipofectamine TM RNAiMAX transfection reagent (Invitrogen, item number: 13778150) and 97 μL of Opti-MEM medium (GIBCO). For each siRNA conjugate to be tested, mix one solution 1A and one solution 1B, respectively, and incubate at room temperature for 20 min to obtain a transfection complex X1. In each culture well (all of which are the above-mentioned culture wells containing HepG2 cells and 1 mL of Opti-MEM medium, the same below), add the transfection complex X1 of each siRNA conjugate, mix uniformly, and add an amount of 200 μL / well to obtain a transfection mixture with a concentration of 50 nM (calculated based on the amount of siRNA, the same below). The transfection complex X1 of each siRNA conjugate transfects 2 culture wells, respectively, to obtain a transfection mixture containing siRNA conjugate, wherein the culture wells containing conjugates 1-9, conjugates 11-24 are recorded as test groups, and the culture wells containing the reference conjugate NC are recorded as negative control groups. Mix one solution 1B with 100 μL of cell maintenance medium to obtain a blank transfection mixture B. In another two culture wells, add the blank transfection mixture B, respectively, and add an amount of 200 μL / well to obtain a transfection mixture without siRNA conjugate, recorded as blank control groups. Place the above-mentioned test groups, negative control groups and blank control groups in an incubator under an atmosphere of air containing 5% CO2, and continue to culture at 37°C for 24 h. [3] Detection Use the MagaBio plus RNA purification kit (purchased from Hangzhou BoRi Science and Technology Co., Ltd., item number: BSC69L1E-A) to extract total RNA from each well of cells according to the method recorded in the instruction manual. For each well of cells, take 1 μg of total RNA, respectively, and use the reverse transcription kit (Promega, item number A3500) to reverse transcribe according to the operation method of the instruction manual to obtain cDNA. The reverse transcription conditions are as follows: for each reverse transcription reaction system, incubate the reverse transcription reaction system at 70°C for 10 min, then at 42°C for 30 min, and finally at 95°C for 5 min. After the reaction is completed, add 80 μL of DEPC water to the reverse transcription reaction system to obtain a solution containing cDNA. For each reverse transcription reaction system, 5 μL of the above cDNA-containing solution was taken as a template to configure a qPCR reaction system 20 μL using reagents provided by SYBR select Master Mix (purchased from Thermo, item number: 4472920), wherein the PCR primer sequences for amplifying the target gene APOE4 and the internal reference gene GAPDH are shown in Table 3, and the final concentration of each primer is 20 μM. Each qPCR reaction system was placed on an ABI StepOnePlus Real-Time PCR instrument (purchased from Thermo Fisher), and amplification was performed using a three-step method, and the amplification program was 95°C pre-denaturation for 10 min, then 95°C denaturation for 30 s, 60°C annealing for 30 s, 72°C extension for 30 s, and the above denaturation, annealing and extension process was repeated for 40 times, and then the product W1 containing the amplified target gene APOE4 and internal reference gene GAPDH was obtained. The product W1 was then subjected to 95°C for 15 s, 60°C for 1 min, gradient heating to 95°C and collecting fluorescence signal every 0.3°C, 95°C for 15 s, and the real-time fluorescence quantitative PCR instrument collected the target gene and internal reference gene GAPDH in the product W1 respectively, and the Ct values of the target gene APOE4 and internal reference gene GAPDH were obtained. Table 3 primer information The comparative Ct (ΔΔCt) method was used to relatively quantify the expression level of the target gene APOE4 mRNA in each test group, and the calculation method was as follows: ΔCt (test group) = Ct (test group target gene) - Ct (test group internal reference gene) ΔCt (control group) = Ct (control group target gene) - Ct (control group internal reference gene) ΔΔCt (test group) = ΔCt (test group) - ΔCt (control group average) ΔΔCt (control group) = ΔCt (control group) - ΔCt (control group average) Wherein, ΔCt (control group average) is the arithmetic mean of ΔCt (control group) of each culture well of the control group. Thus, each culture well of the test group and the control group corresponds to a ΔΔCt value. The expression level of APOE4 mRNA in the test group was normalized based on the average value of the control group, and the average value of the expression level of APOE4 mRNA in the control group was defined as 100%, Test group APOE4 mRNA relative Test group APOE4 mRNA inhibition rate = (1 - test group APOE4 mRNA relative expression level) x 100% The experimental results are shown in Table 4 below. Table 4 Inhibitory activity of siRNA conjugates in HepG2 cells Table 4 shows the relative inhibition rate of APOE4 mRNA in HepG2 human liver cancer cells in vitro after transfection of 50 nM of siRNA conjugates of the present disclosure. The results show that all the tested siRNA conjugates exhibit good inhibitory effect in HepG2 human liver cancer cells in vitro at a concentration of 50 nM, with an inhibition rate of at least 56%, and some conjugates have an inhibition rate of APOE4 mRNA of more than 90%, especially conjugate 17, which has an inhibition rate of APOE4 mRNA of 96.1%, which reflects the good inhibitory effect of siRNA conjugates of the present disclosure on APOE4 mRNA. Experimental Example 2 Inhibitory activity of siRNA conjugates in monkey liver primary cells This experimental example investigates the inhibitory activity of conjugates 1-4 and reference conjugate NC on APOE4 mRNA in monkey liver primary cells. The specific steps are as follows: [1] Cell culture Monkey liver primary cells (purchased from MiaoShun Biotechnology Co., Ltd.) were cultured at 37°C in a culture box containing 5% CO2 / 95% air using DMEM medium (HyClone) supplemented with 10% fetal bovine serum (FBS, RMBIO). Monkey liver primary cells were seeded at 2x10 5 The cells were seeded in a 12-well plate at 2x10 [2] Transfection For each siRNA conjugate to be tested, a conjugate working solution was prepared using PBS, with a concentration of 20 μM (calculated based on the amount of siRNA in the conjugate). The siRNA conjugates to be tested used were conjugates 1-4 and reference conjugate NC. For each siRNA conjugate to be tested, a 2A solution was prepared, with each 2A solution containing 3 μL of the siRNA conjugate working solution and 97 μL of cell maintenance medium. For each siRNA conjugate to be tested, a 2B solution was prepared, with each 2B solution containing 2 μL of Lipofectamine 2000 (Invitrogen) and 98 μL of Opti-MEM medium. TM For each siRNA conjugate to be tested, a 2B solution was prepared, with each 2B solution containing 2 μL of Lipofectamine 2000 (Invitrogen) and 98 μL of Opti-MEM medium. For each siRNA conjugate to be tested, one portion of solution 2A and one portion of solution 2B were mixed to obtain transfection complex X2, which was incubated at room temperature for 20 min. In each culture well (all of which were culture wells containing monkey liver primary cells and 1 mL of Opti-MEM medium, and the same below), the transfection complex X2 of each siRNA conjugate was added, and mixed evenly, with an amount of 200 μL / well, to obtain a transfection mixture with a concentration of 50 nM (calculated by the amount of siRNA, and the same below). The transfection complex X2 of each siRNA conjugate was used to transfect 2 culture wells, respectively, to obtain transfection mixtures containing siRNA conjugates, which were denoted as test groups X1-X4 and negative control group X1', respectively. One portion of solution 1B was mixed with 100 μL of cell maintenance medium to obtain a blank transfection mixture B. In another two culture wells, the blank transfection mixture B was added, with an amount of 200 μL / well, to obtain transfection mixtures without siRNA conjugates, which were denoted as blank control groups. The above test groups X1-X4, negative control group X1' and blank control groups were placed in an incubator with an air atmosphere containing 5% CO2, and incubated at 37°C for 24 h. [3] Detection The detection and calculation were performed according to the detection method in Experimental Example 1, and the inhibition rates of the conjugates on APOE4 mRNA were obtained, as shown in Table 5 below: Table 5 Inhibition rates of conjugates on APOE4 mRNA The results in Table 5 show that, in monkey liver primary cells, the siRNA conjugates provided by the present disclosure all have high inhibition effects on APOE4 mRNA at a concentration of 50 nM, and at least 65% or more, and in particular, the conjugate 4 has an inhibition rate of 98% on APOE4 mRNA, indicating that the conjugates of the present disclosure have excellent inhibition activity on APOE4 mRNA in monkey liver primary cells in vitro. Experimental Example 3 Inhibition activity of siRNA conjugates in mouse liver primary cells This experimental example investigated the inhibition activity of conjugates 1-4 on APOE4 mRNA in mouse liver primary cells. Mouse liver primary cells were isolated from fresh liver tissue of hAPOE4 transgenic mice (6-8 weeks old, purchased from Bionovus (Beijing) Medical Technology Co., Ltd.), and the density of the mouse liver primary cells was adjusted to 1x10 5 cells / mL of cell suspension in DMEM medium (purchased from M&CGENE Co., Ltd.). The cell suspension was inoculated into 12-well plates at 1x10 5 cells / well, with 2 replicate wells for each sample, and 1 mL in each well. For each siRNA conjugate to be tested, a working solution of the conjugate was prepared in PBS at a concentration of 20 μM (based on the amount of siRNA in the conjugate). The siRNA conjugates to be tested were conjugate 1, conjugate 2, conjugate 3 and conjugate 4, respectively. The working solution of the conjugate was then diluted to a dilution solution of 0.6 μM using Opti-MEM medium. 300 μL of Opti-MEM medium and 300 μL of the dilution solution were mixed to obtain a test sample. To 12 culture wells (all of which contained mouse primary hepatocytes and DMEM), 200 μL of the test sample was added to each of the 2 culture wells, and the mixture obtained had a final concentration of 50 nM. The culture wells to which the conjugate was added were designated as the test group. To the other 2 culture wells, 200 μL of Opti-MEM medium was added, and the culture wells were designated as the blank control group. The test group and the blank control group were incubated in an incubator containing 5% CO2 / 95% air at 37°C for 24 hours. The total RNA in the cells in each well was extracted using a MagaBio plus RNA purification kit (purchased from Hangzhou Borys Technology Co., Ltd., item number: BSC69L1E-A) according to the method described in the instructions. For each well of cells, 1 μg of total RNA was taken, and a reverse transcription kit (purchased from Promega Co., Ltd., item number A3500) was used to reverse transcribe the cDNA according to the method described in the instructions. The reverse transcription conditions were as follows: for each reverse transcription reaction system, the reverse transcription reaction system was incubated at 70°C for 10 min, then at 42°C for 30 min, and finally at 95°C for 5 min. After the reaction was completed, 80 μL of DEPC water was added to the reverse transcription reaction system to obtain a solution containing cDNA. For each reverse transcription reaction system, 5 μL of the above cDNA-containing solution was taken as a template to configure a qPCR reaction system of 20 μL using reagents provided by SYBR select Master Mix (purchased from Thermo, item number: 4472920), wherein the PCR primer sequences for amplifying the target gene ApoE4 and the internal reference gene GAPDH were as shown in Table 3 above, and the final concentration of each primer was 20 nM. Each qPCR reaction system was placed on an ABI StepOnePlus Real-Time PCR instrument, and amplification was performed using a three-step method, and the amplification program was 95°C pre-denaturation for 10 min, then 95°C denaturation for 30 s, 60°C annealing for 30 s, 72°C extension for 30 s, and the above denaturation, annealing and extension process was repeated for 40 times, and then a product W1 containing the target gene APOE4 and the internal reference gene GAPDH amplified was obtained. The product W1 was then subjected to 95°C for 15 s, 60°C for 1 min, gradient heating to 95°C and collecting fluorescence signal every 0.3°C, 95°C for 15 s, and the real-time fluorescence quantitative PCR instrument collected the target gene and the internal reference gene GAPDH in the product W1, respectively, to obtain the Ct value of the target gene APOE4 and the internal reference gene GAPDH. According to the calculation method of Example 1, the expression level of the target gene APOE4 mRNA in each test group was relatively quantitatively calculated, and the calculation results are shown in Table 6 below. Table 6 Inhibition rate of each conjugate on APOE4 mRNA It can be seen from the results in Table 6 that the conjugates of the present disclosure exhibit good inhibitory activity on APOE4 mRNA. At a concentration of 50 nM, the siRNA conjugates of the present disclosure all have an inhibition rate on APOE4 mRNA of more than 77%, and the inhibition rate of conjugate 1 and conjugate 4 on APOE4 mRNA is as high as 97.9%, indicating that the conjugates of the present disclosure can achieve effective inhibition of APOE4 mRNA in in vitro cell experiments. Inhibition effect of siRNA of the present disclosure in the central nervous system of cynomolgus monkeys Three healthy male cynomolgus monkeys (purchased from Hainan Xinzhenying Biological Technology Co., Ltd.) weighing 2.0 kg-6.0 kg and aged 2.5-6 years were selected, of which two cynomolgus monkeys were in the experimental group and one cynomolgus monkey was in the control group. The siRNA1 was dissolved in artificial cerebrospinal fluid (abbreviation ACSF, item number: CZ0516, purchased from LEAGENE) to form a siRNA1 solution with a concentration of 40 mg / mL. After the two experimental group cynomolgus monkeys were injected with muscle anesthetics and were completely anesthetized, a needle was inserted along the gap between the lumbar vertebrae L3-L5 until the syringe was back-flushed with clear cerebrospinal fluid. Then, 1.5 mL of cerebrospinal fluid was withdrawn, and 1.5 mL of the siRNA1 solution was injected intrathecally. The injection time was controlled to be more than 5 min. The control group cynomolgus monkey was injected with 1.5 mL of ACSF after being completely anesthetized. The anesthetic and injection processes were the same as those described above. The first day of administration was recorded as D1. The cerebrospinal fluid of the experimental group and the control group cynomolgus monkeys was collected before administration, on D15, D29, and D36, respectively. According to the anesthetic process described above, 1 mL of cerebrospinal fluid was collected from the occipital foramen at the back of the neck of the experimental group and the control group cynomolgus monkeys after they were anesthetized, respectively. An ELISA kit (purchased from AssayGenie, item number: MKFI00009) was used to detect the expression of APOE4 protein in the cerebrospinal fluid of the experimental group and the control group cynomolgus monkeys according to the instructions. The expression of APOE4 protein in the cerebrospinal fluid of the experimental group and the control group cynomolgus monkeys was normalized to 100% based on the expression of APOE4 protein in the cerebrospinal fluid before administration. The inhibition rate of APOE4 protein expression in the cerebrospinal fluid of the cynomolgus monkeys was calculated as follows: inhibition rate of APOE4 protein expression = (1 - APOE4 protein expression on the day of collecting cerebrospinal fluid / APOE4 protein expression before administration) x 100%. The results are shown in Table 7. Table 7 Inhibition rate of APOE4 protein expression in cerebrospinal fluid As can be seen from the results in Table 7, the experimental group cynomolgus monkeys administered with the siRNA1 solution showed a sustained inhibitory effect on APOE4 protein expression during the 36-day experimental period, with the highest inhibition rate being 46%. This indicates that the siRNA provided by the present disclosure has excellent long-acting APOE4 protein inhibitory capacity in the cerebrospinal fluid. On D36, the experimental group cynomolgus monkeys and the control group cynomolgus monkeys were euthanized, and the left brain, the lumbar segment of the spinal cord, the cervical segment of the spinal cord, and the thoracic segment of the spinal cord of each animal were collected and preserved in RNAlater (purchased from Shanghai Biyun Tian Biotechnology Co., Ltd., item number: R0118). RNA was extracted using a MagaBio plus RNA purification kit (purchased from Hangzhou Bo Riheng Technology Co., Ltd., item number: BSC69L1E-A) according to the method recorded in the instructions, and q-PCR was performed to detect the expression of the target gene APOE4. According to the calculation method of Example 1, the inhibition rate of APOE4 mRNA in different regions of the brain, the lumbar segment of the spinal cord, the cervical segment of the spinal cord, and the thoracic segment of the spinal cord was calculated. The results are shown in Table 8. Table 8 Inhibition rate of siRNA1 on APOE4 mRNA As can be seen from the results in Table 8, the double-stranded oligonucleotide provided by the present disclosure shows a very high inhibition rate of APOE4 mRNA in different positions in the central nervous system of cynomolgus monkeys, such as different regions of the brain, the lumbar segment of the spinal cord, the cervical segment of the spinal cord and the thoracic segment of the spinal cord, wherein the inhibition rate of APOE4 mRNA in the spinal cord is maintained at 92% or more, and the inhibition rate of APOE4 mRNA in the thoracic segment of the spinal cord is as high as 96.3%; the inhibition of APOE4 mRNA in the brain tissue is also maintained, and the inhibition rate of APOE4 mRNA in the cortex is maintained at 86% or more, and the inhibition rate of APOE4 mRNA in the occipital lobe region of the left brain is as high as 93.5%, indicating that the double-stranded oligonucleotide provided by the present disclosure can show excellent APOE4 mRNA inhibition effect in the central nervous system of cynomolgus monkeys. The above describes some embodiments of the present disclosure in detail, but the present disclosure is not limited to the specific details in the above-described embodiments, and various simple modifications can be made to the technical solutions of the present disclosure within the technical concept of the present disclosure, and these simple modifications all belong to the protection scope of the present disclosure. In addition, it should be noted that the various specific technical features described in the above-described embodiments can be combined in any appropriate manner without contradiction, and in order to avoid unnecessary repetition, the present disclosure will not further describe various possible combination manners. In addition, various different embodiments of the present disclosure can also be combined in any manner, as long as it does not deviate from the idea of the present disclosure, and it should also be considered as disclosed by the present disclosure.

Claims

1. A single-stranded oligonucleotide of 16-30 nucleotides in length, the single- stranded oligonucleotide having sufficiency of complementarity to an APOE4 mRNA to mediate an RNAi effect; each nucleotide in the single-stranded oligonucleotide is a modified or unmodified nucleotide, wherein, at least one nucleotide in the single-stranded oligonucleotide is a nucleotide X, at least one nucleotide is a fluorine-modified nucleotide; and, in the direction from the 5' end to the 3' end, at least 1 nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide and is spaced 4-7 nucleotides from the 8th nucleotide; and, in the direction from the 5' end to the 3' end, if the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X, and all nucleotides from the 15th nucleotide and after of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide, and a BNA; each nucleotide X is a deoxynucleotide or an unmodified nucleotide.

2. The single stranded oligonucleotide of claim 1, wherein, The single-stranded oligonucleotide has a length of 17-28, 19-26, or 20-24 nucleotides; or the single-stranded oligonucleotide has a length of 19, 21, or 23 nucleotides.

3. The single stranded oligonucleotide of claim 1 or 2, wherein, The number of nucleotides X is 1-3.

4. The single stranded oligonucleotide of any one of claims 1-3, wherein, Each nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide; and, in the direction from the 5' end to the 3' end, each nucleotide X is spaced 3, 5, 7, or 10 nucleotides from the 8th nucleotide of the single-stranded oligonucleotide; or one of the nucleotides X is spaced 5 nucleotides from the 8th nucleotide.

5. The single stranded oligonucleotide of claim 4, wherein, The single-stranded oligonucleotide contains only one nucleotide X, which is spaced 5 nucleotides from the 8th nucleotide of the single-stranded oligonucleotide in the direction from the 5' end to the 3' end; Or, the single-stranded oligonucleotide contains 2 nucleotides X, in which 1 nucleotide X is spaced 5 nucleotides from the 8th nucleotide of the single-stranded oligonucleotide, and the other nucleotide X is spaced 3, 7, or 10 nucleotides from the 8th nucleotide of the single-stranded oligonucleotide, in the direction from the 5' end to the 3' end.

6. The single stranded oligonucleotide of any one of claims 1-5, wherein, The number of modified nucleotides accounts for more than 50%, more than 70%, or more than 85% of the total number of nucleotides in the single-stranded oligonucleotide; or the number of unmodified nucleotides in the single-stranded oligonucleotide is not more than 5, not more than 4, not more than 3, not more than 2, or not more than 1; or each of the total nucleotides in the single-stranded oligonucleotide is independently a modified nucleotide.

7. The single stranded oligonucleotide of any one of claims 1-6, wherein, The number of fluorine-modified nucleotides is 2-7.

8. The single stranded oligonucleotide of claim 7, wherein, In the direction from the 5' end to the 3' end, the fluorine-modified nucleotides refer to 2-5 of the 2nd, 5th, 6th, 7th, 12th, 16th, 18th, and 19th nucleotides of the single-stranded oligonucleotide; Or, in the direction from the 5' end to the 3' end, the fluorine-modified nucleotides refer to 1 or 2 of the 2nd and 12th nucleotides, 1 or 2 of the 5th-7th nucleotides, and 0-2 of the 16th-19th nucleotides of the single-stranded oligonucleotide.

9. The single stranded oligonucleotide of claim 8, wherein, The fluorine-modified nucleotides refer to the 2nd and 6th nucleotides; or the 2nd, 6th and 16th nucleotides; or the 2nd, 5th, 7th, 12th and 16th nucleotides; or the 2nd, 7th, 12th, 16th and 19th nucleotides; or the 2nd, 6th, 12th, 16th and 19th nucleotides in the single-stranded oligonucleotide in the direction from the 5' end to the 3' end.

10. The single stranded oligonucleotide of claim 9, wherein, Each modified nucleotide in the single-stranded oligonucleotide, except for the nucleotide X and the fluorine-modified nucleotides, is independently selected from one of an alkoxy-modified nucleotide, a substituted alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide and a BNA.

11. The single stranded oligonucleotide of claim 10, wherein, There is no thermally unstable nucleotide in the single-stranded oligonucleotide, or the number of thermally unstable nucleotides is 1 or 2; or each modified nucleotide in the single-stranded oligonucleotide, except for the nucleotide X, the fluorine-modified nucleotides and the thermally unstable nucleotides, is selected from an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide.

12. The single stranded oligonucleotide of claim 11, wherein, The single-stranded oligonucleotide has a length of 19-23 nucleotides, and The 14th nucleotide is the nucleotide X, 2 of the 5th-7th nucleotides and the 19th nucleotide and the 2nd, 12th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, the 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide when it is not a fluorine-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide in the direction from the 5' end to the 3' end; or The 12th and 14th nucleotides are the nucleotide X, the 2nd, 7th and 16th nucleotides are fluorine-modified nucleotides, and the 3rd or 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide in the direction from the 5' end to the 3' end; or The 14th and 16th nucleotides are the nucleotide X, the 2nd and 6th nucleotides are fluorine-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide or a BNA, and the 3rd or 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide in the direction from the 5' end to the 3' end; one of the 1st-2nd nucleotides in the single-stranded oligonucleotide is a thermally unstable nucleotide in the direction from the 3' end to the 5' end, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or one of the 16th to 19th nucleotides and the 14th nucleotide is a nucleotide X, the 2nd and 6th nucleotides are fluorinated nucleotides, the 16th nucleotide is a fluorinated nucleotide when the 16th nucleotide is not a nucleotide X, the 13th nucleotide is a substituted alkoxy-modified nucleotide or a BNA, the 3rd or 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, the 20th nucleotide is an alkoxy-modified nucleotide or a thermally unstable nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide.

13. The single stranded oligonucleotide of claim 12, wherein, the single-stranded oligonucleotide is 21 nucleotides in length, and in the 5' end to 3' end direction, the 14th nucleotide is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorinated nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, in the 5' end to 3' end direction, the 14th nucleotide is a deoxynucleotide, the 2nd, 7th, 12th, 16th and 19th nucleotides are fluorinated nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, in the 5' end to 3' end direction, the 14th nucleotide is a deoxynucleotide, the 2nd, 6th, 12th, 16th and 19th nucleotides are fluorinated nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, in the 5' end to 3' end direction, the 12th and 14th nucleotides are deoxynucleotides, the 2nd, 7th and 16th nucleotides are fluorinated nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, in the 5' end to 3' end direction, the 14th nucleotide is a deoxynucleotide, the 16th nucleotide is an unmodified nucleotide, the 2nd and 6th nucleotides are fluorinated nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, in the 3' end to 5' end direction, the 2nd nucleotide of the single-stranded oligonucleotide is a thermally unstable nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, in the 5' end to 3' end direction, the 14th nucleotide is a deoxynucleotide, the 19th nucleotide is an unmodified nucleotide, the 2nd, 6th and 16th nucleotides are fluorinated nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide.

14. The single stranded oligonucleotide of any one of claims 10-13, wherein, each alkoxy-modified nucleotide is a methoxy-modified nucleotide; and / or each substituted alkoxy-modified nucleotide is a 2'-0-methoxyethyl-modified nucleotide; and / or each BNA is a LNA or a cET BNA; and / or each thermally unstable nucleotide is a GNA. each alkoxy-modified nucleotide is a methoxy-modified nucleotide; and / or each substituted alkoxy-modified nucleotide is a 2'-0-methoxyethyl-modified nucleotide; and / or each BNA is a LNA or a cET BNA; and / or each thermally unstable nucleotide is a GNA.

15. The single stranded oligonucleotide of any one of claims 1-14, wherein, Each of the at least 2 of the linking groups between adjacent nucleotides in the single-stranded oligonucleotide is independently a phosphorothioate group.

16. The single stranded oligonucleotide of claim 15, wherein, Each of the 1-4 of the linking groups between adjacent nucleotides in the first 5 nucleotides from the 5' end and / or the 1-4 of the linking groups between adjacent nucleotides in the first 5 nucleotides from the 3' end of the single-stranded oligonucleotide is independently a phosphorothioate group; and / or If there are unmodified nucleotides in the single-stranded oligonucleotide, each of the 1 or 2 of the 2 linking groups between each of the unmodified nucleotides and the adjacent nucleotides is independently a phosphorothioate group. Each of the 2-6, or 4, of the linking groups between adjacent nucleotides in the single-stranded oligonucleotide is independently a phosphorothioate group.

17. The single stranded oligonucleotide of claim 15 or 16, wherein, Each of the linking groups between adjacent nucleotides in the first 3 nucleotides from the 5' end and the linking groups between adjacent nucleotides in the first 3 nucleotides from the 3' end of the single-stranded oligonucleotide is independently a phosphorothioate group; and / or If there are unmodified nucleotides in the single-stranded oligonucleotide, each of the 1 or 2 of the 2 linking groups between each of the unmodified nucleotides and the adjacent nucleotides is independently a phosphorothioate group.

18. The single stranded oligonucleotide of any one of claims 15-17, wherein, Phosphonate groups having a modifying group are phosphorothioate groups having the structure of formula (28):

19. The single stranded oligonucleotide of any one of claims 1-18, wherein, The 5'-terminal nucleotide of the single-stranded oligonucleotide is a 5'-hydroxyl nucleotide, a 5'-phosphate nucleotide, or a 5'-phosphate analog modified nucleotide, the 5'-hydroxyl nucleotide has a structure shown as formula (29); the 5'-phosphate nucleotide has a structure shown as formula (30); and the 5'-phosphate analog modified nucleotide has one selected from structures shown as formula (31) to formula (34): wherein R is selected from one of H, OH, OCH3 and F; Base represents a nucleic acid base selected from A, U, C, G or T.

20. The single stranded oligonucleotide of any one of claims 1-19, wherein, The single-stranded oligonucleotide has a length of 21 nucleotides, and in the direction from the 5' end to the 3' end, the 14th nucleotide is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is a methoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is a methoxy-modified nucleotide; the linking groups between any two adjacent nucleotides in the first 3 nucleotides from the 5' end and the linking groups between any two adjacent nucleotides in the first 3 nucleotides from the 3' end of the single-stranded oligonucleotide are phosphorothioate groups; the 5' terminal nucleotide is a 5'-hydroxyl nucleotide represented by formula (29), a 5'-phosphate nucleotide represented by formula (30), or a 5'-vinyl phosphate-modified nucleotide represented by formula (31).

21. The single stranded oligonucleotide of any one of claims 1-20, wherein, The single-stranded oligonucleotide is substantially, substantially or completely reverse complementary to the APOE4 mRNA over a length of at least 16 nucleotides, over a length of 16-25 nucleotides, over a length of 18-23 nucleotides, or over a length of 19-21 nucleotides; and / or In the direction from the 5' end to the 3' end, the nucleotide sequence of the single-stranded oligonucleotide except for the 1st nucleotide is completely reverse complementary to the APOE4 mRNA; or, all of the nucleotides of the single-stranded oligonucleotide are completely reverse complementary to the APOE4 mRNA.

22. The single stranded oligonucleotide of any one of claims 1-21, wherein, The single-stranded oligonucleotide contains a nucleotide sequence II, which is one selected from the following i)-vi): i) the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 2, and differs from the nucleotide sequence set forth in SEQ ID NO: 2 by no more than 3 base differences: Z2 is U or A, the nucleotide sequence II comprises a nucleotide Z'2 corresponding to the position of Z2, Z'2 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence; ii) the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 4, and differs from the nucleotide sequence set forth in SEQ ID NO: 4 by no more than 3 base differences: Z4 is G, A or U, the nucleotide sequence II comprises a nucleotide Z'4 corresponding to the position of Z4, Z'4 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence; iii) the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 6 and differs from the nucleotide sequence set forth in SEQ ID NO: 6 by no more than 3 base differences: Z6 is C, A or U, the nucleotide sequence II comprises a nucleotide Z'6 corresponding to the position of Z6, Z'6 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence; iv) the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 8 and differs from the nucleotide sequence set forth in SEQ ID NO: 8 by no more than 3 base differences: Z8 is U or A, the nucleotide sequence II comprises a nucleotide Z'8 corresponding to the position of Z8, Z'8 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence; v) the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 44 and differs from the nucleotide sequence set forth in SEQ ID NO: 44 by no more than 3 base differences: Among them, Z 10 The nucleotide sequence II contains a position corresponding to Z, which is G, A, or U. 10 nucleotide Z' 10 The Z' 10 It is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence; vi) the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 46 and differs from the nucleotide sequence set forth in SEQ ID NO: 46 by no more than 3 base differences: Among them, Z 12 The nucleotide sequence II contains a position corresponding to Z, which is C, A, or U. 12 nucleotide Z' 12 The Z' 12 It is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence.

23. The single stranded oligonucleotide of claim 22, wherein, the nucleotide sequence II is not more than 1 base different from the nucleotide sequence shown in SEQ ID NO: 2, 4, 6, 8, 44 or 46; or, the nucleotide sequence II is not different from the nucleotide sequence shown in SEQ ID NO: 2, 4, 6, 8, 44 or 46.

24. The single stranded oligonucleotide of claim 22 or 23, wherein, The single-stranded oligonucleotide further comprises a nucleotide sequence IV, the nucleotide sequence IV is connected at the 3' end of the nucleotide sequence II, the length of the nucleotide sequence IV is 1, 2, 3 or 4 nucleotides, each nucleotide in the nucleotide sequence IV is independently one of non-fluorine modified nucleotides, the nucleotide sequence IV is substantially reverse complementary or completely reverse complementary to APOE4 mRNA, each of the non-fluorine modified nucleotides is independently selected from one of 2'-methoxy modified nucleotides, 2'-alkyl modified nucleotides with carbon atom number of 1-3, 2'-amino modified nucleotides, 2'-substituted amino modified nucleotides and heat unstable nucleotides; or, the length of the nucleotide sequence IV is 2 nucleotides.

25. The single stranded oligonucleotide of any one of claims 22-24, wherein, The single-stranded oligonucleotide further comprises a nucleotide sequence V, each nucleotide in the nucleotide sequence V is non-fluorine modified nucleotide, the length of the nucleotide sequence V is 1-3 nucleotides, the nucleotide sequence V is connected at the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the positive strand, the nucleotide sequence V constitutes the 3' overhanging end of the antisense strand of the double-stranded oligonucleotide; or, the length of the nucleotide sequence V is 2 nucleotides, and in the direction from 5' end to 3' end, the nucleotide sequence V is continuous 2 thymine deoxynucleotides, continuous 2 uracil nucleotides or completely reverse complementary to APOE4 mRNA; or, the length of the nucleotide sequence II is equal to the nucleotide sequence shown in SEQ ID NO: 2, and there are not more than 3 base differences, the nucleotide sequence V is connected at the 3' end of the nucleotide sequence II, and in the direction from 5' end to 3' end, the base composition of the nucleotide sequence V is AU or AT, A is methoxy modified nucleotide or GNA, T or U is methoxy modified nucleotide; Alternatively, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 4, and differs by no more than 3 bases, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and, in the 5' end to 3' end direction, the base composition of the nucleotide sequence V is UU or TT, the T or U being a methoxy modified nucleotide or GNA; Alternatively, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 6, and differs by no more than 3 bases, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and, in the 5' end to 3' end direction, the base composition of the nucleotide sequence V is CU or CT, the C being a methoxy modified nucleotide or GNA, the T or U being a methoxy modified nucleotide; Alternatively, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 8, and differs by no more than 3 bases, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and, in the 5' end to 3' end direction, the base composition of the nucleotide sequence V is UU or GG, each of the G and U being independently a methoxy modified nucleotide or GNA; Alternatively, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 44, and differs by no more than 3 bases, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and, in the 5' end to 3' end direction, the base composition of the nucleotide sequence V is CC or UU, each of the C and U being independently a methoxy modified nucleotide or GNA; Alternatively, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 46, and differs by no more than 3 bases, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and, in the 5' end to 3' end direction, the base composition of the nucleotide sequence V is CA or UU, each of the U, C and A being independently a methoxy modified nucleotide or GNA; Alternatively, the single-stranded oligonucleotide is the antisense strand of any one of siRNAa1 - siRNAf1 listed in Table 1; Alternatively, the single-stranded oligonucleotide is the antisense strand of siRNA1 listed in Table 2A; Alternatively, the single-stranded oligonucleotide is the antisense strand of any one of conjugate 1 - conjugate 9 and conjugate 11 - conjugate 27 listed in Table 2A.

26. A double stranded oligonucleotide comprising a sense strand and an antisense strand, each nucleotide in the sense strand being a modified or unmodified nucleotide, the sense strand and antisense strand being at least partially reverse complementary forming a double stranded region, wherein, The antisense strand is the single-stranded oligonucleotide of any one of claims 1 - 25.

27. The double-stranded oligonucleotide of claim 26, wherein, the length of the sense strand is 19-23 nucleotides; or, the length of the sense strand and the length of the antisense strand are the same, and are 19, 20, or 21 nucleotides; or, the length of the sense strand is 19 nucleotides and the length of the antisense strand is 20-24 nucleotides; or, the length of the sense strand is 20 nucleotides and the length of the antisense strand is 21-24 nucleotides; or, the length of the sense strand is 21 nucleotides and the length of the antisense strand is 22-24 nucleotides; or, the length of the sense strand is 19 nucleotides and the length of the antisense strand is 21 nucleotides; or, the length of the sense strand is 21 nucleotides and the length of the antisense strand is 23 nucleotides.

28. The double-stranded oligonucleotide of any one of claims 26-27, wherein, 2-3 of the 11th-13th nucleotides from the 3' end to the 5' end of the sense strand are fluorine-modified nucleotides, the 1st and / or the last nucleotide is an alkoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions of the sense strand are non-fluorine-modified nucleotides, each of which is independently selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, an amine-modified nucleotide, and a thermally unstable nucleotide.

29. The double-stranded oligonucleotide of claim 28, wherein, 2-3 of the 11th-13th nucleotides from the 3' end to the 5' end of the sense strand are fluorine-modified nucleotides, the 1st and / or the last nucleotide is an alkoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions of the sense strand are non-fluorine-modified nucleotides, each of which is independently selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, an amine-modified nucleotide, and a thermally unstable nucleotide.

30. The double-stranded oligonucleotide of claim 28 or 29, wherein, each of the alkoxy-modified nucleotides is a methoxy-modified nucleotide.

31. The double-stranded oligonucleotide of any one of claims 26-30, wherein, In the sense strand, at least one of the linking groups between adjacent nucleotides is a phosphate group with a modification group, which is present at at least one of the following: between adjacent nucleotides of the 1st-5th nucleotides from the 5' end and between adjacent nucleotides of the 1st-5th nucleotides from the 3' end of the sense strand.

32. The double-stranded oligonucleotide of claim 31, wherein, each of 1-4 of the linking groups between adjacent nucleotides of the 1st-5th nucleotides from the 5' end and / or 1-4 of the linking groups between adjacent nucleotides of the 1st-5th nucleotides from the 3' end of the sense strand is independently a phosphate group with a modification group; or, the phosphate group with a modification group is a phosphorothioate group with a structure as shown in formula (28); or, the sense strand is the sense strand of any one of siRNAa1-siRNAf1 listed in Table 1; or, the sense strand is the sense strand of siRNA1 listed in Table 2A; or, the sense strand is the sense strand of any one of conjugate 1-conjugate 9 and conjugate 11-conjugate 27 listed in Table 2A.

33. The double-stranded oligonucleotide of any one of claims 26-32, wherein, the length of the sense strand is 19-23 nucleotides; or, the length of the sense strand and the length of the antisense strand are the same, and are 19, 20, or 21 nucleotides; or, the length of the sense strand is 19 nucleotides and the length of the antisense strand is 20-24 nucleotides; or, the length of the sense strand is 20 nucleotides and the length of the antisense strand is 21-24 nucleotides; or, the length of the sense strand is 21 nucleotides and the length of the antisense strand is 22-24 nucleotides; or, the length of the sense strand is 19 nucleotides and the length of the antisense strand is 21 nucleotides; or, the length of the sense strand is 21 nucleotides and the length of the antisense strand is 23 nucleotides. In the sense strand, the 11th and 13th nucleotides, or the 11th-13th nucleotides, from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st and / or the last nucleotide is an alkoxy-modified nucleotide or an inverted dealkylated deoxynucleotide, and the nucleotides at the remaining positions are all alkoxy-modified nucleotides; 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides at the 5' end of the sense strand and / or 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides at the 3' end of the sense strand are phosphorothioate groups.

34. The double-stranded oligonucleotide of claim 33, wherein, The sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; In the sense strand, the 11th and 13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide is an inverted dealkylated deoxynucleotide, and the nucleotides at the remaining positions are all alkoxy-modified nucleotides; the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end of the sense strand and / or the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 3' end of the sense strand are phosphorothioate groups. In the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 7th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 6th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 12th and 14th nucleotides from the 5' end to the 3' end are deoxynucleotides, the 2nd, 7th and 16th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 16th nucleotide is an unmodified nucleotide, the 2nd and 6th nucleotides are fluorine-modified nucleotides, and the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 2nd nucleotide from the 3' end to the 5' end is a thermally unstable nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 19th nucleotide is an unmodified nucleotide, the 2nd, 6th and 16th nucleotides are fluorine-modified nucleotides, and the 13th nucleotide is a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; the linkage groups between adjacent nucleotides at the 1st-3rd nucleotides from the 5' end and the 1st-3rd nucleotides from the 3' end of the antisense strand are phosphate groups with a modification group, and if there is an unmodified nucleotide, the linkage group between each of the unmodified nucleotides and the adjacent nucleotides is a phosphate group with a modification group; and the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29), a 5'-phosphate nucleotide represented by formula (30), or a 5'-vinyl phosphate-modified nucleotide represented by formula (31).

35. The double-stranded oligonucleotide of any one of claims 25-34, wherein, the sense strand comprises 19 nucleotides, and the antisense strand comprises 21 nucleotides; In the sense strand, the 11th and 13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide is an inverted de-alkylated deoxynucleotide, and the nucleotides at the remaining positions are methoxy-modified nucleotides; the linking groups between adjacent nucleotides at the 1st-3rd nucleotides at the 5' end of the sense strand are phosphorothioate groups; in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, and the remaining nucleotides in the antisense strand are methoxy-modified nucleotides; the linking groups between adjacent nucleotides at the 1st-3rd nucleotides at the 5' end of the antisense strand and the linking groups between adjacent nucleotides at the 1st-3rd nucleotides at the 3' end of the antisense strand are phosphorothioate groups; the 5' end nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinyl phosphate-modified nucleotide represented by formula (31).

36. The double-stranded oligonucleotide of any one of claims 26-35, wherein, The double-stranded region formed by the sense strand and the antisense strand contains 16-23 base pairs; or, the double-stranded region formed by the sense strand and the antisense strand contains 18, 19, 20 or 21 base pairs; and / or, The sense strand and the antisense strand are substantially inversely complementary or completely inversely complementary within the double-stranded region; and / or, The number of base differences between the sense strand and the APOE4 mRNA is not more than 3, not more than 2 or not more than 1; or, there is no base difference between the sense strand and the APDE4 mRNA.

37. The double-stranded oligonucleotide of claim 36, wherein, The double-stranded oligonucleotide is an siRNA.

38. The double-stranded oligonucleotide of any one of claims 26-37, wherein, The sense strand contains a nucleotide sequence I, and the antisense strand contains a nucleotide sequence II; the nucleotide sequence I and the nucleotide sequence II are selected from one group consisting of the following i)-vi) sequences: i) the nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 1 and differs by no more than 3 bases, and the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 2 and differs by no more than 3 bases: wherein Z1 is A or an inverted de-alkylated deoxynucleotide, Z2 is U or A, the nucleotide sequence I contains a nucleotide Z'1 corresponding to the position of Z1, the nucleotide sequence II contains a nucleotide Z'2 corresponding to the position of Z2, and the Z'2 is the first nucleotide at the 5' end of the antisense strand; ii) the nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 3 and differs by no more than 3 bases, and the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 4 and differs by no more than 3 bases: wherein Z3 is C, A or an inverted de-alkylated deoxynucleotide, Z4 is G, A or U, the nucleotide sequence I contains a nucleotide Z'3 corresponding to the position of Z3, the nucleotide sequence II contains a nucleotide Z'4 corresponding to the position of Z4, and the Z'4 is the first nucleotide at the 5' end of the antisense strand; iii) the nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 5 and differs by no more than 3 bases, and the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 6 and differs by no more than 3 bases: wherein Z5 is G, A or an inverted de-alkylated deoxynucleotide, Z6 is C, A or U, the nucleotide sequence I contains a nucleotide Z'5 corresponding to the position of Z5, the nucleotide sequence II contains a nucleotide Z'6 corresponding to the position of Z6, and the Z'6 is the first nucleotide at the 5' end of the antisense strand; iv) the nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 7 and differs by no more than 3 bases, and the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 8 and differs by no more than 3 bases: wherein Z7 is A or an inverted dideoxy nucleotide, Z8 is U or A, the nucleotide sequence I comprises a nucleotide Z'7 at a position corresponding to Z7, the nucleotide sequence II comprises a nucleotide Z'8 at a position corresponding to Z8, and Z'8 is the first nucleotide at the 5' end of the antisense strand; v) the nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 43 and differs by no more than 3 bases, and the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 44 and differs by no more than 3 bases: Where Z9 is a C or reverse debased deoxynucleotide, Z 10 The nucleotide sequence is G, A, or U, wherein nucleotide sequence I contains a nucleotide Z'9 at position Z9, and nucleotide sequence II contains a nucleotide at position Z... 10 nucleotide Z' 10 The Z' 10 It is the first nucleotide at the 5' end of the antisense strand; vi) the nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 45 and differs by no more than 3 bases, and the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 46 and differs by no more than 3 bases: wherein Z 11 is G or an inverted abasic deoxynucleotide, Z 12 is C, A or U, said nucleotide sequence I comprising a nucleotide Z' 11 at a position corresponding to Z 11 , said nucleotide sequence II comprising a nucleotide Z' 12 at a position corresponding to Z 12 , said Z' 12 being the first nucleotide of the 5' end of the antisense strand.

39. The double-stranded oligonucleotide of claim 38, wherein, the nucleotide sequence I is not more than 1 base different from the nucleotide sequence set forth in SEQ ID NO: 1, 3, 5, 7, 43 or 45, and the nucleotide sequence II is not more than 1 base different from the nucleotide sequence set forth in SEQ ID NO: 2, 4, 6, 8, 44 or 46.

40. The double-stranded oligonucleotide of claim 39, wherein, the double-stranded oligonucleotide is siRNAa1, siRNAb1, siRNAc1, siRNAd1, siRNAe1, siRNAf1 listed in Table 1 or siRNA1 listed in Table 2A.

41. An oligonucleotide conjugate comprising at least one oligonucleotide group and a delivery group conjugated to the oligonucleotide group, the oligonucleotide group being independently a group formed by removing one or more atoms or atom groups from the single-stranded oligonucleotide of any one of claims 1-25 or the double-stranded oligonucleotide of any one of claims 26-40.

42. The oligonucleotide conjugate of claim 41, wherein, the delivery group comprises a linking group and a pharmaceutically acceptable targeting group, and the oligonucleotide group, the linking group and the targeting group are covalently or non-covalently linked in sequence, each of the targeting groups being selected from a ligand capable of binding to a surface receptor of a cell or a group capable of increasing the compatibility with a tissue; or, each of the targeting groups is independently selected from a ligand capable of binding to a surface receptor of a cell in the central nervous system or a group capable of increasing the compatibility with a tissue in the central nervous system; or, the oligonucleotide conjugate comprises an oligonucleotide group formed by the siRNA listed in Table 1; Alternatively, the oligonucleotide conjugate has the structure shown in Formula (403): in formula (403), Nu is an oligonucleotide group; or, the oligonucleotide group is a double-stranded oligonucleotide group, the P atom is covalently linked to the 3' terminal nucleotide of the sense strand of the double-stranded oligonucleotide group; or, the 3' terminal nucleotide of the sense strand of the double-stranded oligonucleotide group is an inverted dideoxy deoxy nucleotide, the P atom is covalently linked to the double-stranded oligonucleotide group by replacing the hydrogen atom in the hydroxyl group via a methylene linkage to the ribose ring in the inverted dideoxy deoxy nucleotide at the 3' terminal of the sense strand of the double-stranded oligonucleotide group; or, the oligonucleotide conjugate is one of conjugates 1-9 and conjugates 11-27 listed in Table 2.

43. A pharmaceutically acceptable salt of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-40 or the oligonucleotide conjugate of claim 41 or 42. or the pharmaceutically acceptable salt is a water-soluble salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate in whole or in part; or the pharmaceutically acceptable salt is a sodium salt or a partial sodium salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate; or the water-soluble salt is an amine salt, an alkali metal salt, or an alkaline earth metal salt; or the amine salt is selected from one or more of an ammonium salt, a methylamine salt, a tertiary amine salt, a quaternary ammonium salt, the alkali metal salt is selected from a potassium salt or a sodium salt, and the alkaline earth metal salt is selected from a calcium salt or a magnesium salt; or the tertiary amine salt is a triethylamine salt, a triisopropylamine salt, or a triisopropyl amine salt.

44. A pharmaceutical composition comprising one or more of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42, and the pharmaceutically acceptable salt of claim 43, and a pharmaceutically acceptable excipient. or the pharmaceutically acceptable excipient is one or more of a solvent, a protective agent, an osmotic pressure adjusting agent, and a pharmaceutically acceptable other carrier; or the solvent is one of deionized water, water for injection, a pH buffer, physiological saline, ethanol, or an aqueous ethanol solution.

45. Use of one or more of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43, and the pharmaceutical composition of claim 44 in the manufacture of a medicament for treating and / or preventing a disease or a condition associated with the expression level of APOE4 mRNA.

46. The use of claim 45, wherein, The disease or the condition associated with the expression level of APOE4 mRNA is a neurodegenerative disease, or the disease or the condition associated with the expression level of APOE4 mRNA is one or more of Alzheimer’s disease (AD), Down’s syndrome, and cerebral amyloid angiopathy.

47. A method of treating and / or preventing a disease or a condition associated with the expression level of APOE4 mRNA, the method comprising administering to a subject in need thereof an effective amount of one or more of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43, and the pharmaceutical composition of claim 44.

48. A method of modulating the level of APOE4 mRNA expression in a cell in vitro or in vivo, the method comprising contacting the cell in vitro or in vivo with an effective amount of one or more of the single stranded oligonucleotide of any one of claims 1-25, the double stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43, and the pharmaceutical composition of claim 44.

49. A kit comprising one or more of the single stranded oligonucleotide of any one of claims 1-25, the double stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43, and the pharmaceutical composition of claim 44.

50. One or more of the single stranded oligonucleotide of any one of claims 1-25, the double stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43, and the pharmaceutical composition of claim 41 for use as a medicament.

51. A cell expressing APOE4 mRNA, the cell comprising one or more of the single stranded oligonucleotide of any one of claims 1-25, the double stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43, and the pharmaceutical composition of claim 44.

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