MICROTUBULE ASSOCIATED PROTEIN TAU (MAPT) iRNA FORMULATIONS AND METHODS OF USE THEREOF

Abstract

The disclosure relates to formulations of double stranded ribonucleic acid (dsRNAi) agents targeting a MAPT gene, as well as methods of inhibiting expression of a MAPT gene and methods of treating subjects having a MAPT-associated neurodegenerative disease or disorder, e.g., Alzheimer's disease, FTD, PSP, or other tauopathy, using such dsRNAi agent formulations.

Description

[0001]Atty Dkt No.: A1088681840WO / ALN-535-WO MICROTUBULE ASSOCIATED PROTEIN TAU (MAPT) iRNA FORMULATIONS AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 708,234, filed on October 16, 2024. The entire contents of the foregoing application are hereby incorporated herein by reference. SEQUENCE LISTING The instant application contains a Sequence Listing which has been filed electronically in eXtensible Markup Language (XML) format and is hereby incorporated by reference in its entirety. Said XML copy, created on October 13, 2025, is named A108868_1840WO_SL.xml and is 4,906,453 bytes in size. FIELD OF THE INVENTION The instant disclosure relates generally to improved formulations for oligonucleotide, e.g., iRNA agent, delivery. methods of manufacture and methods for their use. BACKGROUND OF THE INVENTION The microtubule associated protein tau (MAPT) gene encoding the protein Microtubule- Associated Protein Tau (Mapt), a member of the microtubule-associated protein family, is located in the chromosomal region 17q21.31 (base pairs 45,894,382 to 46,028,334 on chromosome 17). The MAPT gene consists of 16 exons. Alternative mRNA splicing gives rise to six MAPT isoforms with a total of 352–441 amino acids. In three of the six MAPT isoforms, the microtubule- binding domain of MAPT contains three repeated segments, whereas the corresponding domain contains four repeated segments in the other three MAPT isoforms. MAPT transcripts are differentially expressed throughout the body, predominantly in the central and peripheral nervous system. Wild type Tau is involved in stabilizing microtubules in neuronal axons, maintaining dendric spines, and regulating axonal transport, microtubule dynamics, and cell division. Pathogenic variants of MAPT are found in approximately 10% of Page 1 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO patients with primary tauopathy. Variants are primarily missense mutations and localized in exons 9-13 (microtubule binding domains), with many affecting the alternative splicing of exon 10. Tauopathies are a heterogeneous class of progressive neurodegenerative disorders pathologically characterized by the presence of Tau aggregates in the brain. Phenotypically, tauopathies show variable progression of motor, cognitive, and behavioral impairment. Tauopathies include, but are not limited to, Alzheimer’s disease, frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). Tau is a major component of neurofibrillary tangles in the neuronal cytoplasm, a hallmark in Alzheimer’s disease. The aggregation and deposition of Tau were also observed in approximately 50% of the brains of patients with Parkinson’s disease. FTD includes, but is not limited to, behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and corticobasal syndrome (CBS). There are currently no curative therapies for tauopathies, and treatments are only aimed at alleviating the symptoms and improving the patient’s quality of life. Accordingly, there is a need for agents that can selectively and efficiently inhibit or adjust the expression of the MAPT gene such that subjects having a MAPT-associated disease or disorder, e.g., Alzheimer’s disease, FTD, PSP, or other tauopathy, can be effectively treated. BRIEF SUMMARY OF THE INVENTION The present disclosure, at least in part, provides formulations of MAPT dsRNA agents, as well as resultant drug product formulations, associated methods, kits and other compositions. In particular, the compositions herein may be administered via parenteral (e.g., injectable) administration. The present disclosure provides RNAi compositions, which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a MAPT gene. The MAPT gene may be within a cell, e.g., a cell within a subject, such as a human. The use of these iRNAs and formulations enables the targeted degradation of mRNAs of the corresponding gene (MAPT gene) in mammals. The present disclosure provides RNAi compositions, which effect the RNA- induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a MAPT gene. The MAPT gene may be within a cell, e.g., a cell within a subject, such as a human. The use of these iRNAs enables the targeted degradation of mRNAs of the corresponding gene (MAPT gene) in mammals. The present disclosure also provides methods of using the RNAi agent formulations of Page 2 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO the disclosure for inhibiting the expression of a MAPT gene or for treating a subject who would benefit from inhibiting or reducing the expression of a MAPT gene, e.g., a subject suffering or prone to suffering from a MAPT-associated disease or disorder, e.g., such as Alzheimer’s disease, FTD, PSP, or other tauopathy. In one aspect, the present disclosure provides a formulation comprising a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of microtubule associated protein tau (MAPT), wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand and the antisense strand are each represented by a dsRNA listed in Table 1, and wherein the antisense strand is present at no less than equimolar amount or at about a 1% to about a 2% excess relative to the sense strand. In one embodiment, the formulation comprises a dsRNA for inhibiting expression of microtubule associated protein tau (MAPT), wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein (a) the sense strand comprises the nucleotide sequence and all the modifications of 5’ Gm-ps-Um-ps-Gm-Am-Cm-(Chd)-Cm-Am-Af-Gf-Cf-Um-Cm-Gm-Um-Am-Um- Gm-Gm-ps-Um-ps-Am 3’ (SEQ ID NO: 1); and (b) the antisense strand comprises the nucleotide sequence and all the modifications of 5’ VPu-ps-Af-ps-Cm-Cm-dA-Um-dA-Cm-Gm-Am-Gm-Cm-Um-Uf-Gm-Gf-Gm-Um- Cm-Am-Cm-ps-Gm-ps-Um 3’ (SEQ ID NO: 2), wherein Af is 2’-fluoroadenosine, Uf is 2’- fluorouridine, Cf is 2’-fluorocytidine, Gf is 2’-fluoroguanosine, Am is 2’-O-methyladenosine, Um is 2’-O-methyluridine, Cm is 2’-O-methylcytidine, Gm is 2’-O-methylguanosine, dA is 2’- deoxyadenosine, Chd is 2’-O-hexadecylcytidine, VPu is vinylphosphonate 2’-O-methyluridine, ’-’ (hyphen) is 3’-5’ phosphodiester linkage, ’-ps-’ is 3’-5’ phosphorothioate linkage, and wherein the antisense strand is present at no less than equimolar amount or at about a 1% to about a 2% excess relative to the sense strand. In some embodiments, the formulation comprises greater than 1 mg of the dsRNA agent per mL of the formulation, the formulation comprises greater than 5 mg of the dsRNA agent per mL of the formulation, the formulation comprises greater than 10 mg of the dsRNA agent per mL of the formulation, the formulation comprises greater than 25 mg of the dsRNA agent per mL of the formulation, the formulation comprises greater than 50 mg of the dsRNA agent per mL of the Page 3 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO formulation, the formulation comprises greater than 60 mg of the dsRNA agent per mL of the formulation, or the formulation comprises greater than 70 mg of the dsRNA agent per mL of the formulation. In some embodiments, the formulation comprises about 50 mg to about 70 mg of the dsRNA agent per mL of the formulation. In some embodiments, the formulation comprises about 60 mg of the dsRNA agent per mL of the formulation. In some embodiments, the formulation further comprises a sodium source, a potassium source, a magnesium source, and a calcium source. In some embodiments, the formulation further comprises a sodium source, a potassium source, a magnesium source, and / or a calcium source. In some embodiments, the formulation comprises sodium chloride, potassium chloride, magnesium chloride, and calcium chloride. In some embodiments, the formulation comprises sodium chloride, potassium chloride, magnesium chloride, and / or calcium chloride. In some embodiments, the formulation comprises sodium chloride at about 70 mM to about 100 mM. In some embodiments, the formulation comprises sodium chloride at about 85.50 mM. In some embodiments, the formulation comprises sodium chloride at about 85.50 mM ± 10%. In some embodiments, the formulation comprises sodium chloride at about 85.50 mM ± 5%. In some embodiments, the formulation comprises potassium chloride at about 1.0 mM to about 2.5 mM. In some embodiments, the formulation comprises potassium chloride at about 1.68 mM. In some embodiments, the formulation comprises potassium chloride at about 1.68 mM ± 10%. In some embodiments, the formulation comprises potassium chloride at about 1.68 mM ± 5%. In some embodiments, the formulation comprises magnesium chloride at about 0.1 mM to about 1.0 mM. In some embodiments, the formulation comprises magnesium chloride at about 0.45 mM. In some embodiments, the formulation comprises magnesium chloride at about 0.45 mM ± 10%. In some embodiments, the formulation comprises magnesium chloride at about 0.45 mM ± 5%. Page 4 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO In some embodiments, the formulation comprises calcium chloride at about 8.0 mM to about 25.0 mM. In some embodiments, the formulation comprises calcium chloride at about 15.6 mM. In some embodiments, the formulation comprises calcium chloride at about 15.6 mM ± 10%. In some embodiments, the formulation comprises calcium chloride at about 15.6 mM ± 5%. In some embodiments, the formulation has a pH between about 6 and about 10. In some embodiments, the pH of the formulation is between about 6.0 and about 8.0. In some embodiments, the pH of the formulation is between about 6.6. and about 7.0. In some embodiments, the formulation has an osmolality between about 200 and 400 mOsm / kg. In some embodiments, the osmolality of the formulation is about 300 mOsm / kg. In some embodiments, the osmolality of the formulation is about 300 mOsm / kg ± 10%. In some embodiments, the osmolality of the formulation is about 300 mOsm / kg ± 5%. In some embodiments, the formulation is a pharmaceutical formulation for intrathecal administration of the dsRNA agent to a subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is human. In one aspect, the present disclosure provides a formulation for intrathecal administration comprising: a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of microtubule associated protein tau (MAPT), wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand and the antisense strand are each represented by a dsRNA listed in Table 1; sodium chloride at about 70 mM to about 100 mM; potassium chloride at about 1.0 mM to about 2.5 mM; magnesium chloride at about 0.1 mM to about 1.0 mM; calcium chloride at about 8.0 mM to about 25.0 mM; a pH between about 6.0 and about 8.0; and an osmolality between about 200 and 400 mOsm / kg. In one embodiment, the formulation for intrathecal administration comprises (a) a dsRNA agent comprising a sense strand and an antisense strand, wherein the sense strand comprises the nucleotide sequence and all the modifications of Page 5 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO 5’ Gm-ps-Um-ps-Gm-Am-Cm-(Chd)-Cm-Am-Af-Gf-Cf-Um-Cm-Gm-Um-Am-Um- Gm-Gm-ps-Um-ps-Am 3’ (SEQ ID NO: 1) and the antisense strand comprises the nucleotide sequence and all the modifications of 5’ VPu-ps-Af-ps-Cm-Cm-dA-Um-dA-Cm-Gm-Am-Gm-Cm-Um-Uf-Gm-Gf-Gm-Um- Cm-Am-Cm-ps-Gm-ps-Um 3’ (SEQ ID NO: 2), wherein Af is 2’-fluoroadenosine, Uf is 2’- fluorouridine, Cf is 2’-fluorocytidine, Gf is 2’-fluoroguanosine, Am is 2’-O-methyladenosine, Um is 2’-O-methyluridine, Cm is 2’-O-methylcytidine, Gm is 2’-O-methylguanosine, dA is 2’- deoxyadenosine, Chd is 2’-O-hexadecylcytidine, VPu is vinylphosphonate 2’-O-methyluridine, ’-’ (hyphen) is 3’-5’ phosphodiester linkage, ’-ps-’ is 3’-5’ phosphorothioate linkage; (b) sodium chloride at about 70 mM to about 100 mM; (c) potassium chloride at about 1.0 mM to about 2.5 mM; (d) magnesium chloride at about 0.1 mM to about 1.0 mM; (e) calcium chloride at about 8.0 mM to about 25.0 mM; (f) a pH between about 6.0 and about 8.0; and (g) an osmolality between about 200 and 400 mOsm / kg. In some embodiments, the dsRNA agent is AD-1786708. In one aspect, the present disclosure provides a solid prepared by lyophilization of the formulation provided herein. In one aspect, the present disclosure provides a kit, comprising (a) the formulation of any one of claims 1-25, and (b) instructions for use, and (c) optionally, a means for administering the formulation to a subject. In one aspect, the present disclosure provides a method of treating a subject having a disease or disorder that would benefit from a reduction in expression of microtubule associated protein tau (MAPT), the method comprising administering to the subject a therapeutically effective amount of the formulation provided herein, thereby treating said subject. In some embodiments, the subject is a human. In some embodiments, the subject meets at least one diagnostic criterion for a MAPT- associated disease or disorder. In some embodiments, the subject has been diagnosed with a MAPT-associated disease or disorder. In some embodiments, the MAPT-associated disease or disorder is selected from the group consisting of Alzheimer disease, frontotemporal dementia (FTD), behavioral variant Page 6 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA- L), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick’s disease (PiD), argyrophilic grain disease (AGD), multiple system tauopathy with presenile dementia (MSTD), white matter tauopathy with globular glial inclusions (FTLD with GGIs), FTLD with MAPT mutations, neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, amyotrophic lateral sclerosis (ALS), corticobasal syndrome (CBS), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Parkinson’s disease, postencephalitic Parkinsonism, Niemann-Pick disease, Huntington disease, type 1 myotonic dystrophy, and Down syndrome (DS). In some embodiments, the MAPT expression is inhibited by at least about 30%, by at least 50%, or by at least 80% as compared to a control. In some embodiments, the dsRNA of the formulation is administered at a dose of about 0.1 mg / kg to about 50 mg / kg. In some embodiments, the formulation is administered to the subject intrathecally. In some embodiments, treating comprises amelioration or delay of at least one sign or symptom of the disease or disorder. In some embodiments, treating comprises prevention or delay of development or progression of the disease or disorder. In some embodiments, the MAPT-associated disease is characterized by one or more symptoms selected from the group consisting of cognitive dysfunction, memory impairment, speech impairment, gaze dysfunction, extrapyramidal symptoms, limb apraxia, akinesia, bradykinesia, rigidity, dystonia, and move impairment. In some embodiments, the method further comprises administering an additional therapeutic agent to the subject. In one aspect, the present disclosure provides a method of preventing development of a MAPT-associated disease or disorder in a subject meeting at least one diagnostic criterion for a MAPT-associated disease or disorder, the method comprising administering to the subject a therapeutically effective amount of the dsRNA agent provided herein, thereby preventing the Page 7 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO development of a MAPT-associated disease or disorder in the subject meeting at least one diagnostic criterion for a MAPT-associated disease or disorder. In some embodiments, the MAPT-associated disease or disorder is characterized by one or more symptoms selected from the group consisting of cognitive dysfunction, memory impairment, speech impairment, gaze dysfunction, extrapyramidal symptoms, limb apraxia, akinesia, bradykinesia, rigidity, dystonia, and move impairment. In some embodiments, the MAPT-associated disease or disorder is selected from the group consisting of Alzheimer disease, frontotemporal dementia (FTD), behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA- L), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick’s disease (PiD), argyrophilic grain disease (AGD), multiple system tauopathy with presenile dementia (MSTD), white matter tauopathy with globular glial inclusions (FTLD with GGIs), FTLD with MAPT mutations, neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, amyotrophic lateral sclerosis (ALS), corticobasal syndrome (CBS), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Parkinson’s disease, postencephalitic Parkinsonism, Niemann-Pick disease, Huntington disease, type 1 myotonic dystrophy, and Down syndrome (DS). In some embodiments, the subject is human. In some embodiments, the dsRNA agent is administered to the subject at a dose of about 0.01 mg / kg to about 50 mg / kg. In some embodiments, the dsRNA agent is administered to the subject intrathecally. In some embodiments, the method further comprises administering to the subject an additional agent or a therapy suitable for treatment or prevention of a MAPT-associated disease or disorder. In one aspect, the present disclosure provides a method of inhibiting the expression of microtubule associated protein tau (MAPT) in a subject, the method comprising administering to the subject a therapeutically effective amount of the formulation provided herein, thereby inhibiting the expression of MAPT in the subject. In some embodiments, the subject is a human. Page 8 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO In some embodiments, the expression of MAPT is inhibited by at least about 30%, by at least 50%, or by at least 80% in the subject as compared to a control. In some embodiments, the level of MAPT protein is decreased by at least about 30%, by at least 50%, or by at least 80% in the subject as compared to a control. In some embodiments, the subject has been diagnosed with a MAPT-associated disease or disorder. In some embodiments, the MAPT-associated disease or disorder is selected from the group consisting of Alzheimer disease, frontotemporal dementia (FTD), behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA- L), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick’s disease (PiD), argyrophilic grain disease (AGD), multiple system tauopathy with presenile dementia (MSTD), white matter tauopathy with globular glial inclusions (FTLD with GGIs), FTLD with MAPT mutations, neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, amyotrophic lateral sclerosis (ALS), corticobasal syndrome (CBS), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Parkinson’s disease, postencephalitic Parkinsonism, Niemann-Pick disease, Huntington disease, type 1 myotonic dystrophy, and Down syndrome (DS). In some embodiments, the dsRNA agent is administered to the subject at a dose of about 0.01 mg / kg to about 50 mg / kg. In some embodiments, the formulation is administered to the subject by intrathecal injection. In some embodiments, the method further comprises administering to the subject an additional agent or a therapy suitable for treatment or prevention of a MAPT-associated disease or disorder. In one aspect, the present disclosure provides a method for preparing a formulation. The method comprises annealing a sense strand and an antisense strand, wherein one of the sense strand and antisense strand contains a lipophilic modification, to form a duplex solution comprising a double stranded RNA (dsRNA); lyophilizing the duplex solution to provide a duplex composition; and dissolving the duplex composition in an injection solution, wherein the Page 9 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO injection solution comprises a divalent cation and does not comprise a phosphate buffer, wherein the duplex composition comprises no less than equimolar amount or about 1-2% molar excess of antisense strand over sense strand, and wherein the sense strand and the antisense strand are each represented by a dsRNA listed in Table 1. In one embodiment, the method includes annealing a sense strand and an antisense strand, wherein one of the sense strand and antisense strand contains a lipophilic modification, to form a duplex solution comprising a double stranded RNA (dsRNA); lyophilizing the duplex solution to provide a duplex composition; and dissolving the duplex composition in an injection solution, wherein the injection solution comprises a divalent cation and does not comprise a phosphate buffer, wherein the duplex composition comprises no less than equimolar amount or about 1-2% molar excess of antisense strand relative to sense strand, wherein the sense strand comprises the nucleotide sequence and all the modifications of 5’ Gm-ps-Um-ps-Gm-Am-Cm-(Chd)-Cm-Am-Af-Gf-Cf-Um-Cm-Gm-Um-Am-Um- Gm-Gm-ps-Um-ps-Am 3’ (SEQ ID NO: 1), wherein the antisense strand comprises the nucleotide sequence and all the modifications of 5’ VPu-ps-Af-ps-Cm-Cm-dA-Um-dA-Cm-Gm-Am-Gm-Cm-Um-Uf-Gm-Gf-Gm-Um- Cm-Am-Cm-ps-Gm-ps-Um 3’ (SEQ ID NO: 2), and wherein Af is 2’-fluoroadenosine, Uf is 2’- fluorouridine, Cf is 2’-fluorocytidine, Gf is 2’-fluoroguanosine, Am is 2’-O-methyladenosine, Um is 2’-O-methyluridine, Cm is 2’-O-methylcytidine, Gm is 2’-O-methylguanosine, dA is 2’- deoxyadenosine, Chd is 2’-O-hexadecylcytidine, VPu is vinylphosphonate 2’-O-methyluridine, ’-’ (hyphen) is 3’-5’ phosphodiester linkage, ’-ps-’ is 3’-5’ phosphorothioate linkage. In some embodiments, the divalent cation is calcium, magnesium, copper, nickel, zinc, or strontium. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 schematically depicts the structure of AD-1786708drug substance (DS). The sense strand A-3306553 (SEQ ID NO: 1) and the antisense strand A-3019137 (SEQ ID NO: 2) are shown. Page 10 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO FIG.2 schematically depicts the structure of AD-1786708. The sense strand (SEQ ID NO: 1) and antisense strand (SEQ ID NO: 2) are shown with the bases involved in a base pair formation connected with a centered dot. FIG.3 depicts an example chromatogram from the duplex annealing method showing the antisense strand (AS), sense strand (SS), and duplex peaks. The present disclosure is further illustrated by the following detailed description. DETAILED DESCRIPTION OF THE INVENTION The present disclosure, at least in part, provides drug product formulations, associated methods, and kits for CNS-directed delivery (e.g., via intrathecal injection) of dsRNA agents for inhibiting the expression of a microtubule associated protein Tau (MAPT) gene. In order to administer dsRNAs to a subject via parenteral administration, the dsRNA must be formulated into a suitable aqueous solution. In the course of research into preparing such formulations, it has been surprisingly discovered that MAPT dsRNAs having at least one lipophilic modification must be formulated in a particular way to avoid long-term stability problems. In particular, formulation of MAPT dsRNAs in the presence of a bivalent cation (e.g., calcium, magnesium, copper, nickel, zinc, or strontium) can result in problematic precipitation issues where the stoichiometry of the individual strands of a dsRNA in the formulation should be controlled to prevent precipitation of lipophilic molecules in the aqueous solution. The iRNAs of the invention have been designed to target a MAPT gene, e.g., a MAPT gene either with or without nucleotide modifications. The iRNAs of the invention inhibit the expression of the MAPT gene, and reduce the level of sense- and antisense-containing foci. Without intending to be limited by theory, it is believed that a combination or sub-combination of the foregoing properties and the specific target sites, or the specific modifications in these iRNAs confer to the iRNAs of the invention improved efficacy, stability, potency, durability, and safety. The use of these RNAi agents enables the targeted degradation and / or inhibition of mRNAs of a MAPT gene in mammals. Accordingly, the present disclosure also provides methods of using the RNAi compositions of the disclosure for inhibiting the expression of a MAPT gene or for treating a subject having a disorder that would benefit from inhibiting or reducing the expression of a MAPT Page 11 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO gene, e.g., a MAPT-associated disease or disorder, for example, Alzheimer’s disease, FTD, PSP, or other tauopathy. The following detailed description discloses how to make and use formulations containing RNAi agents to inhibit the expression of a MAPT gene, as well as formulations and methods for treating subjects having diseases and disorders that would benefit from inhibition or reduction of the expression of the genes. I. Definitions 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. 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. 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 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 values described herein refer to the exact values described as well as a range that is ± 10% or ± 5% of the value referenced, unless otherwise specified. The term “at least” prior to a number or series of numbers is understood to 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 Page 12 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO present before a series of 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” is understood as the value adjacent to the phrase and logical lower values or integers, 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 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. As used herein, ranges include both the upper and lower limit. In the event of a conflict between an indicated target site and the nucleotide sequence for a sense or antisense strand, the indicated sequence takes precedence. In the event of a conflict between a chemical structure and a chemical name, the chemical structure takes precedence. As used herein, “excess” is any amount of excess of one component over a second component. “excess” can be measured / estimated by non-denaturing Ion-pair reverse phase HPLC (nd-IPRP), which if not equivalent to, approximates molar excess. As such, herein the terms “molar excess” and “excess” are used interchangeably. For example, an excess of antisense strand over sense strand or an excess of sense strand over antisense strand. The molar excess can be any amount. The excess can be about a 1-2% molar excess, a 1-3% molar excess, a 1-4% molar excess, a 1-5% molar excess, a 0-5% molar excess, a 0-1% molar excess, a 2-3% molar excess, a 3-4% molar excess, a 3-5% molar excess, a 2-4% molar excess, a 2-5% molar excess, a 0-10% molar excess, a 5-10% molar excess, a 2-6% molar excess, a 3-7% molar excess, or a 4-8% molar excess of one component over a second component (e.g., of antisense strand over sense strand or sense strand over antisense strand). The term "inorganic phosphate", as used herein, refers to the total amount of free phosphate (PO43-) in a solution and / or composition of the instant disclosure, as determined by art- recognized means, including, e.g., taking a measured amount of an aqueous sample and adding ammonium heptamolybdate reagent in a mixing tube. The tube is then stoppered and vigorously shaken. Dilute stannous chloride reagent, which has been freshly prepared from concentrated stannous chloride reagent and distilled water, to the mixture in the tube. This will produce a blue color (due to the formation of molybdenum blue) and the depth of the blue color Page 13 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO indicates the amount of phosphate in the boiler water. The absorbance of the blue solution can be measured with a colorimeter and the concentration of phosphate in the original solution can be calculated. Alternatively, a direct (but approximate) reading of phosphate concentration can be obtained by using a Lovibond comparator. In certain embodiments, the total amount of inorganic phosphate is less than 100 parts per million (ppm), or is less than 0.64 µg / L. The term “MAPT” gene, also known as “DDPAC,” “FTDP-17,” “MAPTL,” “MSTD,” “MTBT1,” “MTBT2,” “PPND,” “PPP1R103,” “TAU,” and “microtubule-associated protein tau,” refers to the gene encoding for a protein called microtubule-associated protein tau (MAPT). The MAPT mRNA is expressed throughout the body, predominantly in the central nervous system (i.e., the brain and the spinal cord) and the peripheral nervous system. Wild type Tau is involved in stabilizing microtubules in neuronal axons, regulating axonal transport and microtubule dynamics, maintaining dendric spines, and contributing to genomic DNA integrity. Tauopathies are a heterogeneous class of progressive neurodegenerative disorders pathologically characterized by the presence of Tau aggregates in the brain. Intra- and extra- cellular neuronal Tau aggregates cause microtubule disassembly and axonal degeneration, impaired synaptic vesicle release, and prion-like inter-neuronal spread of tau aggregates called “seeding.” Phenotypically, tauopathies show variable progression of motor, cognitive, and behavioral impairment. Tauopathies include, but are not limited to, Alzheimer’s disease, the most common form of presenile dementia that primarily starts with selective memory impairment, and is associated with degeneration of the frontal lobe, temporal lobe (including hippocampus), and parietal lobe of the brain; frontotemporal dementia (FTD), the second most common form of presenile dementia associated with neuronal atrophy of the frontal and temporal lobes, exhibiting a spectrum of behavioral, language, and movement disorders; and progressive supranuclear palsy (PSP), degeneration of brainstem and basal ganglia, exhibiting gaze dysfunction, extrapyramidal symptoms (Parkinsonism symptoms including limb apraxia, akinesia / bradykinesia, rigidity, and dystonia), and cognitive dysfunction, affecting approximately 20,000 people in the United States. FTD further includes, but are not limited to, behavioral variant frontotemporal dementia (bvFTD), associated pathologically with progressive atrophy in the prefrontal and anterior temporal lobes, and clinically with alterations in complex thinking, personality, and behavior, Page 14 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO affecting approximately 30,000 people in the United states; primary progressive aphasia - semantic (PPA-S), degeneration of frontal and temporal lobes associated with difficulty comprehending words and struggle with naming; nonfluent variant primary progressive aphasia (nfvPPA), involving degeneration of left post frontal lobe and insula, and exhibiting poor grammar and inability to understand complex sentences, affecting approximately 1,000 people in the United States; primary progressive aphasia - logopenic (PPA-L), degeneration of the left post / spur temporal lobe and the medial parietal lobe, associated with difficulty retrieving words and frequent pauses; frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), associated pathologically with degeneration of the frontal and temporal lobes, and clinically with speech and movement impairment; Pick’s disease (PiD), degeneration of the frontal and temporal lobes, associated with difficulty in language and thinking and behavioral changes; FTD with motor neuron disease, involving degeneration of the cortex and motor neurons; and corticobasal syndrome (CBS), degeneration of posterior frontal and temporal lobes and basal ganglia [i.e., corticobasal degeneration (CBD)], exhibiting extrapyramidal symptoms (similar to those in Parkinson’s disease and PSP) and cognitive dysfunction, affecting approximately 2,000 people in the United States. Mutations of MAPT are reported in approximately 10% of patients with bvFTD, nfvPPA, CBS, and PSP, respectively. MAPT is a major component of neurofibrillary tangles in the neuronal cytoplasm, a hallmark in Alzheimer’s disease. The aggregation and deposition of MAPT were also observed in approximately 50% of the brains of patients with Parkinson’s disease. Involvement of Tau is indicated in the pathogenesis of other diseases including, but not limited to, argyrophilic grain disease (AGD), multiple system tauopathy with presenile dementia (MSTD), white matter tauopathy with globular glial inclusions (FTLD with GGIs), FTLD with MAPT mutations, neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, amyotrophic lateral sclerosis (ALS), postencephalitic Parkinsonism, Niemann-Pick disease, Huntington disease, type 1 myotonic dystrophy, and Down syndrome (DS). The MAPT gene consists of 16 exons (E1-E16). Alternative mRNA splicing of E2, E3, and E10 gives rise to six tau isoforms (352-441 amino acids). E1, E4, E5, E7, E9, E11, E12, E13 are the constitutively spliced exons. E6 and E8 are not transcribed in human brain. E4a is only Page 15 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO expressed in the peripheral nervous system. E0 (part of the promotor) and E14 are noncoding exons. Pathogenic variants in MAPT are found in approximately 10% of patients with primary tauopathy. Variants are primarily missense and localized in exons 9-13 (microtubule binding domains), with many affecting the alternative splicing of exon 10. Examples of coding region mutations include R5H and R5L in E1; K257T, I260V, L266V, G272V, and G273R in E9; N279K, L284L, ΔN296, N296N, N296H, ΔN298, P301L, P301S, P301T, G303V, G304S, S305I, S305N, and S305S in E10; L315R, K317M, S320F, P332S in E11; G335S, G335V, Q336R, V337M, E342V, S352L, S356T, V363I, P364S, G366R, and K369I in E12; G389R, R406W, and T427M in E13 of the MAPT gene. MAPT (tau) null (- / -) humans are likely non-viable. The MAPT heterozygote (+ / -) humans have unclear or unknown phenotypes. The MAPT over-expressing (+ / + / +) humans are associated with early onset dementia, FTD, PSP, and CBD. Each of the six isoforms of the MAPT (tau) protein contains three or four repeated segments (R1, R2, R3, and R4) in its microtubule-binding domain. Each repeat is 31 or 32 amino acids in length. Splicing of E9, E10, E11, and E12 gives rise to the R1, R2, R3, and R4, respectively, of the repeated segments in the MAPT’s microtubule-binding domain. Three MAPT (tau) isoforms, in which E10 is spliced in, contain four repeated segments (4R), whereas the other three MAPT isoforms, in which E10 is spliced out, contain three repeated segments (3R). Translation of E2 and E3 give rise to the N1 and N2 segments, respectively. Alternative splicing of E2 and E3 gives rise to tau isoforms 0N (E2 and E3 are spliced out, resulting in no N segment), 1N (E2 is spliced in and E3 is spliced out, resulting in one N segment), and 2N (E2 and E3 are spliced in, resulting in two N segments). Accordingly, the six MAPT (tau) isoforms resulting from alternative splicing are 2N4R, 1N4R, 0N4R, 2N3R, 1N3R, and 0N3R. In healthy individuals, the 3R and 4R MAPT transcript isoforms exist in 1:1 ratio. The 3R / 4R isoform ratio is skewed in disease states and the ratio predicts the tau aggregate type. The assembly of four-repeat tau into filaments is characteristic of PSP, CBD, argyrophilic grain disease (AGD), multiple system tauopathy with presenile dementia (MSTD), and white matter tauopathy with globular glial inclusions (FTD with GGIs), which belong to the FTD spectrum (4R tauopathy). In contrast, in Pick’s disease, three-repeat tau predominates in the neuronal inclusions (3R tauopathy). In Alzheimer’s disease, or other neurodegenerative diseases with Page 16 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO neurofibrillary tangles (NFT dementia), both three- and four-repeat tau isoforms make up the neurofibrillary lesions (3 / 4R tauopathy). FTLD with MAPT mutations can be 3R, 4R, or 3 / 4R tauopathy. FTD with motor neuron disease is associated with the FTLD-TDP43 and FTLD-FUS pathology. It is associated with gene mutations of C9ORF72, FUS, TARDBP, and VCP. bvFTD is associated with the FTLD-Tau (3R) and FTLD-TDP43 pathology. Ten percent of the cases involve MAPT mutation. It is associated with gene mutations of C9ORF72, GRN, and VCP. PPA-S may be sporadic. It is associated with the FTLD-TDP43 pathology. nfvPPA is associated with the FTLD-Tau (4R), Alzheimer’s disease, and FTLD-TDP43 pathology, in the order of significance. Ten percent of the cases involve MAPT mutation. nfvPPA is further associated with mutations of GRN. PPA-L may be sporadic. It is associated with the Alzheimer’s disease and FTLD-Tau pathology, in the order of significance. CBS is associated with the FTLD-Tau (4R) and Alzheimer’s disease pathology, in the order of significance. Ten percent of the case is associated with MAPT mutation. The rest of the cases may be sporadic. PSP involves FTLD-Tau (4R) pathology. Ten percent of the case is associated with MAPT mutation. The rest of the cases may be sporadic. Tauopathy generally starts at age 60-80 years, and affects the remaining lifespan of 6-10 years. Tauopathies are phenotypically heterogeneous, with variable involvement of motor, cognitive, and behavioral impairment. In particular, progression of motor symptoms is variable. There are currently no approved disease-modifying therapies for tauopathies. Available treatments are only aimed at alleviating the symptoms and improving the patient’s quality of life as the disease progresses. Drugs in preclinical or clinical development include active and passive immunotherapies; inhibitors of O-deglycosylation, aggregation, kinases, acetylation, caspases or tau expression; phosphatase activators; microtubule stabilizers; and modulators of autophagy or proteosomal degradation. Biomarkers and testing used in clinical trials to assess tauopathy include tau protein phosphorylated at threonine 181 (pTau), total tau protein (tTau), neurofilament light chain (NfL), and volumetric MRI (vMRI). Page 17 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO Exemplary nucleotide and amino acid sequences of MAPT are found, for example, at GenBank Accession No. NM_016841.4 (Homo sapiens MAPT variant 4, SEQ ID NO: 510, reverse complement, SEQ ID NO: 511); GenBank Accession No. NM_005910 (Homo sapiens MAPT variant 2, SEQ ID NO: 512, reverse complement, SEQ ID NO: 513); GenBank Accession No. NM_001038609.2 (Mus musculus MAPT, SEQ ID NO: 514; reverse complement, SEQ ID NO: 515); GenBank Accession No.: XM_005584540.1 (Macaca fascicularis MAPT variant X13, SEQ ID NO: 516, reverse complement, SEQ ID NO: 517); GenBank Accession No.: XM_008768277.2 (Rattus norvegicus MAPT, variant X7, SEQ ID NO: 518, reverse complement, SEQ ID NO: 519) and GenBank Accession No.: XM_005624183.3 (Canis lupus MAPT variant X23, SEQ ID NO: 520, reverse complement, SEQ ID NO: 521). The nucleotide sequence of the genomic region of human chromosome harboring the MAPT gene may be found in, for example, the Genome Reference Consortium Human Build 38 (also referred to as Human Genome build 38 or GRCh38) available at GenBank. The nucleotide sequence of the genomic region of human chromosome 17 harboring the MAPT gene may also be found at, for example, GenBank Accession No. NC_000017.11, corresponding to nucleotides 45894382-46028334 of human chromosome 17. The nucleotide sequence of the human MAPT gene may be found in, for example, GenBank Accession No. NG_007398.2. Further examples of MAPT sequences are found in publically available databases, for example, GenBank, OMIM, and UniProt. Additional information on MAPT are found, for example, at the NCBI web site that refers to gene 100128977. The term MAPT as used herein also refers to variations of the MAPT gene including variants provided in the clinical variant database, for example, at the NCBI clinical variants web site that refers to the term mapt. The entire contents of each of the foregoing GenBank Accession numbers and the Gene database numbers are incorporated herein by reference as of the date of filing this application. As used herein, “target sequence” refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a target gene, including mRNA that is a product of RNA processing of a primary transcription product. In one embodiment, 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 Page 18 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO the transcription of a target gene. In one embodiment, the target sequence is within the protein coding region of the target gene. In another embodiment, the target sequence is within the 3’ UTR of the target gene. 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, 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, 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. In some embodiments, the target sequence is about 19 to about 30 nucleotides in length. In other embodiments, the target sequence is about 19 to about 25 nucleotides in length. In still other embodiments, the target sequence is about 19 to about 23 nucleotides in length. In some embodiments, the target sequence is about 21 to about 23 nucleotides in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure. 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 in the context of a modified or unmodified nucleotide. However, it will be understood that the term “ribonucleotide” or “nucleotide” can also refer to a modified nucleotide, as further detailed below, or a surrogate replacement moiety. 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 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 with guanine and uracil, respectively to form G-U Wobble Page 19 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO base pairing with the target mRNA. Sequences containing such replacement moieties are suitable for the compositions and methods featured in the disclosure. The oligonucleotides used in the formulations and methods 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,” “dsRNA”, “RNAi”, “iRNA”, or “iRNA agent”. The term “dsRNA” refers to a complex of one or more (e.g., two) ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary nucleic acid portions (e.g., strands), referred to as having “sense” and “antisense” orientations with respect to a target RNA, i.e., a MAPT 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 interference or RNAi. In one embodiment, the dsRNA contains two separate strands that form the duplex structure. In another embodiment, the dsRNA is a single oligonucleotide having two separate portions that form the duplex structure, the two portions being part of a hairpin or dumbbell type structure. Hairpin and dumbbell type oligomeric compounds may have a duplex region equal to, or at least, 14, 15, 15, 16, 17, 18, 19, 29, 21, 22, 23, 24, or 25 nucleotide pairs. In some embodiments, the duplex region can be equal to or less than 200, 100, or 50, in length. In some embodiments, ranges for the duplex region are 15-30, 17 to 23, 19 to 23, and 19 to 21 nucleotides pairs in length. In some embodiments, the hairpin oligomeric compounds can have a single strand overhang or terminal unpaired region, in some embodiments at the 3’, and in some embodiments on the antisense side of the hairpin. In some embodiments, the overhangs are 1-4, more generally 2-3 nucleotides in length. The hairpin oligomeric compounds that can induce RNA interference are also referred to as "shRNA" herein. In general, a dsRNA molecule can include ribonucleotides, but as described in detail herein, each or both strands can also include one or more non-ribonucleotides, e.g., a deoxyribonucleotide, a modified nucleotide. In addition, as used in this specification, an “RNAi agent” may include 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, or a modified nucleobase, or a combination thereof. Thus, the term modified nucleotide encompasses Page 20 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO substitutions, additions or removal of, e.g., a functional group 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. As used herein, the term "2’-deoxynucleotide" refers to a 2’-deoxyribonucleotide, or to a 2’-deoxy nucleotide including a ribose analog. In certain embodiments, a "2’-deoxynucleotide" refers to a 2’-deoxyribonucleotide. It is understood that, when present within an RNAi agent, a 2’-deoxy modification is considered a modified nucleotide. In one embodiment, an RNAi agent of the disclosure is a dsRNA agent, each strand of which comprises 19-23 nucleotides that interacts with a MAPT RNA sequence to direct the cleavage of the target RNA. Without wishing 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., (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., (2001) Genes Dev. 15: 188). In one embodiment, an RNAi agent of the disclosure is a dsRNA of 24-30 nucleotides that interacts with a MAPT RNA sequence to direct the cleavage of the target RNA. The term “antisense strand” or "guide strand" refers to the strand of an RNAi agent, e.g., a dsRNA, which includes a region that is substantially complementary to a target sequence, e.g., an MAPT mRNA. 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 MAPT 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 Page 21 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO of the molecule. Generally, the most tolerated mismatches are in the terminal regions, e.g., within 5, 4, 3, or 2 nucleotides of the 5’- or 3’-terminus of the RNAi agent. In some embodiments, a double stranded RNA agent of the disclosure includes a nucleotide mismatch in the antisense strand. The term “sense strand” or "passenger strand" as used herein, refers to the strand of an 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, 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 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., “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. Complementary sequences within an 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 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 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 Page 22 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO regarded as mismatches with regard to 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. “Complementary” sequences, as used herein, can also include, or be formed entirely from, non-Watson-Crick base pairs 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. 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 an 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 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 a target protein). For example, a polynucleotide is complementary to at least a part of a target gene mRNA if the sequence is substantially complementary to a non-interrupted portion of an mRNA encoding MAPT. Accordingly, in some embodiments, the antisense strand polynucleotides disclosed herein are fully complementary to the target MAPT sequence. In one embodiment, at least partial suppression of the expression of a MAPT gene, is assessed by a reduction of the amount of MAPT mRNA which can be isolated from or detected in a first cell or group of cells in which a MAPT gene is transcribed and which has or have been treated such that the expression of a MAPT 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: Page 23 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO 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 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. 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 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 or be coupled to a ligand, e.g., a lipophilic moiety or moieties as described below and further detailed, e.g., in PCT / US2019 / 031170, which is incorporated herein by reference, that directs or otherwise stabilizes the RNAi agent at a site of interest, e.g., the CNS. In some embodiments, the RNAi agent may contain or be coupled to a ligand, e.g., one or more GalNAc derivatives as described below, that directs or otherwise stabilizes the RNAi agent at a site of interest, e.g., the liver. In other embodiments, the RNAi agent may contain or be coupled to a lipophilic moiety or moieties and one or more GalNAc derivatives. 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 an RNAi agent includes “introducing” or “delivering the RNAi agent into the cell” by facilitating or effecting uptake or absorption into the cell. Absorption or uptake of an RNAi agent can occur through unaided diffusive or active cellular processes, or by auxiliary agents or devices. Introducing an RNAi agent into a cell may be in vitro or in vivo. For example, for in vivo introduction, an 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 electroporation and lipofection. Further approaches are described herein below or are known in the art. Page 24 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO The term “artificial cerebrospinal fluid (aCSF)” refers to a solution prepared with a composition representative of human cerebrospinal fluid (hCSF) that closely matches the electrolyte concentrations of hCSF, and may include glucose. Exemplary ion concentrations, as prepared in high purity water, include (in mM): Na+150; K+3.0; Ca2+1.4; Mg2+0.8; P 1.0; Cl- 155 (for example, Tocris Bioscience™ ACSF, Cat. No. 3525, available from Thermo Fisher Scientific, Hampton, NH, USA). An example aCSF formulation includes 127 mM NaCl; 1.0 mM KCl; 1.2 mM KH2PO4; 26 mM NaHCO3; 10 mM D-glucose; 2.4 mM CaCl2; and 1.3 mM MgCl2, with the pH and oxygen level stabilized by bubbling with carbogen (95% O2 and 5% CO2). A solution is considered “isotonic to aCSF” when its effective osmole concentration is the same as that of aCSF. For example, the solutions on either side of a cell membrane are isotonic if the concentration of solutes outside the cell is equal to the concentration of solutes inside the cell. 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), or a non-primate (such as a rat, or a mouse). In a preferred 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 in MAPT expression; a human at risk for a disease, disorder, or condition that would benefit from reduction in MAPT expression; a human having a disease, disorder, or condition that would benefit from reduction in MAPT expression; or human being treated for a disease, disorder, or condition that would benefit from reduction in MAPT expression as described herein. 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 signs or symptoms associated with MAPT gene expression or MAPT protein production, e.g., MAPT-associated disease or disorder, e.g., Alzheimer disease, frontotemporal dementia (FTD), behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA- L), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick’s disease (PiD), argyrophilic grain disease (AGD), multiple system tauopathy with presenile dementia (MSTD), white matter tauopathy with globular glial inclusions (FTLD with GGIs), FTLD with MAPT mutations, neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, amyotrophic lateral sclerosis (ALS), corticobasal syndrome (CBS), corticobasal Page 25 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO degeneration (CBD), progressive supranuclear palsy (PSP), Parkinson’s disease, postencephalitic Parkinsonism, Niemann-Pick disease, Huntington disease, type 1 myotonic dystrophy, and Down syndrome (DS), decreased expression or activity of MAPT in regions of increased neuronal dysfunction or death, in subjects having such neurodegenerative diseases. “Treatment” can also mean prolonging survival as compared to expected survival in the absence of treatment. The term “lower” in the context of the level of MAPT 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%, 15%, 20%, 25%, 30%, %, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more. In certain embodiments, a decrease is at least 20%. In certain embodiments, the decrease is at least 50% in a disease marker, e.g., protein or gene expression level. “Lower” in the context of the level of MAPT in a subject is optionally down to a level accepted as within the range of normal for an individual without such disorder. In certain embodiments, “lower” is the decrease in the difference between the level of a marker or symptom for a subject suffering from a disease and a level accepted within the range of normal for an individual, e.g., the level of decrease in speed of movement (bradykinesia) and ability to regulate posture and balance in an individual having Parkinson’s and an individual not having Parkinson’s or having symptoms that are within the range of normal. As used herein, “prevention” or “preventing,” when used in reference to a disease or disorder, that would benefit from a reduction in expression of a MAPT gene or production of MAPT protein, e.g., in a subject susceptible to a MAPT-associated disease or disorder due to, e.g., genetic factors or age, wherein the subject does not yet meet the diagnostic criteria for the MAPT-associated disease or disorder. As used herein, prevention can be understood as administration of an agent to a subject who does not yet meet the diagnostic criteria for the MAPT- associated disease or disorder to delay or reduce the likelihood that the subject will develop the MAPT-associated disease or disorder. As the agent is a pharmaceutical agent, it is understood that administration typically would be under the direction of a health care professional capable of identifying a subject who does not yet meet the diagnostic criteria for a MAPT-associated disease or disorder as being susceptible to developing a MAPT-associated disease or disorder. A MAPT-associated “disease,” “disorder,” and “condition” are used interchangeably to encompass various conditions that would benefit from a reduction in the expression and / or Page 26 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO activity of MAPT, such as by the MAPT dsRNA treatment of the present disclosure. Example MAPT-associated disease or disorders include Alzheimer disease, frontotemporal dementia (FTD), behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA-L), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick’s disease (PiD), argyrophilic grain disease (AGD), multiple system tauopathy with presenile dementia (MSTD), white matter tauopathy with globular glial inclusions (FTLD with GGIs), FTLD with MAPT mutations, neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, amyotrophic lateral sclerosis (ALS), corticobasal syndrome (CBS), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Parkinson’s disease, postencephalitic Parkinsonism, Niemann-Pick disease, Huntington disease, type 1 myotonic dystrophy, and Down syndrome (DS). "Therapeutically effective amount," as used herein, is intended to include the amount of an RNAi agent that, when administered to a subject having a MAPT-associated disease or 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 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 an RNAi agent that, when administered to a subject having a MAPT-associated disease or 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, the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated. A "therapeutically-effective amount" or “prophylactically effective amount” also includes an amount of an RNAi agent that produces some desired local or systemic effect at a reasonable Page 27 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO benefit / risk ratio applicable to any treatment. An RNAi agent employed in 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, or dosage forms which are, within the scope of 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. As used herein, the phrase "pharmaceutically acceptable salt" refers to both pharmaceutically acceptable acid and base addition salts and solvates. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC-(CH2)n-COOH where n is 0-4, and the like. Non-toxic pharmaceutical base addition salts include salts of bases such as lithium, sodium, potassium, calcium, magnesium, ammonium, and the like.. In certain embodiments, the pharmaceutically acceptable salt is a sodium salt. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts. The phrase "pharmaceutically-acceptable carrier" as used herein means a 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 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; (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) Page 28 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl 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 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 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 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, e.g., striatum, or certain types of cells in the brain, such as, e.g., neurons and glial cells (astrocytes, oligodendrocytes, microglial cells)). In other embodiments, a “sample derived from a subject” refers to liver tissue (or subcomponents thereof) derived from the subject. In some embodiments, a “sample derived from a subject” refers to blood drawn from the subject or plasma or serum derived therefrom. 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 subject. It will be understood that, although the sequences provided herein are described as modified or conjugated sequences, the RNA of the RNAi agent of the disclosure e.g., a dsRNA of the disclosure, may comprise any one of the sequences provided herein that is un-modified, un- conjugated, or modified or conjugated differently than described therein. That is, the modified sequences provided herein do not require the indicated hexadecyl lipophilic moiety, or any ligand. A lipophilic ligand can be included in any of the positions provided in the instant application. II. dsRNA Agents of the Disclosure Described herein are formulations of dsRNA agents which inhibit the expression of a MAPT gene. Non-limiting examples of dsRNA agents that target the MAPT gene are provided in Page 29 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO WO 2021 / 202511, WO 2023 / 049871, WO / 2023 / 010134, and WO 2023 / 154900, which is herein incorporated by reference in its entirety. The exemplified RNAs described herein identify a site(s) in an MAPT 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 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 MAPT gene. A RNAi agent as described herein can contain one or more mismatches to the 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, the strand which is complementary to a region of a MAPT 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 MAPT gene. Consideration of the efficacy of RNAi agents with mismatches in inhibiting expression of an MAPT gene is important, especially if the particular region of complementarity in an MAPT gene is known to have polymorphic sequence variation within the population. In one aspect, a dsRNA of the disclosure includes at least two nucleotide sequences, a sense sequence and an antisense sequence. In one aspect, the dsRNA agent is AD-1786708. The drug substance AD-1786708 (DS)), is a double stranded RNA molecule containing a combination of 2’-deoxy, 2’-F and 2’-Omethyl nucleotides. There is one vinylphosphonate (VP) modified 2’-OMe uridine at the 5’-end of the antisense strand A-3019137 and one 2’-hexadecyl modified cytosine (Chd) near the 5’ end of the sense strand A-3306553. The nucleosides of the sense and antisense strands are connected through 3’-5’ phosphodiester linkages or 3’-5’ phosphorothioate linkages to form the sugar-phosphate backbone of the oligonucleotide. The sense strand (A-3306553) contains 21 nucleosides and the Page 30 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO antisense strand (A-3019137) contains 23 nucleotides. The nucleosides in each strand are connected through 3’-5’ phosphodiester or 3’-5’ phosphorothioate linkages, thus forming the sugarphosphate backbone of the oligonucleotide. The majority of nucleotides in DS are either 2’-H (deoxyribonucleotides), 2’-O-methyl nucleotides (2’-OMe) or 2’-F modified ribonucleotides. There is one vinylphosphonate (VP) modified 2’-OMe uridine (VPu) at the 5’ end of the antisense strand. On the sense strand there is one 2’-O-hexadecyl (C16) modified cytidine (Chd) at the sixth position from the 5’ end of sense strand. DS is schematically presented in FIG.1. The molecular formula of the sodium salt form of AD-1786708 is C470H572F6N165O291P43S8Na44. The formula weight of the sodium form is 15902.445 Da. The molecular formula of the free acid form (H-form) of AD-1786708 is C470H616F6N165O291P43S8. The formula weight of the H-form is 14935.244 Da. The AD-1786708 drug substance may be named using the following accepted oligonucleotide nomenclature: A-3306553, sense strand: 5’ (2’-O-methyl)thioguanylyl-(3’-5’)-(2’-O-methyl)thiourdylyl -(3’-5’)-(2’-O-methyl)guanylyl- (3’-5’)-(2’-O-methyl)adenylyl-(3’-5’)-(2’-O-methyl)cytidylyl-(3’-5’)-(2’-O- hexadecyl)cytidylyl-(3’-5’)-(2’-O-methyl)cytidylyl-(3’-5’)-(2’-O-methyl)adenylyl-(3’-5’)-(2’- fluoro)adenylyl-(3’-5’)-(2’-fluoro)guanylyl-(3’-5’)-(2’-fluoro)cytidylyl-(3’-5’)-(2’-O- methyl)urdylyl-(3’-5’)-(2’-Omethyl)cytidylyl-(3’-5’)-(2’-O-methyl)guanylyl-(3’-5’)-(2’-O- methyl)urdylyl-(3’-5’)-(2’-Omethyl)adenylyl-(3’-5’)-(2’-O-methyl)urdylyl-(3’-5’)-(2’-O- methyl)guanylyl-(3’-5’)-(2’-Omethyl)thioguanylyl-(3’-5’)-(2’-O-methyl)thiourdylyl-(3’-5’)-(2’- O-methyl)adenine, 20 sodium salt 3’ (SEQ ID NO: 1). The sense strand, A-3306553, is base-paired with the antisense strand A-3019137. A-3019137, antisense strand: 5’ (Vinylphosphonate-2’-O-methyl)thiouridylyl-(3’-5’)-(2’-fluoro)thioadenylyl-(3’-5’)-(2’- Omethyl)cytidylyl-(3’-5’)-(2’-O-methyl)cytidylyl -(3’-5’)-(2’-deoxy)adenylyl-(3’-5’)-(2’- Omethyl)urdylyl-(3’-5’)-(2’-deoxy)adenylyl-(3’-5’)-(2’-O-methyl)cytidylyl-(3’-5’)-(2’- Omethyl)guanylyl-(3’-5’)-(2’-O-methyl)adenylyl-(3’-5’)-(2’-O-methyl)guanylyl-(3’-5’)-( 2’- Omethyl)cytidylyl-(3’-5’)-(2’-O-methyl)urdylyl-(3’-5’)-(2’-fluoro)urdylyl-(3’-5’)-(2’-O- methyl)guanylyl-(3’-5’)-(2’-O-fluoro)guanylyl-(3’-5’)-(2’-O-methyl)guanylyl-(3’-5’)-(2’-O- Page 31 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO methyl)urdylyl-(3’-5’)-(2’-O-methyl)cytidylyl-(3’-5’)-(2’-O-methyl)adenylyl-(3’-5’)-(2’-O- methyl)thiocytidylyl-(3’-5’)-(2’-O-methyl)thioguanylyl-(3’-5’)-(2’-O-methyl)uridine, 24 sodium salt 3’ (SEQ ID NO: 2). Alternatively, the AD-1786708 drug substance may be described using the following abbreviated format for each single strand: A-3306553, sense strand 5’ Gm-ps-Um-ps-Gm-Am-Cm-(Chd)-Cm-Am-Af-Gf-Cf-Um-Cm-Gm-Um-Am-Um-Gm-Gm-ps- Um-ps-Am 3’ (SEQ ID NO: 1) base-paired with: A-3019137, antisense strand 5’ VPu-ps-Af-ps-Cm-Cm-dA-Um-dA-Cm-Gm-Am-Gm-Cm-Um-Uf-Gm-Gf-Gm-Um-Cm-Am- Cm-ps-Gm-ps-Um 3’ (SEQ ID NO: 2), wherein: Af = 2’-fluoroadenosine Uf = 2’-fluorouridine Cf = 2’-fluorocytidine Gf = 2’-fluoroguanosine Am = 2’-O-methyladenosine Um = 2’-O-methyluridine Cm = 2’-O-methylcytidine Gm = 2’-O-methylguanosine dA = 2’-deoxyadenosine Chd = 2’-O-hexadecylcytidine VPu = vinylphosphonate 2’-O-methyluridine ’-’ (hyphen) = 3’-5’ phosphodiester linkage, and ’-ps-’ = 3’-5’ phosphorothioate linkage. The AD-1786708 drug substance may also be named using a convention in which the ribonucleosides are designated by three-letter symbols: Page 32 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO A-3306553, sense strand 5’ Guom-ps-Urdm-ps-Guom-Adom-Cydm-(Chd)-Cydm-Adom-Adof-Guof-Cydf-Urdm-Cydm- Guom-Urdm-Adom-Urdm-Guom-Guom-ps-Urdm-ps-Adom 3’ (SEQ ID NO: 1) base-paired with: A-3019137, antisense strand 5’ VPu-ps-Adof-ps-Cydm-Cydm-dAdo-Urdm-dAdo-Cydm-Guom-Adom-Guom-Cydm-Urdm- Urdf-Guom-Guof-Guom-Urdm-Cydm-Adom-Cydm-ps-Guom-ps-Urdm 3’ (SEQ ID NO: 2), wherein: Adof = 2’-fluoroadenosine Urdf = 2’-fluorouridine Cydf = 2’-fluorocytidine Guof= 2’-fluoroguanosine Adom = 2’-O-methyladenosine Urdm = 2’-O-methyluridine Cydm = 2’-O-methylcytidine Guom = 2’-O-methylguanosine dAdo = 2’-deoxyadenosine Chd = 2’-O-hexadecylcytidine VPu = vinylphosphonate 2’-O-methyluridine ’-’ (hyphen) = 3’-5’ phosphodiester linkage, and ’-ps-’ = 3’-5’ phosphorothioate linkage. The molecular formula of the sodium salt form of the sense strand, A-3306553, is C233H291F3N80O138P20S4Na20. The molecular weight of the sodium form of the sense strand is 7684.781 Da. The molecular formula of the H-form of the sense strand is C233H311F3N80O138P20S4. The molecular weight of the free acid is 7245.144 Da. The molecular formula of the sodium salt form of the antisense strand, A-3019137, is C237H281F3N85O153P23S4Na24. The molecular weight of the sodium form of the antisense strand is 8217.664 Da. The molecular formula of the H-form of the sense strand is C237H305F3N85O153P23S4 The molecular weight of the free acid is 7690.100 Da. Page 33 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO The structure of AD-1786708 is schematically depicted in FIG.2 with the bases involved in a base pair formation connected with a centered dot. In one embodiment, the dsRNA agent is selected from Table 1, including the sodium salts thereof. In another example, the dsRNA is one of, or the sodium salt of, AD-1623140, AD- 1786708, or AD-1637701. In one embodiment, the dsRNA agent is AD-1786708. In one embodiment, the dsRNA agent is the sodium salt of AD-1786708. In one embodiment, the dsRNA agent is AD-1623140. In one embodiment, the dsRNA agent is the sodium salt of AD-1623140. In one embodiment, the dsRNA agent is AD-1637701. In one embodiment, the dsRNA agent is the sodium salt of AD- 1637701. Table 1. Modified Sense and Antisense Strand Sequences of MAPT dsRNA Agents Duplex Sense Sequence 5’ to 3’ SEQ Antisense Sequence SEQ mRNA Target Sequence SEQ ID ID 5’ to 3’ ID 5’ to 3’ ID : 1 2 3 4 5 6 7 8 9 0 1 2 3 Page 34 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO Duplex Sense Sequence 5’ to 3’ SEQ Antisense Sequence SEQ mRNA Target Sequence SEQ ID ID 5’ to 3’ ID 5’ to 3’ ID NO: NO: NO: 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 Page 35 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO Duplex Sense Sequence 5’ to 3’ SEQ Antisense Sequence SEQ mRNA Target Sequence SEQ ID ID 5’ to 3’ ID 5’ to 3’ ID NO: NO: NO: 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 Page 36 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO Duplex Sense Sequence 5’ to 3’ SEQ Antisense Sequence SEQ mRNA Target Sequence SEQ ID ID 5’ to 3’ ID 5’ to 3’ ID NO: NO: NO: 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 Page 37 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO Duplex Sense Sequence 5’ to 3’ SEQ Antisense Sequence SEQ mRNA Target Sequence SEQ ID ID 5’ to 3’ ID 5’ to 3’ ID NO: NO: NO: 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 Page 38 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO Duplex Sense Sequence 5’ to 3’ SEQ Antisense Sequence SEQ mRNA Target Sequence SEQ ID ID 5’ to 3’ ID 5’ to 3’ ID NO: NO: NO: 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 Page 39 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO Duplex Sense Sequence 5’ to 3’ SEQ Antisense Sequence SEQ mRNA Target Sequence SEQ ID ID 5’ to 3’ ID 5’ to 3’ ID NO: NO: NO: 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 Page 40 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO Duplex Sense Sequence 5’ to 3’ SEQ Antisense Sequence SEQ mRNA Target Sequence SEQ ID ID 5’ to 3’ ID 5’ to 3’ ID NO: NO: NO: 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 Page 41 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO Duplex Sense Sequence 5’ to 3’ SEQ Antisense Sequence SEQ mRNA Target Sequence SEQ ID ID 5’ to 3’ ID 5’ to 3’ ID NO: NO: NO: 8 9 Table 2. Abbreviations of nucleotide monomers used in nucleic acid sequence representation: It will be understood that these monomers, when present in an oligonucleotide, are mutually linked by 5'-3'-phosphodiester bonds; and it is understood that when the nucleotide contains a 2’- fluoro modification, then the fluoro replaces the hydroxy at that position in the parent nucleotide (i.e., it is a 2’-deoxy-2’-fluoronucleotide). It will also be understood that the abbreviations correspond to nucleotides which omit the 3’-phosphate when found at the 3’-terminal position (i.e., they are 3’-OH). Abbreviation Nucleotide(s) ’ Page 42 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO Abbreviation Nucleotide(s) T 5’-methyluridine-3’-phosphate Page 43 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO Abbreviation Nucleotide(s) dT 2`-deoxythymidine-3`-phosphate '- III. Preparation of dsRNA Agents of the Disclosure 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, 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 oligonucleotides of the disclosure can be prepared using solution- phase or solid-phase organic synthesis or both. An siRNA can be produced, e.g., in bulk, by a variety of methods. Exemplary methods include: organic synthesis and RNA cleavage, e.g., in vitro cleavage. An siRNA can be made by separately synthesizing a single stranded RNA molecule, or each respective strand of a double-stranded RNA molecule, after which the component strands can then be annealed. Page 44 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO A large bioreactor, e.g., the OligoPilot II from Pharmacia Biotec AB (Uppsala Sweden), can be used to produce a large amount of a particular RNA strand for a given siRNA. The OligoPilotII reactor can efficiently couple a nucleotide using only a 1.5 molar excess of a phosphoramidite nucleotide. To make an RNA strand, ribonucleotides amidites are used. Standard cycles of monomer addition can be used to synthesize the 21 to 23 nucleotide strand for the siRNA. Typically, the two complementary strands are produced separately and then annealed, e.g., after release from the solid support and deprotection. Organic synthesis can be used to produce a discrete siRNA species. The complementary of the species to a MAPT gene can be precisely specified. For example, the species may be complementary to a region that includes a polymorphism, e.g., a single nucleotide polymorphism. Further the location of the polymorphism can be precisely defined. In some embodiments, the polymorphism is located in an internal region, e.g., at least 4, 5, 7, or 9 nucleotides from one or both of the termini. In one embodiment, RNA generated is carefully purified to remove ends. iRNA is cleaved in vitro into siRNAs, for example, using a Dicer or comparable RNAse III-based activity. For example, the dsiRNA can be incubated in an in vitro extract from Drosophila or using purified components, e.g., a purified RNAse or RISC (RNA-induced silencing complex). See, e.g., Ketting et al. Genes Dev 2001 Oct 15;15(20): 2654-9 and Hammond Science 2001 Aug 10;293(5532): 1146-50. dsiRNA cleavage generally produces a plurality of siRNA species, each being a particular 21 to 23 nt fragment of a source dsiRNA molecule. For example, siRNAs that include sequences complementary to overlapping regions and adjacent regions of a source dsiRNA molecule may be present. Regardless of the method of synthesis, the siRNA preparation can be prepared in a solution (e.g., an aqueous or organic solution) that is appropriate for formulation. For example, the siRNA preparation can be precipitated and re-dissolved in pure double-distilled water, and lyophilized. The dried siRNA can then be resuspended in a solution appropriate for the intended formulation process. An example manufacturing process is detailed in the examples provided herein for AD- 1786708. Page 45 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO IV. Pharmaceutical Compositions and Formulations of the Disclosure The present disclosure provides pharmaceutical compositions and formulations which include the RNAi agents described herein (e.g., AD-1786708, AD-1623140, AD-1637701, any dsRNA agents set forth in Table 1); however, it is expressly contemplated that the formulations of the instant disclosure can be employed for delivery of any RNAi agent. A. Formulations To administer dsRNAs to a subject via parenteral administration, the dsRNA may be formulated into a suitable aqueous solution. In the course of research into preparing such formulations, it has been surprisingly discovered that dsRNAs having at least one lipophilic modification must be formulated in a particular way to avoid long-term stability problems. In particular, formulation of dsRNAs in the presence of a bivalent cation (e.g., calcium, magnesium, copper, nickel, zinc, or strontium) can result in problematic precipitation issues where the stoichiometry of the individual strands of a dsRNA in the formulation should be controlled to prevent precipitation of lipophilic molecules in the aqueous solution. Exemplary dsRNA formulations and methods of formulating dsRNAs that may be used in the formulations and methods provided herein are provided in PCT / US2024 / 024374, which is herein incorporated by reference in its entirety. In addition to stoichiometry control of the sense and antisense duplexes, the formulations provided herein may also be substantially free of inorganic phosphate. In some embodiments, the formulations provided herein are substantially free of inorganic and also have the addition of a divalent cation (such as calcium). Certain compositions of the disclosure therefore carry an excess of a non-lipophile- modified strand of a dsRNA relative to a lipophile-modified strand of the dsRNA. Some compositions are also substantially free of sources of inorganic phosphate. It is contemplated in certain embodiments that mitigation against particulate formation in nucleic acid formulations of the disclosure can be achieved by reducing sources of inorganic phosphate in such compositions, e.g., to 100 ppm or less, to 50 ppm or less, or to 10 ppm or less. In embodiments, the compositions of the disclosure are employed for delivery of nucleic acid agents, e.g., iRNA agents, including dsRNAs as specifically exemplified herein. The level of nucleic acid agent in a composition of the instant disclosure can range, e.g., from about 5 mg / mL Page 46 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO to about 300 mg / mL. In a related embodiment, the composition includes a nucleic acid agent at about 10 mg / mL to about 200 mg / mL. In a further embodiment, the composition includes a nucleic acid agent at about 20 mg / mL to about 100 mg / mL. In one embodiment, the composition includes a nucleic acid agent at about 40 mg / mL to about 80 mg / mL. In one embodiment, the composition includes a nucleic acid agent at about 50 mg / mL to about 70 mg / mL. Optionally, the composition includes a nucleic acid agent at about 60 mg / mL, such as at 60 mg / mL ± 10% or 60 mg / mL ± 5%. Compositions of the present disclosure may comprise a number of salts that provide sources of physiologically relevant ionic species, such as Na+, K+, Mg2+, Cl-, or Ca2+. These may include, without limitation, sodium chloride, potassium chloride, magnesium chloride, and calcium chloride. The compositions may further comprise other trace elements and their salts, including, but not limited to, selenium, copper, chromium, iodine, fluoride, zinc, manganese, molybdenum, and iron. Sodium ions are included in relatively large concentrations in the formulations of the instant disclosure, at least in part in view of their role in normal physiological functioning. Na+is the major cation of the extracellular fluid. It plays an important role in many physiological processes, including the regulation of blood volume, blood pressure, osmotic equilibrium, and pH, as well as the generation of nerve impulses. Potassium ions are the major cation of intracellular fluid, and, with the sodium ions of the extracellular fluid, K+is a primary generator of the electrical potential across cellular membranes. Accordingly, it plays a significant role in normal functioning, and is relevant to such body functions as neurotransmission, muscle contraction, and heart function. Calcium ions are likewise important to many physiological processes. In particular, Ca2+ions are one of the most widespread second messengers used in signal transduction. In endothelial cells, Ca2+ions may regulate several signaling pathways which cause smooth muscles surrounding blood vessels to relax. Dysfunction within Ca2+-activated pathways can lead to an increase in tone caused by unregulated smooth muscle contraction. This type of dysfunction can be seen in cardiovascular diseases, hypertension, and diabetes. Inclusion of Ca2+ions in the compositions of the instant disclosure also has been identified to mitigate against certain adverse Page 47 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO events (e.g., tremors, twitches, other neurological issues) seen in subjects administered calcium- free or low calcium nucleic acid formulations via intrathecal injection. Magnesium ions are used in relatively large concentrations in normal metabolism. It is recognized that deficiency of magnesium is rare unless it is accompanied by severe losses in other electrolytes such as in vomiting and diarrhea. It is however frequently recognized as deficient in the modern diet with symptoms such as muscle tremors and weakness. This mineral is important in many enzymatic reactions and will stabilize excitable membranes. Administered intravenously, magnesium may produce an anesthetic action and this is indirect evidence of its action on the vascular wall endothelial component to stabilize and normalize the surface of the vascular wall. The values described herein refer to the exact values described as well as a range that is ± 10% or ± 5% of the value referenced, unless otherwise specified. In some embodiments, a composition of the present disclosure includes a sodium ion (Na+) source (e.g., provided as sodium chloride) at a concentration between 0.1 mM and 1 M. In a related embodiment, a Na+source is present at a concentration between about 40 mM and about 300 mM. Optionally, a Na+source is present at a concentration between about 70 mM and about 200 mM. In a related embodiment, a Na+source is present at a concentration between about 70 mM and about 100 mM. In a related embodiment, a Na+source is present at a concentration between about 80 mM and about 120 mM. In a related embodiment, a Na+source is present at a concentration between about 80 mM and about 110 mM. In a related embodiment, a Na+source is present at a concentration between about 85 mM and about 100 mM. In a related embodiment, a Na+source is present at a concentration between about 90 mM and about 100 mM. In an alternative embodiment, a Na+source is present at a concentration between about 90 mM and about 105 mM, optionally between about 95 mM and about 100 mM. In a related embodiment, a Na+source is present at a concentration of about 84 mM to about 87 mM. In one embodiment, a Na+source is present at a concentration of about 85.50 mM, such as at 85.50 mM ± 10% or 85.50 mM ± 5%. In one embodiment, a Na+source is present at a concentration of 85.50 mM. In some embodiments, a composition of the present disclosure comprises a potassium ion (K+) source (e.g., provided as potassium chloride) at a concentration between 0.0 mM and 1 M. In some embodiments, a K+source is present at a concentration between about 0.1 mM and about 100 mM. In a further embodiment, a K+source is present at a concentration between about 0.2 Page 48 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO mM and about 40 mM. In a further embodiment, a K+source is present at a concentration between about 0.5 mM and about 20 mM. In some embodiments, a K+source is present at a concentration between about 1 mM and about 5 mM. In some embodiments, a K+source is present at a concentration between about 1 mM and about 4 mM. In some embodiments, a K+source is present at a concentration between about 1 mM and about 3 mM. In some embodiments, a K+source is present at a concentration between about 1.0 mM and about 2.5 mM. In some embodiments, a K+source is present at a concentration between about 1.5 mM and about 2.5 mM. In some embodiments, a K+source is present at a concentration between about 1.5 mM and about 2.2 mM. Optionally, a K+source is present at a concentration of about 1.0 mM, about 1.1 mM, about 1.2 mM, about 1.3 mM, about 1.4 mM, about 1.5 mM, about 1.6 mM, about 1.7 mM, about 1.8 mM, about 1.9 mM, about 2.0 mM, about 2.1 mM, about 2.2 mM, about 2.3 mM, about 2.4 mM, about 2.5 mM, about 2.6 mM, about 2.7 mM, about 2.8 mM, about 2.9 mM, or about 3.0 mM. In certain embodiments, a K+source is present at a concentration of about 1.6 mM to about 1.8 mM, or about 1.7 mM. In certain embodiments, a K+source is present at a concentration of about 1.68 mM, such as at 1.68 mM ± 10% or 1.68 mM ± 5%. In certain embodiments, a K+source is present at a concentration of 1.68 mM. In certain embodiments, a composition of the present disclosure comprises a magnesium ion (Mg2+) source (e.g., provided as magnesium chloride) at a concentration between 0.0 mM and 1 M. In some embodiments, a Mg2+source is present at a concentration between about 0.01 mM and about 100 mM. In a further embodiment, a Mg2+source is present at a concentration between about 0.1 mM and about 40 mM. In a further embodiment, a Mg2+source is present at a concentration between about 0.2 mM and about 20 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.3 mM and about 5 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.3 mM and about 4 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.3 mM and about 3 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.3 mM and about 2 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.3 mM and about 1 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.1 mM and about 1 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.3 mM and about 0.7 mM. In some embodiments, a Mg2+source is Page 49 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO present at a concentration between about 0.3 mM and about 0.6 mM. In some embodiments, a Mg2+source is present at a concentration between about 0.4 mM and about 0.6 mM. Optionally, a Mg2+source is present at a concentration of about 0.3 mM, about 0.4 mM, about 0.5 mM, about 0.6 mM, about 0.7 mM, about 0.8 mM, or about 0.9 mM. In certain embodiments, a Mg2+source is present at a concentration of about 0.5 mM. In a further embodiment, a Mg2+source is present at a concentration of 0.5 mM. In certain embodiments, a Mg2+source is present at a concentration of about 0.4 mM. In a further embodiment, a Mg2+source is present at a concentration of 0.4 mM. In certain embodiments, a Mg2+source is present at a concentration of about 0.4 mM to about 0.5 mM, or about 0.45 mM, such as at 0.45 mM ± 10% or 0.45 mM ± 5%. Alternatively, a Mg2+source is present at a concentration of 0.45 mM. In certain embodiments, a composition of the present disclosure includes a calcium ion (Ca2+) source (e.g., provided as calcium chloride) at a concentration between 0.1 mM and 1 M. In some embodiments, a Ca2+source is present at a concentration between about 0.1 mM and about 200 mM. In a further embodiment, a Ca2+source is present at a concentration between about 0.5 mM and about 100 mM. Optionally, a Ca2+source is present at a concentration between about 0.8 mM and about 50 mM. In some embodiments, a Ca2+source is present at a concentration between about 1 mM and about 25 mM. In some embodiments, a Ca2+source is present at a concentration between about 2 mM and about 20 mM. In some embodiments, a Ca2+source is present at a concentration between about 8 mM and about 20 mM. In some embodiments, a Ca2+source is present at a concentration between about 8 mM and about 25 mM. In some embodiments, a Ca2+source is present at a concentration between about 5 mM and about 15 mM. Alternatively, a Ca2+source is present at a concentration between about 10 mM and about 18 mM. In some embodiments, a Ca2+source is present at a concentration between about 12 mM and about 18 mM. In some embodiments, a Ca2+source is present at a concentration between about 15 mM and about 17 mM. In some embodiments, a Ca2+source is present at a concentration between about 15.5 mM and about 16.5 mM. Optionally, a Ca2+source is present at a concentration of about 15.5 mM, about 15.75 mM, about 16.0 mM, about 16.25 mM, about 16.3 mM, about 16.5 mM, or about 16.75 mM. In certain embodiments, a Ca2+source is present at a concentration of about 15 mM to about 16 mM, or about 15.6 mM, such as at 15.6 mM ± 10% or 15.6 mM ± 5%. In certain embodiments, a Ca2+source is present at a concentration of 15.6 mM. Page 50 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO In some embodiments, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent of greater than about 2:1. In certain embodiments, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent of greater than about 2.5:1. In further embodiments, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent of greater than about 3:1. In other embodiments, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent of greater than about 3.5:1. In further related embodiments, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent of greater than about 4:1. In certain related embodiments, a composition of the disclosure has a molar ratio of divalent cation source-to- nucleic acid agent between about 2:1 and about 10:1. Optionally, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent between about 3:1 and about 10:1. Optionally, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent between about 3:1 and about 9:1. Optionally, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent between about 3:1 and about 8:1. Optionally, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent between about 3:1 and about 7:1. Optionally, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent between about 3:1 and about 6:1. Optionally, a composition of the disclosure has a molar ratio of divalent cation source-to-nucleic acid agent between about 3:1 and about 5:1. In some embodiments of the solutions provided herein, the pH of the solution is between 4 and 10, optionally between 6 and 10. In related embodiments, the pH of the solution is between about 6.5 and about 8.0. In a further embodiment, the pH of the solution is 6.5-7.8. In certain embodiments of the solutions provided herein, the pH of the solution is 6.7-7.5. In some embodiments, the pH of the solution is 6.8-7.2. In further embodiments, the pH of the solution is about 6.8, such as pH 6.8 ± 10% or pH 6.8 ± 5%. In some embodiments of the compositions provided herein, an aqueous solution of the disclosure has an osmolality between about 100 and 500 mOsm / kg. In a further embodiment, an aqueous solution of the disclosure has an osmolality between about 200 and 400 mOsm / kg. In certain embodiments, an aqueous solution of the disclosure has an osmolality of about 300 Page 51 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO mOsm / kg, such as about 300 mOsm / kg ± 10% or 300 mOsm / kg ± 5%. In a specific embodiment, an aqueous solution of the disclosure has an osmolality of 301 mOsm / kg. In certain embodiments, the compositions (i.e., aqueous compositions) provided herein can be stored for at least 4 hours, at least 6 hours, at least 8 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least one week, at least two weeks, at least three weeks, or at least one month at 25 °C without measurable precipitation of solutes and / or measurable loss of the capability to produce knockdown of a target gene in a subject administered such a solution via intrathecal injection. In some embodiments, the compositions provided herein can be stored for at least 4 hours, at least 6 hours, at least 8 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least one week, at least two weeks, at least three weeks, or at least one month at 2-8 °C without measurable precipitation of solutes and / or measurable loss of the capability of the capability to produce knockdown of a target gene in a subject administered such a solution via intrathecal injection. B. Pharmaceutical Compositions In one embodiment, provided herein are pharmaceutical compositions containing an RNAi agent, as described herein, and a pharmaceutically acceptable carrier. The pharmaceutical compositions containing the RNAi agent are useful for treating a disease or disorder associated with the expression or activity of a gene (e.g., MAPT) to treat a disorder such as, for example, Alzheimer’s disease. The pharmaceutical compositions of the disclosure may be administered in dosages sufficient to inhibit expression of an MAPT gene. In general, a suitable dose of an RNAi agent of the disclosure will be in the range of about 0.001 to about 200.0 milligrams per kilogram body weight of the recipient, generally in the range of about 1 to 50 mg per kilogram body weight Such pharmaceutical compositions are formulated based on the mode of delivery. The formulations / pharmaceutical compositions disclosed herein are primarily formulated for injection, and in certain applications, for direct delivery into the CNS, e.g., by intrathecal or intravitreal routes of injection, optionally by infusion into the brain (e.g., striatum), such as by continuous pump infusion. However, certain compositions of the instant disclosure can also be Page 52 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO formulated for systemic administration via parenteral delivery, e.g., by intravenous (IV), intramuscular (IM), or for subcutaneous (subQ) delivery. In certain embodiments, the pharmaceutical compositions of the disclosure are substantially free of inorganic phosphate. In some embodiments, the molar ratio of a divalent ion source-to-nucleic acid therapeutic of the disclosure within a formulation is greater than about 2:1. In certain embodiments, the pharmaceutical compositions of the disclosure are pyrogen free or non-pyrogenic. The skilled artisan will appreciate that certain factors can influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a composition can include a single treatment or a series of treatments. The pharmaceutical compositions of the present disclosure are primarily formulated for CNS delivery, administered via an intracranial route, e.g., by intrathecal, intraparenchymal, or intraventricular administration. The RNAi agent formulations can be delivered in a manner to target a particular tissue of the CNS (e.g., neuronal, glial or vascular tissue of the brain), or both a non-CNS organ (e.g., the liver) and the CNS. Other formulations amenable to the present disclosure (if made substantially free of sources of inorganic phosphate) are described in United States provisional application serial Nos. 61 / 018,616, filed January 2, 2008; 61 / 018,611, filed January 2, 2008; 61 / 039,748, filed March 26, 2008; 61 / 047,087, filed April 22, 2008 and 61 / 051,528, filed May 8, 2008. PCT application number PCT / US2007 / 080331, filed October 3, 2007, also describes formulations that are amenable to the present disclosure (if made substantially free of sources of inorganic phosphate). The formulations of the instant disclosure are contemplated to function with inclusion of a wide variety of additional components, provided that such additional components do not detract from efficacy / drug product functionality. Examples of such additional components include, without limitation, fats, oils, waxes, fatty acids, fatty alcohols, fatty esters, humectants, hydrophilic colloids, preservatives and antioxidants (Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. Page 53 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO 335; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199), as well as glucose and other sugars / carbon sources. Compositions and formulations suitable for parenteral administration include, but are not limited to, such suitable for intraparenchymal (into the brain, e.g., intracerebrovascular), intrathecal (e.g., lumbar puncture (LP) or intracisterna magna (ICM) injection), intradiscal, periganglionic, and / or intraventricular administration, and can include sterile aqueous solutions which can also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients. In certain embodiments herein, compositions and formulations suitable for parenteral administration do not include buffering components (e.g., phosphate salts). Pharmaceutical compositions of the present disclosure include, but are not limited to, solutions and emulsions. These compositions can be generated from a variety of components that include, but are not limited to, preformed liquids. The pharmaceutical formulations of the present disclosure, which can conveniently be presented in unit dosage form, can be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. The compositions of the present disclosure can be formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions can further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol or dextran. The suspension can also contain stabilizers. C. Excipients In contrast to a carrier compound, a “pharmaceutical carrier” or “excipient” is a pharmaceutically acceptable solvent, suspending agent or any other pharmacologically inert vehicle for delivering one or more nucleic acids to an animal. The excipient can be liquid or solid and is selected, with the planned manner of administration in mind, so as to provide for the desired bulk, consistency, etc., when combined with a nucleic acid and the other components of a given Page 54 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO pharmaceutical composition. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like. Suitable pharmaceutically acceptable excipients include, but are not limited to, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like. D. Other Components The compositions of the present disclosure can additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the compositions can contain additional, compatible, pharmaceutically- active materials such as, for example, antipruritics, astringents, local anesthetics or anti- inflammatory agents. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present disclosure, and for the current disclosure should not provide an appreciable source of inorganic phosphate. The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., preservatives, stabilizers, emulsifiers, salts for influencing osmotic pressure, colorings, flavorings or aromatic substances and the like which do not deleteriously interact with the nucleic acid(s) of the formulation. Aqueous suspensions can contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol or dextran. The suspension can also contain stabilizers. In some embodiments, pharmaceutical compositions contemplated by the disclosure include (a) one or more RNAi agents and (b) one or more agents which function by a non-RNAi mechanism and which are useful in treating a disease or disorder, e.g., an MAPT-associated neurodegenerative disorder. Examples of such agents include, but are not limited to dopamine agonists and promoters, among others, including carbidopa-levodopa, levodopa, entacopone, tolcapone, opicapone, pramipexole, ropinirole, apomorphine, rotigotine, selegiline, rasagiline, safinamide, amantadine, istradefylline, trihexyphenidyl, benztropine, rivastigmine, donepezil, galantamine and memantine. Page 55 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO In addition to their administration, as discussed above, the RNAi agent compositions featured in the disclosure can be administered in combination with other known agents effective in treatment of a disease or disorder. In any event, the administering physician can adjust the amount and timing of RNAi agent administration on the basis of results observed using standard measures of efficacy known in the art or described herein. E. Methods of Preparing a Formulation The present disclosure also provides a method for preparing a formulation comprising annealing a sense strand and an antisense strand, wherein one of the sense strand and antisense strand contains a lipophilic modification, to form a duplex solution comprising a double stranded RNA (dsRNA); lyophilizing the duplex solution to provide a duplex composition; and dissolving the duplex composition in an injection solution, wherein the injection solution comprises a divalent cation source (e.g., calcium) and does not comprise a phosphate buffer; and the duplex composition comprises no less than equimolar amount of the antisense strand relative to the sense strand, or 0 – 5% molar excess (e.g., about 1 – 2 % molar excess) of the antisense strand over sense strand. A “duplex solution” is meant any solution comprising double stranded RNA (dsRNA). By “duplex composition” is meant any composition comprising a dsRNA. In some embodiments, the duplex composition is prepared by lyophilization. In one embodiment, the duplex composition is a lyophilized powder. An “injection solution” is any solution used for dissolving a duplex composition. In some embodiments, the injection solution comprises a divalent cation source. The divalent cation source is calcium, magnesium, copper, nickel, zinc, or strontium, optionally wherein the divalent ion source is calcium. In one embodiment, the injection solution does not comprise a phosphate buffer. In some embodiments, the duplex composition comprises no less than equimolar amount of antisense strand relative to sense strand. In some embodiments, the duplex composition comprises about a 1-2% molar excess, a 1-3% molar excess, a 1-4% molar excess, a 1-5% molar excess, a 0-5% molar excess, a 0-1% molar excess, a 2-3% molar excess, a 3-4% molar excess, a 3-5% molar excess, a 2-4% molar excess, a 2-5% molar excess of antisense strand over sense strand. In one embodiment, the duplex composition comprises about a 1-2% molar excess of antisense strand over sense strand. In another embodiment, the excess of antisense strand over sense strand is less than 1%. In another Page 56 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO embodiment, antisense strand and sense strand are contained at equimolar amounts in the formulation. V. Delivery of dsRNA agents of the Disclosure The delivery of an RNAi agent (or other nucleic acid therapeutic agent) composition of the disclosure to a cell e.g., a cell within a subject, such as a human subject (e.g., a subject in need thereof, such as a subject having a MAPT-associated disease or disorder, e.g., Alzheimer’s disease, FTD, PSP, or other tauopathy) can be achieved in a number of different ways. For example, delivery may be performed by contacting a cell with an RNAi agent composition of the disclosure either in vitro or in vivo. In vivo delivery may also be performed directly by administering a composition comprising an RNAi agent, e.g., a dsRNA, to a subject. Alternatively, in vivo delivery may be performed indirectly by administering one or more vectors that encode and direct the expression of the RNAi agent. In general, methods of delivering a nucleic acid molecule (in vitro or in vivo) can be adapted for use with an RNAi agent composition of the disclosure (see e.g., Akhtar S. and Julian RL., (1992) Trends Cell. Biol.2(5): 139-144 and WO94 / 02595, which are incorporated herein by reference in their entireties). For in vivo delivery, factors to consider for delivering an RNAi agent composition include, for example, biological stability of the delivered agent, prevention of non- specific effects, and accumulation of the delivered agent in the target tissue. The non-specific effects of an RNAi agent can be minimized by local administration, for example, by direct injection or implantation into a tissue or topically administering the preparation. Local administration to a treatment site maximizes local concentration of the agent, limits the exposure of the agent to systemic tissues that can otherwise be harmed by the agent or that can degrade the agent, and permits a lower total dose of the RNAi agent to be administered. Several studies have shown successful knockdown of gene products when an RNAi agent is administered locally. For example, intraocular delivery of a VEGF dsRNA by intravitreal injection in cynomolgus monkeys (Tolentino, MJ. et al., (2004) Retina 24: 132-138) and subretinal injections in mice (Reich, SJ. et al. (2003) Mol. Vis.9: 210-216) were both shown to prevent neovascularization in an experimental model of age-related macular degeneration. In addition, direct intratumoral injection of a dsRNA in mice reduces tumor volume (Pille, J. et al. (2005) Mol. Ther. 11: 267-274) and can prolong survival of tumor-bearing mice (Kim, WJ. et al., (2006) Mol. Ther. 14: 343-350; Li, S. et al., Page 57 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO (2007) Mol. Ther.15: 515-523). RNA interference has also shown success with local delivery to the CNS by direct injection (Dorn, G. et al., (2004) Nucleic Acids 32: e49; Tan, PH. et al. (2005) Gene Ther. 12: 59-66; Makimura, H. et a.l (2002) BMC Neurosci. 3: 18; Shishkina, GT., et al. (2004) Neuroscience 129: 521-528; Thakker, ER., et al. (2004) Proc. Natl. Acad. Sci. U.S.A.101: 17270-17275; Akaneya,Y., et al. (2005) J. Neurophysiol. 93: 594-602) and to the lungs by intranasal administration (Howard, KA. et al., (2006) Mol. Ther. 14: 476-484; Zhang, X. et al., (2004) J. Biol. Chem.279: 10677-10684; Bitko, V. et al., (2005) Nat. Med.11: 50-55). Certain aspects of the instant disclosure relate to a method of reducing the expression of a target gene in a cell or subject, involving contacting said cell or subject with the double-stranded RNAi agent composition of the disclosure. In one embodiment, the cell is an extrahepatic cell, optionally a CNS cell. Another aspect of the disclosure relates to a method of reducing the expression of a target gene in a subject, involving administering to the subject the double-stranded RNAi agent composition of the disclosure. Another aspect of the disclosure relates to a method of treating a subject having a target gene-associated disorder, involving administering to the subject a therapeutically effective amount of the double-stranded RNAi agent-containing composition of the disclosure, thereby treating the subject. In one embodiment, the double-stranded RNAi agent is administered intrathecally. By intrathecal administration of the double-stranded RNAi agent, the method can reduce the expression of a target gene in a brain (e.g., striatum) or spine tissue, for instance, cortex, cerebellum, cervical spine, lumbar spine, and thoracic spine. For ease of exposition the formulations, compositions and methods in this section are discussed largely with regard to modified siRNA compounds. It may be understood, however, that these formulations, compositions and methods can be practiced with other siRNA compounds, e.g., unmodified siRNA compounds, and such practice is within the disclosure. The RNAi agent compositions of the disclosure can be further incorporated into pharmaceutical compositions suitable for parenteral administration. Such compositions typically include one or more species of RNAi agent and a pharmaceutically acceptable carrier. As used herein the language “pharmaceutically acceptable carrier” is intended to include any and all Page 58 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO solvents, antibacterial and antifungal agents, isotonic agents, and the like, compatible with pharmaceutical administration, but in certain aspects, excluding such agents comprising inorganic phosphate (e.g., excluding phosphate-buffered saline (PBS) as an isotonic solution in certain embodiments). The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions. While the primary route of administration for the pharmaceutical compositions of the present disclosure is via parenteral administration, such as intrathecal injection, the pharmaceutical compositions of the present disclosure may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Parenteral administration includes intravenous drip, subcutaneous, intraperitoneal or intramuscular injection, or intrathecal or intraventricular administration. Compositions for intrathecal or intraventricular administration may include sterile aqueous solutions (though excluding agents comprising inorganic phosphate in certain aspects) which may also contain diluents and other suitable additives. Formulations for parenteral administration may include sterile aqueous solutions which may also contain diluents and other suitable additives. Intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir. For intravenous use, the total concentration of solutes may be controlled to render the preparation isotonic. In one embodiment, the administration of the dsRNA compound, e.g., a double-stranded siRNA compound is parenteral, e.g., intravenous (e.g., as a bolus or as a diffusible infusion), intradermal, intraperitoneal, intramuscular, intrathecal, intraventricular, intracranial, subcutaneous or ocular injection. Administration can be provided by the subject or by another person, e.g., a health care provider. Selected modes of delivery are discussed in more detail below. A. Intrathecal Administration In certain embodiments, a nucleic acid agent formulation (e.g., a double-stranded RNAi agent composition) is delivered by intrathecal injection (i.e., injection into the spinal fluid which bathes the brain and spinal cord tissue). Intrathecal injection of nucleic acid (e.g., RNAi) agents into the spinal fluid can be performed as a bolus injection or via minipumps which can be Page 59 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO implanted beneath the skin, providing a regular and constant delivery of nucleic acid into the spinal fluid. The circulation of the spinal fluid occurs from the choroid plexus, where it is produced, down around the spinal cord and dorsal root ganglia and subsequently up past the cerebellum and over the cortex to the arachnoid granulations, where the fluid can exit the CNS, that, depending upon size, stability, and solubility of the compounds injected, allows molecules delivered intrathecally potentially to hit targets throughout the entire CNS. In some embodiments, the intrathecal administration is via a pump. The pump may be a surgically implanted osmotic pump. In one embodiment, the osmotic pump is implanted into the subarachnoid space of the spinal canal to facilitate intrathecal administration. In some embodiments, the intrathecal administration is via an intrathecal delivery system for a pharmaceutical including a reservoir containing a volume of the pharmaceutical agent, and a pump configured to deliver a portion of the pharmaceutical agent contained in the reservoir. More details about this intrathecal delivery system may be found in WO 2015 / 116658, which is incorporated by reference in its entirety. The amount of intrathecally injected nucleic acid agents (e.g., RNAi agents and formulations thereof) may vary from one target gene to another target gene and the appropriate amount that has to be applied may also be determined individually for each target gene. In embodiments, this amount ranges from 10 μg to 100 mg / mL of injectate, optionally 50 μg to 150 mg / mL of injectate, more optionally 20 mg to 100 mg / mL of injectate. VI. Methods of Inhibiting MAPT Expression The present disclosure also provides methods of inhibiting expression of a MAPT gene in a cell. The methods include contacting a cell with an RNAi agent, e.g., double stranded RNAi agent, in an amount effective to inhibit expression and / or activity of MAPT in the cell, thereby inhibiting expression and / or activity of MAPT in the cell. The present disclosure also provides methods of selective inhibition of exon 10-containing MAPT transcripts in a cell. The methods include contacting the cell with a dsRNA agent of the present disclosure, or a pharmaceutical composition of the present disclosure, thereby selectively degrading exon 10-containing MAPT transcripts in the cell. In certain embodiments, the cell is within a subject. In certain embodiments, the subject is a human. In certain embodiments, the subject has a MAPT-associated disease or disorder. In certain embodiments, the MAPT-associated disease or disorder is a neuro- Page 60 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO degenerative disorder. In certain embodiments, the neurodegenerative disorder is associated with an abnormality of MAPT gene encoded protein Tau. In certain embodiments, the abnormality of MAPT gene encoded protein Tau results in aggregation of Tau in subject’s brain. In certain embodiments of the disclosure, MAPT expression level and / or activity (e.g., MAPT mRNA and / or protein level or activity) is inhibited by at least 30% preferentially in CNS (e.g., brain) cells. In specific embodiments, MAPT expression and / or activity is inhibited by at least 30%. In certain embodiments, Tau protein level in serum of the subject is inhibited by at least 30%. In certain other embodiments of the disclosure, MAPT expression and / or activity is inhibited by at least 30% preferentially in hepatocytes. Contacting of a cell with an RNAi agent, e.g., a double stranded RNAi agent, may be done in vitro or in vivo. Contacting a cell in vivo with the RNAi agent includes contacting a cell or group of cells within a subject, e.g., a human subject, with the RNAi agent. Combinations of in vitro and in vivo methods of contacting a cell are also possible. Contacting a cell may be direct or indirect, as discussed above. Furthermore, contacting a cell may be accomplished via a targeting ligand, including any ligand described herein or known in the art. In some embodiments, the targeting ligand is a carbohydrate moiety, e.g., a GalNAc ligand, or any other ligand that directs the RNAi agent to a site of interest. The term “inhibiting,” as used herein, is used interchangeably with “reducing,” “silencing,” “downregulating,” “suppressing” and other similar terms, and includes any level of inhibition. In certain embodiments, a level of inhibition, e.g., for an RNAi agent of the instant disclosure, can be assessed in cell culture conditions, e.g., wherein cells in cell culture are transfected via LipofectamineTM-mediated transfection at a concentration in the vicinity of a cell of 10 nM or less, 1 nM or less, etc. Knockdown of a given RNAi agent can be determined via comparison of pre-treated levels in cell culture versus post-treated levels in cell culture, optionally also comparing against cells treated in parallel with a scrambled or other form of control RNAi agent. Knockdown in cell culture of, e.g., at least about 30%, can thereby be identified as indicative of “inhibiting” or “reducing”, “downregulating” or “suppressing”, etc. having occurred. It is expressly contemplated that assessment of targeted mRNA or encoded protein levels (and therefore an extent of “inhibiting”, etc. caused by an RNAi agent of the disclosure) can also be Page 61 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO assessed in in vivo systems for the RNAi agents of the instant disclosure, under properly controlled conditions as described in the art. The phrase “inhibiting MAPT,” “inhibiting expression of a MAPT gene” or “inhibiting expression of MAPT,” as used herein, includes inhibition of expression of any MAPT gene (such as, e.g., a mouse MAPT gene, a rat MAPT gene, a monkey MAPT gene, or a human MAPT gene) as well as variants or mutants of a MAPT gene that encode a Tau. Thus, the MAPT gene may be a wild-type MAPT gene, a mutant MAPT gene, or a transgenic MAPT gene in the context of a genetically manipulated cell, group of cells, or organism. “Inhibiting expression of a MAPT gene” includes any level of inhibition of a MAPT gene, e.g., at least partial suppression of the expression of a MAPT gene, such as an inhibition by at least about 25%. In certain embodiments, inhibition is at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%, or at least about 99%, relative to a control level. MAPT inhibition can be measured using the in vitro assay with, e.g., A549 cells and a 10 nM concentration of the RNA agent and the PCR assay as provided in the examples herein, are contemplated to be within the scope of the present disclosure. In some embodiments, MAPT inhibition can be measured using the in vitro assay with BE(2)-C cells. In some embodiments, MAPT inhibition can be measured using the in vitro assay with Neuro-2a cells. In another embodiment, MAPT inhibition can be measured using the in vitro assay with Cos-7 (Dual- Luciferase psiCHECK2 vector). In yet another embodiment, MAPT inhibition can be measured using the in vitro assay with primary mouse hepatocytes. The expression of a MAPT gene may be assessed based on the level of any variable associated with MAPT gene expression, e.g., MAPT mRNA level (e.g., sense mRNA, antisense mRNA, total MAPT mRNA, sense MAPT repeat-containing mRNA, and / or antisense MAPT repeat-containing mRNA) or Tau level (e.g., total Tau, wild-type Tau, or expanded repeat- containing protein), or, for example, the level of sense- or antisense-containing foci and / or the level of aberrant dipeptide repeat protein. Inhibition may be assessed by a decrease in an absolute or relative level of one or more of these variables compared with a control level. The control level may be any type of control level that is utilized in the art, e.g., a pre-dose baseline level, or a level determined from a similar Page 62 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO subject, cell, or sample that is untreated or treated with a control (such as, e.g., buffer only control or inactive agent control). For example, in some embodiments of the methods of the disclosure, expression of a MAPT gene (e.g., as assessed by sense- or antisense-containing foci and / or aberrant dipeptide repeat protein level) is inhibited by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, or 95%, relative to a control level, or to below the level of detection of the assay. In other embodiments of the methods of the disclosure, expression of a MAPT gene (e.g., as assessed by mRNA or protein expression level) is inhibited by at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% relative to a control level. In certain embodiments, the methods include a clinically relevant inhibition of expression of MAPT, e.g. as demonstrated by a clinically relevant outcome after treatment of a subject with an agent to reduce the expression of MAPT. Inhibition of the expression of a MAPT gene may be manifested by a reduction of the amount of mRNA expressed by a first cell or group of cells (such cells may be present, for example, in a sample derived from a subject) in which a MAPT gene is transcribed and which has or have been treated (e.g., by contacting the cell or cells with an RNAi agent of the disclosure, or by administering an RNAi agent of the disclosure to a subject in which the cells are or were present) such that the expression of a MAPT 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 not or have not been so treated (control cell(s) not treated with an RNAi agent or not treated with an RNAi agent targeted to the gene of interest). The degree of inhibition (%) may be expressed in terms of: (mRNA in control cells) (mRN -A in treated cells) X 100 (mRNA in control cells In other embodiments, inhibition of the expression of a MAPT gene may be assessed in terms of a reduction of a parameter that is functionally linked to a MAPT gene expression, e.g., Tau expression, sense- or antisense-containing foci and / or the level of aberrant dipeptide repeat protein. MAPT gene silencing may be determined in any cell expressing MAPT, either endogenous or heterologous from an expression construct, and by any assay known in the art. Page 63 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO Inhibition of the expression of MAPT gene may be manifested by a reduction in the level of the Tau protein (or functional parameter, e.g., reduction in microtubule assembly) that is expressed by a cell or group of cells (e.g., the level of protein expressed in a sample derived from a subject). As explained above, for the assessment of mRNA suppression, the inhibition of protein expression levels in a treated cell or group of cells may similarly be expressed as a percentage of the level of protein in a control cell or group of cells. In some embodiments, the phrase “inhibiting MAPT”, can also refer to the inhibition of Tau protein expression, e.g., at least partial suppression Tau expression, such as an inhibition by at least about 25%. In certain embodiments, inhibition of the MAPT activity is by at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%, or at least about 99%, relative to a control level. Tau protein levels can be measured using the in vitro assay with, e.g., the assay described in (Rubenstein et al. (2015) J. Neurotrauma 2015 Mar1: 32 (5):342-352; Lim et al. (2014) Comput Struct Biotechnol J. 2014;12(20-21):7–13). MAPT expression can be measured using the in vitro assay with, e.g., the assay described in (Caillet-Boudin et al. (2015) Mol Neurodegener. 2015; 10:28; Hefti et al. (2018) PLoS ONE 13(4): e0195771). A control cell or group of cells that may be used to assess the inhibition of the expression of a MAPT gene includes a cell or group of cells that has not yet been contacted with an RNAi agent of the disclosure. For example, the control cell or group of cells may be derived from an individual subject (e.g., a human or animal subject) prior to treatment of the subject with an RNAi agent. The level of MAPT mRNA that is expressed by a cell or group of cells may be determined using any method known in the art for assessing mRNA expression. In one embodiment, the level of expression of MAPT in a sample is determined by detecting a transcribed polynucleotide, or portion thereof, e.g., mRNA of the MAPT gene. RNA may be extracted from cells using RNA extraction techniques including, for example, using acid phenol / guanidine isothiocyanate extraction (RNAzol B; Biogenesis), RNeasyTMRNA preparation kits (Qiagen®) or PAXgene (PreAnalytix, Switzerland). Typical assay formats utilizing ribonucleic acid hybridization include nuclear run-on assays, RT-PCR, RNase protection assays, northern blotting, in situ hybridization, and microarray analysis. Strand specific MAPT mRNAs may be detected using the quantitative Page 64 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO RT-PCR and or droplet digital PCR methods described in, for example, Jiang, et al. supra, Lagier- Tourenne, et al., supra and Jiang, et al., supra. Circulating MAPT mRNA may be detected using methods the described in WO2012 / 177906, the entire contents of which are hereby incorporated herein by reference. In some embodiments, the level of expression of MAPT is determined using a nucleic acid probe. The term “probe”, as used herein, refers to any molecule that is capable of selectively binding to a specific MAPT nucleic acid or protein, or fragment thereof. Probes can be synthesized by one of skill in the art, or derived from appropriate biological preparations. Probes may be specifically designed to be labeled. Examples of molecules that can be utilized as probes include, but are not limited to, RNA, DNA, proteins, antibodies, and organic molecules. Isolated mRNA can be used in hybridization or amplification assays that include, but are not limited to, Southern or northern analyses, polymerase chain reaction (PCR) analyses and probe arrays. One method for the determination of mRNA levels involves contacting the isolated mRNA with a nucleic acid molecule (probe) that can hybridize to MAPT mRNA. In one embodiment, the mRNA is immobilized on a solid surface and contacted with a probe, for example by running the isolated mRNA on an agarose gel and transferring the mRNA from the gel to a membrane, such as nitrocellulose. In an alternative embodiment, the probe(s) are immobilized on a solid surface and the mRNA is contacted with the probe(s), for example, in an Affymetrix®gene chip array. A skilled artisan can readily adapt known mRNA detection methods for use in determining the level of MAPT mRNA. An alternative method for determining the level of expression of MAPT in a sample involves the process of nucleic acid amplification or reverse transcriptase (to prepare cDNA) of for example mRNA in the sample, e.g., by RT-PCR (the experimental embodiment set forth in Mullis, 1987, US Patent No.4,683,202), ligase chain reaction (Barany (1991) Proc. Natl. Acad. Sci. USA 88:189-193), self sustained sequence replication (Guatelli et al. (1990) Proc. Natl. Acad. Sci. USA 87:1874-1878), transcriptional amplification system (Kwoh et al. (1989) Proc. Natl. Acad. Sci. USA 86:1173-1177), Q-Beta Replicase (Lizardi et al. (1988) Bio / Technology 6:1197), rolling circle replication (Lizardi et al., US Patent No. 5,854,033) or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection Page 65 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO of nucleic acid molecules if such molecules are present in very low numbers. In particular aspects of the disclosure, the level of expression of MAPT is determined by quantitative fluorogenic RT- PCR (i.e., the TaqManTMSystem), by a Dual-Glo® Luciferase assay, or by other art-recognized method for measurement of MAPT expression or mRNA level. The expression level of MAPT mRNA may be monitored using a membrane blot (such as used in hybridization analysis such as northern, Southern, dot, and the like), or microwells, sample tubes, gels, beads or fibers (or any solid support comprising bound nucleic acids). See US Patent Nos. 5,770,722, 5,874,219, 5,744,305, 5,677,195 and 5,445,934, which are incorporated herein by reference. The determination of MAPT expression level may also comprise using nucleic acid probes in solution. In some embodiments, the level of mRNA expression is assessed using branched DNA (bDNA) assays or real time PCR (qPCR). The use of this PCR method is described and exemplified in the Examples presented herein. Such methods can also be used for the detection of MAPT nucleic acids. The level of Tau expression may be determined using any method known in the art for the measurement of protein levels. Such methods include, for example, electrophoresis, capillary electrophoresis, high performance liquid chromatography (HPLC), thin layer chromatography (TLC), hyperdiffusion chromatography, fluid or gel precipitin reactions, absorption spectroscopy, a colorimetric assays, spectrophotometric assays, flow cytometry, immunodiffusion (single or double), immunoelectrophoresis, western blotting, radioimmunoassay (RIA), enzyme-linked immunosorbent assays (ELISAs), immunofluorescent assays, electrochemiluminescence assays, and the like. Such assays can also be used for the detection of proteins indicative of the presence or replication of Tau. Tau protein levels can be measured using the in vitro assay with, e.g., the assay described in (Rubenstein et al. (2015) J. Neurotrauma 2015 Mar1: 32 (5):342-352; Lim et al. (2014) Comput Struct Biotechnol J.2014;12(20-21):7–13). The level of sense- or antisense-containing foci and the level of aberrant dipeptide repeat protein may be assessed using methods well-known to one of ordinary skill in the art, including, for example, fluorescent in situ hybridization (FISH), immunohistochemistry and immunoassay (see, e.g., Jiang, et al. supra).In some embodiments, the efficacy of the methods of the disclosure in the treatment of a MAPT-associated disease or disorder is assessed by a decrease in MAPT Page 66 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO mRNA level (e.g, by assessment of a CSF sample and / or plasma sample for MAPT level, by brain biopsy, or otherwise). In some embodiments of the methods of the disclosure, the RNAi agent is administered to a subject such that the RNAi agent is delivered to a specific site within the subject. The inhibition of expression of MAPT may be assessed using measurements of the level or change in the level of MAPT mRNA (e.g., sense mRNA, antisense mRNA, total MAPT mRNA), Tau protein (e.g., total Tau protein, wild-type Tau protein), sense-containing foci, antisense-containing foci, aberrant dipeptide repeat protein in a sample derived from a specific site within the subject, e.g., CNS cells. In certain embodiments, the methods include a clinically relevant inhibition of expression of MAPT, e.g. as demonstrated by a clinically relevant outcome after treatment of a subject with an agent to reduce the expression of MAPT, for example, stabilization or inhibition of caudate atrophy (e.g., as assessed by volumetric MRI (vMRI)), a stabilization or reduction in neurofilament light chain (NfL) levels in a CSF sample from a subject, a reduction in mutant MAPT mRNA or a cleaved mutant Tau, e.g., full-length mutant MAPT mRNA or protein and a cleaved mutant MAPT mRNA or protein. As used herein, the terms detecting or determining a level of an analyte are understood to mean performing the steps to determine if a material, e.g., protein, RNA, is present. As used herein, methods of detecting or determining include detection or determination of an analyte level that is below the level of detection for the method used. MAPT SEQUENCES SEQ ID NO: 510 >NM_016841.4 Homo sapiens microtubule associated protein tau (MAPT), transcript variant 4, mRNA SEQ ID NO: 511 >Reverse Complement of SEQ ID NO: 510 SEQ ID NO: 512 >NM_005910.6 Homo sapiens microtubule associated protein tau (MAPT), transcript variant 2, mRNA SEQ ID NO: 513 >Reverse Complement of SEQ ID NO: 512 Page 67 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO SEQ ID NO: 514 >NM_001038609.2 Mus musculus microtubule-associated protein tau (Mapt), transcript variant 1, mRNA SEQ ID NO: 515 >Reverse Complement of SEQ ID NO: 514 SEQ ID NO: 516 >XM_005584540.1 PREDICTED: Macaca fascicularis microtubule associated protein tau (MAPT), transcript variant X13, mRNA SEQ ID NO: 517 >Reverse Complement of SEQ ID NO: 516 SEQ ID NO: 518 >XM_008768277.2 PREDICTED: Rattus norvegicus microtubule- associated protein tau (Mapt), transcript variant X7, mRNA SEQ ID NO: 519 >Reverse Complement of SEQ ID NO: 518 SEQ ID NO: 520 >XM_005624183.3 PREDICTED: Canis lupus familiaris microtubule associated protein tau (MAPT), transcript variant X23, mRNA SEQ ID NO: 521 >Reverse Complement of SEQ ID NO: 520 VII. Methods of Treating or Preventing MAPT-associated disease or disorders The present disclosure also provides methods of using an RNAi agent of the disclosure or a composition containing an RNAi agent of the disclosure to reduce or inhibit MAPT expression in a cell. The methods include contacting the cell with a dsRNA of the disclosure and maintaining the cell for a time sufficient to obtain degradation of the mRNA transcript of a MAPT gene, thereby inhibiting expression of the MAPT gene in the cell. In addition, the present disclosure also provides methods of using an RNAi agent of the disclosure or a composition containing an RNAi agent of the disclosure to reduce the level and / or inhibit formation of sense- and antisense-containing foci in a cell. The methods include contacting the cell with a dsRNA of the disclosure, thereby reducing the level of the MAPT sense- and antisense-containing foci in the cell. The present disclosure also provides methods of using an RNAi agent of the disclosure or a composition containing an RNAi agent of the disclosure to reduce the level and / or inhibit formation of aberrant dipeptide repeat protein in a cell. The methods include contacting the cell with a dsRNA of the disclosure, thereby reducing the level of the aberrant dipeptide repeat protein in the cell. Reduction in gene expression, the level of MAPT sense- and antisense-containing foci, and / or aberrant dipeptide repeat protein can be assessed by any methods known in the art. For Page 68 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO example, a reduction in the expression of MAPT may be determined by determining the mRNA expression level of MAPT using methods routine to one of ordinary skill in the art, e.g., northern blotting, qRT-PCR; by determining the protein level of MAPT using methods routine to one of ordinary skill in the art, such as western blotting, immunological techniques. In the methods of the disclosure the cell may be contacted in vitro or in vivo, i.e., the cell may be within a subject. The subject may be a human. The subject may have a MAPT-associated disease or disorder. The MAPT-associated disease or disorder may be a neurodegenerative disorder. The neurodegenerative disorder of the subject that can be associated with an abnormality of MAPT gene encoded protein Tau. The abnormality of MAPT gene encoded protein Tau may result in aggregation of Tau in subject’s brain. A cell suitable for treatment using the methods of the disclosure may be any cell that expresses a MAPT gene. A cell suitable for use in the methods of the disclosure may be a mammalian cell, e.g., a primate cell (such as a human cell or a non-human primate cell, e.g., a monkey cell or a chimpanzee cell), a non-primate cell (such as a rat cell, or a mouse cell). In one embodiment, the cell is a human cell, e.g., a human CNS cell. MAPT expression (e.g., as assessed by sense mRNA, antisense mRNA, total MAPT mRNA, total Tau protein) is inhibited in the cell by about 20%, 25%, 30%, 35%, 40%, 45%, or 50% relative to the expression in a control cell. In certain embodiments, MAPT expression is inhibited by at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% relative to a control level. In preferred embodiments, MAPT expression is inhibited in the cell by at least 30%. In particular embodiments, inhibiting expression of MAPT may decrease Tau protein level in serum of the subject by at least 30%. Inhibition, as assessed by sense- or antisense-containing foci and / or aberrant dipeptide repeat protein level) is inhibited in the cell by at least 20%, 30%, 40%, preferably at least 50%, 60%, 70%, 80%, 85%, 90%, or 95%, or to below the level of detection of the assay. The in vivo methods of the disclosure may include administering to a subject a composition containing an RNAi agent, where the RNAi agent includes a nucleotide sequence that is complementary to at least a part of an RNA transcript of the MAPT gene of the mammal to be treated. When the organism to be treated is a mammal such as a human, the composition can be Page 69 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO administered by any means known in the art including, but not limited to oral, intraperitoneal, or parenteral routes, including intracranial (e.g., intraventricular, intraparenchymal, and intrathecal), intravenous, intramuscular, intravitreal, subcutaneous, transdermal, airway (aerosol), nasal, rectal, and topical (including buccal and sublingual) administration. In certain embodiments, the compositions are administered by intravenous infusion or injection. In certain embodiments, the compositions are administered by subcutaneous injection. In certain embodiments, the compositions are administered by intrathecal injection. In some embodiments, the administration is via a depot injection. A depot injection may release the RNAi agent in a consistent way over a prolonged time period. Thus, a depot injection may reduce the frequency of dosing needed to obtain a desired effect, e.g., a desired inhibition of MAPT, or a therapeutic or prophylactic effect. A depot injection may also provide more consistent serum concentrations. Depot injections may include subcutaneous injections or intramuscular injections. In preferred embodiments, the depot injection is a subcutaneous injection. In some embodiments, the administration is via a pump. The pump may be an external pump or a surgically implanted pump. In certain embodiments, the pump is a subcutaneously implanted osmotic pump. In other embodiments, the pump is an infusion pump. An infusion pump may be used for intracranial, intravenous, subcutaneous, arterial, or epidural infusions. In preferred embodiments, the infusion pump is a subcutaneous infusion pump. In other embodiments, the pump is a surgically implanted pump that delivers the RNAi agent to the CNS. The mode of administration may be chosen based upon whether local or systemic treatment is desired and based upon the area to be treated. The route and site of administration may be chosen to enhance targeting. In one aspect, the present disclosure also provides methods for inhibiting the expression of a MAPT gene in a mammal. The methods include administering to the mammal a composition comprising a dsRNA that targets a MAPT gene in a cell of the mammal, thereby inhibiting expression of the MAPT gene in the cell. Reduction in gene expression can be assessed by any methods known it the art and by methods, e.g. qRT-PCR, described herein. Reduction in protein production can be assessed by any methods known it the art and by methods, e.g. ELISA, described herein. In one embodiment, a CNS biopsy sample or a cerebrospinal fluid (CSF) sample Page 70 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO serves as the tissue material for monitoring the reduction in MAPT gene or protein expression (or of a proxy therefore). The present disclosure further provides methods of treatment of a subject in need thereof. The treatment methods of the disclosure include administering an RNAi agent of the disclosure to a subject, e.g., a subject that would benefit from inhibition of MAPT expression, such as a subject having a missense and / or deletion mutations in the MAPT gene, in a therapeutically effective amount of an RNAi agent targeting a MAPT gene or a pharmaceutical composition comprising an RNAi agent targeting a MAPT gene. In addition, the present disclosure provides methods of preventing, treating or inhibiting the progression of a MAPT-associated disease or disorder (e.g., Alzheimer’s disease, FTD, PSP, or another tauopathy), in a subject. The methods include administering to the subject a therapeutically effective amount of any of the RNAi agent, e.g., dsRNA agents, or the pharmaceutical composition provided herein, thereby preventing, treating or inhibiting the progression of a MAPT-associated disease or disorder in the subject. A MAPT-associated disease or disorder that can be prevented by the method of the disclosure can be associated with an abnormality of MAPT gene encoded protein Tau. The abnormality of MAPT gene encoded protein Tau results in aggregation of Tau in subject’s brain. The subject may be human. Administration of a dsRNA agent of the disclosure, or a pharmaceutical composition of the disclosure, may cause a decrease in Tau aggregation in the subject’s brain. An RNAi agent of the disclosure may be administered as a “free RNAi agent.” A free RNAi agent is administered in the absence of a pharmaceutical composition. The naked RNAi agent may be in a suitable buffer solution. The buffer solution may comprise acetate, citrate, chloride, carbonate, or phosphate, or any combination thereof. In one embodiment, the buffer solution is phosphate buffered saline (PBS). The pH and osmolarity of the buffer solution containing the RNAi agent can be adjusted such that it is suitable for administering to a subject. Alternatively, an RNAi agent of the disclosure may be administered as a pharmaceutical composition, such as a dsRNA liposomal formulation. Subjects that would benefit from a reduction or inhibition of MAPT gene expression are those having a MAPT-associated disease or disorder. Exemplary MAPT-associated disease or disorders include, but are not limited to, tauopathy, Alzheimer disease, frontotemporal dementia Page 71 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO (FTD), behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA-L), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick’s disease (PiD), argyrophilic grain disease (AGD), multiple system tauopathy with presenile dementia (MSTD), white matter tauopathy with globular glial inclusions (FTLD with GGIs), FTLD with MAPT mutations, neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, amyotrophic lateral sclerosis (ALS), corticobasal syndrome (CBS), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Parkinson’s disease, postencephalitic Parkinsonism, Niemann-Pick disease, Huntington disease, type 1 myotonic dystrophy, and Down syndrome (DS). The disclosure further provides methods for the use of an RNAi agent or a pharmaceutical composition thereof, e.g., for treating a subject that would benefit from reduction or inhibition of MAPT expression, e.g., a subject having a MAPT-associated disease or disorder, in combination with other pharmaceuticals or other therapeutic methods, e.g., with known pharmaceuticals or known therapeutic methods, such as, for example, those which are currently employed for treating these disorders. For example, in certain embodiments, an RNAi agent targeting MAPT is administered in combination with, e.g., an agent useful in treating a MAPT-associated disease or disorder as described elsewhere herein or as otherwise known in the art. For example, additional agents suitable for treating a subject that would benefit from reduction in MAPT expression, e.g., a subject having a MAPT-associated disease or disorder, may include agents currently used to treat symptoms of MAPT-associated disease or disorders. The RNAi agent and additional therapeutic agents may be administered at the same time or in the same combination, e.g., intrathecally, or the additional therapeutic agent can be administered as part of a separate composition or at separate times or by another method known in the art or described herein. Exemplary additional therapeutics include, for example, a monoamine inhibitor, e.g., tetrabenazine (Xenazine), deutetrabenazine (Austedo), and reserpine, an anticonvulsant, e.g., valproic acid (Depakote, Depakene, Depacon), and clonazepam (Klonopin), an antipsychotic agent, e.g., risperidone (Risperdal), and haloperidol (Haldol), and an antidepressant, e.g., paroxetine (Paxil). Page 72 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO In one embodiment, the method includes administering a composition featured herein such that expression of the target MAPT gene is decreased, for at least one month. In preferred embodiments, expression is decreased for at least 2 months, 3 months, or 6 months. Preferably, the RNAi agents useful for the methods and compositions featured herein specifically target RNAs (primary or processed) of the target MAPT gene. Compositions and methods for inhibiting the expression of these genes using RNAi agents can be prepared and performed as described herein. Administration of the dsRNA according to the methods of the disclosure may result in a reduction of the severity, signs, symptoms, or markers of such diseases or disorders in a patient with a MAPT-associated disease or disorder. By “reduction” in this context is meant a statistically significant or clinically significant decrease in such level. The reduction can be, for example, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% relative to a control level. Efficacy of treatment or prevention of disease can be assessed, for example by measuring disease progression, disease remission, symptom severity, reduction in pain, quality of life, dose of a medication required to sustain a treatment effect, level of a disease marker or any other measurable parameter appropriate for a given disease being treated or targeted for prevention. It is well within the ability of one skilled in the art to monitor efficacy of treatment or prevention by measuring any one of such parameters, or any combination of parameters. For example, efficacy of treatment of a MAPT-associated disease or disorder may be assessed, for example, by periodic monitoring of a subject’s. Comparisons of the later readings with the initial readings provide a physician an indication of whether the treatment is effective. It is well within the ability of one skilled in the art to monitor efficacy of treatment or prevention by measuring any one of such parameters, or any combination of parameters. In connection with the administration of an RNAi agent targeting MAPT or pharmaceutical composition thereof, “effective against” a MAPT-associated disease or disorder indicates that administration in a clinically appropriate manner results in a beneficial effect for at least a statistically significant fraction of patients, such as an improvement of symptoms, a cure, a reduction in disease, extension Page 73 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO of life, improvement in quality of life, or other effect generally recognized as positive by medical doctors familiar with treating MAPT-associated disease or disorders and the related causes. A treatment or preventive effect is evident when there is a statistically significant improvement in one or more parameters of disease status, or by a failure to worsen or to develop symptoms where they would otherwise be anticipated. As an example, a favorable change of at least 10% in a measurable parameter of disease, and preferably at least 20%, 30%, 40%, 50% or more can be indicative of effective treatment. Efficacy for a given RNAi agent drug or formulation of that drug can also be judged using an experimental animal model for the given disease as known in the art. When using an experimental animal model, efficacy of treatment is evidenced when a statistically significant reduction in a marker or symptom is observed. Alternatively, the efficacy can be measured by a reduction in the severity of disease as determined by one skilled in the art of diagnosis based on a clinically accepted disease severity grading scale. Any positive change resulting in e.g., lessening of severity of disease measured using the appropriate scale, represents adequate treatment using an RNAi agent or RNAi agent formulation as described herein. In certain embodiments, subjects can be administered a therapeutic amount of dsRNA, such as about 0.01 mg / kg to about 200 mg / kg. In other embodiments, subjects can be administered a therapeutic amount of dsRNA, such as about 0.01 mg / kg to about 500 mg / kg. In yet other embodiments, subjects can be administered a therapeutic amount of dsRNA of about 500 mg / kg or more. The RNAi agent can be administered intrathecally, via intravitreal injection, or by intravenous infusion over a period of time, on a regular basis. In certain embodiments, after an initial treatment regimen, the treatments can be administered on a less frequent basis. Administration of the RNAi agent can reduce MAPT levels, e.g., in a cell, tissue, blood, CSF sample or other compartment of the patient. In one embodiment, administration of the RNAi agent can reduce MAPT levels, e.g., in a cell, tissue, blood, CSF sample or other compartment of the patient by at least about 25%, such as about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% relative to a control level. Before administration of a full dose of the RNAi agent, patients can be administered a smaller dose, such as a 5% infusion reaction, and monitored for adverse effects, such as an allergic Page 74 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO reaction. In another example, the patient can be monitored for unwanted immunostimulatory effects, such as increased cytokine (e.g., TNF-alpha or INF-alpha) levels. Alternatively, the RNAi agent can be administered subcutaneously, i.e., by subcutaneous injection. One or more injections may be used to deliver the desired, e.g., monthly dose of RNAi agent to a subject. The injections may be repeated over a period of time. The administration may be repeated on a regular basis. In certain embodiments, after an initial treatment regimen, the treatments can be administered on a less frequent basis. A repeat-dose regimen may include administration of a therapeutic amount of RNAi agent on a regular basis, such as monthly or extending to once a quarter, twice per year, once per year. In certain embodiments, the RNAi agent is administered about once per month to about once per quarter (i.e., about once every three months). In some embodiments, the disclosure further provides methods for the use of an RNAi agent or a pharmaceutical composition thereof, e.g., for treating a subject that would benefit from reduction or inhibition of MAPT expression, e.g., a subject having an MAPT-associated neurodegenerative disorder, in combination with other pharmaceuticals or other therapeutic methods, e.g., with known pharmaceuticals or known therapeutic methods, such as, for example, those which are currently employed for treating these disorders. For example, in certain embodiments, an RNAi agent targeting MAPT is administered in combination with, e.g., an agent useful in treating an MAPT-associated neurodegenerative disorder as described elsewhere herein or as otherwise known in the art. For example, additional agents and treatments suitable for treating a subject that would benefit from reduction in MAPT expression, e.g., a subject having an MAPT-associated neurodegenerative disorder, may include agents currently used to treat symptoms of MAPT. The RNAi agent and additional therapeutic agents may be administered at the same time or in the same combination, e.g., intrathecally, or the additional therapeutic agent can be administered as part of a separate composition or at separate times or by another method known in the art or described herein. Exemplary additional therapeutics and treatments include dopamine-modulating agents, among others, for example, carbidopa-levodopa, levodopa, entacopone, tolcapone, opicapone, pramipexole, ropinirole, apomorphine, rotigotine, selegiline, rasagiline, safinamide, amantadine, istradefylline, trihexyphenidyl, benztropine, rivastigmine, donepezil, galantamine and Page 75 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO memantine, as well as physical, occupational and speech therapy, an exercise program including cardiorespiratory, resistance, flexibility, and gait and balance exercises, and deep brain stimulation (DBS) involving the implantation of an electrode into a targeted area of the brain. In one embodiment, the method includes administering a composition featured herein such that expression of the target gene is decreased, for at least one month. In certain embodiments, expression is decreased for at least 2 months, 3 months, or 6 months. Optionally, the RNAi agents useful for the methods and compositions featured herein specifically target RNAs (primary or processed) of the target gene (e.g., MAPT). Compositions and methods for inhibiting the expression of these genes using RNAi agents can be prepared and performed as described herein. Administration of the dsRNA according to the methods of the disclosure may result in a reduction of the severity, signs, symptoms, or markers of such diseases or disorders in a patient with a target gene-associated disorder. By “reduction” in this context is meant a statistically significant or clinically significant decrease in such level. The reduction can be, for example, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 100%. Efficacy of treatment or prevention of disease can be assessed, for example by measuring disease progression, disease remission, symptom severity, reduction in pain, quality of life, dose of a medication required to sustain a treatment effect, level of a disease marker or any other measurable parameter appropriate for a given disease being treated or targeted for prevention. It is well within the ability of one skilled in the art to monitor efficacy of treatment or prevention by measuring any one of such parameters, or any combination of parameters. For example, efficacy of treatment of an MAPT-associated neurodegenerative disorder may be assessed, for example, by periodic monitoring of a subject’s cognition, learning, or memory. Comparisons of the later readings with the initial readings provide a physician an indication of whether the treatment is effective. It is well within the ability of one skilled in the art to monitor efficacy of treatment or prevention by measuring any one of such parameters, or any combination of parameters. In connection with the administration of an RNAi agent targeting MAPT or pharmaceutical composition thereof, "effective against" an MAPT-associated neurodegenerative disorder indicates that administration in a clinically appropriate manner results in a beneficial effect for at Page 76 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO least a statistically significant fraction of patients, such as an improvement of symptoms, a cure, a reduction in disease, extension of life, improvement in quality of life, or other effect generally recognized as positive by medical doctors familiar with treating MAPT-associated neurodegenerative disorders and the related causes. A treatment or preventive effect is evident when there is a statistically significant improvement in one or more parameters of disease status, or by a failure to worsen or to develop symptoms where they would otherwise be anticipated. As an example, a favorable change of at least 10% in a measurable parameter of disease, and optionally at least 20%, 30%, 40%, 50% or more can be indicative of effective treatment. Efficacy for a given RNAi agent drug or formulation of that drug can also be judged using an experimental animal model for the given disease as known in the art. When using an experimental animal model, efficacy of treatment is evidenced when a statistically significant reduction in a marker or symptom is observed. Alternatively, the efficacy can be measured by a reduction in the severity of disease as determined by one skilled in the art of diagnosis based on a clinically accepted disease severity grading scale. Any positive change resulting in e.g., lessening of severity of disease measured using the appropriate scale, represents adequate treatment using an RNAi agent or RNAi agent formulation as described herein. Subjects can be administered a therapeutic amount of dsRNA, such as about 0.01 mg / kg to about 200 mg / kg. The RNAi agent can be administered intrathecally, via intravitreal injection, or by intravenous infusion over a period of time, on a regular basis. In certain embodiments, after an initial treatment regimen, the treatments can be administered on a less frequent basis. Administration of the RNAi agent can reduce target gene levels, e.g., in a cell, tissue, blood, CSF sample or other compartment of the patient by at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or at least about 99% or more. In a preferred embodiment, administration of the RNAi agent can reduce target transcript and / or protein levels, e.g., in a cell, tissue, blood, CSF sample or other compartment of the patient by at least 50%. Alternatively, the RNAi agent can be administered subcutaneously, i.e., by subcutaneous injection. One or more injections may be used to deliver the desired, e.g., monthly dose of RNAi Page 77 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO agent to a subject. The injections may be repeated over a period of time. The administration may be repeated on a regular basis. VIII. Kits In certain aspects, the instant disclosure provides kits that include a suitable container containing a pharmaceutical formulation of a nucleic acid agent (e.g., a siRNA compound, e.g., a double-stranded siRNA compound, or a precursor to a siRNA compound (e.g., a precursor, e.g., a larger siRNA compound which can be processed into a siRNA compound, or a DNA which encodes an siRNA compound, e.g., a double-stranded siRNA compound, or siRNA compound, or precursor thereof)), and instructions for its use. In certain embodiments the individual components of the pharmaceutical formulation may be provided in one container. Alternatively, it may be desirable to provide the components of the pharmaceutical formulation separately in two or more containers, e.g., one container for a nucleic acid agent (e.g., a siRNA compound) preparation, and at least another for a carrier compound. The kit may be packaged in a number of different configurations such as one or more containers in a single box. The different components can be combined, e.g., according to instructions provided with the kit. The components can be combined according to a method described herein, e.g., to prepare and administer a pharmaceutical composition. The kit can also include a delivery device. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the RNAi agents and methods featured in the disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. EXAMPLES Example 1: Manufacture of AD-1786708 This Example describes methods for the manufacture of the exemplified MAPT-targeting RNAi agent, AD-1786708 drug substance (DS). Page 78 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO Non-limiting examples of dsRNA agents that target the MAPT gene are provided in WO 2021 / 202511, WO 2023 / 049871, WO / 2023 / 010134, and WO 2023 / 154900, the entire contents of which references are herein incorporated by reference in their entirety. Such oligonucleotides can be prepared with suitable and protected phosphoramidites on an automatic solid phase synthesizer using universal or custom supports, such as controlled pore glass (CPG) (see, e.g., F. Eckstein (ed.), Oligonucleotides and Analogues, a Practical Approach (Oxford University Press, New York 1991)); see also, the methods disclosed in WO2019 / 217459 and WO 2020 / 132227, each of which is hereby incorporated by reference in its entirety. 3’-RNA containing agents can be prepared according to the process disclosed in International Publication no. WO 2021 / 108291which is hereby incorporated by reference in its entirety. Where the source of a reagent is not specifically given herein, such reagent can be obtained from any supplier of reagents for molecular biology at a quality / purity standard for application in molecular biology. Abbreviations and acronyms used herein are provided in Table 3. Table 3. List of Abbreviations and Acronyms Abbreviation Definition DS Drug Substance Duplex Formation To ensure the equimolar ratio between the two single strands, the solution of one strand was titrated with the other strand. The titration process was monitored through non-denaturing ion-paring reverse phase (IPRP) HPLC. Antisense strand excess should be in the range of 1 – 2 % to minimize solubility risk in drug product formulation. Finally, the duplex solution was filtered again through a 0.2 μm filter into a HDPE sterile container of appropriate volume. The solution may be lyophilized for storage and compounding. A typical chromatogram from the duplex annealing method is presented in FIG.3. Page 79 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO Example 2: Manufacture of AD-1786708 Drug Product A. AD-1786708 Drug Product Description The formulation details are as follows and are provided in Table 5. An excipient solution was prepared by adding sodium chloride, potassium chloride, magnesium chloride hexahydrate, and calcium chloride dihydrate to a compounding container followed by addition of water for injection (WFI) with stirring. The excipient solution was filtered through a 0.2-micron filter and stored at 2 – 8 °C until day of compounding. Lyophilized Drug Substance (DS), above, equilibrated at room temperature (15 – 25 ºC) for 2 - 24 h and compounded using the excipient solution. The pH was measured and, if necessary, adjusted with NaOH (0.25 N) or HCl (0.1N) to meet the acceptable range (6.6 – 7.0, for target 6.8). The excipient solution was used to dissolve the DS, and used to arrive at final concentration of 60 mg / mL (free acid basis). The solution was filtered through a 0.2-micron filter and stored at 2 – 8 °C until day of fill. Release osmolality of the formulations was 210-390 mOsm / kg, and the release particulate was >=10 um, NMT 6000 per container; >=25 um, NMT 600 per container where “container” is 5 mL in a 10R vial. The chemical properties of the AD-1786708 DS are presented in Table 4. The sodium salt molecular weight is the powdered form of the drug substance. The free acid molecular weight is related to the weight of the active duplex in solution. The ratio of the two is the molecular weight of the free acid divided by the molecular weight of the sodium salt and is used for conversion between the two forms. Drug product composition is presented in Table 5. There was no significant change in purity between the DS and DP and the current DP compounding process is compatible with MAPT DS. Table 4. Duplex Properties Name AD-1786708DS Page 80 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO Table 5. AD-1786708 Composition Component Conc (g / L) AD-1786708DS 60 (free acid basis) DP lot ELN0326058 had the following attributes: • pH: 6.8 • Concentration: 59 mg / mL • Solubility: NLT 81 mg / mL • Osmolality: 294 mOsm / kg • Density: 1.0314 mg / mL @ 25°C Appearance: clear, colorless to yellow solution free of foreign particles. Example 3: Comparative Formulation Stability Stability testing of AD-1786708 DP (see formulation in Table 5) without phosphate buffer was conducted out to 12-month time point under the following conditions: ^ 5±3°C, inverted ^ 25°C±2°C / 60%±5% relative humidity (RH), inverted ^ 30°C±2°C / 75%±5% RH, inverted ^ 40°C±2°C / 75%±5% RH, inverted ^ -20°C±5°C, upright Page 81 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO The abbreviations used in the stability data tables are defined in Table 6. The DP was prepared with DS annealed with a 1-2% antisense strand excess. The results for a representative lot are shown in Tables 7-11. Table 6. Abbreviations Used in Stability Data Abbreviation Definition AX A i h rted Storage Time (months) Attribute Method Acceptanc e 0 1 3 6 9 12 S S .8 1 0 8 3 7 Page 82 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO Table 8. Stability Data for AD-1786708 DP Representative Lot Stored at 25±2°C / 60±5%, Inverted Storage Time (months) Attribute Method Acceptance Criterion 0 1 3 6 9 12 Report Data (color CPYS CPYS CPYS CPYS CPYS CPYS Table 9. Stability Data for AD-1786708 DP Representative Lot Stored at 30±2°C / 75±5%, Inverted Storage Time (months) Attribute Method Acceptance Criterion 0 1 3 6 9 12 S Page 83 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO Table 10. Stability Data for AD-1786708 DP Representative Lot Stored at 40±2°C / 75±5%, Inverted Attribute Method Acceptance Criterion Storage Time (months) 0 1 3 6 Appearance Visual Inspection Report Data (color, CPYS CPYS CPYS CPYS S 0 0 7 32 Table 11. Stability Data for AD-1786708 DP Representative Lot Stored at -20±5°C, Upright Storage Attribute Method Acceptance Criterion Time s) S S 9 5 8 Page 84 of 93 WBD (US) 4884-6646-1936v1 Atty Dkt No.: A1088681840WO / ALN-535-WO EQUIVALENTS Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the following claims. Page 85 of 93 WBD (US) 4884-6646-1936v1

Claims

Atty Dkt No.: A1088681840WO / ALN-535-WO CLAIMS 1. A formulation comprising a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of microtubule associated protein tau (MAPT), wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand and the antisense strand are each represented by a dsRNA listed in Table 1, and wherein the antisense strand is present at no less than equimolar amount or at about a 1% to about a 2% excess relative to the sense strand.

2. The formulation of claim 1, wherein the sense strand comprises the nucleotide sequence and all the modifications of 5’ Gm-ps-Um-ps-Gm-Am-Cm-(Chd)-Cm-Am-Af-Gf-Cf-Um-Cm-Gm-Um-Am-Um- Gm-Gm-ps-Um-ps-Am 3’ (SEQ ID NO: 1); and the antisense strand comprises the nucleotide sequence and all the modifications of 5’ VPu-ps-Af-ps-Cm-Cm-dA-Um-dA-Cm-Gm-Am-Gm-Cm-Um-Uf-Gm-Gf-Gm-Um- Cm-Am-Cm-ps-Gm-ps-Um 3’ (SEQ ID NO: 2), wherein Af is 2’-fluoroadenosine, Uf is 2’-fluorouridine, Cf is 2’-fluorocytidine, Gf is 2’- fluoroguanosine, Am is 2’-O-methyladenosine, Um is 2’-O-methyluridine, Cm is 2’-O- methylcytidine, Gm is 2’-O-methylguanosine, dA is 2’-deoxyadenosine, Chd is 2’-O- hexadecylcytidine, VPu is vinylphosphonate 2’-O-methyluridine, ’-’ (hyphen) is 3’-5’ phosphodiester linkage, ’-ps-’ is 3’-5’ phosphorothioate linkage, and wherein the antisense strand is present at no less than equimolar amount or at about a 1% to about a 2% excess relative to the sense strand.

3. The formulation of claim 1 or 2, wherein the formulation comprises greater than 1 mg of the dsRNA agent per mL of the formulation, the formulation comprises greater than 5 mg of the dsRNA agent per mL of the formulation, the formulation comprises greater than 10 mg of the dsRNA agent per mL of the formulation, the formulation comprises greater than 25 mg of the dsRNA agent per mL of the formulation, the formulation comprises greater than 50 mg of the Page 86 of 93 WBD (US) 4884-6646-1936v1Atty Dkt No.: A1088681840WO / ALN-535-WO dsRNA agent per mL of the formulation, or the formulation comprises greater than 60 mg of the dsRNA agent per mL of the formulation.

4. The formulation of claim 3, wherein the formulation comprises about 50 mg to about 70 mg of the dsRNA agent per mL of the formulation.

5. The formulation of claim 4, wherein the formulation comprises about 60 mg of the dsRNA agent per mL of the formulation.

6. The formulation of any one of claims 1-5, further comprising a sodium source, a potassium source, a magnesium source, and / or a calcium source.

7. The formulation of claim 6, comprising sodium chloride, potassium chloride, magnesium chloride, and / or calcium chloride.

8. The formulation of claim 7, wherein the formulation comprises sodium chloride at about 70 mM to about 100 mM.

9. The formulation of claim 8, wherein the formulation comprises sodium chloride at about 85.50 mM.

10. The formulation of claim 7, wherein the formulation comprises potassium chloride at about 1.0 mM to about 2.5 mM.

11. The formulation of claim 10, wherein the formulation comprises potassium chloride at about 1.68 mM.

12. The formulation of claim 7, wherein the formulation comprises magnesium chloride at about 0.1 mM to about 1.0 mM. Page 87 of 93 WBD (US) 4884-6646-1936v1Atty Dkt No.: A1088681840WO / ALN-535-WO 13. The formulation of claim 12, wherein the formulation comprises magnesium chloride at about 0.45 mM.

14. The formulation of claim 7, wherein the formulation comprises calcium chloride at about 8.0 mM to about 25.0 mM.

15. The formulation of claim 14, wherein the formulation comprises calcium chloride at about 15.6 mM.

16. The formulation of any one of claims 1-15, having a pH between about 6 and about 10.

17. The formulation of claim 16, wherein the pH is between about 6.0 and about 8.

0.

18. The formulation of claim 17, wherein the pH is between about 6.

6. and about 7.

0.

19. The formulation of any one of claims 1-18, having an osmolality between about 200 and 400 mOsm / kg.

20. The formulation of claim 19, wherein the osmolality is about 300 mOsm / kg.

21. The formulation of any one of claims 1-20, wherein the formulation is a pharmaceutical formulation for intrathecal administration of the dsRNA agent to a subject.

22. The formulation of claim 21, wherein the subject is a mammal.

23. The formulation of claim 22, wherein the subject is human.

24. A formulation for intrathecal administration comprising: a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of microtubule associated protein tau (MAPT), wherein the dsRNA agent comprises a sense strand and an Page 88 of 93 WBD (US) 4884-6646-1936v1Atty Dkt No.: A1088681840WO / ALN-535-WO antisense strand, wherein the sense strand and the antisense strand are each represented by a dsRNA listed in Table 1; sodium chloride at about 70 mM to about 100 mM; potassium chloride at about 1.0 mM to about 2.5 mM; magnesium chloride at about 0.1 mM to about 1.0 mM; calcium chloride at about 8.0 mM to about 25.0 mM; a pH between about 6.0 and about 8.0; and an osmolality between about 200 and 400 mOsm / kg.

25. The formulation of claim 24, wherein the sense strand comprises the nucleotide sequence and all the modifications of 5’ Gm-ps-Um-ps-Gm-Am-Cm-(Chd)-Cm-Am-Af-Gf-Cf-Um-Cm-Gm-Um-Am-Um- Gm-Gm-ps-Um-ps-Am 3’ (SEQ ID NO: 1); and the antisense strand comprises the nucleotide sequence and all the modifications of 5’ VPu-ps-Af-ps-Cm-Cm-dA-Um-dA-Cm-Gm-Am-Gm-Cm-Um-Uf-Gm-Gf-Gm-Um- Cm-Am-Cm-ps-Gm-ps-Um 3’ (SEQ ID NO: 2), wherein Af is 2’-fluoroadenosine, Uf is 2’-fluorouridine, Cf is 2’-fluorocytidine, Gf is 2’- fluoroguanosine, Am is 2’-O-methyladenosine, Um is 2’-O-methyluridine, Cm is 2’-O- methylcytidine, Gm is 2’-O-methylguanosine, dA is 2’-deoxyadenosine, Chd is 2’-O- hexadecylcytidine, VPu is vinylphosphonate 2’-O-methyluridine, ’-’ (hyphen) is 3’-5’ phosphodiester linkage, ’-ps-’ is 3’-5’ phosphorothioate linkage.

26. The formulation of any one of claims 1-25, wherein the dsRNA agent is AD-1786708.

27. A solid prepared by lyophilization of the formulation of any one of claims 1-26.

28. A kit, comprising (a) the formulation or composition of any one of claims 1-27, and (b) instructions for use, and (c) optionally, a means for administering the formulation to a subject. Page 89 of 93 WBD (US) 4884-6646-1936v1Atty Dkt No.: A1088681840WO / ALN-535-WO 29. A method for treating a subject having a disease or disorder that would benefit from a reduction in expression of microtubule associated protein tau (MAPT); preventing development of a MAPT-associated disease or disorder in a subject; or inhibiting the expression of microtubule associated protein tau (MAPT) in a subject, the method comprising administering to the subject a therapeutically effective amount of the formulation of any one of claims 1-26.

30. The method of claim 29, wherein the subject is a human.

31. The method of claim 29 or 30, wherein the subject meets at least one diagnostic criterion for a MAPT-associated disease or disorder.

32. The method of any one of claims 29-31, wherein the subject has a MAPT-associated disease or disorder.

33. The method of any one of claims 29-32, wherein the subject has been diagnosed with a MAPT-associated disease or disorder.

34. The method of any one of claims 29-33, wherein the MAPT-associated disease or disorder is selected from the group consisting of Alzheimer disease, frontotemporal dementia (FTD), behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA-L), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick’s disease (PiD), argyrophilic grain disease (AGD), multiple system tauopathy with presenile dementia (MSTD), white matter tauopathy with globular glial inclusions (FTLD with GGIs), FTLD with MAPT mutations, neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, amyotrophic lateral sclerosis (ALS), corticobasal syndrome (CBS), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Parkinson’s disease, postencephalitic Parkinsonism, Niemann-Pick disease, Huntington disease, type 1 myotonic dystrophy, and Down syndrome (DS). Page 90 of 93 WBD (US) 4884-6646-1936v1Atty Dkt No.: A1088681840WO / ALN-535-WO 35. The method of any one of claims 29-34, wherein the formulation is administered to the subject intrathecally.

36. The method of any one of claims 29-35, wherein treating comprises amelioration or delay of at least one sign or symptom of the disease or disorder.

37. The method of any one of claims 29-36, where treating comprises prevention or delay of development or progression of the disease or disorder.

38. The method of any one of claims 29-37, wherein the MAPT-associated disease is characterized by one or more symptoms selected from the group consisting of cognitive dysfunction, memory impairment, speech impairment, gaze dysfunction, extrapyramidal symptoms, limb apraxia, akinesia, bradykinesia, rigidity, dystonia, and move impairment.

39. A method for preparing a formulation comprising annealing a sense strand and an antisense strand, wherein one of the sense strand and antisense strand contains a lipophilic modification, to form a duplex solution comprising a double stranded RNA (dsRNA); lyophilizing the duplex solution to provide a duplex composition; and dissolving the duplex composition in an injection solution, wherein the injection solution comprises a divalent cation and does not comprise a phosphate buffer, wherein the duplex composition comprises no less than equimolar amount or about 1-2% molar excess of antisense strand over sense strand, and wherein the sense strand and the antisense strand are each represented by a dsRNA listed in Table 1.

40. The method of claim 39, wherein the sense strand comprises the nucleotide sequence and all the modifications of Page 91 of 93 WBD (US) 4884-6646-1936v1Atty Dkt No.: A1088681840WO / ALN-535-WO 5’ Gm-ps-Um-ps-Gm-Am-Cm-(Chd)-Cm-Am-Af-Gf-Cf-Um-Cm-Gm-Um-Am-Um- Gm-Gm-ps-Um-ps-Am 3’ (SEQ ID NO: 1); and the antisense strand comprises the nucleotide sequence and all the modifications of 5’ VPu-ps-Af-ps-Cm-Cm-dA-Um-dA-Cm-Gm-Am-Gm-Cm-Um-Uf-Gm-Gf-Gm-Um- Cm-Am-Cm-ps-Gm-ps-Um 3’ (SEQ ID NO: 2), wherein Af is 2’-fluoroadenosine, Uf is 2’-fluorouridine, Cf is 2’-fluorocytidine, Gf is 2’- fluoroguanosine, Am is 2’-O-methyladenosine, Um is 2’-O-methyluridine, Cm is 2’-O- methylcytidine, Gm is 2’-O-methylguanosine, dA is 2’-deoxyadenosine, Chd is 2’-O- hexadecylcytidine, VPu is vinylphosphonate 2’-O-methyluridine, ’-’ (hyphen) is 3’-5’ phosphodiester linkage, ’-ps-’ is 3’-5’ phosphorothioate linkage.

41. The method of claim 39 or 40, wherein the divalent cation is calcium, magnesium, copper, nickel, zinc, or strontium. Page 92 of 93 WBD (US) 4884-6646-1936v1

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