Amyloid precursor protein (APP) RNAi agent compositions and methods of use thereof

Abstract

20 26 20 45 72 15 J un 2 02 6 A B S T R A C T 2 0 2 6 2 0 4 5 7 2 1 5 J u n 2 0 2 6

Description

RELATED APPLICATION This application is a divisional application of Australian application no. 5   2019405783, the entire disclosure of which is incorporated herein by reference. FIELD OF THE INVENTION The instant disclosure relates generally to APP-targeting RNAi agents and methods. SEQUENCE LISTING 10          The Australian application no. 2019405783 contained a Sequence Listing which was filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on December  18,  2019, was named 53433_500WO01_SequenceListing_ST25.txt and was 632 kB in size. The instant application contains a Sequence Listing which has been filed electronically in XML 15 format and is hereby incorporated by reference in its entirety. Said XML copy, created on 10 June 2026, is named “Sequence listing - M53440431.xml” and is 30,283,078 bytes in size. BACKGROUND OF THE INVENTION The amyloid precursor protein (APP) gene encodes an integral membrane protein 20 expressed in neurons and glia. While the primary function of APP is unknown, secretase-cleaved forms of APP - particularly the Ap cleavage forms of APP, e.g., AP(1-42) (aka Ap42) and AP(1-40) (aka Ap40) commonly found as the predominant protein in amyloid beta plaques - have long been described as associated with the development and progression of Alzheimer’s disease (AD) in affected individuals. 25 Indeed, identification of myloid beta plaques in a subject is necessary for pathological diagnosis of AD. Ap cleavage forms of APP have been particularly described to play a critical and even causal role in the development of two AD-related / associated diseases: cerebral amyloid angiopathy (CAA) and early onset familial Alzheimer disease (EOFAD or eFAD). 2026204572  15 Jun 2026 Inhibition of the expression and / or activity of APP with an agent that can selectively and efficiently inhibit APP, and thereby block or dampen the production and / or levels of Ap cleavage forms of APP, would be useful for preventing or treating a variety of APP-associated diseases and disorders, including AD, CAA and EOFAD, 5 among others. Current treatment options for APP-associated diseases and disorders are both limited and largely ineffective. There are no existing therapies for hereditary CAA, and attempts to treat sporadic forms of AD and EOFAD have to date proven unsuccessful -for example, all trials of BACE1 (p-secretase) inhibitors for treatment of sporadic AD 10 have thus far failed (Egan et al. The New England Journal of Medicine, 378: 16911703; Hung and Fu. Journal of Biomedical Science, 24: 47). Meanwhile, a number of Ap-directed immunotherapies are in various phases of development, while a number of human Y-secretase inhibitor programs have been halted for toxicity (Selkoe and Hardy. EMBO Molecular Medicine, 8: 595-608). To date, approved pharmacologic treatments 15 for APP-associated diseases or disorders are directed to treatment of symptoms, not to prevention or cure, and such treatments are of limited efficacy, particularly as APP-associated diseases or disorders advance in an affected individual. Therefore, there is a need for therapies for subjects suffering from APP-associated diseases and disorders, including a particular need for therepaies for subjects suffering from hereditary CAA 20 and EOFAD. BRIEF SUMMARY OF THE INVENTION The present disclosure provides RNAi compositions which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of an amyloid precursor protein (APP) gene. The APP gene may be within a cell, e.g., a cell within a 25 subject, such as a human. The present disclosure also provides methods of using the RNAi compositions of the disclosure for inhibiting the expression of an APP gene and / or for treating a subject who would benefit from inhibiting or reducing the expression of an APP gene, e.g., a subject suffering or prone to suffering from an APP-associated disease, for example, cerebral amyloid angiopathy (CAA) or Alzheimer’s 30 disease (AD), e.g., early onset familial Alzheimer disease (EOFAD). Accordingly, in one aspect, the instant disclosure provides a double stranded ribonucleic acid (RNAi) agent for inhibiting expression of an amyloid precursor protein (APP) gene, where the RNAi agent includes a sense strand and an antisense strand, and 2026204572  15 Jun 2026 where the antisense strand includes a region of complementarity which includes at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the antisense sequences listed in any one of Tables 2A, 2B, 3, 5A, 5B, 6, 9, 10-15, 16A, 16B, 26, and 30. In certain embodiments, thymine-to-uracil and / or uracil-to-thymine 5 differences between aligned (compared) sequences are not counted as nucleotides that differ between the aligned (compared) sequences. Another aspect of the instant disclosure provides a double stranded RNAi agent for inhibiting expression of an amyloid precursor protein (APP) gene, where the dsRNA agent includes a sense strand and an antisense strand, where the sense strand includes at 10 least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the sense strand sequences presented in Tables 2A, 2B, 3, 5A, 5B, 6, 9, 10-15, 16A, 16B, 26, and 30; and where the antisense strand includes at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of antisense strand nucleotide sequences presented in Tables 2A, 2B, 3, 5A, 5B, 6, 9, 10-15, 16A, 16B, 26, 15 and 30. In one embodiment, at least one of the sense strand and the antisense strand of the double stranded RNAi agent includes one or more lipophilic moieties conjugated to one or more internal nucleotide positions, optionally via a linker or carrier. An additional aspect of the disclosure provides a double stranded RNAi agent for 20 inhibiting expression of an amyloid precursor protein (APP) gene, where the dsRNA agent includes a sense strand and an antisense strand, where the sense strand includes at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 1-14, where a substitution of a uracil for any thymine of SEQ ID NOs: 1-14 (when comparing aligned sequences) does not count as a 25 difference that contributes to the differing by no more than 3 nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 1-14; and where the antisense strand includes at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 15-28, where a substitution of a uracil for any thymine of SEQ ID NOs: 15-28 (when comparing aligned sequences) does 30 not count as a difference that contributes to the differing by no more than 3 nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 15-28, where at least one of the sense strand and the antisense strand includes one or more lipophilic moieties conjugated to one or more internal nucleotide positions, optionally via a linker or carrier. 2026204572  15 Jun 2026 In one embodiment, the double stranded RNAi agent sense strand includes at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of the sense strand nucleotide sequence of an AD-392911, AD-392912, AD-392816, AD-392704, AD-392843, AD-392855, AD-392840, AD-392835, AD-392729, 5  AD-392916, AD-392876, AD-392863, AD-392917, AD-392783, AD-392765, AD- 392791, AD-392800, AD-392711, AD-392801, AD-392826, AD-392818, AD-392792, AD-392802, AD-392766, AD-392767, AD-392834, AD-392974, AD-392784, AD-392744, AD-392752, AD-392737, AD-392918, AD-392919, AD-392803, AD-392804, AD-392827, AD-392828, AD-392785, AD-392829, AD-392920, AD-392921, AD- 10   392768, AD-392805, AD-392769, AD-392753, AD-392714, AD-392703, AD-392715, AD-392836, AD-392966, AD-392832, AD-392972, AD-392961, AD-392967, AD-392894, AD-392864, AD-392865, AD-392922, AD-392833, AD-392968, AD-392962, AD-392963, AD-392969, AD-392973, AD-392923, AD-392866, AD-392877, AD-392707, AD-392926, AD-392927, AD-392717, AD-392700, AD-392878, AD-392718, 15 AD-392929, AD-392819, AD-392745, AD-392770, AD-392806, AD-392771, AD-392820, AD-392821, AD-392786, AD-392772, AD-392699, AD-392868, AD-392719, AD-392880, AD-392930, AD-392932, AD-392869, AD-392870, AD-392896, AD-392720, AD-392746, AD-392773, AD-392807, AD-392730, AD-392721, AD-392933, AD-392881, AD-392897, AD-392898, AD-392899, AD-392935, AD-392882, AD- 20   392738, AD-392739, AD-392936, AD-392900, AD-392901, AD-392937, AD-392883, AD-392975, AD-392938, AD-392902, AD-392941, AD-392942, AD-392943, AD-392944, AD-392903, AD-392775, AD-392758, AD-392945, AD-392884, AD-392947, AD-392748, AD-392759, AD-392837, AD-392970, AD-392976, AD-392965, AD-392831, AD-392904, AD-392885, AD-392886, AD-392776, AD-392887, AD-392722, 25 AD-392760, AD-392731, AD-392709, AD-392723, AD-392948, AD-392724, AD-392949, AD-392725, AD-392950, AD-392732, AD-392726, AD-392862, AD-392951, AD-392871, AD-392872, AD-397183, AD-397175, AD-397177, AD-397176, AD-397260, AD-397266, AD-397267, AD-397178, AD-397180, AD-397184, AD-397179, AD-397224, AD-397225, AD-397203, AD-397185, AD-397195, AD-397204, AD- 30   397191, AD-397251, AD-397240, AD-397205, AD-397254, AD-397259, AD-397247, AD-397233, AD-397181, AD-397196, AD-397197, AD-397226, AD-397212, AD-397182, AD-397227, AD-397217, AD-397213, AD-397229, AD-397264, AD-397265, AD-397209, AD-397192, AD-397210, AD-397219, AD-397214, AD-397220, AD- 2026204572  15 Jun 2026 397230, AD-397231, AD-397193, AD-397190, AD-397200, AD-397248, AD-397207, AD-397211, AD-397243, AD-397246, AD-397223, AD-397202, AD-397256, AD-397257, AD-397258, AD-397250, AD-397244, AD-454972, AD-454973, AD-454842, AD-454843, AD-454844, AD-994379, AD-961583, AD-961584, AD-961585, or AD-5   961586 duplex. In another embodiment, the double stranded RNAi agent antisense strand includes at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the antisense nucleotide sequence of an AD-392911, AD-392912, AD-392816, AD-392704, AD-392843, AD-392855, AD-392840, AD-392835, AD-392729, AD-392916, 10   AD-392876, AD-392863, AD-392917, AD-392783, AD-392765, AD-392791, AD- 392800, AD-392711, AD-392801, AD-392826, AD-392818, AD-392792, AD-392802, AD-392766, AD-392767, AD-392834, AD-392974, AD-392784, AD-392744, AD- 392752, AD-392737, AD-392918, AD-392919, AD-392803, AD-392804, AD-392827, AD-392828, AD-392785, AD-392829, AD-392920, AD-392921, AD-392768, AD- 15   392805, AD-392769, AD-392753, AD-392714, AD-392703, AD-392715, AD-392836, AD-392966, AD-392832, AD-392972, AD-392961, AD-392967, AD-392894, AD- 392864, AD-392865, AD-392922, AD-392833, AD-392968, AD-392962, AD-392963, AD-392969, AD-392973, AD-392923, AD-392866, AD-392877, AD-392707, AD- 392926, AD-392927, AD-392717, AD-392700, AD-392878, AD-392718, AD-392929, 20   AD-392819, AD-392745, AD-392770, AD-392806, AD-392771, AD-392820, AD- 392821, AD-392786, AD-392772, AD-392699, AD-392868, AD-392719, AD-392880, AD-392930, AD-392932, AD-392869, AD-392870, AD-392896, AD-392720, AD- 392746, AD-392773, AD-392807, AD-392730, AD-392721, AD-392933, AD-392881, AD-392897, AD-392898, AD-392899, AD-392935, AD-392882, AD-392738, AD- 25   392739, AD-392936, AD-392900, AD-392901, AD-392937, AD-392883, AD-392975, AD-392938, AD-392902, AD-392941, AD-392942, AD-392943, AD-392944, AD- 392903, AD-392775, AD-392758, AD-392945, AD-392884, AD-392947, AD-392748, AD-392759, AD-392837, AD-392970, AD-392976, AD-392965, AD-392831, AD- 392904, AD-392885, AD-392886, AD-392776, AD-392887, AD-392722, AD-392760, 30   AD-392731, AD-392709, AD-392723, AD-392948, AD-392724, AD-392949, AD- 392725, AD-392950, AD-392732, AD-392726, AD-392862, AD-392951, AD-392871, AD-392872, AD-397183, AD-397175, AD-397177, AD-397176, AD-397260, AD-397266, AD-397267, AD-397178, AD-397180, AD-397184, AD-397179, AD-397224, 2026204572  15 Jun 2026 AD-397225, AD-397203, AD-397185, AD-397195, AD-397204, AD-397191, AD-397251, AD-397240, AD-397205, AD-397254, AD-397259, AD-397247, AD-397233, AD-397181, AD-397196, AD-397197, AD-397226, AD-397212, AD-397182, AD-397227, AD-397217, AD-397213, AD-397229, AD-397264, AD-397265, AD-397209, 5 AD-397192, AD-397210, AD-397219, AD-397214, AD-397220, AD-397230, AD-397231, AD-397193, AD-397190, AD-397200, AD-397248, AD-397207, AD-397211, AD-397243, AD-397246, AD-397223, AD-397202, AD-397256, AD-397257, AD-397258, AD-397250, AD-397244, AD-454972, AD-454973, AD-454842, AD-454843, AD-454844, AD-994379, AD-961583, AD-961584, AD-961585, or AD-961586 duplex. 10          Optionally, the double stranded RNAi agent includes at least one modified nucleotide. In certain embodiments, the lipophilicity of the lipophilic moiety, measured by logKow, exceeds 0. In some embodiments, the hydrophobicity of the double-stranded RNAi agent, 15 measured by the unbound fraction in a plasma protein binding assay of the doublestranded RNAi agent, exceeds 0.2. In a related embodiment, the plasma protein binding assay is an electrophoretic mobility shift assay using human serum albumin protein. In certain embodiments, all of the nucleotides of the sense strand are modified nucleotides. 20          In some embodiments, substantially all of the nucleotides of the antisense strand are modified nucleotides. Optionally, all of the nucleotides of the sense strand are modified nucleotides. In certain embodiments, all of the nucleotides of the antisense strand are modified nucleotides. Optionally, all of the nucleotides of the sense strand and all of the 25 nucleotides of the antisense strand are modified nucleotides. In one embodiment, at least one of the modified nucleotides is a deoxynucleotide, a 3’-terminal deoxy-thymine (dT) nucleotide, a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a 30 constrained ethyl nucleotide, an abasic nucleotide, a 2’-amino-modified nucleotide, a 2’- O-allyl-modified nucleotide, 2’-C-alkyl-modified nucleotide, 2’-hydroxly-modified nucleotide, a 2’-methoxyethyl modified nucleotide, a 2’-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a 2026204572  15 Jun 2026 tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a 5'-phosphorothioate group, a nucleotide comprising a 5'-methylphosphonate group, a nucleotide comprising a 5’ phosphate or 5’ phosphate mimic, a nucleotide comprising vinyl phosphate, a nucleotide 5 comprising adenosine-glycol nucleic acid (GNA), a nucleotide comprising thymidineglycol nucleic acid (GNA) S-Isomer, a nucleotide comprising 2-hydroxymethyl-tetrahydrofurane-5-phosphate, a nucleotide comprising 2’-deoxythymidine-3’phosphate, a nucleotide comprising 2’-deoxyguanosine-3’-phosphate, or a terminal nucleotide linked to a cholesteryl derivative and / or a dodecanoic acid bisdecylamide group. 10          In a related embodiment, the modified nucleotide is a 2'-deoxy-2'-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, 3’-terminal deoxy-thymine nucleotides (dT), a locked nucleotide, an abasic nucleotide, a 2’-amino-modified nucleotide, a 2’-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, and / or a non-natural base comprising nucleotide. 15          In one embodiment, the modified nucleotide includes a short sequence of 3’- terminal deoxy-thymine nucleotides (dT). In another embodiment, the modifications on the nucleotides are 2’-O-methyl, 2’fluoro and GNA modifications. In an additional embodiment, the double stranded RNAi agent includes at least 20 one phosphorothioate internucleotide linkage. Optionally, the double stranded RNAi agent includes 6-8 phosphorothioate internucleotide linkages. In certain embodiments, the region of complementarity is at least 17 nucleotides in length. Optionally, the region of complementarity is 19-23 nucleotides in length. Optionally, the region of complementarity is 19 nucleotides in length. 25          In one embodiment, each strand is no more than 30 nucleotides in length. In another embodiment, at least one strand includes a 3’ overhang of at least 1 nucleotide. Optionally, at least one strand includes a 3’ overhang of at least 2 nucleotides. In certain embodiments, the double stranded RNAi agent further includes a C16 30 ligand conjugated to the 3’ end, the 5’ end, or the 3’ end and the 5’ end of the sense strand through a monovalent or branched bivalent or trivalent linker. In one embodiment, the ligand is 2026204572  15 Jun 2026 O       B O o=pxz OH , where B is a nucleotide base or a nucleotide base analog, optionally where B is adenine, guanine, cytosine, thymine or uracil. In another embodiment, the region of complementarity includes any one of the 5 antisense sequences in any one of Tables 2A, 2B, 3, 5A, 5B, 6, 9, 10-15, 16A, 16B, 26 and 30. In an additional embodiment, the region of complementarity is that of any one of the antisense sequences in any one of Tables 2A, 2B, 3, 5A, 5B, 6, 9, 10-15, 16A, 16B, 26 and 30. 10          In some embodiments, the internal nucleotide positions include all positions except the terminal two positions from each end of the strand. In a related embodiment, the internal positions include all positions except terminal three positions from each end of the strand. Optionally, the internal positions exclude the cleavage site region of the sense strand. 15          In one embodiment, the internal positions exclude positions 9-12, counting from the 5’-end of the sense strand. In another embodiment, the internal positions exclude positions 11-13, counting from the 3’-end of the sense strand. Optionally, the internal positions exclude the cleavage site region of the antisense strand. 20          In one embodiment, the internal positions exclude positions 12-14, counting from the 5’-end of the antisense strand. In another embodiment, the internal positions excluding positions 11-13 on the sense strand, counting from the 3’-end, and positions 12-14 on the antisense strand, counting from the 5’-end. 25          In an additional embodiment, one or more lipophilic moieties are conjugated to one or more of the following internal positions: positions 4-8 and 13-18 on the sense strand, and positions 6-10 and 15-18 on the antisense strand, counting from the 5’end of each strand. Optionally, one or more lipophilic moieties are conjugated to one or more 2026204572  15 Jun 2026 of the following internal positions: positions 5, 6, 7, 15, and 17 on the sense strand, and positions 15 and 17 on the antisense strand, counting from the 5’-end of each strand. In certain embodiments, the lipophilic moiety is an aliphatic, alicyclic, or polyalicyclic compound. Optionally, the lipophilic moiety is lipid, cholesterol, retinoic 5 acid, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethoxytrityl, or phenoxazine. In some embodiments, the lipophilic moiety contains a saturated or unsaturated 10   C4-C30 hydrocarbon chain, and an optional functional group selected that is hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and / or alkyne. In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C6-C18 hydrocarbon chain. Optionally, the lipophilic moiety contains a saturated or unsaturated C16 hydrocarbon chain. In a related embodiment, the lipophilic moiety is 15 conjugated via a carrier that replaces one or more nucleotide(s) in the internal position(s). In certain embodiments, the carrier is a cyclic group that is pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3]dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuranyl, or decalinyl; or is an 20 acyclic moiety based on a serinol backbone or a diethanolamine backbone. In some embodiments, the lipophilic moiety is conjugated to the double-stranded RNAi agent via a linker containing an ether, thioether, urea, carbonate, amine, amide, maleimide-thioether, disulfide, phosphodiester, sulfonamide linkage, a product of a click reaction, or carbamate. 25          In one embodiment, the lipophilic moiety is conjugated to a nucleobase, sugar moiety, or internucleosidic linkage. In another embodiment, the double-stranded RNAi agent further includes a phosphate or phosphate mimic at the 5’-end of the antisense strand. Optionally, the phosphate mimic is a 5’-vinyl phosphonate (VP). 30          In certain embodiments, the double-stranded RNAi agent further includes a targeting ligand that targets a receptor which mediates delivery to a CNS tissue. In one embodiment, the targeting ligand is a C16 ligand. 2026204572  15 Jun 2026 In some embodiments, the double-stranded RNAi agent further includes a targeting ligand that targets a brain tissue. In one embodiment, the lipophilic moeity or targeting ligand is conjugated via a bio-cleavable linker that is DNA, RNA, disulfide, amide, functionalized 5 monosaccharides or oligosaccharides of galactosamine, glucosamine, glucose, galactose, mannose, and / or a combination thereof. In a related embodiment, the 3’ end of the sense strand is protected via an end cap which is a cyclic group having an amine, the cyclic group being pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, 10 [1,3]dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuranyl, or decalinyl. In one embodiment, the RNAi agent includes at least one modified nucleotide that is a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a nucleotide that includes a glycol nucleic acid (GNA) and / or a nucleotide that includes a vinyl 15 phosphate. Optionally, the RNAi agent includes at least one of each of the following modifications: 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a nucleotide comprising a glycol nucleic acid (GNA) and a nucleotide comprising vinyl phosphate. In another embodiment, the RNAi agent includes a pattern of modified 20 nucleotides as shown in FIG. 1A, FIG. 1B, Table 2A, Table 5A, or Table 9 (where locations of 2’-C16, 2’-O-methyl, GNA, phosphorothioate and 2’-fluoro modifications are as displayed in FIG. 1A, FIG. 1B, Table 2A, Table 5A, or Table 9, irrespective of the individual nucleotide base sequences of the displayed RNAi agents). Another aspect of the instant disclosure provides a double stranded RNAi agent 25 for inhibiting expression of an amyloid precursor protein (APP) gene, where the double stranded RNAi agent includes a sense strand complementary to an antisense strand, where the antisense strand includes a region complementary to part of an mRNA encoding APP, where each strand is about 14 to about 30 nucleotides in length, where the double stranded RNAi agent is represented by formula (III): 30 sense:             5' np-Na-(X X X)i-Nb-Y Y Y -Nb -(Z Z Z)j-Na- nq 3' antisense:            3' np‘-Na'-(X'X'X')k-Nb‘-Y'Y'Y‘-Nb'-(Z‘Z'Z‘)i-Na‘- nq‘ 5'    (III) where: i, j, k, and l are each independently 0 or 1; 2026204572  15 Jun 2026 p, p’, q, and q‘ are each independently 0-6; each Na and Na' independently represents an oligonucleotide sequence including 0-25 nucleotides which are either modified or unmodified or combinations thereof, each sequence including at least two differently modified nucleotides; 5 each Nb and Nb' independently represents an oligonucleotide sequence including 0-10 nucleotides which are either modified or unmodified or combinations thereof; each np, np', nq, and nq', each of which may or may not be present, independently represents an overhang nucleotide; XXX, YYY, ZZZ, X'X'X', Y'Y'Y', and Z'Z'Z' each independently represent one motif of 10 three identical modifications on three consecutive nucleotides; modifications on Nb differ from the modification on Y and modifications on Nb' differ from the modification on Y'; and where the sense strand is conjugated to at least one ligand. In one embodiment, i is 0; j is 0; i is 1; j is 1; both i and j are 0; or both i and j are 15             1. In another embodiment, k is 0; l is 0; k is 1; l is 1; both k and l are 0; or both k and l are 1. In certain embodiments, XXX is complementary to X'X'X', YYY is complementary to Y'Y'Y', and ZZZ is complementary to Z'Z'Z'. 20          In another embodiment, the YYY motif occurs at or near the cleavage site of the sense strand. In an additional embodiment, the Y'Y'Y' motif occurs at the 11, 12 and 13 positions of the antisense strand from the 5'-end. Optionally, the Y' is 2'-O-methyl. 25          In some embodiments, formula (III) is represented by formula (IIIa): sense:                5' np -Na -Y Y Y -Na - nq 3' antisense:              3' np'-Na'- Y'Y'Y'- Na'- nq' 5' (IIIa). In another embodiment, formula (III) is represented by formula (IIIb): sense:               5' np -Na -Y Y Y -Nb -Z Z Z -Na - nq 3' 30 antisense:              3' np'-Na'- Y'Y'Y'-Nb'-Z'Z'Z'- Na'- nq' 5' (IIIb) where each Nb and Nb' independently represents an oligonucleotide sequence including 1-5 modified nucleotides. In an additional embodiment, formula (III) is represented by formula (IIIc): 2026204572  15 Jun 2026 sense:               5' np -Na -X X X -Nb -Y Y Y -Na - nq 3' antisense:             3' np‘-Na‘- X'X'X'-Nb’- YYY'- Na’- nq‘ 5' (IIIc) where each Nb and Nb’ independently represents an oligonucleotide sequence including 1-5 modified nucleotides. 5           In certain embodiments, formula (III) is represented by formula (IIId): sense:               5' np -Na -X X X- Nb -Y Y Y -Nb -Z Z Z -Na - nq 3' antisense:            3' np‘-Na‘- XXX'- Nb’-YYY'-Nb’-Z'Z'Z'- Na’- nq‘ 5' (IIId) where each Nb and Nb' independently represents an oligonucleotide sequence including 1-5 modified nucleotides and each Na and Na' independently represents an 10 oligonucleotide sequence including 2-10 modified nucleotides. In another embodiment, the double stranded region is 15-30 nucleotide pairs in length. Optionally, the double stranded region is 17-23 nucleotide pairs in length. In certain embodiments, the double stranded region is 17-25 nucleotide pairs in length. Optionally, the double stranded region is 23-27 nucleotide pairs in length. 15          In some embodiments, the double stranded region is 19-21 nucleotide pairs in length. Optionally, the double stranded region is 21-23 nucleotide pairs in length. In certain embodiments, each strand has 15-30 nucleotides. Optionally, each strand has 19-30 nucleotides. In another embodiment, the modifications on the nucleotides of the RNAi agent 20 are LNA, glycol nucleic acid (GNA), HNA, CeNA, 2‘-methoxyethyl, 2‘-O-alkyl, 2‘-O-allyl, 2‘-C- allyl, 2‘-fluoro, 2‘-deoxy and / or 2’-hydroxyl, and combinations thereof. Optionally, the modifications on nucleotides include 2'-O-methyl, 2'-fluoro and / or GNA, and combinations thereof. In a related embodiment, the modifications on the nucleotides are 2‘-O-methyl or 2'-fluoro modifications. 25          In one embodiment the RNAi agent includes a ligand that is or includes one or more C16 moieties attached through a bivalent or trivalent branched linker. In certain embodiments, the ligand is attached to the 3‘ end of the sense strand. In some embodiments, the RNAi agent further includes at least one phosphorothioate or methylphosphonate internucleotide linkage. In a related 30 embodiment, the phosphorothioate or methylphosphonate internucleotide linkage is at the 3’-terminus of one strand. Optionally, the strand is the antisense strand. In another embodiment, the strand is the sense strand. In a related embodiment, the phosphorothioate or methylphosphonate internucleotide linkage is at the 5’-terminus of 2026204572  15 Jun 2026 one strand. Optionally, the strand is the antisense strand. In another embodiment, the strand is the sense strand. In another embodiment, the phosphorothioate or methylphosphonate internucleotide linkage is at the both the 5’- and 3’-terminus of one strand. Optionally, 5 the strand is the antisense strand. In another embodiment, the strand is the sense strand. In an additional embodiment, the base pair at the 1 position of the 5‘-end of the antisense strand of the RNAi agent duplex is an A:U base pair. In certain embodiments, the Y nucleotides contain a 2‘-fluoro modification. In some embodiments, the Y' nucleotides contain a 2‘-O-methyl modification. 10           In certain embodiments, p‘>0. Optionally, p'=2. In some embodiments, q’=0, p=0, q=0, and p’ overhang nucleotides are complementary to the target mRNA. In certain embodiments, q’=0, p=0, q=0, and p’ overhang nucleotides are non-complementary to the target mRNA. 15          In one embodiment, the sense strand of the RNAi agent has a total of 21 nucleotides and the antisense strand has a total of 23 nucleotides. In another embodiment, at least one np‘ is linked to a neighboring nucleotide via a phosphorothioate linkage. Optionally, all np' are linked to neighboring nucleotides via phosphorothioate linkages. 20          In certain embodiments, the RNAi agent of the instant disclosure is one of those listed in Table 2A, 2B, 3, 5A, 5B, 6 and / or 9. In some embodiments, all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand include a modification. Another aspect of the instant disclosure provides a double stranded RNAi agent 25 for inhibiting expression of an amyloid precursor protein (APP) gene in a cell, where the double stranded RNAi agent includes a sense strand complementary to an antisense strand, where the antisense strand includes a region complementary to part of an mRNA encoding APP, where each strand is about 14 to about 30 nucleotides in length, where the double stranded RNAi agent is represented by formula (III): 30 sense:              5' np-Na-(X X X) i-Nb -Y Y Y -Nb-(Z Z Z)j-Na- nq 3' antisense:            3' np'-Na'-(X'X'X')k-Nb'-Y'Y'Y'-Nb'-(Z'Z'Z')l-Na'- nq' 5' (III) where: i, j, k, and l are each independently 0 or 1; 2026204572  15 Jun 2026 p, p’, q, and q‘ are each independently 0-6; each Na and Na' independently represents an oligonucleotide sequence including 0-25 nucleotides which are either modified or unmodified or combinations thereof, each sequence including at least two differently modified nucleotides; 5 each Nb and Nb' independently represents an oligonucleotide sequence including 0-10 nucleotides which are either modified or unmodified or combinations thereof; each np, np', nq, and nq', each of which may or may not be present independently represents an overhang nucleotide; XXX, YYY, ZZZ, X'X'X', Y'Y'Y', and Z'Z'Z' each independently represent one motif of 10 three identical modifications on three consecutive nucleotides, and where the modifications are 2‘-O-methyl or 2'-fluoro modifications; modifications on Nb differ from the modification on Y and modifications on Nb' differ from the modification on Y'; and where the sense strand is conjugated to at least one ligand. 15          An additional aspect of the instant disclosure provides a double stranded RNAi agent for inhibiting expression of an amyloid precursor protein (APP) gene in a cell, where the double stranded RNAi agent includes a sense strand complementary to an antisense strand, where the antisense strand includes a region complementary to part of an mRNA encoding APP, where each strand is about 14 to about 30 nucleotides in 20 length, where the double stranded RNAi agent is represented by formula (III): sense:              5' np-Na-(X X X) i-Nb -Y Y Y -Nb-(Z Z Z)j-Na- nq 3' antisense:            3' np'-Na'-(X'X'X')k-Nb'-Y'Y'Y'-Nb'-(Z'Z'Z')l-Na'- nq' 5' (III) where: i, j, k, and l are each independently 0 or 1; 25 each np, nq, and nq', each of which may or may not be present, independently represents an overhang nucleotide; p, q, and q' are each independently 0-6; np' >0 and at least one np' is linked to a neighboring nucleotide via a phosphorothioate linkage; 30 each Na and Na' independently represents an oligonucleotide sequence including 0-25 nucleotides which are either modified or unmodified or combinations thereof, each sequence including at least two differently modified nucleotides; 2026204572  15 Jun 2026 each Nb and Nb‘ independently represents an oligonucleotide sequence including 0-10 nucleotides which are either modified or unmodified or combinations thereof; XXX, YYY, ZZZ, X'X'X', Y'Y'Y', and Z'Z'Z' each independently represent one motif of three identical modifications on three consecutive nucleotides, and where the 5 modifications are 2‘-O-methyl, glycol nucleic acid (GNA) or 2'-fluoro modifications; modifications on Nb differ from the modification on Y and modifications on Nb‘ differ from the modification on Y'; and where the sense strand is conjugated to at least one ligand. Another aspect of the instant disclosure provides a double stranded RNAi agent 10 for inhibiting expression of an amyloid precursor protein (APP) gene in a cell, where the double stranded RNAi agent includes a sense strand complementary to an antisense strand, where the antisense strand includes a region complementary to part of an mRNA encoding APP, where each strand is about 14 to about 30 nucleotides in length, where the double stranded RNAi agent is represented by formula (III): 15 sense:             5' np-Na-(X X X) i-Nb -Y Y Y -Nb-(Z Z Z)j-Na- nq 3' antisense:          3' np'-Na'-(X'X'X>Nb'-YY'Y'-Nb'-(Z'Z'Z')l-Na'^ nq' 5' (III) where: i, j, k, and l are each independently 0 or 1; each np, nq, and nq‘, each of which may or may not be present, independently represents 20 an overhang nucleotide; p, q, and q‘ are each independently 0-6; np‘ >0 and at least one np‘ is linked to a neighboring nucleotide via a phosphorothioate linkage; each Na and Na' independently represents an oligonucleotide sequence including 0-25 25 nucleotides which are either modified or unmodified or combinations thereof, each sequence including at least two differently modified nucleotides; each Nb and Nb' independently represents an oligonucleotide sequence including 0-10 nucleotides which are either modified or unmodified or combinations thereof; XXX, YYY, ZZZ, X'X'X', Y'Y'Y', and Z'Z'Z' each independently represent one motif of 30 three identical modifications on three consecutive nucleotides, and where the modifications are 2‘-O-methyl or 2'-fluoro modifications; modifications on Nb differ from the modification on Y and modifications on Nb' differ from the modification on Y'; and 2026204572  15 Jun 2026 where the sense strand is conjugated to at least one ligand, optioanlly where the ligand is one or more C16 ligands. An additional aspect of the instant disclosure provides a double stranded RNAi agent for inhibiting expression of an amyloid precursor protein (APP) gene in a cell, 5 where the double stranded RNAi agent includes a sense strand complementary to an antisense strand, where the antisense strand includes a region complementary to part of an mRNA encoding APP, where each strand is about 14 to about 30 nucleotides in length, where the double stranded RNAi agent is represented by formula (III): sense:             5' np-Na-(X X X)i-Nb-Y Y Y -Nb -(Z Z Z)j-Na- nq 3' 10 antisense:            3' np'-Na'-(X'X'X')k-Nb'-Y'Y'Y'-Nb'-(Z‘Z'Z‘)l-Na‘- nq‘ 5' (III) where: i, j, k, and l are each independently 0 or 1; each np, nq, and nq', each of which may or may not be present, independently represents an overhang nucleotide; 15 p, q, and q' are each independently 0-6; np' >0 and at least one np' is linked to a neighboring nucleotide via a phosphorothioate linkage; each Na and Na' independently represents an oligonucleotide sequence including 0-25 nucleotides which are either modified or unmodified or combinations thereof, each 20 sequence including at least two differently modified nucleotides; each Nb and Nb' independently represents an oligonucleotide sequence including 0-10 nucleotides which are either modified or unmodified or combinations thereof; XXX, YYY, ZZZ, X'X'X', Y'Y'Y', and Z'Z'Z' each independently represent one motif of three identical modifications on three consecutive nucleotides, and where the 25 modifications are 2‘-O-methyl or 2'-fluoro modifications; modifications on Nb differ from the modification on Y and modifications on Nb' differ from the modification on Y'; where the sense strand includes at least one phosphorothioate linkage; and where the sense strand is conjugated to at least one ligand, optionally where the ligand is 30 one or more C16 ligands. Another aspect of the instant disclosure provides a double stranded RNAi agent for inhibiting expression of an amyloid precursor protein (APP) gene in a cell, where the double stranded RNAi agent includes a sense strand complementary to an antisense 2026204572  15 Jun 2026 strand, where the antisense strand includes a region complementary to part of an mRNA encoding APP, where each strand is about 14 to about 30 nucleotides in length, where the double stranded RNAi agent is represented by formula (III): sense:             5' np-Na -Y Y Y - Na- nq 3' 5 antisense:           3' np‘-Na'- YYY- Na’- nq‘ 5' (Illa) where: each np, nq, and nq‘, each of which may or may not be present, independently represents an overhang nucleotide; p, q, and q‘ are each independently 0-6; 10   np’ >0 and at least one np’ is linked to a neighboring nucleotide via a phosphorothioate linkage; each Na and Na‘ independently represents an oligonucleotide sequence including 0-25 nucleotides which are either modified or unmodified or combinations thereof, each sequence including at least two differently modified nucleotides; 15 YYY and Y'Y'Y' each independently represent one motif of three identical modifications on three consecutive nucleotides, and where the modifications are 2‘-O-methyl or 2'-fluoro modifications; where the sense strand includes at least one phosphorothioate linkage; and where the sense strand is conjugated to at least one ligand, optionally where the ligand is 20 one or more C16 ligands. An additional aspect of the instant disclosure provides a double stranded RNAi agent for inhibiting expression of an amyloid precursor protein (APP) gene, where the double stranded RNAi agent includes a sense strand and an antisense strand forming a double stranded region, where the sense strand includes at least 15 contiguous 25 nucleotides differing by no more than 3 nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 1-14 and the antisense strand includes at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 15-28, where substantially all of the nucleotides of the sense strand include a modification that is a 2’-O-methyl modification, a GNA and / or a 2’30 fluoro modification, where the sense strand includes two phosphorothioate internucleotide linkages at the 5’-terminus, where substantially all of the nucleotides of the antisense strand include a modification selected from the group consisting of a 2’-O-methyl modification and a 2’-fluoro modification, where the antisense strand includes 2026204572  15 Jun 2026 two phosphorothioate internucleotide linkages at the 5’-terminus and two phosphorothioate internucleotide linkages at the 3’-terminus, and where the sense strand is conjugated to one or more C16 ligands. Another aspect of the instant disclosure provides a double stranded RNAi agent 5 for inhibiting expression of an amyloid precursor protein (APP) gene, where the double stranded RNAi agent includes a sense strand and an antisense strand forming a double stranded region, where the sense strand includes at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 1-14 and the antisense strand includes at least 15 contiguous nucleotides 10 differing by no more than 3 nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 15-28, where the sense strand includes at least one 3’-terminal deoxythymine nucleotide (dT), and where the antisense strand includes at least one 3’-terminal deoxy-thymine nucleotide (dT). In one embodiment, all of the nucleotides of the sense strand and all of the 15 nucleotides of the antisense strand are modified nucleotides. In another embodiment, each strand has 19-30 nucleotides. In certain embodiments, the antisense strand of the RNAi agent includes at least one thermally destabilizing modification of the duplex within the first 9 nucleotide positions of the 5’ region or a precursor thereof. Optionally, the thermally destabilizing 20 modification of the duplex is one or more of ’ O , and where B is nucleobase. Another aspect of the instant disclosure provides a cell containing a double stranded RNAi agent of the instant disclosure. 2026204572  15 Jun 2026 An additional aspect of the instant disclosure provides a pharmaceutical composition for inhibiting expression of an APP gene that includes a double stranded RNAi agent of the instant disclosure. In one embodiment, the double stranded RNAi agent is administered in an 5 unbuffered solution. Optionally, the unbuffered solution is saline or water. In another embodiment, the double stranded RNAi agent is administered with a buffer solution. Optionally, the buffer solution includes acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof. In another embodiment, the buffer solution is phosphate buffered saline (PBS). 10          Another aspect of the disclosure provides a pharmaceutical composition that includes a double stranded RNAi agent of the instant disclosure and a lipid formulation. In one embodiment, the lipid formulation includes a LNP. An additional aspect of the disclosure provides a method of inhibiting expression of an amyloid precursor protein (APP) gene in a cell, the method involving: (a) 15          contacting the cell with a double stranded RNAi agent of the instant disclosure or a pharmaceutical composition of of the instant disclosure; and (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of an APP gene, thereby inhibiting expression of the APP gene in the cell. In one embodiment, the cell is within a subject. Optionally, the subject is a 20 human. In certain embodiments, the subject is a rhesus monkey, a cynomolgous monkey, a mouse, or a rat. In one embodiment, the human subject suffers from an APP-associated disorder. Optionally, the APP-associated disease is cerebral amyloid angiopathy (CAA). 25          In another embodiment, the APP-associated disorder is early onset familial Alzheimer disease (EOFAD). In an additional embodiment, the APP-associated disorder is Alzheimer’s disease (AD). In certain embodiments APP expression is inhibited by at least about 30% by the RNAi agent. 30          Another aspect of the disclosure provides a method of treating a subject having a disorder that would benefit from a reduction in APP expression, the method involving administering to the subject a therapeutically effective amount of a double stranded 2026204572  15 Jun 2026 RNAi agent of the disclosure or a pharmaceutical composition of the disclosure, thereby treating the subject. In certain embodiments, the method further involves administering an additional therapeutic agent to the subject. 5          In certain embodiments, the double stranded RNAi agent is administered at a dose of about 0.01 mg / kg to about 50 mg / kg. In some embodiments, the double stranded RNAi agent is administered to the subject intrathecally. In certain embodiments, the administration of the double stranded RNAi to the 10 subject causes a decrease in Ap accumulation. Optionally, the administration of the double stranded RNAi to the subject causes a decrease in Ap(1-40) and / or Ap(1-42) accumulation. In related embodiments, the administration of the dsRNA to the subject causes a decrease in amyloid plaque formation and / or accumulation in the subject. 15          In one embodiment, the method reduces the expression of a target gene in a brain or spine tissue. Optionally, the brain or spine tissue is cortex, cerebellum, striatum, cervical spine, lumbar spine, and / or thoracic spine. Another aspect of the instant disclosure provides a method of inhibiting the expression of APP in a subject, the method involving: administering to the subject a 20 therapeutically effective amount of a double stranded RNAi agent of the disclosure or a pharmaceutical composition of the disclosure, thereby inhibiting the expression of APP in the subject. An additional aspect of the disclosure provides a method for treating or preventing an APP-associated disease or disorder in a subject, the method involving 25 administering to the subject a therapeutically effective amount of a double stranded RNAi agent of the disclosure or a pharmaceutical composition of the disclosure, thereby treating or preventing an APP-associated disease or disorder in the subject. In certain embodiments, the APP-associated disease or disorder is cerebral amyloid angiopathy (CAA) and / or Alzheimer’s disease (AD). Optionally, the AD is 30 early onset familial Alzheimer disease (EOFAD). Another aspect of the instant disclosure provides a kit for performing a method of the instant disclosure, the kit including: a) a double stranded RNAi agent of the 2026204572  15 Jun 2026 instant disclosure, and b) instructions for use, and c) optionally, a means for administering the double stranded RNAi agent to the subject. An additional aspect of the instant disclosure provides a double stranded ribonucleic acid (RNAi) agent for inhibiting expression of an amyloid precursor protein 5 (APP) gene, where the RNAi agent possesses a sense strand and an antisense strand, and where the antisense strand includes a region of complementarity which includes at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the antisense strand nucleobase sequences of AD-392911, AD-392912, AD-392816, AD-392704, AD-392843, AD-392855, AD-392840, AD-392835, AD-392729, AD-392916, 10   AD-392876, AD-392863, AD-392917, AD-392783, AD-392765, AD-392791, AD- 392800, AD-392711, AD-392801, AD-392826, AD-392818, AD-392792, AD-392802, AD-392766, AD-392767, AD-392834, AD-392974, AD-392784, AD-392744, AD- 392752, AD-392737, AD-392918, AD-392919, AD-392803, AD-392804, AD-392827, AD-392828, AD-392785, AD-392829, AD-392920, AD-392921, AD-392768, AD- 15   392805, AD-392769, AD-392753, AD-392714, AD-392703, AD-392715, AD-392836, AD-392966, AD-392832, AD-392972, AD-392961, AD-392967, AD-392894, AD- 392864, AD-392865, AD-392922, AD-392833, AD-392968, AD-392962, AD-392963, AD-392969, AD-392973, AD-392923, AD-392866, AD-392877, AD-392707, AD- 392926, AD-392927, AD-392717, AD-392700, AD-392878, AD-392718, AD-392929, 20   AD-392819, AD-392745, AD-392770, AD-392806, AD-392771, AD-392820, AD- 392821, AD-392786, AD-392772, AD-392699, AD-392868, AD-392719, AD-392880, AD-392930, AD-392932, AD-392869, AD-392870, AD-392896, AD-392720, AD- 392746, AD-392773, AD-392807, AD-392730, AD-392721, AD-392933, AD-392881, AD-392897, AD-392898, AD-392899, AD-392935, AD-392882, AD-392738, AD- 25   392739, AD-392936, AD-392900, AD-392901, AD-392937, AD-392883, AD-392975, AD-392938, AD-392902, AD-392941, AD-392942, AD-392943, AD-392944, AD- 392903, AD-392775, AD-392758, AD-392945, AD-392884, AD-392947, AD-392748, AD-392759, AD-392837, AD-392970, AD-392976, AD-392965, AD-392831, AD- 392904, AD-392885, AD-392886, AD-392776, AD-392887, AD-392722, AD-392760, 30   AD-392731, AD-392709, AD-392723, AD-392948, AD-392724, AD-392949, AD- 392725, AD-392950, AD-392732, AD-392726, AD-392862, AD-392951, AD-392871, AD-392872, AD-397183, AD-397175, AD-397177, AD-397176, AD-397260, AD-397266, AD-397267, AD-397178, AD-397180, AD-397184, AD-397179, AD-397224, 2026204572  15 Jun 2026 AD-397225, AD-397203, AD-397185, AD-397195, AD-397204, AD-397191, AD- 397251, AD-397240, AD-397205, AD-397254, AD-397259, AD-397247, AD-397233, AD-397181, AD-397196, AD-397197, AD-397226, AD-397212, AD-397182, AD- 397227, AD-397217, AD-397213, AD-397229, AD-397264, AD-397265, AD-397209, 5  AD-397192, AD-397210, AD-397219, AD-397214, AD-397220, AD-397230, AD- 397231, AD-397193, AD-397190, AD-397200, AD-397248, AD-397207, AD-397211, AD-397243, AD-397246, AD-397223, AD-397202, AD-397256, AD-397257, AD-397258, AD-397250, AD-397244 AD-454972, AD-454973, AD-454842, AD-454843, AD-454844, AD-994379, AD-961583, AD-961584, AD-961585, or AD-961586. 10          In one embodiment, the RNAi agent includes one or more of the following modifications: a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2’-C-alkyl-modified nucleotide, a nucleotide comprising a glycol nucleic acid (GNA), a phosphorothioate (PS) and a vinyl phosphonate (VP). Optionally, the RNAi agent includes at least one of each of the following modifications: a 2'-O-methyl modified 15 nucleotide, a 2'-fluoro modified nucleotide, a 2’-C-alkyl-modified nucleotide, a nucleotide comprising a glycol nucleic acid (GNA), a phosphorothioate and a vinyl phosphonate (VP). In another embodiment, the RNAi agent includes four or more PS modifications, optionally six to ten PS modifications, optionally eight PS modifications. 20          In an additional embodiment, each of the sense strand and the antisense strand of the RNAi agent possesses a 5’-terminus and a 3’-terminus, and the RNAi agent includes eight PS modifications positioned at each of the penultimate and ultimate internucleotide linkages from the respective 3’- and 5’-termini of each of the sense and antisense strands of the RNAi agent. 25          In another embodiment, each of the sense strand and the antisense strand of the RNAi agent includes a 5’-terminus and a 3’-terminus, and the RNAi agent includes only one nucleotide including a GNA. Optionally, the nucleotide including a GNA is positioned on the antisense strand at the seventh nucleobase residue from the 5’-terminus of the antisense strand. 30          In an additional embodiment, each of the sense strand and the antisense strand of the RNAi agent includes a 5’-terminus and a 3’-terminus, and the RNAi agent includes between one and four 2’-C-alkyl-modified nucleotides. Optionally, the 2’-C-alkyl-modified nucleotide is a 2’-C16-modified nucleotide. Optionally, the RNAi agent 2026204572  15 Jun 2026 includes a single 2’-C16-modified nucleotide. Optionally, the single 2’-C16-modified nucleotide is located on the sense strand at the sixth nucleobase position from the 5’-terminus of the sense strand or on the terminal nucleobase position of the 5’ end. In another embodiment, each of the sense strand and the antisense strand of the 5 RNAi agent includes a 5’-terminus and a 3’-terminus, and the RNAi agent includes two or more 2’-fluoro modified nucleotides. Optionally, each of the sense strand and the antisense strand of the RNAi agent includes two or more 2’-fluoro modified nucleotides. Optionally, the 2’-fluoro modified nucleotides are located on the sense strand at nucleobase positions 7, 9, 10 and 11 from the 5’-terminus of the sense strand and on the 10 antisense strand at nucleobase positions 2, 14 and 16 from the 5’-terminus of the antisense strand. In an additional embodiment, each of the sense strand and the antisense strand of the RNAi agent includes a 5’-terminus and a 3’-terminus, and the RNAi agent includes one or more VP modifications. Optionally, the RNAi agent includes a single VP 15 modification at the 5’-terminus of the antisense strand. In another embodiment, each of the sense strand and the antisense strand of the RNAi agent includes a 5’-terminus and a 3’-terminus, and the RNAi agent includes two or more 2'-O-methyl modified nucleotides. Optionally, the RNAi agent includes 2'-O-methyl modified nucleotides at all nucleobase locations not modified by a 2'-fluoro, a 2’ 20 C-alkyl or a glycol nucleic acid (GNA). Optionally, the two or more 2'-O-methyl modified nucleotides are located on the sense strand at positions 1, 2, 3, 4, 5, 8, 12, 13, 14, 15, 16, 17, 18, 19, 20 and 21 from the 5’-terminus of the sense strand and on the antisense strand at positions 1, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 15, 17, 18, 19, 20, 21, 22 and 23 from the 5’-terminus of the antisense strand. 25          Another aspect of the instant disclosure provides a double stranded ribonucleic acid (RNAi) agent for inhibiting expression of an amyloid precursor protein (APP) gene, where the RNAi agent includes a sense strand and an antisense strand, and where the antisense strand includes a region of at least 15 contiguous nucleobases in length that is sufficiently complementary to a target APP sequence of APP NM_00484 positions 30   1891-1919; APP NM_00484 positions 2282-2306; APP NM_00484 positions 2464 2494; APP NM_00484 positions 2475-2638; APP NM_00484 positions 2621-2689; APP NM_00484 positions 2682-2725; APP NM_00484 positions 2705-2746; APP NM_00484 positions 2726-2771; APP NM_00484 positions 2754-2788; APP 2026204572  15 Jun 2026 NM_00484 NM_00484 NM_00484 NM_00484 positions 2782-2813; APP NM_00484 positions 2801-2826; APP positions 2847-2890; APP NM_00484 positions 2871-2896; APP positions 2882-2960; APP NM_00484 positions 2942-2971; APP positions 2951-3057; APP NM_00484 positions 3172-3223; APP 5   NM_00484 positions 3209-3235; NM_00484 positions 3256-3289; NM_00484 positions 3302-3338; APP NM_00484 positions 3318-3353; APP NM_00484 positions 33343361, APP NM_001198823.1 positions 251-284; APP NM_001198823.1 positions 362404; APP NM_001198823.1 positions 471-510; APP NM_001198823.1 positions 532587; APP NM_001198823.1 positions 601-649; APP NM_001198823.1 positions 633 10   662; APP NM_001198823.1 positions 1351-1388; APP NM_001198823.1 positions 1609-1649; APP NM_001198823.1 positions 1675-1698; APP NM_001198823.1 positions 1752-1787; APP NM_001198823.1 positions 2165-2217; APP NM_001198823.1 positions 2280-2344; or APP NM_001198823.1 positions 2403-2431 to effect APP knockdown and that differs by no more than 3 nucleotides across the at 15 least 15 contiguous nucleobases sufficiently complementary to the APP target sequence to effect APP knockdown. Another aspect of the instant disclosure provides a double stranded RNAi agent that includes one or more modifications selected from the group consisting of a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2’-C-alkyl-modified 20 nucleotide, a nucleotide comprising a glycol nucleic acid (GNA), a phosphorothioate (PS) and a vinyl phosphonate (VP), optionally wherein said RNAi agent comprises at least one of each modification selected from the group consisting of a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2’-C-alkyl-modified nucleotide, a nucleotide comprising a glycol nucleic acid (GNA), a phosphorothioate and a vinyl 25 phosphonate (VP). Another aspect of the instant disclosure provides that the RNAi agent comprises four or more PS modifications, optionally six to ten PS modifications, optionally eight PS modifications. Another aspect of the instant disclosure provides that each of the sense strand 30 and the antisense strand of the RNAi agent comprises a 5’-terminus and a 3’-terminus, and wherein the RNAi agent comprises eight PS modifications positioned at the 2026204572  15 Jun 2026 penultimate and ultimate internucleotide linkages from the respective 3’- and 5’-termini of each of the sense and antisense strands of the RNAi agent. Another aspect of the instant disclosure provides that each of the sense strand and the antisense strand of the RNAi agent comprises a 5’-terminus and a 3’-terminus, 5 and wherein the RNAi agent comprises only one nucleotide comprising a GNA, optionally wherein the nucleotide comprising a GNA is positioned on the antisense strand at the seventh nucleobase residue from the 5’-terminus of the antisense strand. Another aspect of the instant disclosure provides that each of the sense strand and the antisense strand of the RNAi agent comprises a 5’-terminus and a 3’-terminus, 10 and wherein the RNAi agent comprises between one and four 2’-C-alkyl-modified nucleotides, optionally wherein the 2’-C-alkyl-modified nucleotide is a 2’-C16-modified nucleotide, optionally wherein the RNAi agent comprises a single 2’-C16-modified nucleotide, optionally the single 2’-C16-modified nucleotide is located on the sense strand at the sixth nucleobase position from the 5’-terminus of the sense strand or on the 15 terminal nucleobase position of the 5’ end. Another aspect of the instant disclosure provides that each of the sense strand and the antisense strand of the RNAi agent comprises a 5’-terminus and a 3’-terminus, and wherein the RNAi agent comprises two or more 2’-fluoro modified nucleotides, optionally wherein each of the sense strand and the antisense strand of the RNAi agent 20 comprises two or more 2’-fluoro modified nucleotides, optionally wherein the 2’-fluoro modified nucleotides are located on the sense strand at nucleobase positions 7, 9, 10 and 11 from the 5’-terminus of the sense strand and on the antisense strand at nucleobase positions 2, 14 and 16 from the 5’-terminus of the antisense strand. Another aspect of the instant disclosure provides that each of the sense strand 25 and the antisense strand of the RNAi agent comprises a 5’-terminus and a 3’-terminus, and wherein the RNAi agent comprises one or more VP modifications, optionally wherein the RNAi agent comprises a single VP modification at the 5’-terminus of the antisense strand. 2026204572  15 Jun 2026 Another aspect of the instant disclosure provides that each of the sense strand and the antisense strand of the RNAi agent comprises a 5’-terminus and a 3’-terminus, and wherein the RNAi agent comprises two or more 2'-O-methyl modified nucleotides, optionally wherein the RNAi agent comprises 2'-O-methyl modified nucleotides at all 5 nucleobase locations not modified by a 2'-fluoro, a 2’-C-alkyl or a glycol nucleic acid (GNA), optionally wherein the two or more 2'-O-methyl modified nucleotides are located on the sense strand at positions 1, 2, 3, 4, 5, 8, 12, 13, 14, 15, 16, 17, 18, 19, 20 and 21 from the 5’-terminus of the sense strand and on the antisense strand at positions 1, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 15, 17, 18, 19, 20, 21, 22 and 23 from the 5’-terminus of 10 the antisense strand. BRIEF DESCRIPTION OF THE DRAWINGS The following detailed description, given by way of example, but not intended to limit the disclosure solely to the specific embodiments described, may best be understood in conjunction with the accompanying drawings, in which: 15         FIG. 1A and FIG. 1B show a schematic image of modified RNAi agents tested for in vivo hsAPP knockdown activity. FIG. 2A and FIG. 2B show in vivo hsAPP knockdown activity results observed for the modified RNAi agents shown in FIG. 1A and FIG. 1B. FIG. 3A is a scheme demonstrating the strategy to identify potent human APP 20 (hAPP) siRNAs in targeting hereditary cerebral amyloid angiopathy (hCAA). FIG. 3B is a plot of percent remaining mRNA in an in vitro endogenous screen of hAPP siRNAs at a concentration of 10nM in Be(2)C cells. FIG. 4A is a scheme demonstrating the timing of APP siRNA transfection in BE(2)C neuronal cells. APP siRNA was transfected at 10, 1, and 0.1 nM and assessed 24 25 and 48 hours after transfection. FIG. 4B is a graph showing the applied concentration of APP duplex siRNA vs the percent remaining mRNA in BE(2)C cells 48 hours after transfection. FIG. 4C is two graphs of soluble APP alpha (top) and beta (bottom) species in BE(2)C cells supernatant 48 hours after transfection. 30         FIG. 5A is a scheme demonstrating the APP siRNA non-human primate (NHP) screening study design. 5 compounds were assessed, and 5 animals were used for each experiment. A single intrathecal (IT) injection of 72 mg of the compound of interest was given at the onset. 2026204572  15 Jun 2026 FIG. 5B is two graphs of soluble APP alpha (top) and beta (bottom) species in BE(2)C (bottom), post IT administration in cyno monkeys of 72mg of AD-454972 targeting APP. FIG. 5C is a graph showing the results of tissue mRNA knockdown at day 29 5 post IT administration in cyno monkeys of 72mg of AD-454972 targeting APP. FIG. 5 D is a scheme demonstrating the structure of the AD-454972 compound targeting APP (top) and a table showing the levels of AD-454972 compound delivery in tissue at day 29 post IT administration in cyno monkeys of 72mg of AD-454972 targeting APP (bottom). 10          FIG. 6 is two graphs showing the results of CSF soluble APP alpha and beta (top) and CSF amyloid beta species (bottom) collected 2-3 months post IT administration in cyno monkeys of 72mg of AD-454972 targeting APP. FIG. 7A is two graphs showing the results of CSF collected at days 8, 15, and 29 and analyzed for soluble APP alpha and beta(top) and amyloid beta 38,40, and 42 15 (bottom), post IT administration in cyno monkeys of 72mg of AD-454842 targeting APP. FIG. 7B is a table showing the levels of AD-454842 compound delivery in tissue at day 29 post IT administration in cyno monkeys of 72mg of AD-454842 targeting APP. 20          FIG. 8A is two graphs showing the results of CSF collected at days 8, 15, and 29 and analyzed for soluble APP alpha and beta (top) and amyloid beta 38,40, and 42 (bottom), post IT administration in cyno monkeys of 72mg of AD-454843 targeting APP. FIG. 8B is a graph showing the results of tissue mRNA knockdown at day 29 25 post IT administration in cyno monkeys of 72mg of AD-454843 targeting APP. FIG. 8C is a table showing the levels of AD-454843 compound delivery in tissue at day 29 post IT administration in cyno monkeys of 72mg of AD-454843 targeting APP. FIG. 9A is two graphs showing the results of CSF soluble APP alpha and beta 30 (top) and CSF amyloid beta species (bottom) collected 2-3 months post IT administration in cyno monkeys of 72mg of AD-454843 targeting APP. FIG. 9B is a graph showing the results of tissue mRNA knockdown at day 85 post IT administration in cyno monkeys of 72mg of AD-454843 targeting APP. 2026204572  15 Jun 2026 FIG. 10A is two graphs showing the results CSF collected at days 8, 15, and 29 and analyzed for soluble APP alpha and beta (top) and amyloid beta 38,40, and 42 (bottom), post IT administration in cyno monkeys of 72mg of AD-454844 targeting APP. 5         FIG. 10B is a graph showing the results of tissue mRNA knockdown at day 29 post IT administration in cyno monkeys of 72mg of AD-454844 targeting APP. FIG. 10C is a scheme demonstrating the structure of the AD-454844 compound targeting APP (top) and a table showing the levels of AD-454844 compound delivery in tissue at day 29 post IT administration in cyno monkeys of 72mg of AD-454844 10 targeting APP (bottom). FIG. 11A is a table showing a high level of compound delivery in tissue at day 29 post IT administration in cyno monkeys of 72mg siRNA targeting APP. FIG. 11B is a graph showing the results of tissue mRNA knockdown at day 29 post IT administration in cyno monkeys of a high level (FIG. 11A) of compound 15 delivery targeting APP. FIG. 11C is two graphs showing the results of CSF collected at days 8, 15, and 29 and analyzed for soluble APP alpha and beta(top) and amyloid beta 38,40, and 42 (bottom), post IT administration in cyno monkeys of 72mg of of a high level of compound delivery (FIG. 11A) targeting APP. 20          FIG. 12A is two plots showing the average of 5 miRNA duplex studies. Top panel is a box plot of the results of 5 compounds at day at day 29 post IT administration in cyno monkeys of 72mg siRNA.Bottom panel is a box plot of the amount of mRNA remaining in each tissue relative to a control 29 days post IT administration in cyno monkeys. 25         FIG. 12B is two two plots showing repeated miRNA duplex studies in which CSF was collected at days 8, 15, and 29 and analyzed for soluble APP alpha and beta (top) and amyloid beta 38,40, and 42 (bottom), post IT administration in cyno monkeys of 72mg of siRNA compounds targeting APP. FIG. 13A is a graph demonstrating the percent APP mRNA remaining in 30 striatum tissue 29 days post IT administration in cyno monkeys of AD-454972 targeting APP. FIG. 13B is a graph demonstrating the percent APP mRNA remaining in striatum tissue 29 days post IT administration in cyno monkeys of AD-454973 targeting APP. 2026204572  15 Jun 2026 FIG. 13C is a graph demonstrating the percent APP mRNA remaining in striatum tissue 29 days post IT administration in cyno monkeys of AD-454842 targeting APP. FIG. 13D is a graph demonstrating the percent APP mRNA remaining in striatum tissue 29 days post IT administration in cyno monkeys of AD-454843 targeting 5 APP. FIG. 13E is a graph demonstrating the percent APP mRNA remaining in striatum tissue 29 days post IT administration in cyno monkeys of AD-454844 targeting APP. FIG. 14A and FIG. 14B are schematic images of modified RNAi agents having AU-rich seeds that were screened for in vivo hsAPP knockdown activity in mice. 10         FIG. 15 is a graph depicting % hs APP knockdown in the liver of AAV8.HsAPP- CDS3TRNC mice treated with AU-rich seeds. PBS, Naive, and AD-392927 (RLD592) controls are included in the graph. FIG. 16A-16D are schematic images of modified lead RNAi agents that were screened for in vivo hsAPP knockdown activity in AAV mice. 15         FIG. 17A and FIG. 17B are graphs depicting % hs APP knockdown in the liver of AAV8.HsAPP-CDS3TRNC mice treated with lead oligonucleotides. PBS and Naive, controls are included in the graphs. FIGS. 18A-18D are schematic images of modified lead RNAi agents that were screened for in vivo hsAPP knockdown activity in AAV mice and which are grouped as 20 families based on the AD-886864 parent (FIG. 18A), AD-886899 parent (FIG. 18B), AD-886919 parent (FIG. 18 C), and AD-886823 parent (FIG. 18D), respectively. FIG. 19 is a scheme demonstrating the APP knock down non-human primate (NHP) screening study design of the AD-454844 4 month study in which a single intrathecal (IT) injection of 60 mg of the compound of interest was given to Cyno 25 monkeys at the onset. FIGs. 20A-20G 6 show data from in vivo screens of C16 siRNA conjugates, including the parent AD-454855, and 5 additional siRNA conjugates derived from structure activity relationship studies of AD-454855. Graphs depict the percent soluble APP alpha and beta collected from the CSF on days 8, 15, and 19 post intrathecal 30 administration of 60 mg of each compound. FIG. 20A is a graph of soluble APP alpha and beta 4 months post dose of AD-454844 for two non-human primate subjects. FIG. 2026204572  15 Jun 2026 20B is a graph depicting the percent soluble APP alpha and beta collected from the CSF at Days 8, 15, and 19 post dose of AD-454844. FIG. 20C is a graph depicting the percent soluble APP alpha and beta collected from the CSF at Days 8, 15, and 19 post dose of the 5’ terminal C16 siRNA conjugate, AD-994379. FIG. 20D is a graph depicting the 5 percent soluble APP alpha and beta collected from the CSF at Days 8, 15, and 19 post dose of AD-961583. FIG. 20E is a graph depicting the percent soluble APP alpha and beta collected from the CSF at Days 8, 15, and 19 post dose of AD-961584. FIG. 20F is a graph depicting the percent soluble APP alpha and beta collected from the CSF at Days 8, 15, and 19 post dose of AD-961585. FIG. 20G is a graph depicting the percent 10 soluble APP alpha and beta collected from the CSF at Days 8, 15, and 19 post dose of AD-961586. FIGs. 21A and 21B are schematic images of C16 modified lead RNAi agents that were screened for in vivo APP knockdown activity in non-human primates. FIG. 21A is a schematic of the parent internal C16 RNAi agent AD-454844 and the 5’ terminal C16 15 siRNA agent AD-994379. FIG. 21B is a schematic of RNAi agents AD-961583, AD-961584, AD-961585, and AD-961586. DETAILED DESCRIPTION OF THE INVENTION The present disclosure provides RNAi compositions, which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of an amyloid 20 precursor protein (APP) gene. The APP gene may be within a cell, e.g., a cell within a subject, such as a human. The present disclosure also provides methods of using the RNAi compositions of the disclosure for inhibiting the expression of an APP gene and / or for treating a subject having a disorder that would benefit from inhibiting or reducing the expression of an APP gene, e.g., an APP-associated disesase, for example, 25 cerebral amyloid angiopathy (CAA) or Alzheimer’s disease (AD), e.g., early onset familial Alzheimer disease (EOFAD). The RNAi agents of the disclosure include an RNA strand (the antisense strand) having a region which is about 30 nucleotides or less in length, e.g., 15-30, 15-29, 1528, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 30    18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19 28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21- 2026204572  15 Jun 2026 24, 21-23, or 21-22 nucleotides in length, which region is substantially complementary to at least part of an mRNA transcript of an APP gene. In certain embodiments, the RNAi agents of the disclosure include an RNA strand (the antisense strand) which can include longer lengths, for example up to 66 5 nucleotides, e.g., 36-66, 26-36, 25-36, 31-60, 22-43, 27-53 nucleotides in length with a region of at least 19 contiguous nucleotides that is substantially complementary to at least a part of an mRNA transcript of an APP gene. These RNAi agents with the longer length antisense strands preferably include a second RNA strand (the sense strand) of 2060 nucleotides in length wherein the sense and antisense strands form a duplex of 18-30 10 contiguous nucleotides. The use of these RNAi agents enables the targeted degradation of mRNAs of an APP gene in mammals. Very low dosages of APP RNAi agents, in particular, can specifically and efficiently mediate RNA interference (RNAi), resulting in significant inhibition of expression of an APP gene. Using cell-based assays, the present inventors 15 have demonstrated that RNAi agents targeting APP can mediate RNAi, resulting in significant inhibition of expression of an APP gene. Thus, methods and compositions including these RNAi agents are useful for treating a subject who would benefit by a reduction in the levels and / or activity of an APP protein, such as a subject having an APP-associated disease, for example, CAA or AD, including, e.g., EOFAD. 20          The following detailed description discloses how to make and use compositions containing RNAi agents to inhibit the expression of an APP gene, as well as compositions and methods for treating subjects having diseases and disorders that would benefit from inhibition and / or reduction of the expression of this gene. 25 I.      Definitions In order that the present disclosure may be more readily understood, certain terms are first defined. In addition, it should be noted that whenever a value or range of values of a parameter are recited, it is intended that values and ranges intermediate to the recited values are also intended to be part of this disclosure. 30           The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element, e.g., a plurality of elements. 2026204572  15 Jun 2026 The term "including" is used herein to mean, and is used interchangeably with, the phrase "including but not limited to". The term "or" is used herein to mean, and is used interchangeably with, the term "and / or," unless context clearly indicates otherwise. The term “about” is used herein to mean within the typical ranges of tolerances 5 in the art. For example, “about” can be understood as about 2 standard deviations from the mean. In certain embodiments, about means ±10%. In certain embodiments, about means ±5%. When about is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range. The term “at least” prior to a number or series of numbers is understood to 10 include the number adjacent to the term “at least”, and all subsequent numbers or integers that could logically be included, as clear from context. For example, the number of nucleotides in a nucleic acid molecule must be an integer. For example, “at least 18 nucleotides of a 21 nucleotide nucleic acid molecule” means that 18, 19, 20, or 21 nucleotides have the indicated property. When at least is present before a series of 15 numbers or a range, it is understood that “at least” can modify each of the numbers in the series or range. As used herein, “no more than” or “less than” is understood as the value adjacent to the phrase and logical lower values or intergers, as logical from context, to zero. For example, a duplex with an overhang of “no more than 2 nucleotides” has a 2, 1, or 0 20 nucleotide overhang. When “no more than” is present before a series of numbers or a range, it is understood that “no more than” can modify each of the numbers in the series or range. The term "APP" amyloid precursor protein (APP), also known as amyloid beta precursor protein, Alzheimer disesase amyloid protein and cerebral vascular amyloid 25 peptide, among other names, having an amino acid sequence from any vertebrate or mammalian source, including, but not limited to, human, bovine, chicken, rodent, mouse, rat, porcine, ovine, primate, monkey, and guinea pig, unless specified otherwise. The term also refers to fragments and variants of native APP that maintain at least one in vivo or in vitro activity of a native APP (including, e.g., the beta-amyloid peptide(1-40), 30 beta-amyloid peptide(1-38) and beta-amyloid peptide(1-42) forms of A0 peptide, among others), including variants of APP fragments that maintain one or more activities of an APP fragment that are neurotoxic in character (e.g., variant forms of Ap42 peptide that maintain neurotoxic character are expressly contemplated). The term encompasses full- 2026204572  15 Jun 2026 length unprocessed precursor forms of APP as well as mature forms resulting from post-translational cleavage of the signal peptide. The term also encompasses peptides that derive from APP via further cleavage, including, e.g., Ap peptides. The nucleotide and amino acid sequence of a human APP can be found at, for example, GenBank Accession 5 No. GI: 228008405 (NM_201414; SEQ ID NO: 1). The nucleotide and amino acid sequence of a human APP may also be found at, for example, GenBank Accession No. GI: 228008403 (NM_000484.3; SEQ ID NO: 2); GenBank Accession No. GI: 228008404 (NM_201413.2; SEQ ID NO: 3); GenBank Accession No. GI: 324021746 (NM_001136016.3; SEQ ID NO: 4); GenBank Accession No. GI: 228008402 10   (NM_001136129.2; SEQ ID NO: 5); GenBank Accession No. GI: 228008401 (NM_001136130.2; SEQ ID NO: 6); GenBank Accession No. GI: 324021747 (NM_001136131.2; SEQ ID NO: 7); GenBank Accession No. GI: 324021737 (NM_001204301.1; SEQ ID NO: 8); GenBank Accession No. GI: 324021735 (NM_001204302.1; SEQ ID NO: 9); and GenBank Accession No. GI: 324021739 15   (NM_001204303.1; SEQ ID NO: 10); and GenBank Accession No. GI: 1370481385 (XM_024452075.1; SEQ ID NO: 11). The nucleotide and amino acid sequence of a Cynomolgus monkey APP can be found at, for example, GenBank Accession No. GI: 982237868 (XM_005548883.2; SEQ ID NO: 12). The nucleotide and amino acid sequence of a mouse APP can be found 20 at, for example, GenBank Accession No. GI: 311893400 (NM_001198823; SEQ ID NO: 13). The nucleotide and amino acid sequence of a rat APP can be found at, for example, GenBank Accession No. GI: 402692725 (NM_019288.2; SEQ ID NO: 14). Additional examples of APP sequences are readily available using publicly available databases, e.g., GenBank, UniProt, and OMIM. 25          The term“APP” as used herein also refers to a particular polypeptide expressed in a cell by naturally occurring DNA sequence variations of the APP gene, such as a single nucleotide polymorphism in the APP gene. Numerous SNPs within the APP gene have been identified and may be found at, for example, NCBI dbSNP (see, e.g., www.ncbi.nlm.nih.gov / snp). Non-limiting examples of SNPs within the APP gene may 30 be found at, NCBI dbSNP Accession Nos. rs193922916, rs145564988, rs193922916, rs214484, rs281865161, rs364048, rs466433, rs466448, rs532876832, rs63749810, rs63749964,  rs63750064,  rs63750066,  rs63750151,  rs63750264,  rs63750363, rs63750399,  rs63750445,  rs63750579,  rs63750643,  rs63750671,  rs63750734, 2026204572  15 Jun 2026 rs63750847,  rs63750851,  rs63750868,  rs63750921,  rs63750973,  rs63751039, rs63751122 and rs63751263. Certain exemplary rare APP variants that have been previously described to play a role in development of EOFAD were identified in Hooli et al. (Neurology 78: 1250-57). In addition, various “non-classical” APP variants that 5 harbor an intraexonic junction within sequenced cDNA have recently been identified as associated with the occurrence of somatic gene recombination in the brains of AD patients (PCT / US2018 / 030520, which is incorporated herein by reference in its entirety). Examples of such “non-classical” APP variants include cAPP-R3 / 16 (SEQ ID NO: 3363), cAPP-R3 / 16-2 (SEQ ID NO: 3364), cAPP-R2 / 18 (SEQ ID NO: 3365), cAPP-10   R6 / 18 (SEQ ID NO: 3366), cAPP-R3 / 14 (SEQ ID NO: 3367), cAPP-R3 / 17 (SEQ ID NO: 3368), cAPP-R1 / 11 (SEQ ID NO: 3369), cAPP-R1 / 13 (SEQ ID NO: 3370), cAPP-R1 / 11-2 (SEQ ID NO: 3371), cAPP-R1 / 14 (SEQ ID NO: 3372), cAPP-R2 / 17 (SEQ ID NO: 3373), cAPP-R2 / 16 (SEQ ID NO: 3374), cAPP-R6 / 17 (SEQ ID NO: 3375), cAPP-R2 / 14 (SEQ ID NO: 3376), cAPP-R14 / 17-d8 (SEQ ID NO: 3377) and cAPP-D2 / 18-3 15 (SEQ ID NO: 3378). It is expressly contemplated that RNAi agents of the instant disclosure can be used to target “non-classical” APP variants and / or that RNAi agents optionally specific for such “non-classical” APP variants can be designed and used, optionally in combination with other RNAi agents of the instant disclosure, including those that target native forms of APP. Such “non-classical” APP variants were described 20 as notably absent from an assayed HIV patient population, with prevalence of AD in the HIV patient population significantly diminished as compared to expected levels, which indicated that reverse transcriptase inhibitors and / or other anti-retroviral therapies commonly used to treat HIV patients likely also exerted a therapeutic / preventative role against AD. It is therefore expressly contemplated that the RNAi agents of the instant 25 disclosure can optionally be employed in combination with reverse transcriptase inhibitors and / or other anti-retroviral therapies, for therapeutic and / or preventative purposes. As used herein, “target sequence” refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of an APP gene, 30 including mRNA that is a product of RNA processing of a primary transcription product. In one embodment, the target portion of the sequence will be at least long enough to serve as a substrate for RNAi-directed cleavage at or near that portion of the nucleotide sequence of an mRNA molecule formed during the transcription of an APP gene. 2026204572  15 Jun 2026 The target sequence may be from about 9-36 nucleotides in length, e.g., about 15-30 nucleotides in length. For example, the target sequence can be from about 15-30 nucleotides, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 1519, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 5    18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20 30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure. 10          As used herein, the term “strand comprising a sequence” refers to an oligonucleotide comprising a chain of nucleotides that is described by the sequence referred to using the standard nucleotide nomenclature. “G,” “C,” “A,” “T” and “U” each generally stand for a nucleotide that contains guanine, cytosine, adenine, thymidine and uracil as a base, respectively. However, it will 15 be understood that the term “ribonucleotide” or “nucleotide” can also refer to a modified nucleotide, as further detailed below, or a surrogate replacement moiety (see, e.g., Table 1). The skilled person is well aware that guanine, cytosine, adenine, thymidine, and uracil can be replaced by other moieties without substantially altering the base pairing properties of an oligonucleotide comprising a nucleotide bearing such replacement 20 moiety. For example, without limitation, a nucleotide comprising inosine as its base can base pair with nucleotides containing adenine, cytosine, or uracil. Hence, nucleotides containing uracil, guanine, or adenine can be replaced in the nucleotide sequences of dsRNA featured in the disclosure by a nucleotide containing, for example, inosine. In another example, adenine and cytosine anywhere in the oligonucleotide can be replaced 25 with guanine and uracil, respectively to form G-U Wobble base pairing with the target mRNA. Sequences containing such replacement moieties are suitable for the compositions and methods featured in the disclosure. The terms “iRNA”, “RNAi agent,” “iRNA agent,” “RNA interference agent” as used interchangeably herein, refer to an agent that contains RNA as that term is defined 30 herein, and which mediates the targeted cleavage of an RNA transcript via an RNA-induced silencing complex (RISC) pathway. RNA interference (RNAi) is a process that directs the sequence-specific degradation of mRNA. RNAi modulates, e.g., inhibits, the expression of APP in a cell, e.g., a cell within a subject, such as a mammalian subject. 2026204572  15 Jun 2026 In one embodiment, an RNAi agent of the disclosure includes a single stranded RNAi that interacts with a target RNA sequence, e.g., an APP target mRNA sequence, to direct the cleavage of the target RNA. Without wishing to be bound by theory it is believed that long double stranded RNA introduced into cells is broken down into 5 double-stranded short interfering RNAs (siRNAs) comprising a sense strand and an antisense strand by a Type III endonuclease known as Dicer (Sharp et al. (2001) Genes Dev. 15:485). Dicer, a ribonuclease-III-like enzyme, processes these dsRNA into 19-23 base pair short interfering RNAs with characteristic two base 3' overhangs (Bernstein, et al., (2001) Nature 409:363). These siRNAs are then incorporated into an RNA-induced 10 silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition (Nykanen, et al., (2001) Cell 107:309). Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001) Genes Dev. 15:188). Thus, in one aspect the disclosure relates to a single 15 stranded RNA (ssRNA) (the antisense strand of a siRNA duplex) generated within a cell and which promotes the formation of a RISC complex to effect silencing of the target gene, i.e., an APP gene. Accordingly, the term “siRNA” is also used herein to refer to an RNAi as described above. In another embodiment, the RNAi agent may be a single-stranded RNA that is 20 introduced into a cell or organism to inhibit a target mRNA. Single-stranded RNAi agents bind to the RISC endonuclease, Argonaute 2, which then cleaves the target mRNA. The single-stranded siRNAs are generally 15-30 nucleotides and are chemically modified. The design and testing of single-stranded RNAs are described in U.S. Patent No. 8,101,348 and in Lima et al., (2012) Cell 150:883-894, the entire contents of each of 25 which are hereby incorporated herein by reference. Any of the antisense nucleotide sequences described herein may be used as a single-stranded siRNA as described herein or as chemically modified by the methods described in Lima et al., (2012) Cell 150:883894. In another embodiment, a “RNAi agent” for use in the compositions and methods 30 of the disclosure is a double stranded RNA and is referred to herein as a “double stranded RNAi agent,” “double stranded RNA (dsRNA) molecule,” “dsRNA agent,” or “dsRNA”. The term “dsRNA” refers to a complex of ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary nucleic 2026204572  15 Jun 2026 acid strands, referred to as having “sense” and “antisense” orientations with respect to a target RNA, i.e., an APP gene. In some embodiments of the disclosure, a double stranded RNA (dsRNA) triggers the degradation of a target RNA, e.g., an mRNA, through a post-transcriptional gene-silencing mechanism referred to herein as RNA 5 interference or RNAi. In general, a number of nucleotides of each strand of a dsRNA molecule are ribonucleotides, but as described in detail herein, each or both strands can also include one or more non-ribonucleotides, e.g., a deoxyribonucleotide and / or a modified nucleotide. In addition, as used in this specification, an “RNAi agent” may include 10 ribonucleotides with chemical modifications; an RNAi agent may include substantial modifications at multiple nucleotides. As used herein, the term “modified nucleotide” refers to a nucleotide having, independently, a modified sugar moiety, a modified internucleotide linkage, and / or a modified nucleobase. Thus, the term modified nucleotide encompasses substitutions, additions or removal of, e.g., a functional group 15 or atom, to internucleoside linkages, sugar moieties, or nucleobases. The modifications suitable for use in the agents of the disclosure include all types of modifications disclosed herein or known in the art. Any such modifications, as used in a siRNA type molecule, are encompassed by “RNAi agent” for the purposes of this specification and claims. 20          In certain embodiments of the instant disclosure, inclusion of a deoxy-nucleotide - which is acknowledged as a naturally occurring form of nucleotide - if present within a RNAi agent can be considered to constitute a modified nucleotide. The duplex region may be of any length that permits specific degradation of a desired target RNA through a RISC pathway, and may range from about 9 to 36 base 25 pairs in length, e.g., about 15-30 base pairs in length, for example, about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 base pairs in length, such as about 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 1825, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 30   19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24,20-23, 20 22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure. 2026204572  15 Jun 2026 The two strands forming the duplex structure may be different portions of one larger RNA molecule, or they may be separate RNA molecules. Where the two strands are part of one larger molecule, and therefore are connected by an uninterrupted chain of nucleotides between the 3’-end of one strand and the 5’-end of the respective other 5 strand forming the duplex structure, the connecting RNA chain is referred to as a “hairpin loop.” A hairpin loop can comprise at least one unpaired nucleotide. In some embodiments, the hairpin loop can comprise at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 23 or more unpaired nucleotides. In some embodiments, the hairpin loop can be 10 or fewer nucleotides. In 10 some embodiments, the hairpin loop can be 8 or fewer unpaired nucleotides. In some embodiments, the hairpin loop can be 4-10 unpaired nucleotides. In some embodiments, the hairpin loop can be 4-8 nucleotides. Where the two substantially complementary strands of a dsRNA are comprised by separate RNA molecules, those molecules need not, but can be covalently connected. 15 In certain embodiments where the two strands are connected covalently by means other than an uninterrupted chain of nucleotides between the 3’-end of one strand and the 5’-end of the respective other strand forming the duplex structure, the connecting structure is referred to as a “linker” (though it is noted that certain other structures defined elsewhere herein can also be referred to as a “linker”). The RNA strands may have the 20 same or a different number of nucleotides. The maximum number of base pairs is the number of nucleotides in the shortest strand of the dsRNA minus any overhangs that are present in the duplex. In addition to the duplex structure, an RNAi may comprise one or more nucleotide overhangs. In one embodiment of the RNAi agent, at least one strand comprises a 3’ overhang of at least 1 nucleotide. In another embodiment, at least one 25 strand comprises a 3’ overhang of at least 2 nucleotides, e.g., 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, or 15 nucleotides. In other embodiments, at least one strand of the RNAi agent comprises a 5’ overhang of at least 1 nucleotide. In certain embodiments, at least one strand comprises a 5’ overhang of at least 2 nucleotides, e.g., 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, or 15 nucleotides. In still other embodiments, both the 3’ and the 5’ end 30 of one strand of the RNAi agent comprise an overhang of at least 1 nucleotide. In one embodiment, an RNAi agent of the disclosure is a dsRNA, each strand of which comprises 19-23 nucleotides, that interacts with a target RNA sequence, e.g., an APP target mRNA sequence, to direct the cleavage of the target RNA. Without wishing 2026204572  15 Jun 2026 to be bound by theory, long double stranded RNA introduced into cells is broken down into siRNA by a Type III endonuclease known as Dicer (Sharp et al. (2001) Genes Dev. 15:485). Dicer, a ribonuclease-III-like enzyme, processes the dsRNA into 19-23 base pair short interfering RNAs with characteristic two base 3' overhangs (Bernstein, et al., 5   (2001) Nature 409:363). The siRNAs are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition (Nykanen, et al., (2001) Cell 107:309). Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., 10   (2001) Genes Dev. 15:188). As used herein, the term “nucleotide overhang” refers to at least one unpaired nucleotide that protrudes from the duplex structure of a RNAi agent, e.g., a dsRNA. For example, when a 3'-end of one strand of a dsRNA extends beyond the 5'-end of the other strand, or vice versa, there is a nucleotide overhang. A dsRNA can comprise an 15 overhang of at least one nucleotide; alternatively the overhang can comprise at least two nucleotides, at least three nucleotides, at least four nucleotides, at least five nucleotides or more. A nucleotide overhang can comprise or consist of a nucleotide / nucleoside analog, including a deoxynucleotide / nucleoside. The overhang(s) can be on the sense strand, the antisense strand or any combination thereof. Furthermore, the nucleotide(s) 20 of an overhang can be present on the 5'-end, 3'-end or both ends of either an antisense or sense strand of a dsRNA. In one embodiment, the antisense strand of a dsRNA has a 1-10 nucleotide, e.g., a 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotide, overhang at the 3’-end and / or the 5’-end. In one embodiment, the sense strand of a dsRNA has a 1-10 nucleotide, e.g., a 1, 2, 3, 4, 5, 25   6, 7, 8, 9, or 10 nucleotide, overhang at the 3’-end and / or the 5’-end. In another embodiment, one or more of the nucleotides in the overhang is replaced with a nucleoside thiophosphate. In certain embodiments, the antisense strand of a dsRNA has a 1-10 nucleotide, e.g., 0-3, 1-3, 2-4, 2-5, 4-10, 5-10, e.g., a 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotide, 30 overhang at the 3’-end and / or the 5’-end. In one embodiment, the sense strand of a dsRNA has a 1-10 nucleotide, e.g., a 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotide, overhang at the 3’-end and / or the 5’-end. In another embodiment, one or more of the nucleotides in the overhang is replaced with a nucleoside thiophosphate. 2026204572  15 Jun 2026 In certain embodiments, the overhang on the sense strand or the antisense strand, or both, can include extended lengths longer than 10 nucleotides, e.g., 1-30 nucleotides, 2-30 nucleotides, 10-30 nucleotides, or 10-15 nucleotides in length. In certain embodiments, an extended overhang is on the sense strand of the duplex. In certain 5 embodiments, an extended overhang is present on the 3’end of the sense strand of the duplex. In certain embodiments, an extended overhang is present on the 5’end of the sense strand of the duplex. In certain embodiments, an extended overhang is on the antisense strand of the duplex. In certain embodiments, an extended overhang is present on the 3’end of the antisense strand of the duplex. In certain embodiments, an extended 10 overhang is present on the 5’end of the antisense strand of the duplex. In certain embodiments, one or more of the nucleotides in the overhang is replaced with a nucleoside thiophosphate. In certain embodiments, the overhang includes a self-complementary portion such that the overhang is capable of forming a hairpin structure that is stable under physiological conditions. 15          The terms “blunt” or “blunt ended” as used herein in reference to a dsRNA mean that there are no unpaired nucleotides or nucleotide analogs at a given terminal end of a dsRNA, i.e., no nucleotide overhang. One or both ends of a dsRNA can be blunt. Where both ends of a dsRNA are blunt, the dsRNA is said to be blunt ended. To be clear, a “blunt ended” dsRNA is a dsRNA that is blunt at both ends, i.e., no nucleotide overhang 20 at either end of the molecule. Most often such a molecule will be double stranded over its entire length. The term “antisense strand” or "guide strand" refers to the strand of a RNAi agent, e.g., a dsRNA, which includes a region that is substantially complementary to a target sequence, e.g., an APP mRNA. 25          As used herein, the term “region of complementarity” refers to the region on the antisense strand that is substantially complementary to a sequence, for example a target sequence, e.g., an APP nucleotide sequence, as defined herein. Where the region of complementarity is not fully complementary to the target sequence, the mismatches can be in the internal or terminal regions of the molecule. Generally, the most tolerated 30 mismatches are in the terminal regions, e.g., within 5, 4, 3, or 2 nucleotides of the 5’-and / or 3’-terminus of the RNAi agent. 2026204572  15 Jun 2026 The term “sense strand” or "passenger strand" as used herein, refers to the strand of a RNAi agent that includes a region that is substantially complementary to a region of the antisense strand as that term is defined herein. As used herein, the term “cleavage region” refers to a region that is located 5 immediately adjacent to the cleavage site. The cleavage site is the site on the target at which cleavage occurs. In some embodiments, the cleavage region comprises three bases on either end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage region comprises two bases on either end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage site specifically occurs at the site 10 bound by nucleotides 10 and 11 of the antisense strand, and the cleavage region comprises nucleotides 11, 12 and 13. As used herein, and unless otherwise indicated, the term “complementary,” when used to describe a first nucleotide sequence in relation to a second nucleotide sequence, refers to the ability of an oligonucleotide or polynucleotide comprising the first 15 nucleotide sequence to hybridize and form a duplex structure under certain conditions with an oligonucleotide or polynucleotide comprising the second nucleotide sequence, as will be understood by the skilled person. Such conditions can, for example, be stringent conditions, where stringent conditions can include: 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50oC or 70oC for 12-16 hours followed by washing (see, e.g., 20 “Molecular Cloning: A Laboratory Manual, Sambrook, et al. (1989) Cold Spring Harbor Laboratory Press). Other conditions, such as physiologically relevant conditions as can be encountered inside an organism, can apply. The skilled person will be able to determine the set of conditions most appropriate for a test of complementarity of two sequences in accordance with the ultimate application of the hybridized nucleotides. 25          Complementary sequences within a RNAi agent, e.g., within a dsRNA as described herein, include base-pairing of the oligonucleotide or polynucleotide comprising a first nucleotide sequence to an oligonucleotide or polynucleotide comprising a second nucleotide sequence over the entire length of one or both nucleotide sequences. Such sequences can be referred to as “fully complementary” with respect to 30 each other herein. However, where a first sequence is referred to as “substantially complementary” with respect to a second sequence herein, the two sequences can be fully complementary, or they can form one or more, but generally not more than 5, 4, 3 or 2 mismatched base pairs upon hybridization for a duplex up to 30 base pairs, while 2026204572  15 Jun 2026 retaining the ability to hybridize under the conditions most relevant to their ultimate application, e.g., inhibition of gene expression via a RISC pathway. However, where two oligonucleotides are designed to form, upon hybridization, one or more single stranded overhangs, such overhangs shall not be regarded as mismatches with regard to 5 the determination of complementarity. For example, a dsRNA comprising one oligonucleotide 21 nucleotides in length and another oligonucleotide 23 nucleotides in length, wherein the longer oligonucleotide comprises a sequence of 21 nucleotides that is fully complementary to the shorter oligonucleotide, can yet be referred to as “fully complementary” for the purposes described herein. 10          “Complementary” sequences, as used herein, can also include, or be formed entirely from, non-Watson-Crick base pairs and / or base pairs formed from non-natural and modified nucleotides, in so far as the above requirements with respect to their ability to hybridize are fulfilled. Such non-Watson-Crick base pairs include, but are not limited to, G:U Wobble or Hoogstein base pairing. 15          The terms “complementary,” “fully complementary” and “substantially complementary” herein can be used with respect to the base matching between the sense strand and the antisense strand of a dsRNA, or between the antisense strand of a RNAi agent and a target sequence, as will be understood from the context of their use. As used herein, a polynucleotide that is “substantially complementary to at least 20 part of” a messenger RNA (mRNA) refers to a polynucleotide that is substantially complementary to a contiguous portion of the mRNA of interest (e.g., an mRNA encoding APP). For example, a polynucleotide is complementary to at least a part of an APP mRNA if the sequence is substantially complementary to a non-interrupted portion of an mRNA encoding APP. 25          Accordingly, in some embodiments, the antisense strand polynucleotides disclosed herein are fully complementary to the target APP sequence. In other embodiments, the antisense strand polynucleotides disclosed herein are substantially complementary to the target APP sequence and comprise a contiguous nucleotide sequence which is at least about 80% complementary over its entire length to the 30 equivalent region of the nucleotide sequence of SEQ ID NOs: 1-14, or a fragment of SEQ ID NOs: 1-14, such as about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about % 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% complementary. 2026204572  15 Jun 2026 In other embodiments, the antisense polynucleotides disclosed herein are substantially complementary to the target APP sequence and comprise a contiguous nucleotide sequence which is at least about 80% complementary over its entire length to any one of the sense strand nucleotide sequences in any one of Tables 2A, 2B, 3, 5A, 5   5B, 6, 9, 10-15, 16A, 16B, or 26, or a fragment of any one of the sense strand nucleotide sequences in any one of Tables 2A, 2B, 3, 5A, 5B, 6, 9, 10-15, 16A, 16B, or 26, such as about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about % 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% complementary. 10          In one embodiment, an RNAi agent of the disclosure includes a sense strand that is substantially complementary to an antisense polynucleotide which, in turn, is the same as a target APP sequence, and wherein the sense strand polynucleotide comprises a contiguous nucleotide sequence which is at least about 80% complementary over its entire length to the equivalent region of the nucleotide sequence of SEQ ID NOs: 15-28, 15 or a fragment of any one of SEQ ID NOs: 15-28, such as about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about % 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% complementary. In one embodiment, at least partial suppression of the expression of an APP gene, is assessed by a reduction of the amount of APP mRNA which can be isolated 20 from or detected in a first cell or group of cells in which an APP gene is transcribed and which has or have been treated such that the expression of an APP gene is inhibited, as compared to a second cell or group of cells substantially identical to the first cell or group of cells but which has or have not been so treated (control cells). The degree of inhibition may be expressed in terms of: 25 (mRNA in control cells) - (mRNA in treated cells) * (mRNA in control cells) The phrase “contacting a cell with an RNAi agent,” such as a dsRNA, as used herein, includes contacting a cell by any possible means. Contacting a cell with an RNAi agent includes contacting a cell in vitro with the RNAi agent or contacting a cell in vivo with the RNAi agent. The contacting may be done directly or indirectly. Thus, for 30 example, the RNAi agent may be put into physical contact with the cell by the individual performing the method, or alternatively, the RNAi agent may be put into a situation that will permit or cause it to subsequently come into contact with the cell. 2026204572  15 Jun 2026 Contacting a cell in vitro may be done, for example, by incubating the cell with the RNAi agent. Contacting a cell in vivo may be done, for example, by injecting the RNAi agent into or near the tissue where the cell is located, or by injecting the RNAi agent into another area, e.g., the central nervous system (CNS), optionally via 5 intrathecal, intravitreal or other injection, or to the bloodstream or the subcutaneous space, such that the agent will subsequently reach the tissue where the cell to be contacted is located. For example, the RNAi agent may contain and / or be coupled to a ligand, e.g., a lipophilic moiety or moieties as described below and further detailed, e.g., in U.S. Application Nos. 62 / 668,072, 62 / 738,747 and / or 62 / 773,082, that directs and / or 10 otherwise stabilizes the RNAi agent at a site of interest, e.g., the CNS. Combinations of in vitro and in vivo methods of contacting are also possible. For example, a cell may also be contacted in vitro with an RNAi agent and subsequently transplanted into a subject. In one embodiment, contacting a cell with a RNAi agent includes “introducing” or “delivering the RNAi agent into the cell” by facilitating or effecting uptake or 15 absorption into the cell. Absorption or uptake of a RNAi agent can occur through unaided diffusive or active cellular processes, or by auxiliary agents or devices. Introducing a RNAi agent into a cell may be in vitro and / or in vivo. For example, for in vivo introduction, a RNAi agent can be injected into a tissue site or administered systemically. In vitro introduction into a cell includes methods known in the art such as 20 electroporation and lipofection. Further approaches are described herein below and / or are known in the art. The term “lipophile” or “lipophilic moiety” broadly refers to any compound or chemical moiety having an affinity for lipids. One way to characterize the lipophilicity of the lipophilic moiety is by the octanol-water partition coefficient, logKow, where Kow 25 is the ratio of a chemical’s concentration in the octanol-phase to its concentration in the aqueous phase of a two-phase system at equilibrium. The octanol-water partition coefficient is a laboratory-measured property of a substance. However, it may also be predicted by using coefficients attributed to the structural components of a chemical which are calculated using first-principle or empirical methods (see, for example, Tetko 30 et al., J. Chem. Inf. Comput. Sci. 41:1407-21 (2001), which is incorporated herein by reference in its entirety). It provides a thermodynamic measure of the tendency of the substance to prefer a non-aqueous or oily milieu rather than water (i.e. its hydrophilic / lipophilic balance). In principle, a chemical substance is lipophilic in 2026204572  15 Jun 2026 character when its logKow exceeds 0. Typically, the lipophilic moiety possesses a logKow exceeding 1, exceeding 1.5, exceeding 2, exceeding 3, exceeding 4, exceeding 5, or exceeding 10. For instance, the logKow of 6-amino hexanol, for instance, is predicted to be approximately 0.7. Using the same method, the logKow of cholesteryl N-(hexan-6-ol) 5 carbamate is predicted to be 10.7. The lipophilicity of a molecule can change with respect to the functional group it carries. For instance, adding a hydroxyl group or amine group to the end of a lipophilic moiety can increase or decrease the partition coefficient (e.g., logKow) value of the lipophilic moiety. 10          Alternatively, the hydrophobicity of the double-stranded RNAi agent, conjugated to one or more lipophilic moieties, can be measured by its protein binding characteristics. For instance, in certain embodiments, the unbound fraction in the plasma protein binding assay of the double-stranded RNAi agent could be determined to positively correlate to the relative hydrophobicity of the double-stranded RNAi agent, 15 which could then positively correlate to the silencing activity of the double-stranded RNAi agent. In one embodiment, the plasma protein binding assay determined is an electrophoretic mobility shift assay (EMSA) using human serum albumin protein. An exemplary protocol of this binding assay is illustrated in detail in, e.g., U.S. Application 20 Nos. 62 / 668,072, 62 / 738,747 and / or 62 / 773,082. The hydrophobicity of the doublestranded RNAi agent, measured by fraction of unbound siRNA in the binding assay, exceeds 0.15, exceeds 0.2, exceeds 0.25, exceeds 0.3, exceeds 0.35, exceeds 0.4, exceeds 0.45, or exceeds 0.5 for an enhanced in vivo delivery of siRNA. Accordingly, conjugating the lipophilic moieties to the internal position(s) of the 25 double-stranded RNAi agent provides optimal hydrophobicity for the enhanced in vivo delivery of siRNA. The term “lipid nanoparticle” or “LNP” is a vesicle comprising a lipid layer encapsulating a pharmaceutically active molecule, such as a nucleic acid molecule, e.g., a rNAi agent or a plasmid from which a RNAi agent is transcribed. LNPs are described 30 in, for example, U.S. Patent Nos. 6,858,225, 6,815,432, 8,158,601, and 8,058,069, the entire contents of which are hereby incorporated herein by reference. As used herein, a “subject” is an animal, such as a mammal, including a primate (such as a human, a non-human primate, e.g., a monkey, and a chimpanzee), a non- 2026204572  15 Jun 2026 primate (such as a cow, a pig, a camel, a llama, a horse, a goat, a rabbit, a sheep, a hamster, a guinea pig, a cat, a dog, a rat, a mouse, a horse, and a whale), or a bird (e.g., a duck or a goose). In an embodiment, the subject is a human, such as a human being treated or assessed for a disease, disorder or condition that would benefit from reduction 5 in APP expression; a human at risk for a disease, disorder or condition that would benefit from reduction in APP expression; a human having a disease, disorder or condition that would benefit from reduction in APP expression; and / or human being treated for a disease, disorder or condition that would benefit from reduction in APP expression as described herein. 10           As used herein, the terms “treating” or “treatment” refer to a beneficial or desired result including, but not limited to, alleviation or amelioration of one or more symptoms associated with APP gene expression and / or APP protein production, e.g., APP-associated diseases or disorders such as AD, CAA (e.g., hereditary CAA) and EOFAD, among others. "Treatment" can also mean prolonging survival as compared to expected 15 survival in the absence of treatment. The term “lower” in the context of the level of APP in a subject or a disease marker or symptom refers to a statistically significant decrease in such level. The decrease can be, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 20   60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more. In certain embodiments, a decrease is at least 20%. ”Lower” in the context of the level of APP in a subject is preferably down to a level accepted as within the range of normal for an individual without such disorder. As used herein, “prevention” or “preventing,” when used in reference to a 25 disease, disorder or condition thereof, that would benefit from a reduction in expression of an APP gene and / or production of APP protein, refers to a reduction in the likelihood that a subject will develop a symptom associated with such a disease, disorder, or condition, e.g., a symptom of APP gene expression, such as the presence of various forms of Ap (e.g., AP38, Ap40 and / or Ap42, etc.), amyloid plaques and / or cerebral 30 amyloid angiopathy (CAA) or Alzheimer’s disease (AD), including, e.g., early onset familial Alzheimer disease (EOFAD). The failure to develop a disease, disorder or condition, or the reduction in the development of a symptom associated with such a disease, disorder or condition (e.g., by at least about 10% on a clinically accepted scale 2026204572  15 Jun 2026 for that disease or disorder), or the exhibition of delayed symptoms delayed (e.g., by days, weeks, months or years) is considered effective prevention. As used herein, the term "APP-associated disease,” is a disease or disorder that is caused by, or associated with APP gene expression or APP protein production. The term 5 "APP-associated disease” includes a disease, disorder or condition that would benefit from a decrease in APP gene expression, replication, or protein activity. Non-limiting examples of APP-associated diseases include, for example, cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD), including, e.g., early onset familial Alzheimer disease (EOFAD). 10           "Therapeutically effective amount," as used herein, is intended to include the amount of an RNAi agent that, when administered to a subject having an APP-associated disorder, is sufficient to effect treatment of the disease (e.g., by diminishing, ameliorating or maintaining the existing disease or one or more symptoms of disease). The "therapeutically effective amount" may vary depending on the RNAi agent, how the 15 agent is administered, the disease and its severity and the history, age, weight, family history, genetic makeup, the types of preceding or concomitant treatments, if any, and other individual characteristics of the subject to be treated. “Prophylactically effective amount,” as used herein, is intended to include the amount of a RNAi agent that, when administered to a subject having an APP-associated 20 disorder, is sufficient to prevent or ameliorate the disease or one or more symptoms of the disease. Ameliorating the disease includes slowing the course of the disease or reducing the severity of later-developing disease. The "prophylactically effective amount" may vary depending on the RNAi agent, how the agent is administered, the degree of risk of disease, and the history, age, weight, family history, genetic makeup, 25 the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated. A "therapeutically-effective amount" or “prophylacticaly effective amount” also includes an amount of a RNAi agent that produces some desired local or systemic effect at a reasonable benefit / risk ratio applicable to any treatment. A RNAi agent employed in 30 the methods of the present disclosure may be administered in a sufficient amount to produce a reasonable benefit / risk ratio applicable to such treatment. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of 2026204572  15 Jun 2026 sound medical judgment, suitable for use in contact with the tissues of human subjects and animal subjects without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The phrase "pharmaceutically-acceptable carrier" as used herein means a 5 pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being 10 compatible with the other ingredients of the formulation and not injurious to the subject being treated. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; 15   (5) malt; (6) gelatin; (7) lubricating agents, such as magnesium state, sodium lauryl sulfate and talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl 20 laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and / or polyanhydrides; (22) bulking agents, such as polypeptides and amino acids (23) serum component, such as serum albumin, HDL and LDL; and (22) other non-toxic 25 compatible substances employed in pharmaceutical formulations. The term “sample,” as used herein, includes a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject. Examples of biological fluids include blood, serum and serosal fluids, plasma, cerebrospinal fluid, ocular fluids, lymph, urine, saliva, and the like. Tissue samples may 30 include samples from tissues, organs or localized regions. For example, samples may be derived from particular organs, parts of organs, or fluids or cells within those organs. In certain embodiments, samples may be derived from the brain (e.g., whole brain or certain segments of brain or certain types of cells in the brain, such as, e.g., neurons and 2026204572  15 Jun 2026 glial cells (astrocytes, oligodendrocytes, microglial cells)). In some embodiments, a “sample derived from a subject” refers to blood or plasma drawn from the subject. In further embodiments, a “sample derived from a subject” refers to brain tissue (or subcomponents thereof) or retinal tissue (or subcomponents thereof) derived from the 5 subject. II. RNAi Agents of the Disclosure Described herein are RNAi agents which inhibit the expression of an APP gene. In one embodiment, the RNAi agent includes double stranded ribonucleic acid (dsRNA) molecules for inhibiting the expression of an APP gene in a cell, such as a cell within a 10 subject, e.g., a mammal, such as a human having an APP-associated disorder, e.g., cerebral amyloid angiopathy (CAA) or Alzheimer’s disease (AD), including, e.g., early onset familial Alzheimer disease (EOFAD). The dsRNA includes an antisense strand having a region of complementarity which is complementary to at least a part of an mRNA formed in the expression of an APP gene, The region of complementarity is 15 about 30 nucleotides or less in length (e.g., about 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, or 18 nucleotides or less in length). Upon contact with a cell expressing the APP gene, the RNAi agent inhibits the expression of the APP gene (e.g., a human, a primate, a non-primate, or a bird APP gene) by at least about 10% as assayed by, for example, a PCR or branched DNA (bDNA)-based method, or by a protein-based method, such as by 20 immunofluorescence analysis, using, for example, Western Blotting or flowcytometric techniques. A dsRNA includes two RNA strands that are complementary and hybridize to form a duplex structure under conditions in which the dsRNA will be used. One strand of a dsRNA (the antisense strand) includes a region of complementarity that is 25 substantially complementary, and generally fully complementary, to a target sequence. The target sequence can be derived from the sequence of an mRNA formed during the expression of an APP gene. The other strand (the sense strand) includes a region that is complementary to the antisense strand, such that the two strands hybridize and form a duplex structure when combined under suitable conditions. As described elsewhere 30 herein and as known in the art, the complementary sequences of a dsRNA can also be contained as self-complementary regions of a single nucleic acid molecule, as opposed to being on separate oligonucleotides. 2026204572  15 Jun 2026 Generally, the duplex structure is between 15 and 30 base pairs in length, e.g., between, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 1820, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 5   20-29, 20-28, 20-27, 20-26, 20-25, 20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21 27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs in length. In certain preferred embodiments, the duplex structure is between 18 and 25 base pairs in length, e.g., 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 2024,20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22-25, 22-24, 22-23, 23-25, 23-24 10 or 24-25 base pairs in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure. Similarly, the region of complementarity to the target sequence is between 15 and 30 nucleotides in length, e.g., between 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 1523, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 15    18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19 23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure. 20         In some embodiments, the dsRNA is between about 15 and about 23 nucleotides in length, or between about 25 and about 30 nucleotides in length. In general, the dsRNA is long enough to serve as a substrate for the Dicer enzyme. For example, it is well known in the art that dsRNAs longer than about 21-23 nucleotides can serve as substrates for Dicer. As the ordinarily skilled person will also recognize, the region of an 25 RNA targeted for cleavage will most often be part of a larger RNA molecule, often an mRNA molecule. Where relevant, a “part” of an mRNA target is a contiguous sequence of an mRNA target of sufficient length to allow it to be a substrate for RNAi-directed cleavage (i.e., cleavage through a RISC pathway). One of skill in the art will also recognize that the duplex region is a primary 30 functional portion of a dsRNA, e.g., a duplex region of about 9 to 36 base pairs, e.g., about 10-36, 11-36, 12-36, 13-36, 14-36, 15-36, 9-35, 10-35, 11-35, 12-35, 13-35, 1435, 15-35, 9-34, 10-34, 11-34, 12-34, 13-34, 14-34, 15-34, 9-33, 10-33, 11-33, 12-33, 13-33, 14-33, 15-33, 9-32, 10-32, 11-32, 12-32, 13-32, 14-32, 15-32, 9-31, 10-31, 11-31, 2026204572  15 Jun 2026 12-31, 13-32, 14-31, 15-31, 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 1522, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 1922, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24,20-23, 20-22, 20-21, 5   21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs. Thus, in one embodiment, to the extent that it becomes processed to a functional duplex, of e.g., 15-30 base pairs, that targets a desired RNA for cleavage, an RNA molecule or complex of RNA molecules having a duplex region greater than 30 base pairs is a dsRNA. Thus, an ordinarily skilled artisan will recognize that in one embodiment, a miRNA is a 10 dsRNA. In another embodiment, a dsRNA is not a naturally occurring miRNA. In another embodiment, a RNAi agent useful to target APP expression is not generated in the target cell by cleavage of a larger dsRNA. A dsRNA as described herein can further include one or more single-stranded nucleotide overhangs e.g., 1, 2, 3, or 4 nucleotides. dsRNAs having at least one 15 nucleotide overhang can have unexpectedly superior inhibitory properties relative to their blunt-ended counterparts. A nucleotide overhang can comprise or consist of a nucleotide / nucleoside analog, including a deoxynucleotide / nucleoside. The overhang(s) can be on the sense strand, the antisense strand or any combination thereof. Furthermore, the nucleotide(s) of an overhang can be present on the 5'-end, 3'-end or both ends of 20 either an antisense or sense strand of a dsRNA. A dsRNA can be synthesized by standard methods known in the art as further discussed below, e.g., by use of an automated DNA synthesizer, such as are commercially available from, for example, Biosearch, Applied Biosystems, Inc. RNAi agents of the disclosure may be prepared using a two-step procedure. First, 25 the individual strands of the double stranded RNA molecule are prepared separately. Then, the component strands are annealed. The individual strands of the siRNA compound can be prepared using solution-phase or solid-phase organic synthesis or both. Organic synthesis offers the advantage that the oligonucleotide strands comprising unnatural or modified nucleotides can be easily prepared. Single-stranded 30 oligonucleotides of the disclosure can be prepared using solution-phase or solid-phase organic synthesis or both. In one aspect, a dsRNA of the disclosure includes at least two nucleotide sequences, a sense sequence and an antisense sequence. The sense strand sequence may 2026204572  15 Jun 2026 be selected from the group of sequences provided in any one of Tables 2A, 2B, 3, 5A, 5B, 6, 9, 10-15, 16A, 16B, and 26 and the corresponding nucleotide sequence of the antisense strand of the sense strand may be selected from the group of sequences of any one of Tables 2A, 2B, 3, 5A, 5B, 6, 9, 10-15, 16A, 16B, and 26. In this aspect, one of 5 the two sequences is complementary to the other of the two sequences, with one of the sequences being substantially complementary to a sequence of an mRNA generated in the expression of an APP gene. As such, in this aspect, a dsRNA will include two oligonucleotides, where one oligonucleotide is described as the sense strand (passenger strand) in any one of Tables 2A, 2B, 3, 5A, 5B, 6, 9, 10-15, 16A, 16B, and 26, and the 10 second oligonucleotide is described as the corresponding antisense strand (guide strand) of the sense strand in any one of Tables 2A, 2B, 3, 5A, 5B, 6, 9, 10-15, 16A, 16B, and 26. Accordingly, by way of example, the following pairwise selections of sense and antisense strand sequences of Table 3 are expressly contemplated as forming duplexes of the instant disclosure: SEQ ID NOs: 855 and 856; SEQ ID NOs: 857 and 858; SEQ ID 15 NOs: 859 and 860; SEQ NOs: 865 and 866; SEQ NOs: 871 and 872; SEQ NOs: 877 and 878; SEQ NOs: 883 and 884; SEQ 20 NOs: 889 and 890; SEQ NOs: 895 and 896; SEQ NOs: 901 and 902; SEQ NOs: 907 and 908; SEQ NOs: 913 and 914; SEQ 25 NOs: 919 and 920; SEQ NOs: 925 and 926; SEQ NOs: 931 and 932; SEQ NOs: 937 and 938; SEQ NOs: 943 and 944; SEQ 30 NOs: 949 and 950; SEQ NOs: 955 and 956; SEQ NOs: 961 and 962; SEQ NOs: 967 and 968; SEQ ID NOs: 861 and 862; SEQ ID NOs: 867 and 868; SEQ ID NOs: 873 and 874; SEQ ID NOs: 879 and 880; SEQ ID NOs: 885 and 886; SEQ ID NOs: 891 and 892; SEQ ID NOs: 897 and 898; SEQ ID NOs: 903 and 904; SEQ ID NOs: 909 and 910; SEQ ID NOs: 915 and 916; SEQ ID NOs: 921 and 922; SEQ ID NOs: 927 and 928; SEQ ID NOs: 933 and 934; SEQ ID NOs: 939 and 940; SEQ ID NOs: 945 and 946; SEQ ID NOs: 951 and 952; SEQ ID NOs: 957 and 958; SEQ ID NOs: 963 and 964; SEQ ID NOs: 969 and 970; SEQ ID NOs: 863 and 864; SEQ ID ID NOs: 869 and 870; SEQ ID ID NOs: 875 and 876; SEQ ID ID NOs: 881 and 882; SEQ ID ID NOs: 887 and 888; SEQ ID ID NOs: 893 and 894; SEQ ID ID NOs: 899 and 900; SEQ ID ID NOs: 905 and 906; SEQ ID ID NOs: 911 and 912; SEQ ID ID NOs: 917 and 918; SEQ ID ID NOs: 923 and 924; SEQ ID ID NOs: 929 and 930; SEQ ID ID NOs: 935 and 936; SEQ ID ID NOs: 941 and 942; SEQ ID ID NOs: 947 and 948; SEQ ID ID NOs: 953 and 954; SEQ ID ID NOs: 959 and 960; SEQ ID ID NOs: 965 and 966; SEQ ID ID NOs: 971 and 972; SEQ ID 2026204572  15 Jun 2026 NOs: 973 and 974; SEQ ID NOs: 975 and 976; SEQ ID NOs: 977 and 978; SEQ ID NOs: 979 and 980; SEQ ID NOs: 981 and 982; SEQ ID NOs: 983 and 984; SEQ ID NOs: 985 and 986; SEQ ID NOs: 987 and 988; SEQ ID NOs: 989 and 990; SEQ ID NOs: 991 and 992; SEQ ID NOs: 993 and 994; SEQ ID NOs: 995 and 996; SEQ ID 5 NOs: 997 and 998; SEQ ID NOs: 999 and 1000; SEQ ID NOs: 1001 and 1002; SEQ ID NOs: 1003 and 1004; SEQ ID NOs: 1005 and 1006; SEQ ID NOs: 1007 and 1008; SEQ ID NOs: 1009 and 1010; SEQ ID NOs: 1011 and 1012; SEQ ID NOs: 1013 and 1014; SEQ ID NOs: 1015 and 1016; SEQ ID NOs: 1017 and 1018; SEQ ID NOs: 1019 and 1020; SEQ ID NOs: 1021 and 1022; SEQ ID NOs: 1023 and 1024; SEQ ID NOs: 1025 10 and 1026; SEQ ID NOs: 1027 and 1028; SEQ ID NOs: 1029 and 1030; SEQ ID NOs: 1031 and 1032; SEQ ID NOs: 1033 and 1034; SEQ ID NOs: 1035 and 1036; SEQ ID NOs: 1037 and 1038; SEQ ID NOs: 1039 and 1040; SEQ ID NOs: 1041 and 1042; SEQ ID NOs: 1043 and 1044; SEQ ID NOs: 1045 and 1046; SEQ ID NOs: 1047 and 1048; SEQ ID NOs: 1049 and 1050; SEQ ID NOs: 1051 and 1052; SEQ ID NOs: 1053 and 15   1054; SEQ ID NOs: 1055 and 1056; SEQ ID NOs: 1057 and 1058; SEQ ID NOs: 1059 and 1060; SEQ ID NOs: 1061 and 1062; SEQ ID NOs: 1063 and 1064; SEQ ID NOs: 1065 and 1066; SEQ ID NOs: 1067 and 1068; SEQ ID NOs: 1069 and 1070; SEQ ID NOs: 1071 and 1072; SEQ ID NOs: 1073 and 1074; SEQ ID NOs: 1075 and 1076; SEQ ID NOs: 1077 and 1078; SEQ ID NOs: 1079 and 1080; SEQ ID NOs: 1081 and 1082; 20 SEQ ID NOs: 1083 and 1084; SEQ ID NOs: 1085 and 1086; SEQ ID NOs: 1087 and 1088; SEQ ID NOs: 1089 and 1090; SEQ ID NOs: 1091 and 1092; SEQ ID NOs: 1093 and 1094; SEQ ID NOs: 1095 and 1096; SEQ ID NOs: 1097 and 1098; SEQ ID NOs: 1099 and 1100; SEQ ID NOs: 1101 and 1102; SEQ ID NOs: 1103 and 1104; SEQ ID NOs: 1105 and 1106; SEQ ID NOs: 1107 and 1108; SEQ ID NOs: 1109 and 1110; SEQ 25 ID NOs: 1111 and 1112; SEQ ID NOs: 1113 and 1114; SEQ ID NOs: 1115 and 1116; SEQ ID NOs: 1117 and 1118; SEQ ID NOs: 1119 and 1120; SEQ ID NOs: 1121 and 1122; SEQ ID NOs: 1123 and 1124; SEQ ID NOs: 1125 and 1126; SEQ ID NOs: 1127 and 1128; SEQ ID NOs: 1129 and 1130; SEQ ID NOs: 1131 and 1132; SEQ ID NOs: 1133 and 1134; SEQ ID NOs: 1135 and 1136; SEQ ID NOs: 1137 and 1138; SEQ ID 30 NOs: 1139 and 1140; SEQ ID NOs: 1141 and 1142; SEQ ID NOs: 1143 and 1144; SEQ ID NOs: 1145 and 1146; SEQ ID NOs: 1147 and 1148; SEQ ID NOs: 1149 and 1150; SEQ ID NOs: 1151 and 1152; SEQ ID NOs: 1153 and 1154; SEQ ID NOs: 1155 and 1156; SEQ ID NOs: 1157 and 1158; SEQ ID NOs: 1159 and 1160; SEQ ID NOs: 1161 2026204572  15 Jun 2026 and 1162; SEQ ID NOs: 1163 and 1164; SEQ ID NOs: 1165 and 1166; SEQ ID NOs: 1167 and 1168; SEQ ID NOs: 1169 and 1170; SEQ ID NOs: 1171 and 1172; SEQ ID NOs: 1173 and 1174; SEQ ID NOs: 1175 and 1176; SEQ ID NOs: 1177 and 1178; SEQ ID NOs: 1179 and 1180; SEQ ID NOs: 1181 and 1182; SEQ ID NOs: 1183 and 1184; 5 SEQ ID NOs: 1185 and 1186; SEQ ID NOs: 1187 and 1188; SEQ ID NOs: 1189 and 1190; SEQ ID NOs: 1191 and 1192; SEQ ID NOs: 1193 and 1194; SEQ ID NOs: 1195 and 1196; SEQ ID NOs: 1197 and 1198; SEQ ID NOs: 1199 and 1200; SEQ ID NOs: 1201 and 1202; SEQ ID NOs: 1203 and 1204; SEQ ID NOs: 1205 and 1206; SEQ ID NOs: 1207 and 1208; SEQ ID NOs: 1209 and 1210; SEQ ID NOs: 1211 and 1212; SEQ 10 ID NOs: 1213 and 1214; SEQ ID NOs: 1215 and 1216; SEQ ID NOs: 1217 and 1218; SEQ ID NOs: 1219 and 1220; SEQ ID NOs: 1221 and 1222; SEQ ID NOs: 1223 and 1224; SEQ ID NOs: 1225 and 1226; SEQ ID NOs: 1227 and 1228; SEQ ID NOs: 1229 and 1230; SEQ ID NOs: 1231 and 1232; SEQ ID NOs: 1233 and 1234; SEQ ID NOs: 1235 and 1236; SEQ ID NOs: 1237 and 1238; SEQ ID NOs: 1239 and 1240; SEQ ID 15 NOs: 1241 and 1242; SEQ ID NOs: 1243 and 1244; SEQ ID NOs: 1245 and 1246; SEQ ID NOs: 1247 and 1248; SEQ ID NOs: 1249 and 1250; SEQ ID NOs: 1251 and 1252; SEQ ID NOs: 1253 and 1254; SEQ ID NOs: 1255 and 1256; SEQ ID NOs: 1257 and 1258; SEQ ID NOs: 1259 and 1260; SEQ ID NOs: 1261 and 1262; SEQ ID NOs: 1263 and 1264; SEQ ID NOs: 1265 and 1266; SEQ ID NOs: 1267 and 1268; SEQ ID NOs: 20   1269 and 1270; SEQ ID NOs: 1271 and 1272; SEQ ID NOs: 1273 and 1274; SEQ ID NOs: 1275 and 1276; SEQ ID NOs: 1277 and 1278; SEQ ID NOs: 1279 and 1280; SEQ ID NOs: 1281 and 1282; SEQ ID NOs: 1283 and 1284; SEQ ID NOs: 1285 and 1286; SEQ ID NOs: 1287 and 1288; SEQ ID NOs: 1289 and 1290; SEQ ID NOs: 1291 and 1292; SEQ ID NOs: 1293 and 1294; SEQ ID NOs: 1295 and 1296; SEQ ID NOs: 1297 25 and 1298; SEQ ID NOs: 1299 and 1300; SEQ ID NOs: 1301 and 1302; SEQ ID NOs: 1303 and 1304; SEQ ID NOs: 1305 and 1306; SEQ ID NOs: 1307 and 1308; SEQ ID NOs: 1309 and 1310; SEQ ID NOs: 1311 and 1312; SEQ ID NOs: 1313 and 1314; SEQ ID NOs: 1315 and 1316; SEQ ID NOs: 1317 and 1318; SEQ ID NOs: 1319 and 1320; SEQ ID NOs: 1321 and 1322; SEQ ID NOs: 1323 and 1324; SEQ ID NOs: 1325 and 30   1326; SEQ ID NOs: 1327 and 1328; SEQ ID NOs: 1329 and 1330; SEQ ID NOs: 1331 and 1332; SEQ ID NOs: 1333 and 1334; SEQ ID NOs: 1335 and 1336; SEQ ID NOs: 1337 and 1338; SEQ ID NOs: 1339 and 1340; SEQ ID NOs: 1341 and 1342; SEQ ID NOs: 1343 and 1344; SEQ ID NOs: 1345 and 1346; SEQ ID NOs: 1347 and 1348; SEQ 2026204572  15 Jun 2026 ID NOs: 1349 and 1350; SEQ ID NOs: 1351 and 1352; SEQ ID NOs: 1353 and 1354; SEQ ID NOs: 1355 and 1356; SEQ ID NOs: 1357 and 1358; SEQ ID NOs: 1359 and 1360; SEQ ID NOs: 1361 and 1362; SEQ ID NOs: 1363 and 1364; SEQ ID NOs: 1365 and 1366; SEQ ID NOs: 1367 and 1368; SEQ ID NOs: 1369 and 1370; SEQ ID NOs: 5   1371 and 1372; SEQ ID NOs: 1373 and 1374; SEQ ID NOs: 1375 and 1376; SEQ ID NOs: 1377 and 1378; SEQ ID NOs: 1379 and 1380; SEQ ID NOs: 1381 and 1382; SEQ ID NOs: 1383 and 1384; SEQ ID NOs: 1385 and 1386; SEQ ID NOs: 1387 and 1388; SEQ ID NOs: 1389 and 1390; SEQ ID NOs: 1391 and 1392; SEQ ID NOs: 1393 and 1394; SEQ ID NOs: 1395 and 1396; SEQ ID NOs: 1397 and 1398; SEQ ID NOs: 1399 10 and 1400; and SEQ ID NOs: 1401 and 1402. Similarly, pairwise combinations of sense and antisense strands of Tables 2A, 2B, 3, 5A, 5B, 6, 9, 10-15, 16A, 16B, and 26 of the instant disclosure are also expressly contemplated, including, e.g., a sense strand selected from Table 2A together with an antisense strand selected from Table 2B, or vice versa, etc. 15          In one embodiment, the substantially complementary sequences of the dsRNA are contained on separate oligonucleotides. In another embodiment, the substantially complementary sequences of the dsRNA are contained on a single oligonucleotide. It will be understood that, although the sequences in Tables 2A, 2B, 5A, 5B, 9, 10, 12, 14, 16A, 16B, and 26 are described as modified and / or conjugated sequences, the 20 RNA of the RNAi agent of the disclosure e.g., a dsRNA of the disclosure, may comprise any one of the sequences set forth in any one of Tables 2A, 2B, 3, 5A, 5B, 6, 9, 10-15, 16A, 16B, and 26 that is un-modified, un-conjugated, and / or modified and / or conjugated differently than described therein. The skilled person is well aware that dsRNAs having a duplex structure of 25 between about 20 and 23 base pairs, e.g., 21, base pairs have been hailed as particularly effective in inducing RNA interference (Elbashir et al., (2001) EMBO J., 20:68776888). However, others have found that shorter or longer RNA duplex structures can also be effective (Chu and Rana (2007) RNA 14:1714-1719; Kim et al. (2005) Nat Biotech 23:222-226). In the embodiments described above, by virtue of the nature of the 30 oligonucleotide sequences provided herein, dsRNAs described herein can include at least one strand of a length of minimally 21 nucleotides. It can be reasonably expected that shorter duplexes minus only a few nucleotides on one or both ends can be similarly effective as compared to the dsRNAs described above. Hence, dsRNAs having a 2026204572  15 Jun 2026 sequence of at least 15, 16, 17, 18, 19, 20, or more contiguous nucleotides derived from one of the sequences provided herein, and differing in their ability to inhibit the expression of an APP gene by not more than about 5, 10, 15, 20, 25, or 30 % inhibition from a dsRNA comprising the full sequence, are contemplated to be within the scope of 5 the present disclosure. In addition, the RNAs described herein identify a site(s) in an APP transcript that is susceptible to RISC-mediated cleavage. As such, the present disclosure further features RNAi agents that target within this site(s). As used herein, a RNAi agent is said to target within a particular site of an RNA transcript if the RNAi agent promotes 10 cleavage of the transcript anywhere within that particular site. Such a RNAi agent will generally include at least about 15 contiguous nucleotides from one of the sequences provided herein coupled to additional nucleotide sequences taken from the region contiguous to the selected sequence in an APP gene. A RNAi agent as described herein can contain one or more mismatches to the 15 target sequence. In one embodiment, a RNAi agent as described herein contains no more than 3 mismatches. In certain embodiments, if the antisense strand of the RNAi agent contains mismatches to the target sequence, the mismatch can optionally be restricted to be within the last 5 nucleotides from either the 5’- or 3’-end of the region of complementarity. For example, in such embodiments, for a 23 nucleotide RNAi agent, 20 the strand which is complementary to a region of an APP gene, generally does not contain any mismatch within the central 13 nucleotides. The methods described herein or methods known in the art can be used to determine whether a RNAi agent containing a mismatch to a target sequence is effective in inhibiting the expression of an APP gene. Consideration of the efficacy of RNAi agents with mismatches in inhibiting expression 25 of an APP gene is important, especially if the particular region of complementarity in an APP gene is known to have polymorphic sequence variation within the population. III. Modified RNAi Agents of the Disclosure In one embodiment, the RNA of the RNAi agent of the disclosure e.g., a dsRNA, 30 is un-modified, and does not comprise, e.g., chemical modifications and / or conjugations known in the art and described herein. In another embodiment, the RNA of a RNAi agent of the disclosure, e.g., a dsRNA, is chemically modified to enhance stability or other beneficial characteristics. In certain embodiments of the disclosure, substantially 2026204572  15 Jun 2026 all of the nucleotides of a RNAi agent of the disclosure are modified. In other embodiments of the disclosure, all of the nucleotides of a RNAi agent of the disclosure are modified. RNAi agents of the disclosure in which “substantially all of the nucleotides are modified” are largely but not wholly modified and can include not more 5 than 5, 4, 3, 2, or 1 unmodified nucleotides. In still other embodiments of the disclosure, RNAi agents of the disclosure can include not more than 5, 4, 3, 2 or 1 modified nucleotides. The nucleic acids featured in the disclosure can be synthesized and / or modified by methods well established in the art, such as those described in “Current protocols in 10 nucleic acid chemistry,” Beaucage, S.L. et al. (Edrs.), John Wiley & Sons, Inc., New York, NY, USA, which is hereby incorporated herein by reference. Modifications include, for example, end modifications, e.g., 5’-end modifications (phosphorylation, conjugation, inverted linkages) or 3’-end modifications (conjugation, DNA nucleotides, inverted linkages, etc.); base modifications, e.g., replacement with stabilizing bases, 15 destabilizing bases, or bases that base pair with an expanded repertoire of partners, removal of bases (abasic nucleotides), or conjugated bases; sugar modifications (e.g., at the 2’-position or 4’-position) or replacement of the sugar; and / or backbone modifications, including modification or replacement of the phosphodiester linkages. Specific examples of RNAi agents useful in the embodiments described herein include, 20 but are not limited to RNAs containing modified backbones or no natural internucleoside linkages. RNAs having modified backbones include, among others, those that do not have a phosphorus atom in the backbone. For the purposes of this specification, and as sometimes referenced in the art, modified RNAs that do not have a phosphorus atom in their internucleoside backbone can also be considered to be 25 oligonucleosides. In some embodiments, a modified RNAi agent will have a phosphorus atom in its internucleoside backbone. Modified RNA backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3'-alkylene phosphonates and chiral 30 phosphonates, phosphinates, phosphoramidates including 3'-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3'-5' linkages, 2'-5'-linked analogs of these, and those having inverted polarity wherein the adjacent pairs of 2026204572  15 Jun 2026 nucleoside units are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'. Various salts, mixed salts and free acid forms are also included. Representative U.S. patents that teach the preparation of the above phosphorus- containing linkages include, but are not limited to, U.S. Patent Nos. 3,687,808; 5 4,469,863; 4,476,301;  5,023,243;  5,177,195;  5,188,897;  5,264,423; 5,276,019; 5,278,302; 5,286,717;  5,321,131;  5,399,676;  5,405,939;  5,453,496; 5,455,233; 5,466,677; 5,476,925;  5,519,126;  5,536,821;  5,541,316;  5,550,111; 5,563,253; 5,571,799; 5,587,361;  5,625,050;  6,028,188;  6,124,445;  6,160,109; 6,169,170; 6,172,209; 6,  239,265;  6,277,603;  6,326,199;  6,346,614;  6,444,423; 6,531,590; 10 6,534,639; 6,608,035;  6,683,167;  6,858,715;  6,867,294;  6,878,805; 7,015,315; 7,041,816; 7,273,933; 7,321,029; and US Pat RE39464, the entire contents of each of which are hereby incorporated herein by reference. Modified RNA backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, 15 mixed heteroatoms and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; alkene 20 containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH2 component parts. Representative U.S. patents that teach the preparation of the above oligonucleosides include, but are not limited to, U.S. Patent Nos. 5,034,506; 5,166,315; 25   5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,64,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677;  5,470,967;  5,489,677;  5,541,307;  5,561,225;  5,596,086;  5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437; and, 5,677,439, the entire contents of each of which are hereby incorporated herein by reference. 30          In other embodiments, suitable RNA mimetics are contemplated for use in RNAi agents, in which both the sugar and the internucleoside linkage, i.e., the backbone, of the nucleotide units are replaced with novel groups. The base units are maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric 2026204572  15 Jun 2026 compound, an RNA mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar backbone of an RNA is replaced with an amide containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or 5 indirectly to aza nitrogen atoms of the amide portion of the backbone. Representative U.S. patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Patent Nos. 5,539,082; 5,714,331; and 5,719,262, the entire contents of each of which are hereby incorporated herein by reference. Additional PNA compounds suitable for use in the RNAi agents of the disclosure are described in, for example, in Nielsen et 10 al., Science, 1991, 254, 1497-1500. Some embodiments featured in the disclosure include RNAs with phosphorothioate backbones and oligonucleosides with heteroatom backbones, and in particular  --CH2--NH--CH2-,  --CH2--N(CH3)--O--CH2--[known  as a methylene (methylimino) or MMI backbone], --CH2--O--N(CH3)--CH2--, --CH2--N(CH3)--N(CH3)-15   -CH2-- and --N(CH3)--CH2--CH2--[wherein the native phosphodiester backbone is represented as --O--P--O--CH2--] of the above-referenced U.S. Patent No. 5,489,677, and the amide backbones of the above-referenced U.S. Patent No. 5,602,240. In some embodiments, the RNAs featured herein have morpholino backbone structures of the above-referenced U.S. Patent No. 5,034,506. 20          Modified RNAs can also contain one or more substituted sugar moieties. The RNAi agents, e.g., dsRNAs, featured herein can include one of the following at the 2'-position: OH; F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl can be substituted or unsubstituted C1 to C10 alkyl or C2 to C10 alkenyl and alkynyl. Exemplary suitable modifications 25   include O[(CH2)nO] mCH3, O(CH2).nOCH3, O(CH2)nNH2, O(CH2) nCH3, O(CH2)nONH2, and O(CH2)nON[(CH2)nCH3)]2, where n and m are from 1 to about 10. In other embodiments, dsRNAs include one of the following at the 2' position: C1 to C10 lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH3, OCN, Cl, Br, CN, CF3, OCF3, SOCH3, SO2CH3, ONO2, NO2, N3, NH2, heterocycloalkyl, 30 heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group,  a reporter group, an intercalator,  a group  for improving the pharmacokinetic properties of a RNAi agent, or a group for improving the pharmacodynamic properties of a RNAi agent, and other substituents having similar 2026204572  15 Jun 2026 properties. In some embodiments, the modification includes a 2'-methoxyethoxy (2'-O--CH2CH2OCH3, also known as 2'-O-(2-methoxyethyl) or 2'-MOE) (Martin et al., Helv. Chim. Acta, 1995, 78:486-504) i.e., an alkoxy-alkoxy group. Another exemplary modification is 2'-dimethylaminooxyethoxy, i.e., a O(CH2)2ON(CH3)2 group, also 5 known as 2'-DMAOE, as described in examples herein below, and 2'-dimethylaminoethoxyethoxy (also known in the art as 2'-O-dimethylaminoethoxyethyl or 2'-DMAEOE), i.e., 2'-O--CH2--O--CH2--N(CH2)2. Further exemplary modifications include   :   5’-Me-2’-F   nucleotides,   5’-Me-2’-OMe   nucleotides,   5’-Me-2’- deoxynucleotides, (both R and S isomers in these three families); 2’-alkoxyalkyl; and 2’ 10 NMA (N-methylacetamide). Other modifications include 2'-methoxy (2'-OCH3), 2'-aminopropoxy (2'-OCH2CH2CH2NH2), 2’-O-hexadecyl, and 2'-fluoro (2'-F). Similar modifications can also be made at other positions on the RNA of a RNAi agent, particularly the 3' position of the sugar on the 3' terminal nucleotide or in 2'-5' linked dsRNAs and the 5' position of 5' 15 terminal nucleotide. RNAi agents can also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar. Representative U.S. patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos. 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785;  5,519,134;  5,567,811;  5,576,427;  5,591,722;  5,597,909;  5,610,300; 20   5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; and 5,700,920, certain of which are commonly owned with the instant application. The entire contents of each of the foregoing are hereby incorporated herein by reference. A RNAi agent of the disclosure can also include nucleobase (often referred to in the art simply as “base”) modifications or substitutions. As used herein, “unmodified” or 25 “natural” nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified nucleobases include other synthetic and natural nucleobases such as 5-methylcytosine (5-me-C), 5- hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine 30 and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl anal other 8-substituted adenines and guanines, 5-halo, particularly 5-bromo, 5-trifluoromethyl and 2026204572  15 Jun 2026 other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-daazaadenine and 3-deazaguanine and 3-deazaadenine. Further nucleobases include those disclosed in U.S. Pat. No. 3,687,808, those disclosed in Modified Nucleosides in Biochemistry, Biotechnology and 5 Medicine, Herdewijn, P. ed. Wiley-VCH, 2008; those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859, Kroschwitz, J. L, ed. John Wiley & Sons, 1990, these disclosed by Englisch et al., (1991) Angewandte Chemie, International Edition, 30:613, and those disclosed by Sanghvi, Y S., Chapter 15, dsRNA Research and Applications, pages 289-302, Crooke, S. T. and Lebleu, B., 10 Ed., CRC Press, 1993. Certain of these nucleobases are particularly useful for increasing the binding affinity of the oligomeric compounds featured in the disclosure. These include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability 15 by 0.6-1.2 °C (Sanghvi, Y. S., Crooke, S. T. and Lebleu, B., Eds., dsRNA Research and Applications, CRC Press, Boca Raton, 1993, pp. 276-278) and are exemplary base substitutions, even more particularly when combined with 2'-O-methoxyethyl sugar modifications. Representative U.S. patents that teach the preparation of certain of the above 20 noted modified nucleobases as well as other modified nucleobases include, but are not limited to, the above noted U.S. Patent Nos. 3,687,808, 4,845,205; 5,130,30; 5,134,066; 5,175,273;  5,367,066;  5,432,272;  5,457,187;  5,459,255;  5,484,908;  5,502,177; 5,525,711;  5,552,540;  5,587,469;  5,594,121,  5,596,091;  5,614,617;  5,681,941; 5,750,692;  6,015,886;  6,147,200;  6,166,197;  6,222,025;  6,235,887;  6,380,368; 25   6,528,640; 6,639,062; 6,617,438; 7,045,610; 7,427,672; and 7,495,088, the entire contents of each of which are hereby incorporated herein by reference. A RNAi agent of the disclosure can also be modified to include one or more locked nucleic acids (LNA). A locked nucleic acid is a nucleotide having a modified ribose moiety in which the ribose moiety comprises an extra bridge connecting the 2' 30 and 4' carbons. This structure effectively "locks" the ribose in the 3'-endo structural conformation. The addition of locked nucleic acids to siRNAs has been shown to increase siRNA stability in serum, and to reduce off-target effects (Elmen, J. et al., 2026204572  15 Jun 2026 (2005) Nucleic Acids Research 33(1):439-447; Mook, OR. et al., (2007) Mol Canc Ther 6(3):833-843; Grunweller, A. et al., (2003) Nucleic Acids Research 31(12):3185-3193). A RNAi agent of the disclosure can also be modified to include one or more bicyclic sugar moities. A “bicyclic sugar” is a furanosyl ring modified by the bridging of 5 two atoms. A“bicyclic nucleoside” (“BNA”) is a nucleoside having a sugar moiety comprising a bridge connecting two carbon atoms of the sugar ring, thereby forming a bicyclic ring system. In certain embodiments, the bridge connects the 4‘-carbon and the 2'-carbon of the sugar ring. Thus, in some embodiments an agent of the disclosure may include one or more locked nucleic acids (LNA). A locked nucleic acid is a nucleotide 10 having a modified ribose moiety in which the ribose moiety comprises an extra bridge connecting the 2' and 4' carbons. In other words, an LNA is a nucleotide comprising a bicyclic sugar moiety comprising a 4'-CH2-O-2' bridge. This structure effectively "locks" the ribose in the 3'-endo structural conformation. The addition of locked nucleic acids to siRNAs has been shown to increase siRNA stability in serum, and to reduce off- 15 target effects (Elmen, J. et al., (2005) Nucleic Acids Research 33(1):439-447; Mook, OR. et al., (2007) Mol Canc Ther 6(3):833-843; Grunweller, A. et al., (2003) Nucleic Acids Research 31(12):3185-3193). Examples of bicyclic nucleosides for use in the polynucleotides of the disclosure include without limitation nucleosides comprising a bridge between the 4’ and the 2' ribosyl ring atoms. In certain embodiments, the 20 antisense polynucleotide agents of the disclosure include one or more bicyclic nucleosides comprising a 4' to 2' bridge. Examples of such 4' to 2' bridged bicyclic nucleosides, include but are not limited to 4'-(CH2)—O-2' (LNA); 4'-(CH2)—S-2'; 4'-(CH2)2—O-2' (ENA); 4'-CH(CH3)—O-2' (also referred to as “constrained ethyl” or “cEt”) and 4'-CH(CH2OCH3)—O-2' (and analogs thereof; see, e.g., U.S. Pat. No. 25   7,399,845); 4'-C(CH3)(CH3)—O-2' (and analogs thereof; see e.g., US Patent No. 8,278,283); 4'-CH2—N(OCH3)-2' (and analogs thereof; see e.g., US Patent No. 8,278,425);  4'-CH2—O—N(CH3)-2' (see, e.g.,U.S. Patent Publication No. 2004 / 0171570); 4'-CH2—N(R)—O-2', wherein R is H, C1-C12 alkyl, or a protecting group (see, e.g., U.S. Pat. No. 7,427,672);  4'-CH2—C(H)(CH3)-2' (see, e.g., 30 Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118-134); and 4'-CH2—C(=CH2)-2' (and analogs thereof; see, e.g., US Patent No. 8,278,426). The entire contents of each of the foregoing are hereby incorporated herein by reference. 2026204572  15 Jun 2026 Additional representative U.S. Patents and US Patent Publications that teach the preparation of locked nucleic acid nucleotides include, but are not limited to, the following: U.S. Patent Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484;  7,053,207;  7,034,133;7,084,125;  7,399,845;  7,427,672;  7,569,686; 5   7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278,283; US 2008 / 0039618; and US 2009 / 0012281, the entire contents of each of which are hereby incorporated herein by reference. Any of the foregoing bicyclic nucleosides can be prepared having one or more stereochemical sugar configurations including for example a-L-ribofuranose and P—D-10 ribofuranose (see WO 99 / 14226). A RNAi agent of the disclosure can also be modified to include one or more constrained ethyl nucleotides. As used herein, a "constrained ethyl nucleotide" or "cEt" is a locked nucleic acid comprising a bicyclic sugar moiety comprising a 4'-CH(CH3)-0-2' bridge. In one embodiment, a constrained ethyl nucleotide is in the S conformation 15 referred to herein as “S-cEt.” A RNAi agent of the disclosure may also include one or more “conformationally restricted nucleotides” (“CRN”). CRN are nucleotide analogs with a linker connecting the C2’and C4’ carbons of ribose or the C3 and -C5‘ carbons of ribose. CRN lock the ribose ring into a stable conformation and increase the hybridization affinity to mRNA. 20 The linker is of sufficient length to place the oxygen in an optimal position for stability and affinity resulting in less ribose ring puckering. Representative publications that teach the preparation of certain of the above noted CRN include, but are not limited to, US Patent Publication No. 2013 / 0190383; and PCT publication WO 2013 / 036868, the entire contents of each of which are hereby 25 incorporated herein by reference. In some embodiments, a RNAi agent of the disclosure comprises one or more monomers that are UNA (unlocked nucleic acid) nucleotides. UNA is unlocked acyclic nucleic acid, wherein any of the bonds of the sugar has been removed, forming an unlocked "sugar" residue. In one example, UNA also encompasses monomer with bonds 30 between C1'-C4' have been removed (i.e. the covalent carbon-oxygen-carbon bond between the C1' and C4' carbons). In another example, the C2'-C3' bond (i.e. the covalent carbon-carbon bond between the C2' and C3' carbons) of the sugar has been 2026204572  15 Jun 2026 removed (see Nuc. Acids Symp. Series, 52, 133-134 (2008) and Fluiter et al., Mol. Biosyst., 2009, 10, 1039 hereby incorporated by reference). Representative U.S. publications that teach the preparation of UNA include, but are not limited to, US Patent No. 8,314,227; and US Patent Publication Nos. 5   2013 / 0096289; 2013 / 0011922; and 2011 / 0313020, the entire contents of each of which are hereby incorporated herein by reference. Potentially stabilizing modifications to the ends of RNA molecules can include N- (acetylaminocaproyl)-4-hydroxyprolinol (Hyp-C6-NHAc), N-(caproyl-4-hydroxyprolinol (Hyp-C6), N-(acetyl-4-hydroxyprolinol (Hyp-NHAc), thymidine-2'-0-10 deoxythymidine (ether), N-(aminocaproyl)-4-hydroxyprolinol (Hyp-C6-amino), 2-docosanoyl-uridine-3"- phosphate, inverted base dT(idT) and others. Disclosure of this modification can be found in PCT Publication No. WO 2011 / 005861. Other modifications of a RNAi agent of the disclosure include a 5’ phosphate or 5’ phosphate mimic, e.g., a 5’-terminal phosphate or phosphate mimic on the antisense 15 strand of a RNAi agent. Suitable phosphate mimics are disclosed in, for example US Patent Publication No. 2012 / 0157511, the entire contents of which are incorporated herein by reference. A. Modified RNAi agents Comprising Motifs of the Disclosure In certain aspects of the disclosure, the double-stranded RNAi agents of the 20 disclosure include agents with chemical modifications as disclosed, for example, in WO 2013 / 075035, filed on November 16, 2012, the entire contents of which are incorporated herein by reference. As shown herein and in PCT Publication No. WO 2013 / 075035, a superior result may be obtained by introducing one or more motifs of three identical modifications on three consecutive nucleotides into a sense strand and / or antisense 25 strand of an RNAi agent, particularly at or near the cleavage site. In some embodiments, the sense strand and antisense strand of the RNAi agent may otherwise be completely modified. The introduction of these motifs interrupts the modification pattern, if present, of the sense and / or antisense strand. The RNAi agent may be optionally conjugated with a C16 ligand, for instance on the sense strand. The RNAi agent may be optionally 30 modified with a (S)-glycol nucleic acid (GNA) modification, for instance on one or more residues of the antisense strand. The resulting RNAi agents present superior gene silencing activity. 2026204572  15 Jun 2026 More specifically, it has been surprisingly discovered that when the sense strand and antisense strand of the double-stranded RNAi agent are completely modified to have one or more motifs of three identical modifications on three consecutive nucleotides at or near the cleavage site of at least one strand of an RNAi agent, the gene silencing 5 acitivity of the RNAi agent was superiorly enhanced. Accordingly, the disclosure provides double stranded RNAi agents capable of inhibiting the expression of a target gene (i.e., an APP gene) in vivo. The RNAi agent comprises a sense strand and an antisense strand. Each strand of the RNAi agent may range from 12-30 nucleotides in length. For example, each strand may be between 14-30 10 nucleotides in length, 17-30 nucleotides in length, 25-30 nucleotides in length, 27-30 nucleotides in length, 17-23 nucleotides in length, 17-21 nucleotides in length, 17-19 nucleotides in length, 19-25 nucleotides in length, 19-23 nucleotides in length, 19-21 nucleotides in length, 21-25 nucleotides in length, or 21-23 nucleotides in length. The sense strand and antisense strand typically form a duplex double stranded 15 RNA (“dsRNA”), also referred to herein as an “RNAi agent.” The duplex region of an RNAi agent may be 12-30 nucleotide pairs in length. For example, the duplex region can be between 14-30 nucleotide pairs in length, 17-30 nucleotide pairs in length, 27-30 nucleotide pairs in length, 17-23 nucleotide pairs in length, 17-21 nucleotide pairs in length, 17-19 nucleotide pairs in length, 19-25 nucleotide pairs in length, 19-23 20 nucleotide pairs in length, 19-21 nucleotide pairs in length, 21-25 nucleotide pairs in length, or 21-23 nucleotide pairs in length. In another example, the duplex region is selected from 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27 nucleotides in length. In one embodiment, the RNAi agent may contain one or more overhang regions and / or capping groups at the 3’-end, 5’-end, or both ends of one or both strands. The 25 overhang can be 1-6 nucleotides in length, for instance 2-6 nucleotides in length, 1-5 nucleotides in length, 2-5 nucleotides in length, 1-4 nucleotides in length, 2-4 nucleotides in length, 1-3 nucleotides in length, 2-3 nucleotides in length, or 1-2 nucleotides in length. The overhangs can be the result of one strand being longer than the other, or the result of two strands of the same length being staggered. The overhang 30 can form a mismatch with the target mRNA or it can be complementary to the gene sequences being targeted or can be another sequence. The first and second strands can also be joined, e.g., by additional bases to form a hairpin, or by other non-base linkers. 2026204572  15 Jun 2026 In one embodiment, the nucleotides in the overhang region of the RNAi agent can each independently be a modified or unmodified nucleotide including, but no limited to 2’-sugar modified, such as, 2-F, 2’-Omethyl, thymidine (T), and any combinations thereof. 5          For example, TT can be an overhang sequence for either end on either strand. The overhang can form a mismatch with the target mRNA or it can be complementary to the gene sequences being targeted or can be another sequence. The 5’- or 3’- overhangs at the sense strand, antisense strand or both strands of the RNAi agent may be phosphorylated. In some embodiments, the overhang region(s) 10 contains two nucleotides having a phosphorothioate between the two nucleotides, where the two nucleotides can be the same or different. In one embodiment, the overhang is present at the 3’-end of the sense strand, antisense strand, or both strands. In one embodiment, this 3’-overhang is present in the antisense strand. In one embodiment, this 3’-overhang is present in the sense strand. 15          The RNAi agent may contain only a single overhang, which can strengthen the interference activity of the RNAi, without affecting its overall stability. For example, the single-stranded overhang may be located at the 3'-terminal end of the sense strand or, alternatively, at the 3'-terminal end of the antisense strand. The RNAi may also have a blunt end, located at the 5’-end of the antisense strand (or the 3’-end of the sense strand) 20 or vice versa. Generally, the antisense strand of the RNAi has a nucleotide overhang at the 3’-end, and the 5’-end is blunt. While not wishing to be bound by theory, the asymmetric blunt end at the 5’-end of the antisense strand and 3’-end overhang of the antisense strand favor the guide strand loading into RISC process. In one embodiment, the RNAi agent is a double ended bluntmer of 19 25 nucleotides in length, wherein the sense strand contains at least one motif of three 2’-F modifications on three consecutive nucleotides at positions 7, 8, 9 from the 5’end. The antisense strand contains at least one motif of three 2’-O-methyl modifications on three consecutive nucleotides at positions 11, 12, 13 from the 5’end. In another embodiment, the RNAi agent is a double ended bluntmer of 20 30 nucleotides in length, wherein the sense strand contains at least one motif of three 2’-F modifications on three consecutive nucleotides at positions 8, 9, 10 from the 5’end. The antisense strand contains at least one motif of three 2’-O-methyl modifications on three consecutive nucleotides at positions 11, 12, 13 from the 5’end. 2026204572  15 Jun 2026 In yet another embodiment, the RNAi agent is a double ended bluntmer of 21 nucleotides in length, wherein the sense strand contains at least one motif of three 2’-F modifications on three consecutive nucleotides at positions 9, 10, 11 from the 5’end. The antisense strand contains at least one motif of three 2’-O-methyl modifications on three 5 consecutive nucleotides at positions 11, 12, 13 from the 5’end. In one embodiment, the RNAi agent comprises a 21 nucleotide sense strand and a 23 nucleotide antisense strand, wherein the sense strand contains at least one motif of three 2’-F modifications on three consecutive nucleotides at positions 9, 10, 11 from the 5’end; the antisense strand contains at least one motif of three 2’-O-methyl 10 modifications on three consecutive nucleotides at positions 11, 12, 13 from the 5’end, wherein one end of the RNAi agent is blunt, while the other end comprises a 2 nucleotide overhang. Preferably, the 2 nucleotide overhang is at the 3’-end of the antisense strand. When the 2 nucleotide overhang is at the 3’-end of the antisense strand, there may be two phosphorothioate internucleotide linkages between the terminal three 15 nucleotides, wherein two of the three nucleotides are the overhang nucleotides, and the third nucleotide is a paired nucleotide next to the overhang nucleotide. In one embodiment, the RNAi agent additionally has two phosphorothioate internucleotide linkages between the terminal three nucleotides at both the 5’-end of the sense strand and at the 5’-end of the antisense strand. In one embodiment, every nucleotide in the 20 sense strand and the antisense strand of the RNAi agent, including the nucleotides that are part of the motifs are modified nucleotides. In one embodiment each residue is independently modified with a 2’-O-methyl or 3’-fluoro, e.g., in an alternating motif. Optionally, the RNAi agent further comprises a ligand (optionally a C16 ligand). In one embodiment, the RNAi agent comprises a sense and an antisense strand, 25 wherein the sense strand is 25-30 nucleotide residues in length, wherein starting from the 5' terminal nucleotide (position 1) positions 1 to 23 of the first strand comprise at least 8 ribonucleotides; the antisense strand is 36-66 nucleotide residues in length and, starting from the 3' terminal nucleotide, comprises at least 8 ribonucleotides in the positions paired with positions 1- 23 of sense strand to form a duplex; wherein at least 30 the 3 ' terminal nucleotide of antisense strand is unpaired with sense strand, and up to 6 consecutive 3' terminal nucleotides are unpaired with sense strand, thereby forming a 3' single stranded overhang of 1-6 nucleotides; wherein the 5' terminus of antisense strand comprises from 10-30 consecutive nucleotides which are unpaired with sense strand, 2026204572  15 Jun 2026 thereby forming a 10-30 nucleotide single stranded 5' overhang; wherein at least the sense strand 5' terminal and 3' terminal nucleotides are base paired with nucleotides of antisense strand when sense and antisense strands are aligned for maximum complementarity, thereby forming a substantially duplexed region between sense and 5 antisense strands; and antisense strand is sufficiently complementary to a target RNA along at least 19 ribonucleotides of antisense strand length to reduce target gene expression when the double stranded nucleic acid is introduced into a mammalian cell; and wherein the sense strand contains at least one motif of three 2’-F modifications on three consecutive nucleotides, where at least one of the motifs occurs at or near the 10 cleavage site. The antisense strand contains at least one motif of three 2’-O-methyl modifications on three consecutive nucleotides at or near the cleavage site. In one embodiment, the RNAi agent comprises sense and antisense strands, wherein the RNAi agent comprises a first strand having a length which is at least 25 and at most 29 nucleotides and a second strand having a length which is at most 30 15 nucleotides with at least one motif of three 2’-O-methyl modifications on three consecutive nucleotides at position 11, 12, 13 from the 5’ end; wherein the 3’ end of the first strand and the 5’ end of the second strand form a blunt end and the second strand is 1-4 nucleotides longer at its 3’ end than the first strand, wherein the duplex region region which is at least 25 nucleotides in length, and the second strand is sufficiently 20 complemenatary to a target mRNA along at least 19 nucleotide of the second strand length to reduce target gene expression when the RNAi agent is introduced into a mammalian cell, and wherein dicer cleavage of the RNAi agent preferentially results in an siRNA comprising the 3’ end of the second strand, thereby reducing expression of the target gene in the mammal. Optionally, the RNAi agent further comprises a ligand. 25          In one embodiment, the sense strand of the RNAi agent contains at least one motif of three identical modifications on three consecutive nucleotides, where one of the motifs occurs at the cleavage site in the sense strand. In one embodiment, the antisense strand of the RNAi agent can also contain at least one motif of three identical modifications on three consecutive nucleotides, where 30 one of the motifs occurs at or near the cleavage site in the antisense strand. For an RNAi agent having a duplex region of 17-23 nucleotide in length, the cleavage site of the antisense strand is typically around the 10, 11 and 12 positions from the 5’-end. Thus the motifs of three identical modifications may occur at the 9, 10, 11 2026204572  15 Jun 2026 positions; 10, 11, 12 positions; 11, 12, 13 positions; 12, 13, 14 positions; or 13, 14, 15 positions of the antisense strand, the count starting from the 1st nucleotide from the 5’-end of the antisense strand, or, the count starting from the 1st paired nucleotide within the duplex region from the 5’- end of the antisense strand. The cleavage site in the 5 antisense strand may also change according to the length of the duplex region of the RNAi from the 5’-end. The sense strand of the RNAi agent may contain at least one motif of three identical modifications on three consecutive nucleotides at the cleavage site of the strand; and the antisense strand may have at least one motif of three identical 10 modifications on three consecutive nucleotides at or near the cleavage site of the strand. When the sense strand and the antisense strand form a dsRNA duplex, the sense strand and the antisense strand can be so aligned that one motif of the three nucleotides on the sense strand and one motif of the three nucleotides on the antisense strand have at least one nucleotide overlap, i.e., at least one of the three nucleotides of the motif in the sense 15 strand forms a base pair with at least one of the three nucleotides of the motif in the antisense strand. Alternatively, at least two nucleotides may overlap, or all three nucleotides may overlap. In one embodiment, the sense strand of the RNAi agent may contain more than one motif of three identical modifications on three consecutive nucleotides. The first 20 motif may occur at or near the cleavage site of the strand and the other motifs may be a wing modification. The term “wing modification” herein refers to a motif occurring at another portion of the strand that is separated from the motif at or near the cleavage site of the same strand. The wing modification is either adajacent to the first motif or is separated by at least one or more nucleotides. When the motifs are immediately adjacent 25 to each other then the chemistry of the motifs are distinct from each other and when the motifs are separated by one or more nucleotide than the chemistries can be the same or different. Two or more wing modifications may be present. For instance, when two wing modifications are present, each wing modification may occur at one end relative to the first motif which is at or near cleavage site or on either side of the lead motif. 30          Like the sense strand, the antisense strand of the RNAi agent may contain more than one motifs of three identical modifications on three consecutive nucleotides, with at least one of the motifs occurring at or near the cleavage site of the strand. This antisense 2026204572  15 Jun 2026 strand may also contain one or more wing modifications in an alignment similar to the wing modifications that may be present on the sense strand. In one embodiment, the wing modification on the sense strand or antisense strand of the RNAi agent typically does not include the first one or two terminal nucleotides at 5 the 3’-end, 5’-end or both ends of the strand. In another embodiment, the wing modification on the sense strand or antisense strand of the RNAi agent typically does not include the first one or two paired nucleotides within the duplex region at the 3’-end, 5’-end or both ends of the strand. When the sense strand and the antisense strand of the RNAi agent each contain at 10 least one wing modification, the wing modifications may fall on the same end of the duplex region, and have an overlap of one, two or three nucleotides. When the sense strand and the antisense strand of the RNAi agent each contain at least two wing modifications, the sense strand and the antisense strand can be so aligned that two modifications each from one strand fall on one end of the duplex region, having 15 an overlap of one, two or three nucleotides; two modifications each from one strand fall on the other end of the duplex region, having an overlap of one, two or three nucleotides; two modifications one strand fall on each side of the lead motif, having an overlap of one, two or three nucleotides in the duplex region. 20          In one embodiment, the RNAi agent comprises mismatch(es) with the target, within the duplex, or combinations thereof. The mistmatch may occur in the overhang region or the duplex region. The base pair may be ranked on the basis of their propensity to promote dissociation or melting (e.g., on the free energy of association or dissociation of a particular pairing, the simplest approach is to examine the pairs on an individual 25 pair basis, though next neighbor or similar analysis can also be used). In terms of promoting dissociation: A:U is preferred over G:C; G:U is preferred over G:C; and I:C is preferred over G:C (I=inosine). Mismatches, e.g., non-canonical or other than canonical pairings (as described elsewhere herein) are preferred over canonical (A:T, A:U, G:C) pairings; and pairings which include a universal base are preferred over 30 canonical pairings. In one embodiment, the RNAi agent comprises at least one of the first 1, 2, 3, 4, or 5 base pairs within the duplex regions from the 5’- end of the antisense strand independently selected from the group of: A:U, G:U, I:C, and mismatched pairs, e.g., 2026204572  15 Jun 2026 non-canonical or other than canonical pairings or pairings which include a universal base, to promote the dissociation of the antisense strand at the 5’-end of the duplex. In one embodiment, the nucleotide at the 1 position within the duplex region from the 5’-end in the antisense strand is selected from the group consisting of A, dA, 5 dU, U, and dT. Alternatively, at least one of the first 1, 2 or 3 base pair within the duplex region from the 5’- end of the antisense strand is an AU base pair. For example, the first base pair within the duplex region from the 5’- end of the antisense strand is an AU base pair. In another embodiment, the nucleotide at the 3’-end of the sense strand is deoxy-10 thymine (dT). In another embodiment, the nucleotide at the 3’-end of the antisense strand is deoxy-thymine (dT). In one embodiment, there is a short sequence of deoxythymine nucleotides, for example, two dT nucleotides on the 3’-end of the sense and / or antisense strand. In one embodiment, the sense strand sequence may be represented by formula 15    (I): 5' np-Na-(X X X )i-Nb-Y Y Y -Nb-(Z Z Z )j-Na-nq 3' (I) wherein: i and j are each independently 0 or 1; p and q are each independently 0-6; 20          each Na independently represents an oligonucleotide sequence comprising 0-25 modified nucleotides, each sequence comprising at least two differently modified nucleotides; each Nb independently represents an oligonucleotide sequence comprising 0-10 modified nucleotides; 25          each np and nq independently represent an overhang nucleotide; wherein Nb and Y do not have the same modification; and XXX, YYY and ZZZ each independently represent one motif of three identical modifications on three consecutive nucleotides. Preferably YYY is all 2’-F modified nucleotides. 30          In one embodiment, the Na and / or Nb comprise modifications of alternating pattern. In one embodiment, the YYY motif occurs at or near the cleavage site of the sense strand. For example, when the RNAi agent has a duplex region of 17-23 2026204572  15 Jun 2026 nucleotides in length, the YYY motif can occur at or the vicinity of the cleavage site (e.g.: can occur at positions 6, 7, 8, 7, 8, 9, 8, 9, 10, 9, 10, 11, 10, 11,12 or 11, 12, 13) of - the sense strand, the count starting from the 1st nucleotide, from the 5’-end; or optionally, the count starting at the 1st paired nucleotide within the duplex region, from 5 the 5’- end. In one embodiment, i is 1 and j is 0, or i is 0 and j is 1, or both i and j are 1. The sense strand can therefore be represented by the following formulas: 5' np-Na-YYY-Nb-ZZZ-Na-nq 3' (Ib); 5' np-Na-XXX-Nb-YYY-Na-nq 3' (Ic); or 10          5' np-Na-XXX-Nb-YYY-Nb-ZZZ-Na-nq 3' (Id). When the sense strand is represented by formula (Ib), Nb represents an oligonucleotide sequence comprising 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each Na independently can represent an oligonucleotide sequence comprising 220, 2-15, or 2-10 modified nucleotides. 15          When the sense strand is represented as formula (Ic), Nb represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each Na can independently represent an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. When the sense strand is represented as formula (Id), each Nb independently 20 represents an oligonucleotide sequence comprising 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Preferably, Nb is 0, 1, 2, 3, 4, 5 or 6. Each Na can independently represent an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. Each of X, Y and Z may be the same or different from each other. In other embodiments, i is 0 and j is 0, and the sense strand may be represented 25 by the formula: 5' np-Na-YYY- Na-nq 3' (Ia). When the sense strand is represented by formula (Ia), each Na independently can represent an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 30          In one embodiment, the antisense strand sequence of the RNAi may be represented by formula (II): 5' nq’-Na‘-(Z’Z'Z‘)k-Nb‘-Y'Y'Y'-Nb'-(X'X'X')i-N‘a-np‘ 3'      (II) wherein: 2026204572  15 Jun 2026 k and l are each independently 0 or 1; p’ and q’ are each independently 0-6; each Na’ independently represents an oligonucleotide sequence comprising 0-25 modified nucleotides, each sequence comprising at least two differently modified 5 nucleotides; each Nb‘ independently represents an oligonucleotide sequence comprising 0-10 modified nucleotides; each np’ and nq‘ independently represent an overhang nucleotide; wherein Nb’ and Y’ do not have the same modification; 10 and X‘X‘X‘, Y‘Y‘Y‘ and Z‘Z‘Z‘ each independently represent one motif of three identical modifications on three consecutive nucleotides. In one embodiment, the Na’ and / or Nb’ comprise modifications of alternating pattern. The Y‘Y‘Y' motif occurs at or near the cleavage site of the antisense strand. For 15 example, when the RNAi agent has a duplex region of 17-23nucleotidein length, the Y‘Y‘Y‘ motif can occur at positions 9, 10, 11, 10, 11, 12; 11, 12, 13; 12, 13, 14 ; or 13, 14, 15 of the antisense strand, with the count starting from the 1st nucleotide, from the 5’-end; or optionally, the count starting at the 1st paired nucleotide within the duplex region, from the 5’- end. Preferably, the Y‘Y‘Y‘ motif occurs at positions 11, 12, 13. 20          In one embodiment, Y‘Y‘Y‘ motif is all 2’-OMe modified nucleotides. In one embodiment, k is 1 and l is 0, or k is 0 and l is 1, or both k and l are 1. The antisense strand can therefore be represented by the following formulas: 5' nq’-Na'-Z‘Z‘Z'-Nb‘-Y‘Y‘Y‘-Na'-np’ 3'        (IIb); 5' nq’-Na'-Y‘Y‘Y‘-Nb‘-X‘X‘X‘-np’ 3' (IIc); or 25            5' nq’-Na'- Z‘Z'Z‘-Nb‘-Y‘Y‘Y‘-Nb‘- X‘X‘X‘-Na'-np’ 3' (IId). When the antisense strand is represented by formula (IIb), Nb’ represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each Na’ independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 30           When the antisense strand is represented as formula (IIc), Nb’ represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each Na’ independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 2026204572  15 Jun 2026 When the antisense strand is represented as formula (IId), each Nb’ independently represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each Na’ independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 5   Preferably, Nb is 0, 1, 2, 3, 4, 5 or 6. In other embodiments, k is 0 and l is 0 and the antisense strand may be represented by the formula: 5' np’-Na’-Y’Y’Y’- Na’-nq’ 3' (Ia). When the antisense strand is represented as formula (IIa), each Na’ independently 10 represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. Each of X', Y' and Z' may be the same or different from each other. Each nucleotide of the sense strand and antisense strand may be independently modified with LNA, HNA, CeNA, 2’-methoxyethyl, 2’-O-methyl, 2’-O-allyl, 2’-C-15 allyl, 2’-hydroxyl, or 2’-fluoro. For example, each nucleotide of the sense strand and antisense strand is independently modified with 2’-O-methyl or 2’-fluoro. Each X, Y, Z, X', Y' and Z', in particular, may represent a 2’-O-methyl modification or a 2’-fluoro modification. In one embodiment, the sense strand of the RNAi agent may contain YYY motif 20 occurring at 9, 10 and 11 positions of the strand when the duplex region is 21 nt, the count starting from the 1st nucleotide from the 5’-end, or optionally, the count starting at the 1st paired nucleotide within the duplex region, from the 5’- end; and Y represents 2’-F modification. The sense strand may additionally contain XXX motif or ZZZ motifs as wing modifications at the opposite end of the duplex region; and XXX and ZZZ each 25 independently represents a 2’-OMe modification or 2’-F modification. In one embodiment the antisense strand may contain Y'Y'Y' motif occurring at positions 11, 12, 13 of the strand, the count starting from the 1st nucleotide from the 5’-end, or optionally, the count starting at the 1st paired nucleotide within the duplex region, from the 5’- end; and Y' represents 2’-O-methyl modification. The antisense 30 strand may additionally contain X'X'X' motif or Z'Z'Z' motifs as wing modifications at the opposite end of the duplex region; and X'X'X' and Z'Z'Z' each independently represents a 2’-OMe modification or 2’-F modification. 2026204572  15 Jun 2026 The sense strand represented by any one of the above formulas (Ia), (Ib), (Ic), and (Id) forms a duplex with a antisense strand being represented by any one of formulas (IIa), (IIb), (IIc), and (IId), respectively. Accordingly, the RNAi agents for use in the methods of the disclosure may 5 comprise a sense strand and an antisense strand, each strand having 14 to 30 nucleotides, the RNAi duplex represented by formula (III): sense:        5' np -Na-(X X X)i-Nb- Y Y Y -Nb-(Z Z Z)j-Na-nq 3' antisense:     3' np’-Na’-(X’X'X')k-Nb’-YTT'-Nb’-(Z'Z'Z>^^    5' (III) 10          wherein: i, j, k, and l are each independently 0 or 1; p, p', q, and q' are each independently 0-6; each Na and Na’ independently represents an oligonucleotide sequence comprising 0-25 modified nucleotides, each sequence comprising at least two differently 15 modified nucleotides; each Nb and Nb’ independently represents an oligonucleotide sequence comprising 0-10 modified nucleotides; wherein each np’, np, nq’, and nq, each of which may or may not be present, independently 20 represents an overhang nucleotide; and XXX, YYY, ZZZ, X'X'X', Y'Y'Y', and Z'Z'Z' each independently represent one motif of three identical modifications on three consecutive nucleotides. In one embodiment, i is 0 and j is 0; or i is 1 and j is 0; or i is 0 and j is 1; or both i and j are 0; or both i and j are 1. In another embodiment, k is 0 and l is 0; or k is 1 and l 25 is 0; k is 0 and l is 1; or both k and l are 0; or both k and l are 1. Exemplary combinations of the sense strand and antisense strand forming a RNAi duplex include the formulas below: 5' np- Na-Y Y Y -Na-nq 3' 3' np’-Na’-Y'Y'Y' -Na’nq’ 5' 30                             (IIIa) 5' np-Na-Y Y Y -Nb -Z Z Z -Na-nq 3' 3' np’-Na’-Y'Y'Y'-Nb’-Z'Z'Z'-Na’nq’ 5' (IIIb) 2026204572  15 Jun 2026 5' np-Na- X X X -Nb -Y Y Y - Na-nq 3' 3' np’-Na’-X’X’X’-Nb-Y’Y'Y'-Na’-nq’ 5' (IIIc) 5' np-Na-X X X -Nb-Y Y Y -Nb- Z Z Z -Na-nq 3' 5            3' np’-Na’-X'X'X'-Nb-Y'Y'Y'-Nb-Z'Z'Z'-Na-nq’ 5' (IIId) When the RNAi agent is represented by formula (IIIa), each Na independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 10          When the RNAi agent is represented by formula (IIIb), each Nb independently represents an oligonucleotide sequence comprising 1-10, 1-7, 1-5 or 1-4 modified nucleotides. Each Na independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. When the RNAi agent is represented as formula (IIIc), each Nb, Nb’ 15 independently represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0modified nucleotides. Each Na independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. When the RNAi agent is represented as formula (IIId), each Nb, Nb’ independently represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 20   0-5, 0-4, 0-2 or 0 modified nucleotides. Each Na, Na’ independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. Each of Na, Na’, Nb and Nb’ independently comprises modifications of alternating pattern. In one embodiment, when the RNAi agent is represented by formula (IIId), the Na modifications are 2‘-O-methyl or 2‘-fluoro modifications. In another embodiment, 25 when the RNAi agent is represented by formula (IIId), the Na modifications are 2'-O-methyl or 2'-fluoro modifications and np' >0 and at least one np' is linked to a neighboring nucleotide a via phosphorothioate linkage. In yet another embodiment, when the RNAi agent is represented by formula (IIId), the Na modifications are 2'-O-methyl or 2'-fluoro modifications , np' >0 and at least one np' is linked to a neighboring 30 nucleotide via phosphorothioate linkage, and the sense strand is conjugated to one or more C16 (or related) moieties attached through a bivalent or trivalent branched linker (described below). In another embodiment, when the RNAi agent is represented by formula (IIId), the Na modifications are 2'-O-methyl or 2'-fluoro modifications , np' >0 2026204572  15 Jun 2026 and at least one np‘ is linked to a neighboring nucleotide via phosphorothioate linkage, the sense strand comprises at least one phosphorothioate linkage, and the sense strand is conjugated to one or more C16 (or related) moieties, optionally attached through a bivalent or trivalent branched linker. 5          In one embodiment, when the RNAi agent is represented by formula (IIIa), the Na modifications are 2‘-O-methyl or 2‘-fluoro modifications , np‘ >0 and at least one np‘ is linked to a neighboring nucleotide via phosphorothioate linkage, the sense strand comprises at least one phosphorothioate linkage, and the sense strand is conjugated to one or more C16 (or related) moieties attached through a bivalent or trivalent branched 10 linker. In one embodiment, the RNAi agent is a multimer containing at least two duplexes represented by formula (III), (IIIa), (IIIb), (IIIc), and (IIId), wherein the duplexes are connected by a linker. The linker can be cleavable or non-cleavable. Optionally, the multimer further comprises a ligand. Each of the duplexes can target the 15 same gene or two different genes; or each of the duplexes can target same gene at two different target sites. In one embodiment, the RNAi agent is a multimer containing three, four, five, six or more duplexes represented by formula (III), (IIIa), (IIIb), (IIIc), and (IIId), wherein the duplexes are connected by a linker. The linker can be cleavable or non-20 cleavable. Optionally, the multimer further comprises a ligand. Each of the duplexes can target the same gene or two different genes; or each of the duplexes can target same gene at two different target sites. In one embodiment, two RNAi agents represented by formula (III), (IIIa), (IIIb), (IIIc), and (IIId) are linked to each other at the 5’ end, and one or both of the 3’ ends and 25 are optionally conjugated to to a ligand. Each of the agents can target the same gene or two different genes; or each of the agents can target same gene at two different target sites. Various publications describe multimeric RNAi agents that can be used in the methods of the disclosure. Such publications include WO2007 / 091269, US Patent No. 30   7858769, WO2010 / 141511, WO2007 / 117686, WO2009 / 014887 and WO2011 / 031520 the entire contents of each of which are hereby incorporated herein by reference. In certain embodiments, the RNAi agents of the disclosure may include GalNAc ligands, 2026204572  15 Jun 2026 even if such GalNAc ligands are currently projected to be of limited value for the preferred intrathecal / CNS delivery route(s) of the instant disclosure. As described in more detail below, the RNAi agent that contains conjugations of one or more carbohydrate moieties to a RNAi agent can optimize one or more properties 5 of the RNAi agent. In many cases, the carbohydrate moiety will be attached to a modified subunit of the RNAi agent. For example, the ribose sugar of one or more ribonucleotide subunits of a dsRNA agent can be replaced with another moiety, e.g., a non-carbohydrate (preferably cyclic) carrier to which is attached a carbohydrate ligand. A ribonucleotide subunit in which the ribose sugar of the subunit has been so replaced is 10 referred to herein as a ribose replacement modification subunit (RRMS). A cyclic carrier may be a carbocyclic ring system, i.e., all ring atoms are carbon atoms, or a heterocyclic ring system, i.e., one or more ring atoms may be a heteroatom, e.g., nitrogen, oxygen, sulfur. The cyclic carrier may be a monocyclic ring system, or may contain two or more rings, e.g. fused rings. The cyclic carrier may be a fully saturated ring system, or it may 15 contain one or more double bonds. The ligand may be attached to the polynucleotide via a carrier. The carriers include (i) at least one “backbone attachment point,” preferably two “backbone attachment points” and (ii) at least one “tethering attachment point.” A “backbone attachment point” as used herein refers to a functional group, e.g. a hydroxyl group, or 20 generally, a bond available for, and that is suitable for incorporation of the carrier into the backbone, e.g., the phosphate, or modified phosphate, e.g., sulfur containing, backbone, of a ribonucleic acid. A “tethering attachment point” (TAP) in some embodiments refers to a constituent ring atom of the cyclic carrier, e.g., a carbon atom or a heteroatom (distinct from an atom which provides a backbone attachment point), that 25 connects a selected moiety. The moiety can be, e.g., a carbohydrate, e.g. monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide and polysaccharide. Optionally, the selected moiety is connected by an intervening tether to the cyclic carrier. Thus, the cyclic carrier will often include a functional group, e.g., an amino group, or generally, provide a bond, that is suitable for incorporation or tethering 30 of another chemical entity, e.g., a ligand to the constituent ring. The RNAi agents may be conjugated to a ligand via a carrier, wherein the carrier can be cyclic group or acyclic group; preferably, the cyclic group is selected from pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, 2026204572  15 Jun 2026 piperazinyl, [1,3]dioxolane, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuryl and and decalin; preferably, the acyclic group is selected from serinol backbone or diethanolamine backbone. 5          In certain specific embodiments, the RNAi agent for use in the methods of the disclosure is an agent selected from the group of agents listed in any one of Tables 2A, 2B, 3, 5A, 5B, 6, 9, 10-15, 16A, 16B, and 26. These agents may further comprise a ligand. IV. APP Knockdown to Treat APP-Associated Diseases 10          Certain aspects of the instant disclosure are directed to RNAi agent-mediated knockdown of APP-associated diseases or disorders, which include CAA and AD, including hereditary CAA and EOFAD, as well as sporadic and / or late onset AD. Hereditary CAA (hCAA) is a vascular proteinopathy, for which the amyloid therapeutic hypothesis is relatively straightforward and clinically testable. It is a 15 devastating and rare disease, with no existing therapy. Both biochemical and imaging biomarkers exist for clinical validation of anti-APP siRNA-mediated treatment of hCAA. One particular type of hCAA contemplated for treatment using the RNAi agents of the instant disclosure is “Dutch type” Ap hCAA, which has an estimated patient 20 population in the hundreds, primarily located in the Netherlands and Western Australia. Among APP-associated diseases, hCAA is unique in being purely vascular: in CAA, amyloid fibrils deposit in arterioles and capillaries of CNS parenchyma and leptomeninges, leading to cognitive decline due to cerebral ischemia and microhemorrhages in subjects suffering from CAA. CAA is present in greater than 80% 25 of all AD subjects (with 25% of AD subjects having moderate-severe CAA), and the incidence of CAA rises with the age of a subject, at approximately 50% incidence in elderly over 70 years of age. The following are exemplary manifestations of hereditary CAA: Amyloid-beta - Sporadic CAA, HCHWA-Dutch and Italian type EOFAD, 30               LOAD, Trisomy 21 ABri - Familial British Dementia ADan - Familial Danish Dementia 2026204572  15 Jun 2026 Cystatin C - HCHWA-Icelandic type (HCHWA-Hereditary cerebral hemorrhage with amyloidosis) Gelsolin - Familial Amyloidosis-Finnish type Prion protein - Prion disease 5              Transthyretin - Hereditary systemic amyloidosis As noted above, Ap-hCAA (aka APP-hCAA) is a rapidly progressive, dementing disease associated with intracerebral hemorrhage. Known indications of CAA include both APP-hCAA and sporadic CAA. Possible additional CAA indications include: CAA associated with EOFAD (PSEN1; APP; PSEN2); CAA associated with Down syndrome; 10 and CAA associated with late-onset Alzheimer’s disease (for which prevalence is common, as noted above). For APP-hCAA as an indication, the prevalence of APP-hCAA is not known; however, pure APP-hCAA is less common than EOFAD (Dutch type hCAA (involving an APP E693Q mutation) has been reported in several hundred individuals). Typically, 15 onset of APP-hCAA symptoms occur from age 35-45; and APP-hCAA typically progresses to serious CVA within 2-5 years, resulting in a peak age at death from CVA at age 55. Sporadic CAA as an indication exhibits relatively high prevalence: it is the common cause of lobar intracerebral hemorrhage (ICH) in the elderly. It is also a rapidly 20 progressive disease, with 86 (36%) of 316 patients developed recurrent ICH over a mean follow up time of 5 years (Van Etten et al. 2016 Neurology). Cumulative dementia incidence in sporadic CAA was observed in one study to be 14% at 1 year and 73% at 5 years (Xiong et al. 2017 J Cerebr Blood Flow Metab). Sporadic CAA also overlaps extensively with AD, as advanced CAA has been identified as present in approximately 25   25% of AD brains; however, less than 50% of CAA cases actually meet the pathological criteria for AD. To assess the efficacy of APP knockdown in a subject treated with a RNAi agent of the instant disclosure, it is expressly contemplated that soluble forms of APP, particularly including APPa and APPp can serve as cerebrospinal fluid (CSF) 30 biomarkers for assessing APP knockdown efficiency. Amyloid-p production, elimination and deposition in CAA: converging evidence indicates that the major source of Ap is neuronal. It is generated by sequential cleavage of amyloid precursor protein (APP) by p— and Y—secretases, in proportion to neuronal 2026204572  15 Jun 2026 activity. Ap is eliminated from the brain by four major pathways: (a) proteolytic degradation by endopeptidases (such as neprilysin and insulin degrading enzyme (IDE)); (b) receptor mediated clearance by cells in the brain parenchyma (microglia, astrocytes and to a lesser extent neurones); (c) active transport into the blood through the blood- 5 brain barrier (BBB); (d) elimination along the perivascular pathways by which interstitial fluid drains from the brain. Specialized carriers (e.g., ApoE) and / or receptor transport mechanisms (eg, the low density lipoprotein receptor (LDLR) and LDLR related protein (LRP1)) are involved in all major cellular clearance pathways. Vascular deposition is facilitated by factors that increase the Ap40:Ap42 ratio (while increased 10 Ap42 leads to oligomerization and amyloid plaques) and impede perivascular passage. As the clearance mechanisms fail with age, Ap is increasingly entrapped from the perivascular drainage pathways into the basement membranes of capillaries and arterioles of the brain leading to CAA. ApoE alleles have a differential effect on different molecular and cellular processes of Ap production, elimination and deposition 15 in a way that they either increase or decrease the risk of developing CAA (Charidimou A et al. J Neurol Neurosurg Psychiatry 2012; 83: 124-137). Sequential cleavage of APP occurs by two pathways. The APP family of proteins is noted as having large, biologically active, N-terminal ectodomains as well as a shorter C-terminus that contains a crucial Tyrosine-Glutamic Acid-Asparagine-Proline-20 Threonine-Tyrosine (YENPTY; SEQ ID NO: 3361) protein-sorting domain to which the adaptor proteins X11 and Fe65 bind. The resulting Ap peptide cleavage product starts within the ectodomain and continues into the transmembrane region. In one pathway, APP is cleaved by a-secretase followed by Y-secretase in performing nonamyloidogenic processing of APP. In a second pathway, amyloidogenic processing of APP involves 25 BACE1 cleavage followed by Y-secretase. Both processes generate soluble ectodomains (sAPPa and sAPPp) and identical intracellular C-terminal fragments (AICD; SEQ ID NO: 3362; Thinakaran and Koo. J. Biol. Chem. 283: 29615-19; Reinhard et al. The EMBO Journal, 24: 3996-4006; Walsh et al. Biochemical Society Transactions, 35: 416420; O'Brien and Wong. Annu Rev Neurosci. 34: 185-204). 30          CAA histopathology includes morphological changes of vessel walls (as revealed by haematoxylin-eosin staining) and Ap deposition. In leptomeningeal arterioles, significant structural alterations and double barreling have been observed (Charidimou et al. J Neurol Neurosurg Psychiatry 83: 124-137). In mild and moderate CAA, only 2026204572  15 Jun 2026 minimal structural changes have been detected; however, in advanced CAA, significant structural alterations have been detected, the most extreme of which is double barrelling (detachment and delamination of the outer part of the tunica media). A similar pathological range of CAA related changes in leptomeningeal arterioles have also been 5 observed using immunohistochemical detection of Ap. In mild CAA, patchy deposition of amyloid has been observed in the wall of examined vessels. Moderate CAA has shown more dense amyloid deposition which spans the entire vessel wall, while severe CAA has shown double balled vessels and endothelial involvement. Pathological findings of CAA in cortical arterioles has revealed progressive Ap deposition in 10 proportion to disease severity. Moderate CAA has shown pan-mural deposition of Ap along with Ap deposition in the surrounding brain parenchyma, while in severe CAA, a double barrel vessel has been observed, although this was less common as compared with leptomeningeal vessels (Charidimou et al.). Pathogenesis of CAA has also been examined. Amyloid beta produced by the 15 brain parenchyma is normally cleared via a perivascular route. Excessive production of Ap expression of specific CAA-prone Ap variants and delayed drainage of Ap has been observed to lead to amyloid deposition in the media of small arteries in the CNS. Soluble and insoluble amyloid fibrils have been identified as toxic to vascular smooth muscle and such fibrils replace these cells, disabling vascular reactivity. Further damage 20 to the endothelium has been observed to lead to microhemorrhages, microinfarcts and tissue destruction leading to dementia. Further progression has caused intracerebral hemorrhage, which has often been observed to be lethal. CAA has been observed to occur most frequently in the occipital lobe, less frequently in the hippocampus, cerebellum, basal ganglia, and not normally in the deep central grey matter, subcortical 25 white matter and brain stem (Charidimou et al.). Many potential outcome markers have been identified for performance of CAA human studies. In addition to symptomatic intracerebral haemorrhage, microbleeds, white matter hyperintensities (WMH) and amyloid imaging have been associated with disease severity and progression (Greenburg et al., Lancet Neurol 13: 419-28). 30          Available assays can also be used to detect soluble APP levels in human CSF samples. In particular, sAPPa and sAPPp are soluble forms of APP and have been identified as serving as PD (pharmacodynamic) biomarkers. Analytes have also been detected in non-human primate (NHP) CSF samples, and such assays can enable 2026204572  15 Jun 2026 efficacy studies in NHPs. Detection of AP40 / 42 / 38 peptides and Total tau / P181 Tau has also been described and is being implemented in the current studies. Imaging biomarkers are also available for CAA studies, as cerebrovascular function has been identified to reflect pathology in CAA. Imaging has been specifically 5 used to measure blood-oxygen-level-dependent (BOLD) signal after visual stimulation (Van Opstal et al., The lancet Neurology; 16(2); 2017; Peca S et al., Neurology. 2013; 81(19); Switzer A et al., NeuroImage Clinical; 2016). In performing BOLD fMRI in CAA subjects (assessing group blood oxygen level-dependent functional MRI responses for motor and visual tasks), reduced functional MRI activation has been observed for 10 patients with CAA. In particular, BOLD fMRI activity in visual cortex has been observed to be correlated with higher WMH volume and higher microbleed count (Peca et al., Neurology 2013; 81(19); Switzer et al. NeuroImage Clinical 2016). Animal models of CAA have also been described, which allow for determination of the effect of APP knockdown on CAA pathology and identification of translatable 15 biomarkers. In particular, multiple rodent models that express mutant human APP and show CAA pathology have been developed, including Tg-SwDI / NOS2- / -. In Tg-SwDI / NOS2- / - model mice, increased Ap levels have been identified with increased age of model mice. Perivascular hyperphosphorylated tau protein has also been associated with capillary amyloid not only in Tg-SwDI / NOS2- / - mice but also in human CAA-type 20   1 samples (Hall and Roberson. Brain Res Bull. 2012; 88(1): 3-12; Attems et al., Nephrology and Applied Neurobiology, 2011, 37, 75-93). A CVN mouse model of AD (APPSDI / NOS2 KO) also exhibited phenotypes including amyloid plaques in the hippocampus, thalamus and cortex, increased tissue inflammation and behavioral deficits. A transgenic rat model (harboring hAPP mutations) has also been developed. 25          Thus, APP has been identified as a target for hereditary cerebral amyloid angiopathy (CAA). Mutations in APP that have been reported to cause severe forms of CAA include A692G (Flemish), E693Q (Dutch), E693K (Italian), and D694N (Iowa). Meanwhile, mutations in APP that have been described to cause early onset AD include E665D, K670N, M671L (Swedish), T714A (Iranian), T714I (Austrian), V715M 30 (French), V715A (German), I716V (Florida), I716T, V717I (London), V717F, V717G and V717L. In particular, the APP E693Q (Dutch) mutation causes severe CAA with few parenchymal neurofibrillary tangles; E693Q increases amyloid beta aggregation and toxicity; E693K (Italian) is similar but E693G (Arctic), E693A and E693delta mutations 2026204572  15 Jun 2026 cause EOFAD with little or no CAA; and APP D694N (Iowa) causes severe CAA with typical AD pathology. In addition to the preceding point mutations, APP duplications that result in APP overexpression have also been identified to cause Ap deposition. Meanwhile, no known APP mutations have been described that prevent or delay APP-5 hCAA. In addition to APP mutants, Ap CAA has also been observed for PSEN1 (L282V) and PSEN2 (N141I) mutations. Meanwhile, ApoE s2 (independent of AD) and ApoE o4 (dependent on AD) have also been reported as risk factors for CAA (Rensink A et al., Brain Research Reviews, 43 (2) 2003). Certain aspects of the instant disclosure are directed towards targeting of APP for 10 knockdown in individuals having APP-hCAA. A need exists for such agents because there are currently no disease-modifying therapies for CAA. In certain embodiments, the RNAi agents of the instant disclosure should provide approximately 60-80% knockdown of both mutant and WT APP levels throughout the CNS. Humans with heterozygous APP mutations exist in the general population with 15 pLI score of 0.3; however, no Human APP knockout has been identified thus far. Pharmacological attempts to treat human CAA include the following: Ponezumab, an amyloid beta 40 antibody was studied by Pfizer in 36 individuals with late-onset CAA Three infusions of ponezumab or placebo over the course of 60 days were evaluated for changes in cerebrovascular 20             reactivity as measured by BOLD fMRI, as well as for cerebral edema, infarcts, Ap, cognitive change and other secondary outcomes. Ponezumab showed drug-placebo differences, but did not meet the primary endpoint. BAN2401- . Amyloid beta therapeutic antibodies delivered systemically were identified to be safe but also could cause local cerebral edema. In a 25             recent phase II 18-mo trial of BAN2401 in LOAD, the incidence of SAEs was 17.6% for placebo and 15.5% for the highest dose (10 mg / kg biweekly). Amyloid Related Imaging Abnormalities-Edema (ARIA-E) was 14.6% at the highest dose in APOE4 carriers. Against animal CAA models, ponezumab was noted as effective in a mouse 30 model of CAA with respect to lowering amyloid beta burden and vascular reactivity (Bales, 2018). Meanwhile, global APP knockout mice have further been noted as viable. The following exemplary biomarker and pathological data have also provided further validation for the primary role for amyloid beta protein in pathogenesis of CAA: 2026204572  15 Jun 2026 Hereditary forms of “pure” CAA (i.e., lacking parenchymal plaque amyloid) have been observed as characterized by predominant Ap40 deposition in amyloid, as opposed to Ap42 in parenchymal AD; CAA has been observed as not a “tauopathy”, with normal levels of T-tau 5              and P-tau in the CSF, in contrast to elevated levels observed in AD; The inverse correlation of increasing brain amyloid burden, measured by PiB PET, with decreasing CSF Ap40 levels has been identified as unique to CAA; and In vitro and in vivo experimental data have provided increasing support to 10             a prion hypothesis in CAA, wherein Ap40 containing hereditary CAA mutations has a propensity to misfold and induce misfolding in WT protein, so that both are present in amyloid fibrils (akin to transthyretin (TTR)). As disclosed in the below Examples, the instant disclosure provides a number of mouse / rat cross reactive APP-targeting duplexes (including, e.g., AD-397177, 15  AD397192, AD-397196, AD-397182, AD397190, AD-397265 and AD-397203), based upon screening results obtained for APP liver mRNA, when duplexes were administered at 2 mg / Kg in a single dose, as assessed at day 21 post-dosing. The instant disclosure also provides a number of human / cynomolgus cross-reactive duplexes (including, e.g., AD-392911, AD-392912, AD-392703, AD-392866, AD-392927, AD-392913, AD- 20   392843, AD-392916, AD-392714, AD-392844, AD-392926, AD-392824, AD-392704 and AD-392790), based upon screening results obtained for treatment of primary cynomolgus hepatocytes and human BE(2)C cells. RNAi agent-mediated knockdown of EOFAD is also expressly contemplated. Like hCAA, EOFAD is a devastating and rare disease and - as for hCAA - a causal role 25 of APP is well-established and phenotyping of the disease can be performed with greater accuracy and over a shorter duration of time than, e.g., sporadic and / or late onset AD (optionally late onset AD with severe CAA as a subclass of late onset AD). EOFAD is a progressive, dementing neurodegenerative disease in young adults, possessing an age of onset before age 60 to 65 years and often before 55 years of age. 30          The prevalence of EOFAD has been estimated to be 41.2 per 100,000 for the population at risk (i.e., persons aged 40-59 years), with 61% of those affected by EOFAD having a positive family history of EOFAD (among these, 13% had affected individuals in three generations). EOFAD comprises less than 3% of all AD (Bird, 2026204572  15 Jun 2026 Genetics in Medicine, 10: 231-239; Brien and Wang. Annu Rev Neu Sci, 2011, 34: 185204; NCBI Gene Reviews). Providing human genetic validation of the APP target (OMIM 104300), certain APP mutations have been identified that cause EOFAD, including E665D, K670N, 5   M671L (Swedish), T714A (Iranian), T714I (Austrian), V715M (French), V715A (German), I716V (Florida), I716T, V717I (London), V717F, V717G and V717L, as described above. In addition, dominant amyloid beta precursor protein mutations have also been identified that cause EOFAD and CAA. Without wishing to be bound by theory, the pathogenesis of AD is believed to 10 begin in the hippocampus, a ridge of grey matter immediately superior to both lateral ventricles. Degeneration of this tissue is believed to cause the memory loss characteristic of early disease. While the mechanism of neurodegeneration at the protein level has been a matter of great debate, duplications of APP associated with EOFAD have indicated that overexpression of APP may be sufficient to cause AD. (Haass and Selkoe. 15   Nature Reviews Molecular Cell Biology, 8: 101-112). In contrast to EOFAD and CAA, the pathogenic mechanisms of sporadic AD are not yet understood and the population of clinically defined sporadic AD is probably mechanistically heterogeneous. Certain aspects of the instant disclosure are directed towards targeting of APP for 20 knockdown in individuals having EOFAD. A need exists for such agents because only symptom-directed treatments (of limited efficacy) exist for AD more generally and EOFAD in particular. In certain embodiments, the RNAi agents of the instant disclosure should provide approximately 60-80% knockdown of both mutant and WT APP levels throughout the CNS. One further observation from human genetics that speaks to the 25 likely therapeutic efficacy of an APP-targeted therapy capable of knocking down APP levels in CNS cells is that an A673T mutation was identified that protected carriers from AD and dementia in the general population (Jonsson et al. Nature Letter, 488. doi:doi:10.1038 / nature11283). The A673T substitution is adjacent to a P-secretase cleavage site, and has been described as resulting in a 40% reduction in amyloid beta in 30 cell assays. Thus, a dominant negative APP point mutant appeared to protect families from AD, further reinforcing that RNAi agent-mediated knockdown of APP could exert a similar protective and / or therapeutic effect in at least certain forms of AD, including EOFAD. 2026204572  15 Jun 2026 Aiding initial stages of APP-targeting RNAi agent development, it has been noted that APP knockout mice are viable (OMIM 104300), which is expected to allow for viable use of mouse as a model system during lead compound development. In contrast to mice, while humans possessing heterozygous APP mutations exist in the 5 general population with EXAC score of 0.3, no human APP knockout has been identified to date. Biomarkers available for development of APP-targeting RNAi agents include APP and MAPT peptides in CSF, which should allow for rapid assessment and useful efficacy even in a genetically homogeneous population (Mo et al. (2017) Alzheimers & Dementia: Diagnosis, Assessment & Disease Monitoring, 6: 201-209). 10          As noted above, attempts to treat sporadic forms of AD and EOFAD have to date proven unsuccessful - for example, all trials of BACE1 (P-secretase) inhibitors (BACE1i) for treatment of sporadic AD have thus far failed (Egan et al. The New England Journal of Medicine, 378: 1691-1703; Hung and Fu. Journal of Biomedical Science, 24: 47). In such BACEi testing, there have been no completed studies in 15 genetically-defined populations (only studies initiated). Notably, the most recent BACE1i study showed that verubecestat lowered amyloid beta levels by 60% in a population selected based on age and clinical criteria that suggested a probable diagnosis of AD (Egan et al. The New England Journal of Medicine, 378: 1691-1703; Hung and Fu. Journal of Biomedical Science, 24:  47). Meanwhile, among AP-directed 20 immunotherapies, one such immunotherapy demonstrated proof-of-concept in a recent trial in sporadic AD, supporting initiation of an ongoing Phase III trial (Selkoe and Hardy. EMBO Molecular Medicine, 8: 595-608). Given its role in APP cleavage, y-secretase has also been targeted in certain AD-directed trials. However, to date no y-secretase inhibitor trials have been completed in a genetically-defined population; and 25 several programs have been discontinued for toxicity (Selkoe and Hardy). A need therefore exists for agents that can treat or prevent APP-associated diseases or disorders in an affected individual. It is expressly contemplated that all APP-associated diseases or disorders can ultimately be targeted using the RNAi agents of the instant disclosure - specifically, 30 targeting of sporadic CAA and sporadic and / or late onset AD is also contemplated for the RNAi agents of the instant disclosure, even in view of the diagnostic / phenotyping issues presently confronted for these particular APP-associated diseases (it is further contemplated that diagnostics for these diseases will also continue to improve). 2026204572  15 Jun 2026 V. RNAi agents Conjugated to Ligands Another modification of the RNA of a RNAi agent of the disclosure involves chemically linking to the RNA one or more ligands, moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the RNAi. Such moieties include 5 but are not limited to lipid moieties such as a cholesterol moiety (Letsinger et al., (1989) Proc. Natl. Acid. Sci. USA, 86: 6553-6556), cholic acid (Manoharan et al., (1994) Biorg. Med. Chem. Let., 4:1053-1060), a thioether, e.g., beryl-S-tritylthiol (Manoharan et al., (1992) Ann. N.Y. Acad. Sci., 660:306-309; Manoharan et al., (1993) Biorg. Med. Chem. Let., 3:2765-2770), a thiocholesterol (Oberhauser et al., (1992) Nucl. Acids Res., 20:53310   538), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al., (1991) EMBO J, 10:1111-1118; Kabanov et al., (1990) FEBS Lett., 259:327-330; Svinarchuk et al., (1993) Biochimie, 75:49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-phosphonate (Manoharan et al., (1995) Tetrahedron Lett., 36:3651-3654; Shea et al., (1990) Nucl. 15 Acids Res., 18:3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., (1995) Nucleosides & Nucleotides,  14:969-973), or adamantane acetic acid (Manoharan et al., (1995) Tetrahedron Lett., 36:3651-3654), a palmityl moiety (Mishra et al., (1995) Biochim. Biophys. Acta, 1264:229-237), or an octadecylamine or hexylamino-carbonyloxycholesterol moiety (Crooke et al., (1996) J. Pharmacol. Exp. 20 Ther., 277:923-937). In one embodiment, a ligand alters the distribution, targeting or lifetime of a RNAi agent into which it is incorporated. In preferred embodiments a ligand provides an enhanced affinity for a selected target, e.g., molecule, cell or cell type, compartment, e.g., a cellular or organ compartment, tissue, organ or region of the body, as, e.g., 25 compared to a species absent such a ligand. Preferred ligands will not take part in duplex pairing in a duplexed nucleic acid. Ligands can include a naturally occurring substance, such as a protein (e.g., human serum albumin (HSA), low-density lipoprotein (LDL), or globulin); carbohydrate (e.g., a dextran, pullulan, chitin, chitosan, inulin, cyclodextrin, N-acetylglucosamine, N-30 acetylgalactosamine or hyaluronic acid); or a lipid. The ligand can also be a recombinant or synthetic molecule, such as a synthetic polymer, e.g., a synthetic polyamino acid. Examples of polyamino acids include polyamino acid is a polylysine (PLL), poly L-aspartic acid, poly L-glutamic acid, styrene-maleic acid anhydride copolymer, poly(L- 2026204572  15 Jun 2026 lactide-co-glycolied) copolymer, divinyl ether-maleic anhydride copolymer, N-(2-hydroxypropyl)methacrylamide copolymer (HMPA), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyurethane, poly(2-ethylacryllic acid), N-isopropylacrylamide polymers, or polyphosphazine. Example of polyamines include: 5 polyethylenimine, polylysine (PLL), spermine, spermidine, polyamine, pseudopeptidepolyamine, peptidomimetic polyamine, dendrimer polyamine, arginine, amidine, protamine, cationic lipid, cationic porphyrin, quaternary salt of a polyamine, or an alpha helical peptide. Ligands can also include targeting groups, e.g., a cell or tissue targeting agent, 10 e.g., a lectin, glycoprotein, lipid or protein, e.g., an antibody, that binds to a specified cell type such as a kidney cell. A targeting group can be a thyrotropin, melanotropin, lectin, glycoprotein, surfactant protein A, Mucin carbohydrate, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-gulucosamine multivalent mannose, multivalent fucose, glycosylated polyaminoacids, multivalent galactose, 15 transferrin, bisphosphonate, polyglutamate, polyaspartate, a lipid, cholesterol, a steroid, bile acid, folate, vitamin B12, vitamin A, biotin, or an RGD peptide or RGD peptide mimetic. Other examples of ligands include dyes, intercalating agents (e.g. acridines), cross-linkers (e.g. psoralene, mitomycin C), porphyrins (TPPC4, texaphyrin, Sapphyrin), 20 polycyclic aromatic hydrocarbons (e.g., phenazine, dihydrophenazine), artificial endonucleases (e.g. EDTA), lipophilic molecules, e.g., cholesterol, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-Bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid,O3-(oleoyl)lithocholic 25 acid, O3-(oleoyl)cholenic acid, dimethoxytrityl, or phenoxazine)and peptide conjugates (e.g., antennapedia peptide, Tat peptide), alkylating agents, phosphate, amino, mercapto, PEG (e.g., PEG-40K), MPEG,  [MPEG]2, polyamino, alkyl, substituted alkyl, radiolabeled markers, enzymes, haptens (e.g. biotin), transport / absorption facilitators (e.g., aspirin, vitamin E, folic acid), synthetic ribonucleases (e.g., imidazole, 30 bisimidazole, histamine, imidazole clusters, acridine-imidazole conjugates, Eu3+ complexes of tetraazamacrocycles), dinitrophenyl, HRP, or AP. Ligands can be proteins, e.g., glycoproteins, or peptides, e.g., molecules having a specific affinity for a co-ligand, or antibodies e.g., an antibody, that binds to a specified 2026204572  15 Jun 2026 cell type such as a CNS cell. Ligands can also include hormones and hormone receptors. They can also include non-peptidic species, such as lipids, lectins, carbohydrates, vitamins, cofactors, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-gulucosamine multivalent mannose, or multivalent fucose. 5          The ligand can be a substance, e.g., a drug, which can increase the uptake of the RNAi agent into the cell, for example, by disrupting the cell’s cytoskeleton, e.g., by disrupting the cell’s microtubules, microfilaments, and / or intermediate filaments. The drug can be, for example, taxon, vincristine, vinblastine, cytochalasin, nocodazole, japlakinolide, latrunculin A, phalloidin, swinholide A, indanocine, or myoservin. 10          In some embodiments, a ligand attached to a RNAi agent as described herein acts as a pharmacokinetic modulator (PK modulator). PK modulators include lipophiles, bile acids, steroids, phospholipid analogues, peptides, protein binding agents, PEG, vitamins etc. Exemplary PK modulators include, but are not limited to, cholesterol, fatty acids, cholic acid, lithocholic acid, dialkylglycerides, diacylglyceride, phospholipids, 15 sphingolipids, naproxen, ibuprofen, vitamin E, biotin etc. Oligonucleotides that comprise a number of phosphorothioate linkages are also known to bind to serum protein, thus short oligonucleotides, e.g., oligonucleotides of about 5 bases, 10 bases, 15 bases or 20 bases, comprising multiple of phosphorothioate linkages in the backbone are also amenable to the present disclosure as ligands (e.g. as PK modulating ligands). In 20 addition, aptamers that bind serum components (e.g. serum proteins) are also suitable for use as PK modulating ligands in the embodiments described herein. Ligand-conjugated oligonucleotides of the disclosure may be synthesized by the use of an oligonucleotide that bears a pendant reactive functionality, such as that derived from the attachment of a linking molecule onto the oligonucleotide (described below). 25 This reactive oligonucleotide may be reacted directly with commercially-available ligands, ligands that are synthesized bearing any of a variety of protecting groups, or ligands that have a linking moiety attached thereto. The oligonucleotides used in the conjugates of the present disclosure may be conveniently and routinely made through the well-known technique of solid-phase 30 synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, Calif.). Any other means for such synthesis known in the art may additionally or alternatively be employed. It is also known to use 2026204572  15 Jun 2026 similar techniques to prepare other oligonucleotides, such as the phosphorothioates and alkylated derivatives. In the ligand-conjugated oligonucleotides and ligand-molecule bearing sequencespecific linked nucleosides of the present disclosure, the oligonucleotides and 5 oligonucleosides may be assembled on a suitable DNA synthesizer utilizing standard nucleotide or nucleoside precursors, or nucleotide or nucleoside conjugate precursors that already bear the linking moiety, ligand-nucleotide or nucleoside-conjugate precursors that already bear the ligand molecule, or non-nucleoside ligand-bearing building blocks. 10          When using nucleotide-conjugate precursors that already bear a linking moiety, the synthesis of the sequence-specific linked nucleosides is typically completed, and the ligand molecule is then reacted with the linking moiety to form the ligand-conjugated oligonucleotide. In some embodiments, the oligonucleotides or linked nucleosides of the present disclosure are synthesized by an automated synthesizer using phosphoramidites 15 derived from ligand-nucleoside conjugates in addition to the standard phosphoramidites and non-standard phosphoramidites that are commercially available and routinely used in oligonucleotide synthesis. A. Lipophilic Moieties In certain embodiments, the lipophilic moiety is an aliphatic, cyclic such as 20 alicyclic, or polycyclic such as polyalicyclic compound, such as a steroid (e.g., sterol) or a linear or branched aliphatic hydrocarbon. The lipophilic moiety may generally comprises a hydrocarbon chain, which may be cyclic or acyclic. The hydrocarbon chain may comprise various substituents and / or one or more heteroatoms, such as an oxygen or nitrogen atom. Such lipophilic aliphatic moieties include, without limitation, saturated 25 or unsaturated C4-C30 hydrocarbon (e.g., C6-C18 hydrocarbon), saturated or unsaturated fatty acids, waxes (e.g., monohydric alcohol esters of fatty acids and fatty diamides), terpenes (e.g., C10 terpenes, C15 sesquiterpenes, C20 diterpenes, C30 triterpenes, and C40 tetraterpenes), and other polyalicyclic hydrocarbons. For instance, the lipophilic moiety may contain a C4-C30 hydrocarbon chain (e.g., C4-C30 alkyl or alkenyl). In some 30 embodiment the lipophilic moiety contains a saturated or unsaturated C6-C18 hydrocarbon chain (e.g., a linear C6-C18 alkyl or alkenyl). In one embodiment, the lipophilic moiety contains a saturated or unsaturated C16 hydrocarbon chain (e.g., a linear C16 alkyl or alkenyl). 2026204572  15 Jun 2026 The lipophilic moiety may be attached to the RNAi agent by any method known in the art, including via a functional grouping already present in the lipophilic moiety or introduced into the RNAi agent, such as a hydroxy group (e.g., —CO—CH2—OH). The functional groups already present in the lipophilic moiety or introduced into the RNAi 5 agent include, but are not limited to, hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne. Conjugation of the RNAi agent and the lipophilic moiety may occur, for example, through formation of an ether or a carboxylic or carbamoyl ester linkage between the hydroxy and an alkyl group R—, an alkanoyl group RCO— or a substituted 10 carbamoyl group RNHCO—. The alkyl group R may be cyclic (e.g., cyclohexyl) or acyclic (e.g., straight-chained or branched; and saturated or unsaturated). Alkyl group R may be a butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl group, or the like. In some embodiments, the lipophilic moiety is conjugated to the double-stranded 15 RNAi agent via a linker a linker containing an ether, thioether, urea, carbonate, amine, amide, maleimide-thioether, disulfide, phosphodiester, sulfonamide linkage, a product of a click reaction (e.g., a triazole from the azide-alkyne cycloaddition), or carbamate. In another embodiment, the lipophilic moiety is a steroid, such as sterol. Steroids are polycyclic compounds containing a perhydro-1,2-cyclopentanophenanthrene ring 20 system. Steroids include, without limitation, bile acids (e.g., cholic acid, deoxycholic acid and dehydrocholic acid), cortisone, digoxigenin, testosterone, cholesterol, and cationic steroids, such as cortisone. A “cholesterol derivative” refers to a compound derived from cholesterol, for example by substitution, addition or removal of substituents. 25          In another embodiment, the lipophilic moiety is an aromatic moiety. In this context, the term “aromatic” refers broadly to mono- and polyaromatic hydrocarbons. Aromatic groups include, without limitation, C6-C14 aryl moieties comprising one to three aromatic rings, which may be optionally substituted; “aralkyl” or “arylalkyl” groups comprising an aryl group covalently linked to an alkyl group, either of which 30 may independently be optionally substituted or unsubstituted; and “heteroaryl” groups. As used herein, the term “heteroaryl” refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14n electrons shared in a cyclic 2026204572  15 Jun 2026 array, and having, in addition to carbon atoms, between one and about three heteroatoms selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S). As employed herein, a “substituted” alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is one having between one and about four, preferably between one 5 and about three, more preferably one or two, non-hydrogen substituents. Suitable substituents include, without limitation, halo, hydroxy, nitro, haloalkyl, alkyl, alkaryl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, alkoxycarbonyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, 10 cyano, and ureido groups. In some embodiments, the lipophilic moiety is an aralkyl group, e.g., a 2-arylpropanoyl moiety. The structural features of the aralkyl group are selected so that the lipophilic moiety will bind to at least one protein in vivo. In certain embodiments, the structural features of the aralkyl group are selected so that the lipophilic moiety binds to 15 serum, vascular, or cellular proteins. In certain embodiments, the structural features of the aralkyl group promote binding to albumin, an immunoglobulin, a lipoprotein, a-2-macroglubulin, or a-1-glycoprotein. In certain embodiments, the ligand is naproxen or a structural derivative of naproxen. Procedures for the synthesis of naproxen can be found in U.S. Pat. No. 20   3,904,682 and U.S. Pat. No. 4,009,197, which are herey incorporated by reference in their entirety. Naproxen has the chemical name  (S)-6-Methoxy-a-methyl-2- T naphthaleneacetic acid and the structure is                                  . In certain embodiments, the ligand is ibuprofen or a structural derivative of ibuprofen. Procedures for the synthesis of ibuprofen can be found in U.S. Pat. No. 25   3,228,831, which are herey incorporated by reference in their entirety. The structure of ibuprofen is ■ ’                                  . Additional exemplary aralkyl groups are illustrated in U.S. Patent No. 7,626,014, which is incorporated herein by reference in its entirety. 2026204572  15 Jun 2026 In another embodiment, suitable lipophilic moieties include lipid, cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone,        1,3-bis-O(hexadecyl)glycerol,        geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, 5 myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine. In certain embodiments, more than one lipophilic moieties can be incorporated into the double-strand RNAi agent, particularly when the lipophilic moiety has a low lipophilicity or hydrophobicity. In one embodiment, two or more lipophilic moieties are 10 incorporated into the same strand of the double-strand RNAi agent. In one embodiment, each strand of the double-strand RNAi agent has one or more lipophilic moieties incorporated. In one embodiment, two or more lipophilic moieties are incorporated into the same position (i.e., the same nucleobase, same sugar moiety, or same internucleosidic linkage) of the double-strand RNAi agent. This can be achieved by, e.g., 15 conjugating the two or more lipophilic moieties via a carrier, and / or conjugating the two or more lipophilic moieties via a branched linker, and / or conjugating the two or more lipophilic moieties via one or more linkers, with one or more linkers linking the lipophilic moieties consecutively. The lipophilic moiety may be conjugated to the RNAi agent via a direct 20 attachment to the ribosugar of the RNAi agent. Alternatively, the lipophilic moiety may be conjugated to the double-strand RNAi agent via a linker or a carrier. In certain embodiments, the lipophilic moiety may be conjugated to the RNAi agent via one or more linkers (tethers). In one embodiment, the lipophilic moiety is conjugated to the double-stranded 25 RNAi agent via a linker containing an ether, thioether, urea, carbonate, amine, amide, maleimide-thioether, disulfide, phosphodiester, sulfonamide linkage, a product of a click reaction (e.g., a triazole from the azide-alkyne cycloaddition), or carbamate. Exemplary linkers, tethers, carriers, nucleic acid modifications, conjugates, ligands and other moieties useful for achieving central nervous system-directed delivery 30 of the APP-targeting RNAi agents of the instant disclosure are described in additional detail, e.g., in U.S. Application Nos. 62 / 668,072, 62 / 738,747 and / or 62 / 773,082, the entire contents of which are incorporated herein by this reference. B. Lipid Conujugates 2026204572  15 Jun 2026 In one embodiment, the ligand or conjugate is a lipid or lipid-based molecule. Such a lipid or lipid-based molecule preferably binds a serum protein, e.g., human serum albumin (HSA). An HSA binding ligand allows for vascular distribution of the conjugate to a target tissue, e.g., a non-kidney target tissue of the body. In certain embodiments, 5 the target tissue can be the CNS, including glial cells of the brain. Other molecules that can bind HSA can also be used as ligands. For example, neproxin or aspirin can be used. A lipid or lipid-based ligand can (a) increase resistance to degradation of the conjugate, (b) increase targeting or transport into a target cell or cell membrane, and / or (c) can be used to adjust binding to a serum protein, e.g., HSA. 10           A lipid based ligand can be used to inhibit, e.g., control the binding of the conjugate to a target tissue. For example, a lipid or lipid-based ligand that binds to HSA more strongly will be less likely to be targeted to the kidney and therefore less likely to be cleared from the body. A lipid or lipid-based ligand that binds to HSA less strongly can be used to target the conjugate to the kidney. 15          Optionally, the lipid based ligand binds HSA. Preferably, it binds HSA with a sufficient affinity such that the conjugate will be preferably distributed to a non-kidney tissue. However, it is preferred that the affinity not be so strong that the HSA-ligand binding cannot be reversed. In another preferred embodiment, the lipid based ligand binds HSA weakly or 20 not at all, such that the conjugate will be preferably distributed to the kidney. Other moieties that target to kidney cells can also be used in place of or in addition to the lipid based ligand. In another aspect, the ligand is a moiety, e.g., a vitamin, which is taken up by a target cell, e.g., a proliferating cell. These are particularly useful for treating disorders 25 characterized by unwanted cell proliferation, e.g., of the malignant or non-malignant type, e.g., cancer cells. Exemplary vitamins include vitamin A, E, and K. Other exemplary vitamins include are B vitamin, e.g., folic acid, B12, riboflavin, biotin, pyridoxal or other vitamins or nutrients taken up by target cells such as brain cells. Also included are HSA and low density lipoprotein (LDL). 30          C. Cell Permeation Agents In another aspect, the ligand is a cell-permeation agent, preferably a helical cellpermeation agent. Preferably, the agent is amphipathic. An exemplary agent is a peptide such as tat or antennopedia. If the agent is a peptide, it can be modified, including a 2026204572  15 Jun 2026 peptidylmimetic, invertomers, non-peptide or pseudo-peptide linkages, and use of D-amino acids. The helical agent is preferably an alpha-helical agent, which preferably has a lipophilic and a lipophobic phase. The ligand can be a peptide or peptidomimetic. A peptidomimetic (also referred 5 to herein as an oligopeptidomimetic) is a molecule capable of folding into a defined three-dimensional structure similar to a natural peptide. The attachment of peptide and peptidomimetics to RNAi agents can affect pharmacokinetic distribution of the RNAi agent, such as by enhancing cellular recognition and absorption. The peptide or peptidomimetic moiety can be about 5-50 amino acids long, e.g., about 5, 10, 15, 20, 25, 10   30, 35, 40, 45, or 50 amino acids long. A peptide or peptidomimetic can be, for example, a cell permeation peptide, cationic peptide, amphipathic peptide, or hydrophobic peptide (e.g., consisting primarily of Tyr, Trp or Phe). The peptide moiety can be a dendrimer peptide, constrained peptide or crosslinked peptide. In another alternative, the peptide moiety can include a 15 hydrophobic membrane translocation sequence (MTS). An exemplary hydrophobic MTS-containing peptide is RFGF having the amino acid sequence AAVALLPAVLLALLAP (SEQ ID NO: 29). An RFGF analogue (e.g., amino acid sequence AALLPVLLAAP (SEQ ID NO: 30) containing a hydrophobic MTS can also be a targeting moiety. The peptide moiety can be a “delivery” peptide, which can carry 20 large polar molecules including peptides, oligonucleotides, and protein across cell membranes. For example, sequences from the HIV Tat protein (GRKKRRQRRRPPQ (SEQ ID NO: 31) and the Drosophila Antennapedia protein (RQIKIWFQNRRMKWKK (SEQ ID NO: 32) have been found to be capable of functioning as delivery peptides. A peptide or peptidomimetic can be encoded by a random sequence of DNA, such as a 25 peptide identified from a phage-display library, or one-bead-one-compound (OBOC) combinatorial library (Lam et al., Nature, 354:82-84, 1991). Examples of a peptide or peptidomimetic tethered to a dsRNA agent via an incorporated monomer unit for cell targeting purposes is an arginine-glycine-aspartic acid (RGD)-peptide, or RGD mimic. A peptide moiety can range in length from about 5 amino acids to about 40 amino acids. 30 The peptide moieties can have a structural modification, such as to increase stability or direct conformational properties. Any of the structural modifications described below can be utilized. 2026204572  15 Jun 2026 An RGD peptide for use in the compositions and methods of the disclosure may be linear or cyclic, and may be modified, e.g., glyciosylated or methylated, to facilitate targeting to a specific tissue(s). RGD-containing peptides and peptidiomimemtics may include D-amino acids, as well as synthetic RGD mimics. In addition to RGD, one can 5 use other moieties that target the integrin ligand. Preferred conjugates of this ligand target PECAM-1 or VEGF. A “cell permeation peptide” is capable of permeating a cell, e.g., a microbial cell, such as a bacterial or fungal cell, or a mammalian cell, such as a human cell. A microbial cell-permeating peptide can be, for example, an a-helical linear peptide (e.g., 10   LL-37 or Ceropin P1), a disulfide bond-containing peptide (e.g., a -defensin, P-defensin or bactenecin), or a peptide containing only one or two dominating amino acids (e.g., PR-39 or indolicidin). A cell permeation peptide can also include a nuclear localization signal (NLS). For example, a cell permeation peptide can be a bipartite amphipathic peptide, such as MPG, which is derived from the fusion peptide domain of HIV-1 gp41 15 and the NLS of SV40 large T antigen (Simeoni et al., Nucl. Acids Res. 31:2717-2724, 2003). D. Carbohydrate Conjugates and Ligands In some embodiments of the compositions and methods of the disclosure, an RNAi agent oligonucleotide further comprises a carbohydrate. The carbohydrate 20 conjugated RNAi agents are advantageous for the in vivo delivery of nucleic acids, as well as compositions suitable for in vivo therapeutic use, as described herein. As used herein, “carbohydrate” refers to a compound which is either a carbohydrate per se made up of one or more monosaccharide units having at least 6 carbon atoms (which can be linear, branched or cyclic) with an oxygen, nitrogen or sulfur atom bonded to each 25 carbon atom; or a compound having as a part thereof a carbohydrate moiety made up of one or more monosaccharide units each having at least six carbon atoms (which can be linear, branched or cyclic), with an oxygen, nitrogen or sulfur atom bonded to each carbon atom. Representative carbohydrates include the sugars (mono-, di-, tri- and oligosaccharides containing from about 4, 5, 6, 7, 8, or 9 monosaccharide units), and 30 polysaccharides such as starches, glycogen, cellulose and polysaccharide gums. Specific monosaccharides include C5 and above (e.g., C5, C6, C7, or C8) sugars; di- and trisaccharides include sugars having two or three monosaccharide units (e.g., C5, C6, C7, or C8). 2026204572  15 Jun 2026 In one embodiment, a carbohydrate conjugate for use in the compositions and methods of the disclosure is a monosaccharide. In certain embodiments, the compositions and methods of the disclosure include a C16 ligand. In exemplary embodiments, the C16 ligand of the disclosure has the 5 following structure (exemplified here below for a uracil base, yet attachment of the C16 ligand is contemplated for a nucleotide presenting any base (C, G, A, etc.) and / or possessing any other modification as presented herein, provided that 2’ ribo attachment is preserved) and is attached at the 2’ position of the ribo within a residue that is so modified: OH Chemical Formula: C25H43N2O8P Exact Mass: 530.2757 10           Molecular Weight: 530.5913 As shown above, a C16 ligand-modified residue presents a straight chain alkyl at the 2’-ribo position of an exemplary residue (here, a Uracil) that is so modified. In some embodiments, a carbohydrate conjugate of a RNAi agent of the instant disclosure further comprises one or more additional ligands as described above, such as, 15 but not limited to, a PK modulator and / or a cell permeation peptide. Additional carbohydrate conjugates (and linkers) suitable for use in the present disclosure include those described in PCT Publication Nos. WO 2014 / 179620 and WO 2014 / 179627, the entire contents of each of which are incorporated herein by reference. In certain embodiments, the compositions and methods of the disclosure include 20 a vinyl phosponate (VP) modification of an RNAi agent as described herein. In exemplary embodiments, a vinyl phosphonate of the disclosure has the following structure: 2026204572  15 Jun 2026 A vinyl phosponate of the instant disclosure may be attached to either the antisense or the sense strand of a dsRNA of the disclosure. In certain preferred embodiments, a vinyl phosphonate of the instant disclosure is attached to the antisense strand of a dsRNA, optionally at the 5’ end of the antisense strand of the dsRNA. Vinyl phosphate modifications are also contemplated for the compositions and methods of the instant disclosure. An exemplary vinyl phosphate structure is: E. Thermally Destabilizing Modifications 10         In certain embodiments, a dsRNA molecule can be optimized for RNA interference by incorporating thermally destabilizing modifications in the seed region of the antisense strand (i.e., at positions 2-9 of the 5’-end of the antisense strand) to reduce or inhibit off-target gene silencing. It has been discovered that dsRNAs with an antisense strand comprising at least one thermally destabilizing modification of the 15 duplex within the first 9 nucleotide positions, counting from the 5’ end, of the antisense strand have reduced off-target gene silencing activity. Accordingly, in some embodiments, the antisense strand comprises at least one (e.g., one, two, three, four, five or more) thermally destabilizing modification of the duplex within the first 9 nucleotide positions of the 5’ region of the antisense strand. In some embodiments, one or more 20 thermally destabilizing modification(s) of the duplex is / are located in positions 2-9, or preferably positions 4-8, from the 5’-end of the antisense strand. In some further embodiments, the thermally destabilizing modification(s) of the duplex is / are located at position 6, 7 or 8 from the 5’-end of the antisense strand. In still some further embodiments, the thermally destabilizing modification of the duplex is located at 2026204572  15 Jun 2026 position 7 from the 5’-end of the antisense strand. The term “thermally destabilizing modification(s)” includes modification(s) that would result with a dsRNA with a lower overall melting temperature (Tm) (preferably a Tm with one, two, three or four degrees lower than the Tm of the dsRNA without having such modification(s). In some 5 embodiments, the thermally destabilizing modification of the duplex is located at position 2, 3, 4, 5 or 9 from the 5’-end of the antisense strand. The thermally destabilizing modifications can include, but are not limited to, abasic modification; mismatch with the opposing nucleotide in the opposing strand; and sugar modification such as 2’-deoxy modification or acyclic nucleotide, e.g., unlocked 10 nucleic acids (UNA) or glycol nucleic acid (GNA). Exemplified abasic modifications include, but are not limited to the following: Wherein R = H, Me, Et or OMe; R’ = H, Me, Et or OMe; R” = H, Me, Et or OMe Mod2 (2'-OMe Abasic Spacer) Mod3 (3'-OMe) Mod4 (5'-Me) X = OMe, F Mod5 (Hyp-spacer) 15 wherein B is a modified or unmodified nucleobase. Exemplified sugar modifications include, but are not limited to the following: 2026204572  15 Jun 2026 o 2'-deoxy glycol nucleic acid R= H, OH, O-alkyl unlocked nucleic acid R= H, OH, O-alkyl unlocked nucleic acid R= H, OH, CH3, CH2CH3, O-alkyl, NH2, NHMe, NMe2 R' = H, OH, CH3, CH2CH3, O-alkyl, NH2, NHMe, NMe2 R" = H, OH, CH3, CH2CH3, O-alkyl, NH2, NHMe, NMe2 R’M = H, OH, CH3, CH2CH3, O-alkyl, NH2, NHMe, NMe2 R"” = H, OH, CH3, CH2CH3, O-alkyl, NH2, NHMe, NMe2 glycol nucleic acid R= H, OH, O-alkyl R = H, methyl, ethyl wherein B is a modified or unmodified nucleobase. In some embodiments the thermally destabilizing modification of the duplex is 5 selected from the group consisting of: , and wherein B is a modified or unmodified nucleobase and the asterisk on each structure represents either R, S or racemic. 10          The term "acyclic nucleotide" refers to any nucleotide having an acyclic ribose sugar, for example, where any of bonds between the ribose carbons (e.g., C1’-C2’, C2’-C3’, C3’-C4’, C4’-O4’, or C1’-O4’) is absent and / or at least one of ribose carbons or oxygen (e.g., C1’, C2’, C3’, C4’ or O4’) are independently or in combination absent 2026204572  15 Jun 2026 from the nucleotide. In some embodiments, acyclic nucleotide wherein B is a is modified or unmodified nucleobase, R1 and R2 independently are H, halogen, OR3, or alkyl; and R3 is H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or sugar). The term “UNA” 10 refers to unlocked acyclic nucleic acid, wherein any of the bonds of the sugar has been removed, forming an unlocked "sugar" residue. In one example, UNA also encompasses monomers with bonds between C1'-C4' being removed (i.e. the covalent carbon-oxygen-carbon bond between the C1' and C4' carbons). In another example, the C2'-C3' bond (i.e. the covalent carbon-carbon bond between the C2' and C3' carbons) of the sugar is removed (see Mikhailov et. al., Tetrahedron Letters, 26 (17): 2059 (1985); and Fluiter et al., Mol. Biosyst., 10: 1039 (2009), which are hereby incorporated by reference in their entirety). The acyclic derivative provides greater backbone flexibility without affecting the Watson-Crick pairings. The acyclic nucleotide can be linked via 2’-5’ or 3’-5’ 15 linkage. The term ‘GNA’ refers to glycol nucleic acid which is a polymer similar to DNA or RNA but differing in the composition of its “backbone” in that is composed of repeating glycerol units linked by phosphodiester bonds: (R)-GXA 2026204572  15 Jun 2026 10 The thermally destabilizing modification of the duplex can be mismatches (i.e., noncomplementary base pairs) between the thermally destabilizing nucleotide and the opposing nucleotide in the opposite strand within the dsRNA duplex. Exemplary mismatch base pairs include G:G, G:A, G:U, G:T, A:A, A:C, C:C, C:U, C:T, U:U, T:T, U:T, or a combination thereof. Other mismatch base pairings known in the art are also amenable to the present invention. A mismatch can occur between nucleotides that are either naturally occurring nucleotides or modified nucleotides, i.e., the mismatch base pairing can occur between the nucleobases from respective nucleotides independent of the modifications on the ribose sugars of the nucleotides. In certain embodiments, the dsRNA molecule contains at least one nucleobase in the mismatch pairing that is a 2’-deoxy nucleobase; e.g., the 2’-deoxy nucleobase is in the sense strand. In some embodiments, the thermally destabilizing modification of the duplex in the seed region of the antisense strand includes nucleotides with impaired W-C H-bonding to complementary base on the target mRNA, such as: 15 N NH H2N More examples of abasic nucleotide, acyclic nucleotide modifications (including UNA and GNA), and mismatch modifications have been described in detail in WO 2011 / 133876, which is herein incorporated by reference in its entirety. The thermally destabilizing modifications may also include universal base with 20 reduced or abolished capability to form hydrogen bonds with the opposing bases, and phosphate modifications. In some embodiments, the thermally destabilizing modification of the duplex includes nucleotides with non-canonical bases such as, but not limited to, nucleobase modifications with impaired or completely abolished capability to form hydrogen bonds 2026204572  15 Jun 2026 with bases in the opposite strand. These nucleobase modifications have been evaluated for destabilization of the central region of the dsRNA duplex as described in WO 2010 / 0011895, which is herein incorporated by reference in its entirety. Exemplary nucleobase modifications are: inosine          nebularine 2-aminopurine 2,4- difluorotoluene F 4-Fluoro-6- methylbenzimidazole 3-nitropyrrole 4-Methylbenzimidazole In some embodiments, the thermally destabilizing modification of the duplex in the seed region of the antisense strand includes one or more a-nucleotide complementary to the base on the target mRNA, such as: 10 15 wherein R is H, OH, OCH3, F, NH2, NHMe, NMe2 or O-alkyl. Exemplary phosphate modifications known to decrease the thermal stability of dsRNA duplexes compared to natural phosphodiester linkages are: 0 1 0 1 1 0 1 0 1 0 1 0 O=P-SH o=p-ch3 o=p-ch2-cooh O=P-R O=P—NH-R O=P-O-R 0 6 1 0 1 0 1 0 1 0 1 R = alkyl 1 1 1 1 1 The alkyl for the R group can be a C1-C6alkyl. Specific alkyls for the R group include, but are not limited to methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl. As the skilled artisan will recognize, in view of the functional role of nucleobases is defining specificity of a RNAi agent of the disclosure, while nucleobase modifications can be performed in the various manners as described herein, e.g., to introduce destabilizing modifications into a RNAi agent of the disclosure, e.g., for purpose of 2026204572  15 Jun 2026 enhancing on-target effect relative to off-target effect, the range of modifications available and, in general, present upon RNAi agents of the disclosure tends to be much greater for non-nucleobase modifications, e.g., modifications to sugar groups and / or phosphate backbones of polyribonucleotides. Such modifications are described in 5 greater detail in other sections of the instant disclosure and are expressly contemplated for RNAi agents of the disclosure, either possessing native nucleobases or modified nucleobases as described above and / or elsewhere herein. In addition to the antisense strand comprising a thermally destabilizing modification, the dsRNA can also comprise one or more stabilizing modifications. For 10 example, the dsRNA can comprise at least two (e.g., two, three, four, five, six, seven, eight, nine, ten or more) stabilizing modifications. Without limitations, the stabilizing modifications all can be present in one strand. In some embodiments, both the sense and the antisense strands comprise at least two stabilizing modifications. The stabilizing modification can occur on any nucleotide of the sense strand or antisense strand. For 15 instance, the stabilizing modification can occur on every nucleotide on the sense strand and / or antisense strand; each stabilizing modification can occur in an alternating pattern on the sense strand or antisense strand; or the sense strand or antisense strand comprises both stabilizing modification in an alternating pattern. The alternating pattern of the stabilizing modifications on the sense strand may be the same or different from the 20 antisense strand, and the alternating pattern of the stabilizing modifications on the sense strand can have a shift relative to the alternating pattern of the stabilizing modifications on the antisense strand. In some embodiments, the antisense strand comprises at least two (e.g., two, three, four, five, six, seven, eight, nine, ten or more) stabilizing modifications. Without 25 limitations, a stabilizing modification in the antisense strand can be present at any positions. In some embodiments, the antisense comprises stabilizing modifications at positions 2, 6, 8, 9, 14 and 16 from the 5’-end. In some other embodiments, the antisense comprises stabilizing modifications at positions 2, 6, 14 and 16 from the 5’-end. In still some other embodiments, the antisense comprises stabilizing modifications at positions 30   2, 14 and 16 from the 5’-end. In some embodiments, the antisense strand comprises at least one stabilizing modification adjacent to the destabilizing modification. For example, the stabilizing modification can be the nucleotide at the 5’-end or the 3’-end of the destabilizing 2026204572  15 Jun 2026 modification, i.e., at position -1 or +1 from the position of the destabilizing modification. In some embodiments, the antisense strand comprises a stabilizing modification at each of the 5’-end and the 3’-end of the destabilizing modification, i.e., positions -1 and +1 from the position of the destabilizing modification. 5          In some embodiments, the antisense strand comprises at least two stabilizing modifications at the 3’-end of the destabilizing modification, i.e., at positions +1 and +2 from the position of the destabilizing modification. In some embodiments, the sense strand comprises at least two (e.g., two, three, four, five, six, seven, eight, nine, ten or more) stabilizing modifications. Without 10 limitations, a stabilizing modification in the sense strand can be present at any positions. In some embodiments, the sense strand comprises stabilizing modifications at positions 7, 10 and 11 from the 5’-end. In some other embodiments, the sense strand comprises stabilizing modifications at positions 7, 9, 10 and 11 from the 5’-end. In some embodiments, the sense strand comprises stabilizing modifications at positions opposite 15 or complimentary to positions 11, 12 and 15 of the antisense strand, counting from the 5’-end of the antisense strand. In some other embodiments, the sense strand comprises stabilizing modifications at positions opposite or complimentary to positions 11, 12, 13 and 15 of the antisense strand, counting from the 5’-end of the antisense strand. In some embodiments, the sense strand comprises a block of two, three or four stabilizing 20 modifications. In some embodiments, the sense strand does not comprise a stabilizing modification in position opposite or complimentary to the thermally destabilizing modification of the duplex in the antisense strand. Exemplary thermally stabilizing modifications include, but are not limited to 2’ 25 fluoro modifications. Other thermally stabilizing modifications include, but are not limited to LNA. In some embodiments, the dsRNA of the disclosure comprises at least four (e.g., four, five, six, seven, eight, nine, ten or more) 2’-fluoro nucleotides. Without limitations, the 2’-fluoro nucleotides all can be present in one strand. In some embodiments, both the 30 sense and the antisense strands comprise at least two 2’-fluoro nucleotides. The 2’-fluoro modification can occur on any nucleotide of the sense strand or antisense strand. For instance, the 2’-fluoro modification can occur on every nucleotide on the sense strand and / or antisense strand; each 2’-fluoro modification can occur in an alternating pattern 2026204572  15 Jun 2026 on the sense strand or antisense strand; or the sense strand or antisense strand comprises both 2’-fluoro modifications in an alternating pattern. The alternating pattern of the 2’-fluoro modifications on the sense strand may be the same or different from the antisense strand, and the alternating pattern of the 2’-fluoro modifications on the sense strand can 5 have a shift relative to the alternating pattern of the 2’-fluoro modifications on the antisense strand. In some embodiments, the antisense strand comprises at least two (e.g., two, three, four, five, six, seven, eight, nine, ten or more) 2’-fluoro nucleotides. Without limitations, a 2’-fluoro modification in the antisense strand can be present at any 10 positions. In some embodiments, the antisense comprises 2’-fluoro nucleotides at positions 2, 6, 8, 9, 14 and 16 from the 5’-end. In some other embodiments, the antisense comprises 2’-fluoro nucleotides at positions 2, 6, 14 and 16 from the 5’-end. In still some other embodiments, the antisense comprises 2’-fluoro nucleotides at positions 2, 14 and 16 from the 5’-end. 15          In some embodiments, the antisense strand comprises at least one 2’-fluoro nucleotide adjacent to the destabilizing modification. For example, the 2’-fluoro nucleotide can be the nucleotide at the 5’-end or the 3’-end of the destabilizing modification, i.e., at position -1 or +1 from the position of the destabilizing modification. In some embodiments, the antisense strand comprises a 2’-fluoro 20 nucleotide at each of the 5’-end and the 3’-end of the destabilizing modification, i.e., positions -1 and +1 from the position of the destabilizing modification. In some embodiments, the antisense strand comprises at least two 2’-fluoro nucleotides at the 3’-end of the destabilizing modification, i.e., at positions +1 and +2 from the position of the destabilizing modification. 25          In some embodiments, the sense strand comprises at least two (e.g., two, three, four, five, six, seven, eight, nine, ten or more) 2’-fluoro nucleotides. Without limitations, a 2’-fluoro modification in the sense strand can be present at any positions. In some embodiments, the antisense comprises 2’-fluoro nucleotides at positions 7, 10 and 11 from the 5’-end. In some other embodiments, the sense strand comprises 2’-fluoro 30 nucleotides at positions 7, 9, 10 and 11 from the 5’-end. In some embodiments, the sense strand comprises 2’-fluoro nucleotides at positions opposite or complimentary to positions 11, 12 and 15 of the antisense strand, counting from the 5’-end of the antisense strand. In some other embodiments, the sense strand comprises 2’-fluoro nucleotides at 2026204572  15 Jun 2026 positions opposite or complimentary to positions 11, 12, 13 and 15 of the antisense strand, counting from the 5’-end of the antisense strand. In some embodiments, the sense strand comprises a block of two, three or four 2’-fluoro nucleotides. In some embodiments, the sense strand does not comprise a 2’-fluoro nucleotide 5 in position opposite or complimentary to the thermally destabilizing modification of the duplex in the antisense strand. In some embodiments, the dsRNA molecule of the disclosure comprises a 21 nucleotides (nt) sense strand and a 23 nucleotides (nt) antisense, wherein the antisense strand contains at least one thermally destabilizing nucleotide, where the at least one 10 thermally destabilizing nucleotide occurs in the seed region of the antisense strand (i.e., at position 2-9 of the 5’-end of the antisense strand), wherein one end of the dsRNA is blunt, while the other end is comprises a 2 nt overhang, and wherein the dsRNA optionally further has at least one (e.g., one, two, three, four, five, six or all seven) of the following characteristics: (i) the antisense comprises 2, 3, 4, 5 or 6 2’-fluoro 15 modifications; (ii) the antisense comprises 1,  2,  3,  4 or 5 phosphorothioate internucleotide linkages; (iii) the sense strand is conjugated with a ligand; (iv) the sense strand comprises 2, 3, 4 or 5 2’-fluoro modifications; (v) the sense strand comprises 1, 2, 3, 4 or 5 phosphorothioate internucleotide linkages; (vi) the dsRNA comprises at least four 2’-fluoro modifications; and (vii) the dsRNA comprises a blunt end at 5’-end of the 20 antisense strand. Preferably, the 2 nt overhang is at the 3’-end of the antisense. In some embodiments, the dsRNA molecule of the disclosure comprising a sense and antisense strands, wherein: the sense strand is 25-30 nucleotide residues in length, wherein starting from the 5' terminal nucleotide (position 1), positions 1 to 23 of said sense strand comprise at least 8 ribonucleotides; antisense strand is 36-66 nucleotide 25 residues in length and, starting from the 3' terminal nucleotide, at least 8 ribonucleotides in the positions paired with positions 1- 23 of sense strand to form a duplex; wherein at least the 3 ' terminal nucleotide of antisense strand is unpaired with sense strand, and up to 6 consecutive 3' terminal nucleotides are unpaired with sense strand, thereby forming a 3' single stranded overhang of 1-6 nucleotides; wherein the 5' terminus of antisense 30 strand comprises from 10-30 consecutive nucleotides which are unpaired with sense strand, thereby forming a 10-30 nucleotide single stranded 5' overhang; wherein at least the sense strand 5' terminal and 3' terminal nucleotides are base paired with nucleotides of antisense strand when sense and antisense strands are aligned for maximum 2026204572  15 Jun 2026 complementarity, thereby forming a substantially duplexed region between sense and antisense strands; and antisense strand is sufficiently complementary to a target RNA along at least 19 ribonucleotides of antisense strand length to reduce target gene expression when said double stranded nucleic acid is introduced into a mammalian cell; 5 and wherein the antisense strand contains at least one thermally destabilizing nucleotide, where at least one thermally destabilizing nucleotide is in the seed region of the antisense strand (i.e. at position 2-9 of the 5’-end of the antisense strand). For example, the thermally destabilizing nucleotide occurs between positions opposite or complimentary to positions 14-17 of the 5’-end of the sense strand, and wherein the 10 dsRNA optionally further has at least one (e.g., one, two, three, four, five, six or all seven) of the following characteristics: (i) the antisense comprises 2, 3, 4, 5 or 6 2’-fluoro modifications; (ii) the antisense comprises 1, 2, 3, 4 or 5 phosphorothioate internucleotide linkages; (iii) the sense strand is conjugated with a ligand; (iv) the sense strand comprises 2, 3, 4 or 5 2’-fluoro modifications; (v) the sense strand comprises 1, 2, 15   3, 4 or 5 phosphorothioate internucleotide linkages; and (vi) the dsRNA comprises at least four 2’-fluoro modifications; and (vii) the dsRNA comprises a duplex region of 1230 nucleotide pairs in length. In some embodiments, the dsRNA molecule of the disclosure comprises a sense and antisense strands, wherein said dsRNA molecule comprises a sense strand having a 20 length which is at least 25 and at most 29 nucleotides and an antisense strand having a length which is at most 30 nucleotides with the sense strand comprises a modified nucleotide that is susceptible to enzymatic degradation at position 11 from the 5’end, wherein the 3’ end of said sense strand and the 5’ end of said antisense strand form a blunt end and said antisense strand is 1-4 nucleotides longer at its 3’ end than the sense 25 strand, wherein the duplex region which is at least 25 nucleotides in length, and said antisense strand is sufficiently complementary to a target mRNA along at least 19 nt of said antisense strand length to reduce target gene expression when said dsRNA molecule is introduced into a mammalian cell, and wherein dicer cleavage of said dsRNA preferentially results in an siRNA comprising said 3’ end of said antisense strand, 30 thereby reducing expression of the target gene in the mammal, wherein the antisense strand contains at least one thermally destabilizing nucleotide, where the at least one thermally destabilizing nucleotide is in the seed region of the antisense strand (i.e. at position 2-9 of the 5’-end of the antisense strand), and wherein the dsRNA optionally 2026204572  15 Jun 2026 further has at least one (e.g., one, two, three, four, five, six or all seven) of the following characteristics: (i) the antisense comprises 2, 3, 4, 5 or 6 2’-fluoro modifications; (ii) the antisense comprises 1, 2, 3, 4 or 5 phosphorothioate internucleotide linkages; (iii) the sense strand is conjugated with a ligand; (iv) the sense strand comprises 2, 3, 4 or 5 2’5 fluoro modifications; (v) the sense strand comprises 1, 2, 3, 4 or 5 phosphorothioate internucleotide linkages; and (vi) the dsRNA comprises at least four 2’-fluoro modifications; and (vii) the dsRNA has a duplex region of 12-29 nucleotide pairs in length. In some embodiments, every nucleotide in the sense strand and antisense strand 10 of the dsRNA molecule may be modified. Each nucleotide may be modified with the same or different modification which can include one or more alteration of one or both of the non-linking phosphate oxygens and / or of one or more of the linking phosphate oxygens; alteration of a constituent of the ribose sugar, e.g., of the 2’ hydroxyl on the ribose sugar; wholesale replacement of the phosphate moiety with “dephospho” linkers; 15 modification or replacement of a naturally occurring base; and replacement or modification of the ribose-phosphate backbone. As nucleic acids are polymers of subunits, many of the modifications occur at a position which is repeated within a nucleic acid, e.g., a modification of a base, or a phosphate moiety, or a non-linking O of a phosphate moiety. In some cases the 20 modification will occur at all of the subject positions in the nucleic acid but in many cases it will not. By way of example, a modification may only occur at a 3’ or 5’ terminal position, may only occur in a terminal region, e.g., at a position on a terminal nucleotide or in the last 2, 3, 4, 5, or 10 nucleotides of a strand. A modification may occur in a double strand region, a single strand region, or in both. A modification may 25 occur only in the double strand region of a RNA or may only occur in a single strand region of a RNA. E.g., a phosphorothioate modification at a non-linking O position may only occur at one or both termini, may only occur in a terminal region, e.g., at a position on a terminal nucleotide or in the last 2, 3, 4, 5, or 10 nucleotides of a strand, or may occur in double strand and single strand regions, particularly at termini. The 5’ end or 30 ends can be phosphorylated. It may be possible, e.g., to enhance stability, to include particular bases in overhangs, or to include modified nucleotides or nucleotide surrogates, in single strand overhangs, e.g., in a 5’ or 3’ overhang, or in both. E.g., it can be desirable to include 2026204572  15 Jun 2026 purine nucleotides in overhangs. In some embodiments all or some of the bases in a 3’ or 5’ overhang may be modified, e.g., with a modification described herein. Modifications can include, e.g., the use of modifications at the 2’ position of the ribose sugar with modifications that are known in the art, e.g., the use of deoxyribonucleotides, 2’-deoxy-5   2’-fluoro (2’-F) or 2’-O-methyl modified instead of the ribosugar of the nucleobase, and modifications in the phosphate group, e.g., phosphorothioate modifications. Overhangs need not be homologous with the target sequence. In some embodiments, each residue of the sense strand and antisense strand is independently modified with LNA, HNA, CeNA, 2’-methoxyethyl, 2’- O-methyl, 2’-O-10 allyl, 2’-C- allyl, 2’-deoxy, or 2’-fluoro. The strands can contain more than one modification. In some embodiments, each residue of the sense strand and antisense strand is independently modified with 2’-O-methyl or 2’-fluoro. It is to be understood that these modifications are in addition to the at least one thermally destabilizing modification of the duplex present in the antisense strand. 15           At least two different modifications are typically present on the sense strand and antisense strand. Those two modifications may be the 2’-deoxy, 2’- O-methyl or 2’-fluoro modifications, acyclic nucleotides or others. In some embodiments, the sense strand and antisense strand each comprises two differently modified nucleotides selected from 2’-O-methyl or 2’-deoxy. In some embodiments, each residue of the sense strand 20 and antisense strand is independently modified with 2'-O-methyl nucleotide, 2’-deoxy nucleotide, 2'-deoxy-2’-fluoro nucleotide, 2'-O-N-methylacetamido (2'-O-NMA) nucleotide, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleotide, 2'-O-aminopropyl (2'-O-AP) nucleotide, or 2'-ara-F nucleotide. Again, it is to be understood that these modifications are in addition to the at least one thermally destabilizing 25 modification of the duplex present in the antisense strand. In some embodiments, the dsRNA molecule of the disclosure comprises modifications of an alternating pattern, particular in the B1, B2, B3, B1’, B2’, B3’, B4’ regions. The term “alternating motif” or “alternative pattern” as used herein refers to a motif having one or more modifications, each modification occurring on alternating 30 nucleotides of one strand. The alternating nucleotide may refer to one per every other nucleotide or one per every three nucleotides, or a similar pattern. For example, if A, B and C each represent one type of modification to the nucleotide, the alternating motif 2026204572  15 Jun 2026 can be “ABABABABABAB...,” “AABBAABBAABB ..,” “AABAABAABAAB..,” “AAABAAABAAAB...,” “AAABBBAAABBB.,” or “ABCABCABCABC.,” etc. The type of modifications contained in the alternating motif may be the same or different. For example, if A, B, C, D each represent one type of modification on the 5 nucleotide, the alternating pattern, i.e., modifications on every other nucleotide, may be the same, but each of the sense strand or antisense strand can be selected from several possibilities of modifications within the alternating motif such as “ABABAB.”, “ACACAC.” “BDBDBD.” or “CDCDCD.,” etc. In some embodiments, the dsRNA molecule of the disclosure comprises the 10 modification pattern for the alternating motif on the sense strand relative to the modification pattern for the alternating motif on the antisense strand is shifted. The shift may be such that the modified group of nucleotides of the sense strand corresponds to a differently modified group of nucleotides of the antisense strand and vice versa. For example, the sense strand when paired with the antisense strand in the dsRNA duplex, 15 the alternating motif in the sense strand may start with “ABABAB” from 5’-3’ of the strand and the alternating motif in the antisense strand may start with “BABABA” from 3’-5’of the strand within the duplex region. As another example, the alternating motif in the sense strand may start with “AABBAABB” from 5’-3’ of the strand and the alternating motif in the antisense strand may start with “BBAABBAA” from 3’-5’of the 20 strand within the duplex region, so that there is a complete or partial shift of the modification patterns between the sense strand and the antisense strand. The dsRNA molecule of the disclosure may further comprise at least one phosphorothioate or methylphosphonate internucleotide linkage. The phosphorothioate or methylphosphonate internucleotide linkage modification may occur on any nucleotide 25 of the sense strand or antisense strand or both in any position of the strand. For instance, the internucleotide linkage modification may occur on every nucleotide on the sense strand and / or antisense strand; each internucleotide linkage modification may occur in an alternating pattern on the sense strand or antisense strand; or the sense strand or antisense strand comprises both internucleotide linkage modifications in an alternating 30 pattern. The alternating pattern of the internucleotide linkage modification on the sense strand may be the same or different from the antisense strand, and the alternating pattern of the internucleotide linkage modification on the sense strand may have a shift relative 2026204572  15 Jun 2026 to the alternating pattern of the internucleotide linkage modification on the antisense strand. In some embodiments, the dsRNA molecule comprises the phosphorothioate or methylphosphonate internucleotide linkage modification in the overhang region. For 5 example, the overhang region comprises two nucleotides having a phosphorothioate or methylphosphonate internucleotide linkage between the two nucleotides. Internucleotide linkage modifications also may be made to link the overhang nucleotides with the terminal paired nucleotides within duplex region. For example, at least 2, 3, 4, or all the overhang nucleotides may be linked through phosphorothioate or methylphosphonate 10 internucleotide linkage, and optionally, there may be additional phosphorothioate or methylphosphonate internucleotide linkages linking the overhang nucleotide with a paired nucleotide that is next to the overhang nucleotide. For instance, there may be at least two phosphorothioate internucleotide linkages between the terminal three nucleotides, in which two of the three nucleotides are overhang nucleotides, and the 15 third is a paired nucleotide next to the overhang nucleotide. Preferably, these terminal three nucleotides may be at the 3’-end of the antisense strand. In some embodiments, the sense strand of the dsRNA molecule comprises 1-10 blocks of two to ten phosphorothioate or methylphosphonate internucleotide linkages separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 phosphate 20 internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is placed at any position in the oligonucleotide sequence and the said sense strand is paired with an antisense strand comprising any combination of phosphorothioate, methylphosphonate and phosphate internucleotide linkages or an antisense strand comprising either phosphorothioate or methylphosphonate or phosphate 25 linkage. In some embodiments, the antisense strand of the dsRNA molecule comprises two blocks of two phosphorothioate or methylphosphonate internucleotide linkages separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate 30 internucleotide linkages is placed at any position in the oligonucleotide sequence and the said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate and phosphate internucleotide linkages or an 2026204572  15 Jun 2026 antisense strand comprising either phosphorothioate or methylphosphonate or phosphate linkage. In some embodiments, the antisense strand of the dsRNA molecule comprises two blocks of three phosphorothioate or methylphosphonate internucleotide linkages 5 separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is placed at any position in the oligonucleotide sequence and the said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate and phosphate internucleotide linkages or an 10 antisense strand comprising either phosphorothioate or methylphosphonate or phosphate linkage. In some embodiments, the antisense strand of the dsRNA molecule comprises two blocks of four phosphorothioate or methylphosphonate internucleotide linkages separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 phosphate internucleotide 15 linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is placed at any position in the oligonucleotide sequence and the said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate and phosphate internucleotide linkages or an antisense strand comprising either phosphorothioate or methylphosphonate or phosphate linkage. 20          In some embodiments, the antisense strand of the dsRNA molecule comprises two blocks of five phosphorothioate or methylphosphonate internucleotide linkages separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is placed at any position in the oligonucleotide sequence and the said antisense strand is 25 paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate and phosphate internucleotide linkages or an antisense strand comprising either phosphorothioate or methylphosphonate or phosphate linkage. In some embodiments, the antisense strand of the dsRNA molecule comprises two blocks of six phosphorothioate or methylphosphonate internucleotide linkages 30 separated by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is placed at any position in the oligonucleotide sequence and the said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate and 2026204572  15 Jun 2026 phosphate internucleotide linkages or an antisense strand comprising either phosphorothioate or methylphosphonate or phosphate linkage. In some embodiments, the antisense strand of the dsRNA molecule comprises two blocks of seven phosphorothioate or methylphosphonate internucleotide linkages 5 separated by 1, 2, 3, 4, 5, 6, 7 or 8 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is placed at any position in the oligonucleotide sequence and the said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate and phosphate internucleotide linkages or an antisense strand comprising either 10 phosphorothioate or methylphosphonate or phosphate linkage. In some embodiments, the antisense strand of the dsRNA molecule comprises two blocks of eight phosphorothioate or methylphosphonate internucleotide linkages separated by 1, 2, 3, 4, 5 or 6 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is placed at any 15 position in the oligonucleotide sequence and the said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate and phosphate internucleotide linkages or an antisense strand comprising either phosphorothioate or methylphosphonate or phosphate linkage. In some embodiments, the antisense strand of the dsRNA molecule comprises 20 two blocks of nine phosphorothioate or methylphosphonate internucleotide linkages separated by 1, 2, 3 or 4 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is placed at any position in the oligonucleotide sequence and the said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate and 25 phosphate internucleotide linkages or an antisense strand comprising either phosphorothioate or methylphosphonate or phosphate linkage. In some embodiments, the dsRNA molecule of the disclosure further comprises one or more phosphorothioate or methylphosphonate internucleotide linkage modification within 1-10 of the termini position(s) of the sense and / or antisense strand. 30 For example, at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleotides may be linked through phosphorothioate or methylphosphonate internucleotide linkage at one end or both ends of the sense and / or antisense strand. 2026204572  15 Jun 2026 In some embodiments, the dsRNA molecule of the disclosure further comprises one or more phosphorothioate or methylphosphonate internucleotide linkage modification within 1-10 of the internal region of the duplex of each of the sense and / or antisense strand. For example, at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleotides may be 5 linked through phosphorothioate methylphosphonate internucleotide linkage at position 8-16 of the duplex region counting from the 5’-end of the sense strand; the dsRNA molecule can optionally further comprise one or more phosphorothioate or methylphosphonate internucleotide linkage modification within 1-10 of the termini position(s). 10          In some embodiments, the dsRNA molecule of the disclosure further comprises one to five phosphorothioate or methylphosphonate internucleotide linkage modification(s) within  position  1-5 and one to five phosphorothioate  or methylphosphonate internucleotide linkage modification(s) within position 18-23 of the sense strand (counting from the 5’-end), and one to five phosphorothioate or 15 methylphosphonate internucleotide linkage modification at positions 1 and 2 and one to five within positions 18-23 of the antisense strand (counting from the 5’-end). In some embodiments, the dsRNA molecule of the disclosure further comprises one phosphorothioate internucleotide linkage modification within position 1-5 and one phosphorothioate or methylphosphonate internucleotide linkage modification within 20 position 18-23 of the sense strand (counting from the 5’-end), and one phosphorothioate internucleotide linkage modification at positions 1 and 2 and two phosphorothioate or methylphosphonate internucleotide linkage modifications within positions 18-23 of the antisense strand (counting from the 5’-end). In some embodiments, the dsRNA molecule of the disclosure further comprises 25 two phosphorothioate internucleotide linkage modifications within position 1-5 and one phosphorothioate internucleotide linkage modification within position 18-23 of the sense strand (counting from the 5’-end), and one phosphorothioate internucleotide linkage modification at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications within positions 18-23 of the antisense strand (counting from the 5’-end). 30          In some embodiments, the dsRNA molecule of the disclosure further comprises two phosphorothioate internucleotide linkage modifications within position 1-5 and two phosphorothioate internucleotide linkage modifications within position 18-23 of the sense strand (counting from the 5’-end), and one phosphorothioate internucleotide 2026204572  15 Jun 2026 linkage modification at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications within positions 18-23 of the antisense strand (counting from the 5’-end). In some embodiments, the dsRNA molecule of the disclosure further comprises 5 two phosphorothioate internucleotide linkage modifications within position 1-5 and two phosphorothioate internucleotide linkage modifications within position 18-23 of the sense strand (counting from the 5’-end), and one phosphorothioate internucleotide linkage modification at positions 1 and 2 and one phosphorothioate internucleotide linkage modification within positions 18-23 of the antisense strand (counting from the 10    5’-end). In some embodiments, the dsRNA molecule of the disclosure further comprises one phosphorothioate internucleotide linkage modification within position 1-5 and one phosphorothioate internucleotide linkage modification within position 18-23 of the sense strand (counting from the 5’-end), and two phosphorothioate internucleotide linkage 15 modifications at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications within positions 18-23 of the antisense strand (counting from the 5’-end). In some embodiments, the dsRNA molecule of the disclosure further comprises one phosphorothioate internucleotide linkage modification within position 1-5 and one within position 18-23 of the sense strand (counting from the 5’-end), and two 20 phosphorothioate internucleotide linkage modification at positions 1 and 2 and one phosphorothioate internucleotide linkage modification within positions 18-23 of the antisense strand (counting from the 5’-end). In some embodiments, the dsRNA molecule of the disclosure further comprises one phosphorothioate internucleotide linkage modification within position 1-5 (counting 25 from the 5’-end) of the sense strand, and two phosphorothioate internucleotide linkage modifications at positions 1 and 2 and one phosphorothioate internucleotide linkage modification within positions 18-23 of the antisense strand (counting from the 5’-end). In some embodiments, the dsRNA molecule of the disclosure further comprises two phosphorothioate internucleotide linkage modifications within position 1-5 30 (counting from the 5’-end) of the sense strand, and one phosphorothioate internucleotide linkage modification at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications within positions 18-23 of the antisense strand (counting from the 5’-end). 2026204572  15 Jun 2026 In some embodiments, the dsRNA molecule of the disclosure further comprises two phosphorothioate internucleotide linkage modifications within position 1-5 and one within position 18-23 of the sense strand (counting from the 5’-end), and two phosphorothioate internucleotide linkage modifications at positions 1 and 2 and one 5 phosphorothioate internucleotide linkage modification within positions 18-23 of the antisense strand (counting from the 5’-end). In some embodiments, the dsRNA molecule of the disclosure further comprises two phosphorothioate internucleotide linkage modifications within position 1-5 and one phosphorothioate internucleotide linkage modification within position 18-23 of the sense 10 strand (counting from the 5’-end), and two phosphorothioate internucleotide linkage modifications at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications within positions 18-23 of the antisense strand (counting from the 5’-end). In some embodiments, the dsRNA molecule of the disclosure further comprises two phosphorothioate internucleotide linkage modifications within position 1-5 and one 15 phosphorothioate internucleotide linkage modification within position 18-23 of the sense strand (counting from the 5’-end), and one phosphorothioate internucleotide linkage modification at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications within positions 18-23 of the antisense strand (counting from the 5’-end). In some embodiments, the dsRNA molecule of the disclosure further comprises 20 two phosphorothioate internucleotide linkage modifications at position 1 and 2, and two phosphorothioate internucleotide linkage modifications at position 20 and 21 of the sense strand (counting from the 5’-end), and one phosphorothioate internucleotide linkage modification at positions 1 and one at position 21 of the antisense strand (counting from the 5’-end). 25          In some embodiments, the dsRNA molecule of the disclosure further comprises one phosphorothioate internucleotide linkage modification at position 1, and one phosphorothioate internucleotide linkage modification at position 21 of the sense strand (counting from the 5’-end), and two phosphorothioate internucleotide linkage modifications at positions 1 and 2 and two phosphorothioate internucleotide linkage 30 modifications at positions 20 and 21 the antisense strand (counting from the 5’-end). In some embodiments, the dsRNA molecule of the disclosure further comprises two phosphorothioate internucleotide linkage modifications at position 1 and 2, and two phosphorothioate internucleotide linkage modifications at position 21 and 22 of the 2026204572  15 Jun 2026 sense strand (counting from the 5’-end), and one phosphorothioate internucleotide linkage modification at positions 1 and one phosphorothioate internucleotide linkage modification at position 21 of the antisense strand (counting from the 5’-end). In some embodiments, the dsRNA molecule of the disclosure further comprises 5 one phosphorothioate internucleotide linkage modification at position 1, and one phosphorothioate internucleotide linkage modification at position 21 of the sense strand (counting from the 5’-end), and two phosphorothioate internucleotide linkage modifications at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications at positions 21 and 22 the antisense strand (counting from the 5’-end). 10          In some embodiments, the dsRNA molecule of the disclosure further comprises two phosphorothioate internucleotide linkage modifications at position 1 and 2, and two phosphorothioate internucleotide linkage modifications at position 22 and 23 of the sense strand (counting from the 5’-end), and one phosphorothioate internucleotide linkage modification at positions 1 and one phosphorothioate internucleotide linkage 15 modification at position 21 of the antisense strand (counting from the 5’-end). In some embodiments, the dsRNA molecule of the disclosure further comprises one phosphorothioate internucleotide linkage modification at position 1, and one phosphorothioate internucleotide linkage modification at position 21 of the sense strand (counting from the 5’-end), and two phosphorothioate internucleotide linkage 20 modifications at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications at positions 23 and 23 the antisense strand (counting from the 5’-end). In some embodiments, compound of the disclosure comprises a pattern of backbone chiral centers. In some embodiments, a common pattern of backbone chiral centers comprises at least 5 internucleotidic linkages in the Sp configuration. In some 25 embodiments, a common pattern of backbone chiral centers comprises at least 6 internucleotidic linkages in the Sp configuration. In some embodiments, a common pattern of backbone chiral centers comprises at least 7 internucleotidic linkages in the Sp configuration. In some embodiments, a common pattern of backbone chiral centers comprises at least 8 internucleotidic linkages in the Sp configuration. In some 30 embodiments, a common pattern of backbone chiral centers comprises at least 9 internucleotidic linkages in the Sp configuration. In some embodiments, a common pattern of backbone chiral centers comprises at least 10 internucleotidic linkages in the Sp configuration. In some embodiments, a common pattern of backbone chiral centers 2026204572  15 Jun 2026 comprises at least 11 internucleotidic linkages in the Sp configuration. In some embodiments, a common pattern of backbone chiral centers comprises at least 12 internucleotidic linkages in the Sp configuration. In some embodiments, a common pattern of backbone chiral centers comprises at least 13 internucleotidic linkages in the 5 Sp configuration. In some embodiments, a common pattern of backbone chiral centers comprises at least 14 internucleotidic linkages in the Sp configuration. In some embodiments, a common pattern of backbone chiral centers comprises at least 15 internucleotidic linkages in the Sp configuration. In some embodiments, a common pattern of backbone chiral centers comprises at least 16 internucleotidic linkages in the 10 Sp configuration. In some embodiments, a common pattern of backbone chiral centers comprises at least 17 internucleotidic linkages in the Sp configuration. In some embodiments, a common pattern of backbone chiral centers comprises at least 18 internucleotidic linkages in the Sp configuration. In some embodiments, a common pattern of backbone chiral centers comprises at least 19 internucleotidic linkages in the 15 Sp configuration. In some embodiments, a common pattern of backbone chiral centers comprises no more than 8 internucleotidic linkages in the Rp configuration. In some embodiments, a common pattern of backbone chiral centers comprises no more than 7 internucleotidic linkages in the Rp configuration. In some embodiments, a common pattern of backbone chiral centers comprises no more than 6 internucleotidic linkages in 20 the Rp configuration. In some embodiments, a common pattern of backbone chiral centers comprises no more than 5 internucleotidic linkages in the Rp configuration. In some embodiments, a common pattern of backbone chiral centers comprises no more than 4 internucleotidic linkages in the Rp configuration. In some embodiments, a common pattern of backbone chiral centers comprises no more than 3 internucleotidic 25 linkages in the Rp configuration. In some embodiments, a common pattern of backbone chiral centers comprises no more than 2 internucleotidic linkages in the Rp configuration. In some embodiments, a common pattern of backbone chiral centers comprises no more than 1 internucleotidic linkages in the Rp configuration. In some embodiments, a common pattern of backbone chiral centers comprises no more than 8 30 internucleotidic linkages which are not chiral (as a non-limiting example, a phosphodiester). In some embodiments, a common pattern of backbone chiral centers comprises no more than 7 internucleotidic linkages which are not chiral. In some embodiments, a common pattern of backbone chiral centers comprises no more than 6 2026204572  15 Jun 2026 internucleotidic linkages which are not chiral. In some embodiments, a common pattern of backbone chiral centers comprises no more than 5 internucleotidic linkages which are not chiral. In some embodiments, a common pattern of backbone chiral centers comprises no more than 4 internucleotidic linkages which are not chiral. In some 5 embodiments, a common pattern of backbone chiral centers comprises no more than 3 internucleotidic linkages which are not chiral. In some embodiments, a common pattern of backbone chiral centers comprises no more than 2 internucleotidic linkages which are not chiral. In some embodiments, a common pattern of backbone chiral centers comprises no more than 1 internucleotidic linkages which are not chiral. In some 10 embodiments, a common pattern of backbone chiral centers comprises at least 10 internucleotidic linkages in the Sp configuration, and no more than 8 internucleotidic linkages which are not chiral. In some embodiments, a common pattern of backbone chiral centers comprises at least 11 internucleotidic linkages in the Sp configuration, and no more than 7 internucleotidic linkages which are not chiral. In some embodiments, a 15 common pattern of backbone chiral centers comprises at least 12 internucleotidic linkages in the Sp configuration, and no more than 6 internucleotidic linkages which are not chiral. In some embodiments, a common pattern of backbone chiral centers comprises at least 13 internucleotidic linkages in the Sp configuration, and no more than 6 internucleotidic linkages which are not chiral. In some embodiments, a common 20 pattern of backbone chiral centers comprises at least 14 internucleotidic linkages in the Sp configuration, and no more than 5 internucleotidic linkages which are not chiral. In some embodiments, a common pattern of backbone chiral centers comprises at least 15 internucleotidic linkages in the Sp configuration, and no more than 4 internucleotidic linkages which are not chiral. In some embodiments, the internucleotidic linkages in the 25 Sp configuration are optionally contiguous or not contiguous. In some embodiments, the internucleotidic linkages in the Rp configuration are optionally contiguous or not contiguous. In some embodiments, the internucleotidic linkages which are not chiral are optionally contiguous or not contiguous. In some embodiments, compound of the disclosure comprises a block is a 30 stereochemistry block. In some embodiments, a block is an Rp block in that each internucleotidic linkage of the block is Rp. In some embodiments, a 5’-block is an Rp block. In some embodiments, a 3’-block is an Rp block. In some embodiments, a block is an Sp block in that each internucleotidic linkage of the block is Sp. In some 2026204572  15 Jun 2026 embodiments, a 5’-block is an Sp block. In some embodiments, a 3’-block is an Sp block. In some embodiments, provided oligonucleotides comprise both Rp and Sp blocks. In some embodiments, provided oligonucleotides comprise one or more Rp but no Sp blocks. In some embodiments, provided oligonucleotides comprise one or more 5 Sp but no Rp blocks. In some embodiments, provided oligonucleotides comprise one or more PO blocks wherein each internucleotidic linkage in a natural phosphate linkage. In some embodiments, compound of the disclosure comprises a 5’-block is an Sp block wherein each sugar moiety comprises a 2’-F modification. In some embodiments, a 5’-block is an Sp block wherein each of internucleotidic linkage is a modified 10 internucleotidic linkage and each sugar moiety comprises a 2’-F modification. In some embodiments, a 5’-block is an Sp block wherein each of internucleotidic linkage is a phosphorothioate linkage and each sugar moiety comprises a 2’-F modification. In some embodiments, a 5’-block comprises 4 or more nucleoside units. In some embodiments, a 5’-block comprises 5 or more nucleoside units. In some embodiments, a 5’-block 15 comprises 6 or more nucleoside units. In some embodiments, a 5’-block comprises 7 or more nucleoside units. In some embodiments, a 3’-block is an Sp blo...

Claims

1. A double-stranded ribonucleic acid agent (RNAi) for inhibiting expression of an amyloidprecursor protein (APP) gene, wherein the RNAi agent comprises:(a) an antisense strand comprising at least the first 19 modified nucleotides of a sequence selected from the group consisting of:(i)    VPusUfsaggu(Tgn)ggaudTuUfcdGuagccsgsu (SEQ ID NO: 2742);(ii) VPusUfsaggu(Tgn)ggaudTuUfcguagccsgsu (SEQ ID NO: 2401);(iii)   VPuUfagdGu(Tgn)ggaudTuUfcdGuagccsgsu     (SEQ ID NO: 2429);(iv)   VPuUfagdGu(Tgn)ggaudTuUfcguagccsgsu (SEQ ID NO: 2808);(v)   VPusUfsaggu(Tgn)ggauuuUfcGfuagccsgsu (SEQ ID NO: 1869);(vi)   VPuUfaggu(Tgn)ggauuuUfcGfuagccsgsu  (SEQ ID NO: 2387);(vii)  VPusUfsaggu(Tgn)ggauuuUfcguagccsgsu  (SEQ ID NO: 2389);(viii)  VPusUfsaggu(Tgn)ggauuuUfcdGuagccsgsu (SEQ ID NO: 2391);(ix)   VPusUfsaggu(Tgn)ggauUfuUfcdGuagccsgsu     (SEQ ID NO: 2397);(x)   VPusUfsaggu(Tgn)ggauUfuUfcguagccsgsu (SEQ ID NO: 2405);(xi)   VPuUfagdGu(Tgn)ggauuuUfcguagccsgsu  (SEQ ID NO: 2425); and(xii)  VPuUfagdGu(Tgn)ggauuuUfcdGuagccsgsu (SEQ ID NO: 2427);whereina, g, c and u are 2‘-O-methyl (2‘-OMe) A, G, C, and U, respectively;s is a phosphorothioate linkage;Gf and Uf are 2‘-fluoro G and U, respectively;dG and dT are 2‘-deoxy G and T, respectively;(Tgn) is Thymidine-glycol nucleic acid (GNA) S-Isomer; andVP is 5’-vinyl phosphonate;(b) a sense strand that is substantially complementary to the antisense strand and forms a duplex region that is 14-30 nucleotide pairs in length; and(c) a targeting ligand that targets a receptor which mediates delivery to a CNS tissue, wherein the ligand is conjugated to the sense strand.

2. The double-stranded RNAi agent of claim 1, wherein:2026204572   15 Jun 2026(a) the antisense strand comprises at least the first 20 contiguous modified nucleotides of a sequence selected from the group consisting of (i) - (xii); and / or(b) the antisense strand comprises at least the first 21 contiguous modified nucleotides of a sequence selected from the group consisting of (i) - (xii).

3. The double-stranded RNAi agent of claim 1, wherein:(a) the antisense strand comprises, VPusUfsaggu(Tgn)ggaudTuUfcdGuagccsgsu (SEQ ID NO: 2742); and / or(b) the antisense strand consists of, VPusUfsaggu(Tgn)ggaudTuUfcdGuagccsgsu (SEQ ID NO: 2742).

4. The double-stranded RNAi agent of claim 1, wherein:(a) the antisense strand comprises, VPusUfsaggu(Tgn)ggauuuUfcGfuagccsgsu (SEQ ID NO: 1869); and / or(b) the antisense strand consists of, VPusUfsaggu(Tgn)ggauuuUfcGfuagccsgsu (SEQ ID NO: 1869).

5. The double stranded RNAi agent of any one of claims 1-3, wherein the sense strandcomprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence 5’-GGCUACGAAAAUCCAACCUAA-3’ (SEQ ID NO: 2735).

6. The double stranded RNAi agent of claim 5, wherein all of the nucleotides of the sensestrand are modified nucleotides.

7. The double stranded RNAi agent of claim 6, wherein:(a) at least one of the modified nucleotides is selected from the group consisting of a deoxynucleotide, a 3’-terminal deoxy-thymidine (dT) nucleotide, a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2’-amino-modified nucleotide, a 2’-2026204572   15 Jun 2026O-allyl-modified nucleotide, 2’-C-alkyl-modified nucleotide, 2’-hydroxy-modified nucleotide, a 2’-methoxyethyl modified nucleotide, a 2’-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a 5'-phosphorothioate group, a nucleotide comprising a 5'-methylphosphonate group, a nucleotide comprising a 5’ phosphate or 5’ phosphate mimic, a nucleotide comprising vinyl phosphate, a nucleotide comprising adenosine-glycol nucleic acid (GNA), a nucleotide comprising thymidineglycol nucleic acid (GNA) S-Isomer, a nucleotide comprising 2-hydroxymethyl-tetrahydrofurane-5-phosphate, a nucleotide comprising 2’-deoxythymidine-3’phosphate, a nucleotide comprising 2’-deoxyguanosine-3’-phosphate, and a terminal nucleotide linked to a cholesteryl derivative and a dodecanoic acid bisdecylamide group;(b) the modifications on the nucleotides of the sense strand are independently selected from the group consisting of LNA, glycol nucleic acid (GNA), HNA, CeNA, 2’-methoxyethyl, 2’-O-alkyl, 2’-O-allyl, 2’-C- allyl, 2’-fluoro, and 2’-deoxy; or(c) the sense strand modifications on the nucleotides are 2’-O-methyl, GNA, and 2’fluoro modifications.

8. The double stranded RNAi agent of any one of claims 1-7, wherein:(a) the duplex region is 19-21 nucleotide pairs in length;(b) the double stranded RNAi agent comprises 6-8 phosphorothioate internucleotide linkages; and / or(c)    the RNAi agent has a blunt end at the 5’-end of the antisense strand.

9. The double stranded RNAi agent of any one of claims 1-8, wherein:(a)    the duplex region is 19 nucleotide pairs in length;(b)    the duplex region is 20 nucleotide pairs in length; or(c)    the duplex region is 21 nucleotide pairs in length.

10. The double stranded RNAi agent of claim 8 or 9, wherein the double stranded RNAiagent comprises 6-8 phosphorothioate internucleotide linkages, and wherein:2026204572   15 Jun 2026(a) a phosphorothioate modification only occurs at a position in the last 5 nucleotides of a strand; and / or(b) the RNAi agent comprises two phosphorothioate internucleotide linkages between the terminal three nucleotides at both the 5’-end of the sense strand and at the 5’-end of the antisense strand.

11. The double stranded RNAi agent of any one of claims 8-10, wherein the double stranded RNAi agent has a blunt end at the 5’-end of the antisense strand, and wherein the antisense strand comprises a 3’ overhang of 2 nucleotides.

12. The double stranded RNAi agent of claim 11, wherein the 3’-end of the antisense strand comprises at least two phosphorothioate internucleotide linkages between the terminal three nucleotides, in which two of the three nucleotides are overhang nucleotides, and the third is a paired nucleotide next to the overhang nucleotide.

13. A method of inhibiting expression of an amyloid precursor protein (APP) gene in a cell, the method comprising:(a)    introducing into the cell the double stranded RNAi agent of any one of claims 1-12; and(b)    maintaining the cell produced in step (a) for a time sufficient to obtain degradation of themRNA transcript of an APP gene, thereby inhibiting expression of the APP gene in the cell.

14. Use of the double stranded RNAi agent of any one of claims 1-12 in the manufacture of a medicament for inhibiting expression of an amyloid precursor protein (APP) gene in a cell,wherein the medicament is to be introduced into the cell, andwherein the cell is maintained for a time sufficient to obtain degradation of the mRNA transcript of an APP gene, thereby inhibiting expression of the APP gene in the cell.

15. The method of claim 13 or the use of claim 14, wherein said cell is within a subject.2026204572   15 Jun 202616. The method or use of claim 15, wherein the subject is a human.

17. The method or use of claim 16, wherein the human subject suffers from an APP-associated disorder.

18. A method of treating a human subject having an APP-associated disorder, comprising administering to the subject a therapeutically effective amount of the double stranded RNAi agent of any one of claims 1-12, thereby treating said subject.

19. Use of the double stranded RNAi agent of any one of claims 1-12 in the manufacture of a medicament for treating a human subject having an APP-associated disorder.

20. The method or use of any one of claims 17-19, wherein the APP-associated disorder is cerebral amyloid angiopathy (CAA).

21. The method or use of any one of claims 17-19, wherein the APP-associated disorder is early onset familial Alzheimer disease (EOFAD).

22. The method or use of any one of claims 17-19, wherein the APP-associated disorder is Alzheimer’s disease (AD).

23. The method or use of any one of claims 15-22, wherein an additional therapeutic agent is administered or to be administered to the subject.

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