Compositions and methods for treating neurocognitive disorders

Abstract

To provide compositions and methods for treating patients with or at risk of developing neurocognitive impairment such as Alzheimer's disease, Parkinson's disease, and / or frontotemporal lobar dementia.SOLUTION: Using the compositions and methods of the disclosure, a patient, such as an adult patient, may be provided with one or more agents that elevate expression and / or activity levels of a protein or series of proteins whose deficiency is associated with the corresponding disease. To this end, exemplary agents that can be used in conjunction with the compositions and methods of the present disclosure include cells, such as cells containing nucleic acids encoding one or more proteins of interest, as well as, vectors such as viral vectors encoding the one or more proteins of interest. Additional examples of the agents include the one or more proteins themselves, as well as interfering RNA molecules that stimulate their endogenous expression.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on January 29, 2020, is titled "51182-020WO2_Sequence_Listing_1.29.20_ST25" and is 605,736 bytes in size.

[0002] The present disclosure relates to compositions and methods for treating various neurocognitive disorders, such as Alzheimer's disease, Parkinson's disease, and frontotemporal lobar dementia. [Background technology]

[0003] To date, the treatment of neurocognitive disorders has posed a challenge to the medical community. Examples of these disorders include Alzheimer's disease, Parkinson's disease, and frontotemporal lobar dementia. Alzheimer's disease is a late-onset neurodegenerative disorder that accounts for the majority of dementia cases in the elderly. Patients with Alzheimer's disease suffer from progressive cognitive decline characterized by symptoms including insidious loss of short- and long-term memory, attention deficits, language-specific problems, disorientation, impulse control, social withdrawal, anhedonia, and other symptoms. Current treatments for this indication strive to alleviate disease symptoms, but no treatments target the underlying neurodegeneration. Similarly, treatments for Parkinson's disease, a progressive disorder of the nervous system that affects movement and results in symptoms such as resting tremor, rigidity, and bradykinesia, primarily focus on increasing dopamine levels, highlighting the need for treatments that target the underlying biochemical etiology. Additionally, treatments for frontotemporal lobar degeneration, a neurodegenerative disorder characterized by a complex clinical symptomatology that may include deficits in speech comprehension and production, poor motor planning and coordination, and / or loss of executive function characterized by impulse control and a predominance of perseverative behaviors, also strive to ameliorate disease symptoms. There remains a need for improved therapeutic modalities that target the underlying causes of these types of disorders at the genomic and proteomic levels. Summary of the Invention

[0004] The present disclosure relates to compositions and methods for treating neurocognitive disorders (NCDs), such as Alzheimer's disease, Parkinson's disease, and frontotemporal lobar degeneration, in patients, such as human patients. The compositions and methods of the present disclosure can be used to provide a patient, e.g., an adult patient suffering from an NCD described herein, with one or more agents that together increase the expression and / or activity of one or more proteins in the patient. The patient may be suffering from an NCD, e.g., Alzheimer's disease, Parkinson's disease, or frontotemporal lobar degeneration (FTLD). Providing such agents to the patient can help reverse the pathophysiology of the disease. Without being limited by mechanism, the compositions and methods of the present disclosure can be used to regulate the patient's gene expression and / or protein activity patterns, restoring physiologically normal amounts and functionality of proteins whose deficiency is associated with the aforementioned disorder, thereby treating the underlying disease pathology. Thus, the compositions and methods described herein can be used not only to ameliorate one or more symptoms associated with an NCD, but can also be used as curative therapeutic agents.

[0005] For example, the compositions and methods described herein can be used to administer to a patient, such as an adult patient, one or more agents that function together to increase the level of expression and / or activity of a protein or subset of proteins whose deficiency has been found to be associated with the development of a disease state. Specifically, the compositions and methods of the present disclosure can be administered to patients with an NCD (e.g., Alzheimer's disease) using a combination of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF 224, and AP2A2, e.g., one or more agents that together enhance the expression and / or activity of one or more proteins selected from PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1. The one or more agents may, for example, serve to increase the expression and / or activity levels of a subset of the aforementioned proteins, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of these proteins.

[0006] Similarly, the compositions and methods of the disclosure can be administered to patients with an NCD (e.g., Parkinson's disease) using a combination of the following: FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, One or more agents that together enhance the expression and / or activity of one or more proteins selected from BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD, e.g., one or more agents that together enhance the expression and / or activity of one or more proteins selected from FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2, can be used to provide one or more agents that together enhance the expression and / or activity of one or more proteins selected from BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD, e.g., one or more agents that together enhance the expression and / or activity of one or more proteins selected from FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2, which may, for example, serve to increase the expression and / or activity levels of a subset of the aforementioned proteins, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of these proteins.

[0007] As another example, the compositions and methods of the disclosure can be used to provide a patient with an NCD (e.g., FTLD) with one or more agents that together enhance the expression and / or activity of one or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT, e.g., one or more agents that together enhance the expression and / or activity of one or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF. The one or more agents may, for example, serve to increase the expression and / or activity levels of a subset of the aforementioned proteins, for example, a subset of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of these proteins.

[0008] In yet another example, the compositions and methods of the present disclosure can be used to administer to a patient with an NCD (e.g., AD, PD, or FTLD) a combination of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PI CALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF2 24, AP2A2, FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, It can be used to provide one or more agents that together enhance the expression and / or activity of one or more proteins selected from STX1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT, where the one or more agents can serve, for example, to increase the expression and / or activity levels of a subset of the aforementioned proteins, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of these proteins.

[0009] Agents that increase the expression and / or activity levels of one or more proteins of interest and can be used in conjunction with the compositions and methods of the present disclosure include nucleic acids encoding proteins or multiple proteins (e.g., nucleic acids that can be expressed in macrophages or microglial cells). Such nucleic acid molecules can be provided to a patient (e.g., a patient diagnosed with an NCD such as Alzheimer's disease, Parkinson's disease, or FTLD) in the form of, for example, a population of cells, e.g., cells containing the nucleic acid molecule, e.g., a population of pluripotent cells (e.g., embryonic stem cells (ESCs) or induced pluripotent stem cells (ISPCs)), pluripotent cells (e.g., CD34+ cells, e.g., hematopoietic stem cells (HSCs) or myeloid progenitor cells (MPCs)), blood lineage progenitor cells (BLPCs; e.g., monocytes), macrophages, microglial progenitor cells, or microglia. Such cells may contain the nucleic acid molecule of interest, for example, in the form of an episome or as an integrated component of the cellular genome. Additionally or alternatively, nucleic acid molecules encoding one or more of the proteins of interest can be provided to a patient in the form of one or more viral vectors that collectively encode the one or more proteins. Exemplary viral vectors that can be used in conjunction with the compositions and methods of the present disclosure include, among others, retroviridae viral vectors described herein, such as lentiviruses, alpharetroviruses, or gammaretroviruses. In some embodiments, the nucleic acid molecule(s) are administered directly to the patient. Additional agents that can be provided to a patient for the purpose of enhancing the level of one or more proteins of interest include, in addition to the one or more proteins themselves, interfering RNA molecules, such as short interfering RNA (siRNA), short hairpin RNA (shRNA), and microRNA (miRNA) molecules, as well as small molecule agents that regulate gene expression.

[0010] The compositions and methods of the present disclosure are based, in part, on the discovery that modulating the expression levels of specific genes and / or the activity of their corresponding protein products in patients with NCDs can effectively treat the disease and alleviate associated symptomatic outcomes. Additionally, the present disclosure stems, in part, from the surprising discovery that altering the expression patterns and / or activity levels of various assortments of genes and their protein products, respectively, can also be used to treat the aforementioned disorders. This latter concept is particularly innovative. To date, many gene therapy techniques have focused on delivering a single gene to a patient for the treatment of a single congenital disorder. The present disclosure is unique in that it provides compositions and methods for manipulating multiple gene expression levels and / or corresponding protein activity levels, for example, to treat a given NCD.

[0011] The disclosed compositions and methods offer a range of important clinical benefits. For example, the compositions and methods described herein can be used to treat patients suffering from NCDs in a manner that targets the underlying genetic etiology of the disease and also alleviates associated symptoms. Furthermore, compositions and methods involving manipulation of two or more gene or protein products offer the added advantage of facilitating treatment of larger patient populations compared to those receiving gene or protein monotherapy approaches. This is due, in part, to the discovery that compositions that enhance the expression and / or activity levels of multiple proteins can be safely administered to patients deficient in only one of these proteins. This unexpected discovery makes it possible to use a single therapeutic product—e.g., a single population of cells, viral vector, or other agent—that promotes the expression and / or activity of multiple proteins to treat a broad patient population composed of patients with deleterious mutations across various genes. Using traditional monotherapy approaches, each patient within such a patient population would require a unique gene or protein delivery vehicle based on the specific protein deficiency they exhibit. The compositions and methods of the present disclosure offer the advantageous effect of being able to treat diverse patient populations with a single therapeutic product that modulates the expression and / or activity of multiple proteins, despite any redundancy that may exist between the proteins upregulated by the therapeutic product and the proteins already expressed endogenously by the patient.

[0012] In a first aspect, the present disclosure provides a method of treating an NCD (e.g., Alzheimer's disease) in a patient (e.g., a mammalian patient, such as a human patient (e.g., an adult patient)) in need thereof, comprising administering to the patient one or more of: APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1 , MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, and AP2A2, e.g., one or more proteins selected from PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1.

[0013] In some embodiments of the foregoing aspects, the one or more agents are selected from the group consisting of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRI The expression and / or activity of two or more proteins selected from P4, MSRA, HS3ST1, ZNF224, and AP2A2, for example, two or more proteins selected from PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1, are increased in combination.For example, the one or more agents may be three, four, five, or more of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, and AP2A2. The expression and / or activity of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20 or more genes may be increased collectively, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20 or more genes selected from PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1.

[0014] In some embodiments of the foregoing aspects, the one or more agents are selected from the group consisting of proteins APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, D 2-20 of ISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, and AP2A2, e.g., 2-19, 2-18, 2-17, 2-16, 2-15, 2-14, 2-13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-20, 3-19, 3-18, 3-17, 3-16, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-20, 4-19, 4-18, 4-17, 4-16, 4-18, 4-20, 4-19, 4-18, 4-17, 4-16, 4-20, 4-16, 4-20, 4-18, 4-17, 4-16, 4-20, 4-16, 4-20, 4-19, 4-18, 4-17, 4-16, 4-20, 4-16, 4-20, 4-18, 4-19, 4-16, 4-20 ... ~15, 4~14, 4~13, 4~12, 4~11, 4~10, 4~9, 4~8, 4~7, 4~6, 5~20, 5~19, 5~18, 5~17, 5~16, 5~15, 5~14, 5~13, 5~12, 5~11, 5~10, 5~9, 5~8, 5~7, 6~20, 6~19, 6~1 8, 6-17, 6-16, 6-15, 6-14, 6-13, 6-12, 6-11, 6-10, 6-9, 6-8, 7-20, 7-19, 7-18, 7-17, 7-16, 7-15, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 8-20, 8-19, 8-18, 8 ~17, 8~16, 8~15, 8~14, 8~13, 8~12, 8~11, 8~10, 9~20, 9~19, 9~18, 9~17, 9~16, 9~15, 9~14, 9~13, 9~12, 9~11, 10~20, 10~19, 10~18, 10~17, 10~16, 10~15, 10-14, 10-13, 10-12, 11-20, 11-19, 11-18, 11-17, 11-16, 11-15, 11-14, 11-13, 12-20, 12-19, 12-18, 12-17, 12-16, 12-15, 12-14, 13-20, 13-19, 13-18,13-17, 13-16, 13-15, 14-20, 14-19, 14-18, 14-17, 14-16, 15-20, 15-19, 15-18, 15-17, 16-20, 16-19, 16-18, 17-20, 17-19, or 18-20 species (e.g., proteins PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD 2-19, 2-18, 2-17, 2-16, 2-15, 2-14, 2-13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-20, 3-19, 3-18, 3-17, 3-16, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-20, 4-19, 4-18, 4-17, 4-16, 4-15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9 of 4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1 , 4-8, 4-7, 4-6, 5-20, 5-19, 5-18, 5-17, 5-16, 5-15, 5-14, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 6-20, 6-19, 6-18, 6-17, 6-16, 6-15, 6-14, 6-13, 6-12 , 6-11, 6-10, 6-9, 6-8, 7-20, 7-19, 7-18, 7-17, 7-16, 7-15, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 8-20, 8-19, 8-18, 8-17, 8-16, 8-15, 8-14, 8-13, 8-12, 8- 11, 8-10, 9-20, 9-19, 9-18, 9-17, 9-16, 9-15, 9-14, 9-13, 9-12, 9-11, 10-20, 10-19, 10-18, 10-17, 10-16, 10-15, 10-14, 10-13, 10-12, 11-20, 11-19, 1 1-18, 11-17, 11-16, 11-15, 11-14, 11-13, 12-20, 12-19, 12-18, 12-17, 12-16, 12-15, 12-14, 13-20, 13-19, 13-18, 13-17, 13-16, 13-15, 14-20, 14-19,14-18, 14-17, 14-16, 15-20, 15-19, 15-18, 15-17, 16-20, 16-19, 16-18, 17-20, 17-19, or 18-20 species) are collectively increased.

[0015] In some embodiments, the proteins comprise a panel as set forth in Table 1 below. Each row in Table 1 represents a "panel" of protein pairs. [Table 1] JPEG2025062601000003.jpg255137JPEG2025062601000004.jpg255137JPEG2025062601000005.jpg255137JPEG20250626010 00006.jpg255137JPEG2025062601000007.jpg255137JPEG2025062601000008.jpg255137JPEG2025062601000009.jpg249138

[0016] In some embodiments of the foregoing aspects, the patient has been diagnosed with an NCD. In some embodiments, the NCD is a severe NCD. In some embodiments, the severe NCD interferes with the patient's independence and / or normal daily functioning (e.g., social, occupational, or academic functioning, personal hygiene, grooming, dressing, toilet hygiene, functional mobility (e.g., ability to walk, get in and out of bed), and self-feeding). In some embodiments, a severe NCD is associated with a score achieved by the patient on a cognitive test that is at least two standard deviations away from the mean score of a reference population. In some embodiments, the NCD is a mild NCD. In some embodiments, a mild NCD does not interfere with the patient's independence and / or normal daily functioning. In some embodiments, a mild NCD is associated with a score achieved by the patient on a cognitive test that is at least one to two standard deviations away from the mean score of a reference population. In some embodiments, the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE. In some embodiments, the NCD is associated with impairments in one or more of complex attention, executive function, learning and memory, language, sensorimotor function, and social cognition. In some embodiments, the NCD is not due to delirium or another psychiatric disorder (e.g., schizophrenia, bipolar disorder, or major depression). In some embodiments, the reference population is the general population. In some embodiments, the reference population is selected based on the patient's age, medical history, education, socioeconomic status, and lifestyle. In some embodiments, the NCD is Alzheimer's disease.

[0017] In a second aspect, the present disclosure provides a method of treating an NCD (e.g., Parkinson's disease) in a patient (e.g., a mammalian patient, such as a human patient (e.g., an adult patient)) in need thereof, comprising administering to the patient an agent selected from the group consisting of FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PA by providing one or more agents that collectively increase the expression and / or activity of one or more proteins selected from RK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD, e.g., one or more proteins selected from FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2.

[0018] In some embodiments of the foregoing aspects, the one or more agents are selected from the group consisting of FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SM The expression and / or activity of two or more proteins selected from PD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD, for example, two or more proteins selected from FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2, are increased in combination. For example, the one or more agents may be selected from the group consisting of FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, The expression and / or activity of three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, four, thirteen, fourteen, fifteen, seventeen, eighteen, nineteen, twenty, or more of MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD, or three, four, five, six, seven, eight, nine, or more of FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2, is increased collectively.

[0019] In some embodiments of the foregoing aspects, the one or more agents are selected from 2 to 20 of the proteins, e.g., proteins FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, P Among ARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD, 2–19, 2–18, 2–17, 2–16, 2–15, 2–14, 2–13, 2–12, 2–11, 2–10, 2–9, 2–8, 2–7, 2–6, 2–5, 2–4, 3–20, 3–19, 3–18, 3–17, 3–16, 3–15, 3–14, 3–13, 3–14, 3–15, 3–16, 3–17, 3–18, 3–19, 3–20, 3–21, 3–22, 3–23, 3–24, 3–25, 3–26, 3–27, 3–28, 3–29, 3–30, 3–31, 3–32, 3–33, 3–34, 3–35, 3–36, 3–37, 3–38, 3–39, 3–40, 3–41, 3–42, 3–43, 3–44, 3–45, 3–46, 3–47, 3–48, 3–49, 3–50, 3–51, 3–52, 3–53, 3–54, 3–55, 3–56, 3–57, 3–58, 2, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-20, 4-19, 4-18, 4-17, 4-16, 4-15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 5-20, 5-19, 5-18, 5-17, 5 ~16, 5~15, 5~14, 5~13, 5~12, 5~11, 5~10, 5~9, 5~8, 5~7, 6~20, 6~19, 6~18, 6~17, 6~16, 6~15, 6~14, 6~13, 6~12, 6~11, 6~10, 6~9, 6~8, 7~20, 7~19, 7~18, 7 ~17, 7~16, 7~15, 7~14, 7~13, 7~12, 7~11, 7~10, 7~9, 8~20, 8~19, 8~18, 8~17, 8~16, 8~15, 8~14, 8~13, 8~12, 8~11, 8~10, 9~20, 9~19, 9~18, 9~17, 9~16, 9~ 15, 9-14, 9-13, 9-12, 9-11, 10-20, 10-19, 10-18, 10-17, 10-16, 10-15, 10-14, 10-13, 10-12, 11-20, 11-19, 11-18, 11-17, 11-16, 11-15, 11-14, 11-13,12-20, 12-19, 12-18, 12-17, 12-16, 12-15, 12-14, 13-20, 13-19, 13-18, 13-17, 13-16, 13-15, 14-20, 14-19, 14-18, 14-17, 14-16, 15-20, 15-19, 15-18, 15-17, 16-20, 16-19, 16-18, 17-20, 17-19, or 18-20 species (e.g., proteins FCGR2A, SCAF11, D The expression and / or activity of 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 4 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 5 to 10, 5 to 9, 5 to 8, 5 to 7, 6 to 10, 6 to 9, 6 to 8, 7 to 10, 7 to 9, or 8 to 10 species selected from NAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2 is collectively increased.

[0020] In some embodiments, the proteins comprise a panel as set forth in Table 2 below. Each row in Table 2 represents a "panel" of protein pairs. [Table 2] JPEG2025062601000011.jpg49150

[0021] In some embodiments of the second aspect, the patient has been diagnosed with an NCD. In some embodiments, the NCD is a severe NCD. In some embodiments, the severe NCD interferes with the patient's independence and / or normal daily functioning (e.g., social, occupational, or academic functioning, personal hygiene, grooming, dressing, toilet hygiene, functional mobility (e.g., ability to walk, get in and out of bed), and self-feeding). In some embodiments, the severe NCD is associated with a score achieved by the patient on a cognitive test that is at least two standard deviations away from the mean score of a reference population. In some embodiments, the NCD is a mild NCD. In some embodiments, the mild NCD does not interfere with the patient's independence and / or normal daily functioning. In some embodiments, the mild NCD is associated with a score achieved by the patient on a cognitive test that is at least one to two standard deviations away from the mean score of a reference population. In some embodiments, the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE. In some embodiments, the NCD is associated with impairments in one or more of complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition. In some embodiments, the NCD is not due to delirium or another psychiatric disorder (e.g., schizophrenia, bipolar disorder, or major depression). In some embodiments, the reference population is the general population. In some embodiments, the reference population is selected based on the patient's age, medical history, education, socioeconomic status, and lifestyle. In some embodiments, the NCD is a movement disorder. In some embodiments, the movement disorder is Parkinson's disease.

[0022] In a third aspect, the present disclosure provides methods of treating an NCD (e.g., an FTLD such as behavioral abnormality frontotemporal dementia, semantic dementia, or progressive incompetent aphasia) in a patient (e.g., a mammalian patient, such as a human patient (e.g., an adult patient)) in need thereof by providing said patient with one or more agents that collectively increase the expression and / or activity of one or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT, e.g., one or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF.

[0023] In some embodiments of the foregoing aspects, the one or more agents collectively increase the expression and / or activity of two or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT, e.g., two or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF. For example, the one or more agents can collectively increase the expression and / or activity of three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more of HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT, e.g., three, four, five, six, or more of HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF.

[0024] In some embodiments of the foregoing aspects, the one or more agents are selected from 2 to 15 of the proteins, e.g., 2 to 14, 2 to 3 of proteins HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT. 13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 5-15, 5-14, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 6-15, 6-14 , 6-13, 6-12, 6-11, 6-10, 6-9, 6-8, 7-15, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 8-15, 8-14, 8-13, 8-12, 8-11, 8-10, 9-15, 9-14, 9-13, 9-12, 9-11, 10-15, 10-14, 10-13, 10-12, 11-15, 11-14, 11-13, 12-15, or 12-14 species, e.g., HLA-DRA, The expression and / or activity of two or more proteins selected from HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF (e.g., 2 to 6, 2 to 5, 2 to 4, 3 to 6, 3 to 5, 4 to 10, or 4 to 6 of the proteins HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF) is increased collectively.

[0025] In some embodiments, the proteins comprise a panel as set forth in Table 3 below. Each row in Table 3 represents a "panel" of pairs of proteins. [Table 3]

[0026] In some embodiments of the third aspect, the patient has been diagnosed with an NCD. In some embodiments, the NCD is a severe NCD. In some embodiments, the severe NCD interferes with the patient's independence and / or normal daily functioning (e.g., social, occupational, or academic functioning, personal hygiene, grooming, dressing, toilet hygiene, functional mobility (e.g., ability to walk, get in and out of bed), and self-feeding). In some embodiments, a severe NCD is associated with a score achieved by the patient on a cognitive test that is at least two standard deviations away from the mean score of a reference population. In some embodiments, the NCD is a mild NCD. In some embodiments, a mild NCD does not interfere with the patient's independence and / or normal daily functioning. In some embodiments, a mild NCD is associated with a score achieved by the patient on a cognitive test that is at least one to two standard deviations away from the mean score of a reference population. In some embodiments, the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE. In some embodiments, the NCD is associated with impairments in one or more of complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition. In some embodiments, the NCD is not due to delirium or another psychiatric disorder (e.g., schizophrenia, bipolar disorder, or major depression). In some embodiments, the reference population is the general population. In some embodiments, the reference population is selected based on the patient's age, medical history, education, socioeconomic status, and lifestyle. In some embodiments, the NCD is a frontotemporal NCD. In some embodiments, the frontotemporal NCD is FTLD. In some embodiments, the FTLD is behavioral disorder frontotemporal dementia. In some embodiments, the FTLD is semantic dementia. In some embodiments, the FTLD is progressive incompetent aphasia.

[0027] In a fourth aspect, the present disclosure provides a method of treating an NCD (e.g., Alzheimer's disease, Parkinson's disease, or frontotemporal lobar degeneration) in a patient in need thereof, comprising administering to the patient an antibody to one of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33 , MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4 , MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH 1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKD K, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, D by providing one or more agents that collectively increase the expression and / or activity of one or more proteins selected from GKQ, STX1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.For example, the one or more agents are selected from the group consisting of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIM P, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, SCAF11, HLA-D QB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1 , LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM 175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, ACMSD, HLA The expression and / or activity of two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, seventeen, eighteen, nineteen, twenty, or more of -DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT can be increased collectively.

[0028] In some embodiments of the foregoing aspects, the one or more agents are selected from 2 to 20 of the proteins, e.g., proteins APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRG K1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ , STX1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP2 2-19, 2-18, 2-17, 2-16, 2-15, 2-14, 2-13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-20, 3-19, 3-18, 3-17, 3-16, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-20, 4-19, 4-18, 4-17, 4-16, 4-15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 5-20, 5-19,5~18, 5~17, 5~16, 5~15, 5~14, 5~13, 5~12, 5~11, 5~10, 5~9, 5~8, 5~7, 6~2 6~19, 6~18, 6~17, 6~16, 6~15, 6~14, 6~13, 6~12, 6~11, 6~10, 6~9, 6~8, 7~2 7~19, 7~18, 7~17, 7~16, 7~15, 7~14, 7~13, 7~12, 7~11, 7~10, 7~9, 8~20, 8~1 9, 8~18, 8~17, 8~16, 8~15, 8~14, 8~13, 8~12, 8~11, 8~10, 9~20, 9~19, 9~1 ~17, 9~16, 9~15, 9~14, 9~13, 9~12, 9~11, 10~20, 10~19, 10~18, 10~17, 10~1 6, 10~15, 10~14, 10~13, 10~12, 11~20, 11~19, 11~18, 11~17, 11~16, 11~1 1~14, 11~13, 12~20, 12~19, 12~18, 12~17, 12~16, 12~15, 12~14, 13~20, 13~ 19, 13~18, 13~17, 13~16, 13~15, 14~20, 14~19, 14~18, 14~17, 14~16, 15~2 15~19, 15~18, 15~17, 16~20, 16~19, 16~18, 17~20, 17~19, APP PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1 ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCI MP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA HS3ST1, ZNF224, AP2A2, FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GP NMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIP A1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20.DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP 13A2, DGKQ, STX1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, P 2-19, 2-18, 2-17, 2-16, 2-15, 2-14, 2-13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-20, 3-19, 3-18, 3-17, 3-16, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-20, 4-19, 4-18, 4-17, 4-16, 4-15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 5-20, 5-19, 5-18, 5-17, 5-16, 5-15, 5-14, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 6-20, 6-19, 6-18, 6-17, 6-16, 6-15, 6-14, 6-13, 6-12, 6-11, 6-10, 6- 9, 6-8, 7-20, 7-19, 7-18, 7-17, 7-16, 7-15, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 8-20, 8-19, 8-18, 8-17, 8-16, 8-15, 8-14, 8-13, 8-12, 8-11, 8-10, 9-20, 9-19, 9-18, 9-17, 9-16, 9-15, 9-14, 9-13, 9-12, 9-11, 10-20, 10-19, 10-18, 10-17, 10-16, 10-15, 10-14, 10-13, 10-12, 11-20, 11-19, 11-18, 11-17, 1 1-16, 11-15, 11-14, 11-13, 12-20, 12-19, 12-18, 12-17, 12-16, 12-15, 12-14, 13-20, 13-19, 13-18, 13-17, 13-16, 13-15, 14-20, 14-19, 14-18, 14-17,14-16, 15-20, 15-19, 15-18, 15-17, 16-20, 16-19, 16-18, 17-20, 17-19, or 18-20 species) are collectively increased.

[0029] In some embodiments, the proteins comprise a panel as set forth in Table 4 below. Each row in Table 4 represents a "panel" of protein pairs. [Table 4] JPEG2025062601000014.jpg253149JPEG2025062601000015.jpg253149JPEG2025062601000016.jpg253149JPEG20250626010 00017.jpg253149JPEG2025062601000018.jpg253149JPEG2025062601000019.jpg253149JPEG2025062601000020.jpg232150

[0030] In some embodiments of the foregoing aspects, the patient has been diagnosed with an NCD. In some embodiments, the NCD is a severe NCD. In some embodiments, the severe NCD interferes with the patient's independence and / or normal daily functioning (e.g., social, occupational, or academic functioning, personal hygiene, grooming, dressing, toilet hygiene, functional mobility (e.g., ability to walk, get in and out of bed), and self-feeding). In some embodiments, a severe NCD is associated with a score achieved by the patient on a cognitive test that is at least two standard deviations away from the mean score of a reference population. In some embodiments, the NCD is a mild NCD. In some embodiments, a mild NCD does not interfere with the patient's independence and / or normal daily functioning. In some embodiments, a mild NCD is associated with a score achieved by the patient on a cognitive test that is at least one to two standard deviations away from the mean score of a reference population. In some embodiments, the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE. In some embodiments, the NCD is associated with impairments in one or more of complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition. In some embodiments, the NCD is not due to delirium or another psychiatric disorder (e.g., schizophrenia, bipolar disorder, or major depression). In some embodiments, the reference population is the general population. In some embodiments, the reference population is selected based on the patient's age, medical history, education, socioeconomic status, and lifestyle. In some embodiments, the NCD is Alzheimer's disease. In some embodiments, the NCD is a movement disorder. In some embodiments, the movement disorder is Parkinson's disease. In some embodiments, the NCD is a frontotemporal NCD. In some embodiments, the frontotemporal NCD is FTLD. In some embodiments, the FTLD is behavioral disorder frontotemporal dementia. In some embodiments, the FTLD is semantic dementia. In some embodiments, the FTLD is progressive incompetent aphasia.

[0031] In some embodiments of any of the aforementioned aspects of the disclosure, the one or more agents comprise: (i) one or more nucleic acid molecules that collectively encode one or more proteins (e.g., nucleic acids that can be expressed in macrophages or microglia); (ii) one or more interfering RNA molecules that collectively increase the expression and / or activity of one or more proteins; (iii) one or more nucleic acid molecules that encode one or more interfering RNA molecules (e.g., short interfering RNA (siRNA), short hairpin RNA (shRNA), and / or microRNA (miRNA)); (iv) one or more proteins themselves; and / or (v) one or more small molecules that collectively increase the expression and / or activity of one or more proteins.

[0032] In some embodiments, the one or more agents comprise one or more nucleic acid molecules that collectively encode the one or more proteins. For example, when treating Alzheimer's disease, the patient may be administered one or more of the following: APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MS One or more nucleic acid molecules can be provided that collectively encode one or more proteins selected from RA, HS3ST1, ZNF224, and AP2A2, for example, one or more proteins selected from PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1.

[0033] For example, when treating Alzheimer's disease, the patient may be administered one or more of the following: APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, One or more nucleic acid molecules can be provided that collectively encode two or more proteins selected from HS3ST1, ZNF224, and AP2A2, for example, two or more proteins selected from PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1.For example, the one or more nucleic acid molecules may be selected from the group consisting of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, and AP2A2. The genes may collectively encode 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20 or more of, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20 or more of PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1.

[0034] In some embodiments, the one or more nucleic acid molecules are selected from 2 to 20 of the proteins, such as proteins APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2, A, 2–19, 2–18, 2–17, 2–16, 2–15, 2–14, 2–13, 2–12, 2–11, 2–10, 2–9, 2–8, 2–7, 2–6, 2–5, 2–4, 3–20, 3–19, 3–18, 3–17, 3–16, 3–15, 3–14, 3–13, 3–12, 3–11, 3–10, 3–9, 3–8, 3–7, 3–6, 3–5, 4–20, 4–19, 4–18, 4–17, 4–16, 4–1 5, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 5-20, 5-19, 5-18, 5-17, 5-16, 5-15, 5-14, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 6-20, 6-19, 6-18 , 6-17, 6-16, 6-15, 6-14, 6-13, 6-12, 6-11, 6-10, 6-9, 6-8, 7-20, 7-19, 7-18, 7-17, 7-16, 7-15, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 8-20, 8-19, 8-18, 8- 17, 8-16, 8-15, 8-14, 8-13, 8-12, 8-11, 8-10, 9-20, 9-19, 9-18, 9-17, 9-16, 9-15, 9-14, 9-13, 9-12, 9-11, 10-20, 10-19, 10-18, 10-17, 10-16, 10-15, 1 0-14, 10-13, 10-12, 11-20, 11-19, 11-18, 11-17, 11-16, 11-15, 11-14, 11-13, 12-20, 12-19, 12-18, 12-17, 12-16, 12-15, 12-14, 13-20, 13-19, 13-18,13-17, 13-16, 13-15, 14-20, 14-19, 14-18, 14-17, 14-16, 15-20, 15-19, 15-18, 15-17, 16-20, 16-19, 16-18, 17-20, 17-19, or 18-20 species (e.g., proteins PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD 2-19, 2-18, 2-17, 2-16, 2-15, 2-14, 2-13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-20, 3-19, 3-18, 3-17, 3-16, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-20, 4-19, 4-18, 4-17, 4-16, 4-15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9 of 4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1 , 4-8, 4-7, 4-6, 5-20, 5-19, 5-18, 5-17, 5-16, 5-15, 5-14, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 6-20, 6-19, 6-18, 6-17, 6-16, 6-15, 6-14, 6-13, 6-12 , 6-11, 6-10, 6-9, 6-8, 7-20, 7-19, 7-18, 7-17, 7-16, 7-15, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 8-20, 8-19, 8-18, 8-17, 8-16, 8-15, 8-14, 8-13, 8-12, 8- 11, 8-10, 9-20, 9-19, 9-18, 9-17, 9-16, 9-15, 9-14, 9-13, 9-12, 9-11, 10-20, 10-19, 10-18, 10-17, 10-16, 10-15, 10-14, 10-13, 10-12, 11-20, 11-19, 1 1-18, 11-17, 11-16, 11-15, 11-14, 11-13, 12-20, 12-19, 12-18, 12-17, 12-16, 12-15, 12-14, 13-20, 13-19, 13-18, 13-17, 13-16, 13-15, 14-20, 14-19,In some embodiments, the one or more nucleic acid molecules collectively encode a panel of proteins listed in Table 1 herein.

[0035] Similarly, when treating Parkinson's disease, the patient may be administered one or more of the following: FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, T One or more nucleic acid molecules can be provided that collectively encode one or more proteins selected from MEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD, for example, one or more proteins selected from FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2.

[0036] For example, when treating Parkinson's disease, the patient may be administered one or more of the following: FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM One or more nucleic acid molecules can be provided that collectively encode two or more proteins selected from 175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD, for example, two or more proteins selected from FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2. For example, the one or more nucleic acid molecules may be selected from the group consisting of FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, The vector may collectively encode three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, seventeen, eighteen, nineteen, twenty or more of BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD, for example, three, four, five, six, seven, eight, nine or more of FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2.

[0037] In some embodiments, the one or more nucleic acid molecules encode between 2 and 20 of the proteins, for example, proteins FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, 2-19, 2-18, 2-17, 2-16, 2-15, 2-14, 2-13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-20, 3-19, 3-18, 3-17, 3-16, 3-15, 3-14, 3-13, 3-12, 3-13, 3-14, 3-15, 3-16, 3-17, 3-16, 3-15, 3-14, 3-13, 3-12, 3-16, 3-17, 3-18, 3-19, 3-20, 3-21, 3-22, 3-23, 3-24, 3-25, 3-26, 3-27, 3-28, 3-29, 3-30, 3-31, 3-32, 3-33, 3-34, 3-35, 3-36, 3-37, 3-38, 3-39, 3-40, 3-41, 3-42, 3-43, 3-44, 3-45, 3-46, 3-47, 3-48, 3-49, 3-50, 3-51, 3-52, 3-53, 3-54, 3-55, 3-56, 3-57, 3-58, 3-59, 3-60, 3-61, 3-62, 3-63, 3-64, 3-65, 3-66, 1, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-20, 4-19, 4-18, 4-17, 4-16, 4-15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 5-20, 5-19, 5-18, 5-17, 5-16, 5- 15, 5-14, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 6-20, 6-19, 6-18, 6-17, 6-16, 6-15, 6-14, 6-13, 6-12, 6-11, 6-10, 6-9, 6-8, 7-20, 7-19, 7-18, 7-17, 7- 16, 7-15, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 8-20, 8-19, 8-18, 8-17, 8-16, 8-15, 8-14, 8-13, 8-12, 8-11, 8-10, 9-20, 9-19, 9-18, 9-17, 9-16, 9-15, 9-1 4, 9-13, 9-12, 9-11, 10-20, 10-19, 10-18, 10-17, 10-16, 10-15, 10-14, 10-13, 10-12, 11-20, 11-19, 11-18, 11-17, 11-16, 11-15, 11-14, 11-13, 12-20,12-19, 12-18, 12-17, 12-16, 12-15, 12-14, 13-20, 13-19, 13-18, 13-17, 13-16, 13-15, 14-20, 14-19, 14-18, 14-17, 14-16, 15-20, 15-19, 15-18, 15-17, 16-20, 16-19, 16-18, 17-20, 17-19, or 18-20 species (e.g., protein FCGR2A, SCAF1 1, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2). In some embodiments, the one or more nucleic acid molecules collectively encode a panel of proteins listed in Table 2 herein.

[0038] Similarly, when treating FTLD, such as behavioral abnormality frontotemporal dementia, semantic dementia, or progressive incompetent aphasia, a patient can be provided with one or more nucleic acid molecules that collectively encode one or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT, e.g., one or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF.

[0039] For example, when treating FTLD, a patient can be provided with one or more nucleic acid molecules that collectively encode two or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT, e.g., two or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF. For example, the one or more nucleic acid molecules may collectively encode three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more of HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT, e.g., three, four, five, six, or more of HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF.

[0040] In some embodiments, the one or more nucleic acid molecules encode between 2 and 15 of the proteins, e.g., between 2 and 14, 2 to 3 of proteins HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT. 13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 5-15, 5-14, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 6-15, 6-14, 6-13, 6-12, 6-11, 6-10, 6-9, 6-8, 7-15, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 8-15, 8-14, 8-13, 8-12, 8-11, 8-10, 9-15, 9-14, 9-13, 9-12, 9-11, 10-15, 10-14, 10-13, 10-12, 11-15, 11-14, 11-13, 12-15, or 12-14 species, e.g., H In some embodiments, the one or more nucleic acid molecules collectively encode two or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF (e.g., 2-6, 2-5, 2-4, 3-6, 3-5, 4-10, or 4-6 of the proteins HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF). In some embodiments, the one or more nucleic acid molecules collectively encode a panel of proteins listed in Table 3 herein.

[0041] Similarly, when treating a patient diagnosed with Alzheimer's disease, Parkinson's disease, or FTLD, such as behavioral disorder frontotemporal dementia, semantic dementia, or progressive incompetent aphasia, the patient should be administered one or more of the following: APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZC WPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC 4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F , DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDR GK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, One or more nucleic acid molecules can be provided that collectively encode one or more proteins selected from ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.

[0042] For example, when treating Alzheimer's disease, Parkinson's disease, or FTLD, the patient may be administered one or more of the following: APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CA1 SS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, A P2A2, FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, R AB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2 , RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, D One or more nucleic acid molecules can be provided that collectively encode two or more of the proteins selected from GKQ, STX1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.For example, the one or more nucleic acid molecules may be selected from the group consisting of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PL CG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, S CAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1 L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, ST Two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or more of X1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT may be collectively encoded.

[0043] In some embodiments, the one or more nucleic acid molecules are directed to 2 to 15 of the proteins, such as proteins APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL 2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO 7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, S REBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1 B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, B TNL2 and MAPT, 2-14, 2-13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 5-15, 5-14, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 6-15, 6-14, 6-13, 6-12, 6-11, 6-10, 6-9, 6-8, 7-15, 7-14,In some embodiments, the one or more nucleic acid molecules collectively encode a panel of proteins listed in Table 4 herein.

[0044] In some embodiments of any of the aforementioned aspects of the present disclosure, one or more nucleic acid molecules are provided to a patient by administering to the patient a composition comprising a population of cells that together comprise one or more transgenes encoding one or more proteins. The cells may be, for example, pluripotent cells, ESCs, iPSCs, pluripotent cells, CD34+ cells, HSCs, MPCs, BLPCs, monocytes, macrophages, microglial progenitor cells, or microglia. The population may be a homogeneous population of cells that comprise the nucleic acids encoding the one or more proteins. A homogeneous population may be, for example, a population of cells in which at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or more (e.g., 100%) of the cells comprise nucleic acids encoding the one or more proteins. In some embodiments, the population is a heterogeneous population of cells that together comprise nucleic acids encoding one or more proteins.

[0045] In some embodiments of any of the aforementioned aspects of the present disclosure, the composition is administered to the patient systemically. For example, the composition can be administered to the patient by intravenous injection. In some embodiments, the composition is administered directly to the patient's central nervous system, for example, directly to the patient's cerebrospinal fluid (CSF). In some embodiments, the composition is administered to the patient by intracerebroventricular (ICV) injection, intrathecal injection, stereotactic injection, intraparenchymal injection, or a combination thereof.

[0046] In some embodiments, the patient has been diagnosed with an NCD. In some embodiments, the NCD is a severe NCD. In some embodiments, the severe NCD interferes with the patient's independence and / or normal daily functioning (e.g., social, occupational, or academic functioning, personal hygiene, grooming, dressing, toilet hygiene, functional mobility (e.g., ability to walk, get in and out of bed), and self-feeding). In some embodiments, a severe NCD is associated with a score achieved by the patient on a cognitive test that is at least two standard deviations away from the mean score of a reference population. In some embodiments, the NCD is a mild NCD. In some embodiments, a mild NCD does not interfere with the patient's independence and / or normal daily functioning. In some embodiments, a mild NCD is associated with a score achieved by the patient on a cognitive test that is at least one to two standard deviations away from the mean score of a reference population. In some embodiments, the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE. In some embodiments, the NCD is associated with impairments in one or more of complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition. In some embodiments, the NCD is not due to delirium or another psychiatric disorder (e.g., schizophrenia, bipolar disorder, or major depression). In some embodiments, the reference population is the general population. In some embodiments, the reference population is selected based on the patient's age, medical history, education, socioeconomic status, and lifestyle. In some embodiments, the NCD is Alzheimer's disease. In some embodiments, the NCD is a movement disorder. In some embodiments, the movement disorder is Parkinson's disease. In some embodiments, the NCD is a frontotemporal NCD. In some embodiments, the frontotemporal NCD is FTLD. In some embodiments, the FTLD is behavioral disorder frontotemporal dementia. In some embodiments, the FTLD is semantic dementia. In some embodiments, the FTLD is progressive incompetent aphasia.

[0047] In some embodiments, the compositions are administered to a patient both systemically and directly into the central nervous system. For example, the compositions can be administered to a patient by intravenous injection and directly into the patient's CSF. In some embodiments, the compositions are administered to a patient by intravenous injection and by ICV injection, intrathecal injection, stereotactic injection, intraparenchymal injection, or a combination thereof.

[0048] In some embodiments, the cells are autologous cells. In some embodiments, the cells are allogeneic cells.

[0049] In some embodiments, the cells are transduced ex vivo to express one or more proteins. For example, the cells may be transduced with a viral vector selected from the group consisting of adeno-associated virus (AAV), adenovirus, parvovirus, coronavirus, rhabdovirus, paramyxovirus, picornavirus, alphavirus, herpesvirus, poxvirus, and retroviridae virus. In some embodiments, the viral vector is a retroviridae viral vector, such as a lentivirus vector, an alpharetrovirus vector, or a gammaretrovirus vector. In some embodiments, the retroviridae viral vector comprises a central polypurine tract, a woodchuck hepatitis virus posttranscriptional regulatory element, a 5'-LTR, an HIV signal sequence, an HIV Psi signal 5'-splice site, a delta-GAG element, a 3'-splice site, and a 3'-self-inactivating LTR. In some embodiments, the viral vector is an AAV selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, and AAVrh74. In some embodiments, the viral vector is a pseudotyped viral vector, such as a pseudotyped AAV, pseudotyped adenovirus, pseudotyped parvovirus, pseudotyped coronavirus, pseudotyped rhabdovirus, pseudotyped paramyxovirus, pseudotyped picornavirus, pseudotyped alphavirus, pseudotyped herpesvirus, pseudotyped poxvirus, and pseudotyped retroviridae virus.

[0050] In some embodiments, the cells are transfected ex vivo to express one or more proteins. For example, the cells may be transfected using an agent selected from the group including cationic polymers, diethylaminoethyl dextran, polyethyleneimine, cationic lipids, liposomes, calcium phosphate, activated dendrimers, and magnetic beads. In some embodiments, the cells are transfected using a technique selected from the group including electroporation, nucleofection, squeeze-poration, sonoporation, optical transfection, magnetofection, and impalefection.

[0051] In some embodiments, one or more nucleic acid molecules are provided to a patient by administering one or more viral vectors that together comprise one or more nucleic acid molecules to the patient. In some embodiments, a patient is administered multiple viral vectors that together comprise one or more nucleic acid molecules. In some embodiments, a patient is administered multiple viral vectors, each of which individually comprises one or more nucleic acid molecules. In some embodiments, a patient is administered a single viral vector that comprises one or more nucleic acid molecules.

[0052] In some embodiments, one or more viral vectors are administered to patients systemically. For example, one or more viral vectors can be administered to patients by intravenous injection. In some embodiments, one or more viral vectors are administered directly to the patient's central nervous system, for example, directly to the patient's cerebrospinal fluid (CSF). In some embodiments, one or more viral vectors are administered to patients by intracerebroventricular (ICV) injection, intrathecal injection, stereotactic injection, intraparenchymal injection, or a combination thereof.

[0053] In some embodiments, one or more viral vectors are administered to a patient both systemically and directly into the central nervous system. For example, one or more viral vectors can be administered intravenously and directly into the patient's CSF. In some embodiments, one or more viral vectors are administered to a patient intravenously and via ICV injection, intrathecal injection, stereotactic injection, intraparenchymal injection, or a combination thereof.

[0054] In some embodiments, the one or more viral vectors include AAV, adenovirus, parvovirus, coronavirus, rhabdovirus, paramyxovirus, picornavirus, alphavirus, herpesvirus, poxvirus, and retroviridae virus. In some embodiments, the viral vector is a retroviridae viral vector, such as a lentivirus vector, an alpharetrovirus vector, or a gammaretrovirus vector. In some embodiments, the retroviridae viral vector comprises a central polypurine tract, a woodchuck hepatitis virus posttranscriptional regulatory element, a 5'-LTR, an HIV signal sequence, an HIV Psi signal 5'-splice site, a delta-GAG element, a 3'-splice site, and a 3'-self-inactivating LTR. In some embodiments, the viral vector is an AAV selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, and AAVrh74. In some embodiments, the viral vector is a pseudotyped viral vector, e.g., a pseudotyped viral vector selected from the group consisting of a pseudotyped AAV, a pseudotyped adenovirus, a pseudotyped parvovirus, a pseudotyped coronavirus, a pseudotyped rhabdovirus, a pseudotyped paramyxovirus, a pseudotyped picornavirus, a pseudotyped alphavirus, a pseudotyped herpesvirus, a pseudotyped poxvirus, and a pseudotyped retroviridae virus.

[0055] In some embodiments of any of the aforementioned aspects of the present disclosure, the one or more nucleic acid molecules comprise a transgene encoding one or more of the proteins operably linked to a ubiquitous promoter. The ubiquitous promoter may be, for example, the elongation factor 1-alpha promoter or the phosphoglycerate kinase 1 promoter. In some embodiments, the one or more nucleic acid molecules comprise a transgene encoding one or more of the proteins operably linked to a cell lineage-specific promoter. The cell lineage-specific promoter may be, for example, the PGRN promoter, the CD11b promoter, the CD68 promoter, the C-X3-C motif chemokine receptor 1 promoter, the allograft inflammatory factor 1 promoter, the purinergic receptor P2Y12 promoter, the transmembrane protein 119 promoter, or the colony-stimulating factor 1 receptor promoter. In some embodiments, the one or more nucleic acid molecules comprise a transgene encoding one or more of the proteins operably linked to a synthetic promoter.

[0056] In some embodiments, one or more of the proteins further comprises a receptor binding (Rb) domain of apolipoprotein E (ApoE). The Rb domain may include a portion of ApoE, such as a portion having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105. In some embodiments, the Rb domain comprises a region having at least 70% sequence identity to the amino acid sequence of residues 159-167 of SEQ ID NO: 105 (e.g., a region having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 100% sequence identity).

[0057] In some embodiments, the one or more nucleic acid molecules comprise a microRNA (miRNA) targeting sequence in the 3'-UTR. In some embodiments, the miRNA targeting sequence is a miR-126 targeting sequence.

[0058] In some embodiments, when the one or more nucleic acid molecules are provided to a patient, the one or more proteins penetrate the patient's blood-brain barrier.

[0059] In some embodiments, the patient is depleted of a population of endogenous microglia before providing the patient with the composition (e.g., the one or more nucleic acid molecules). In some embodiments, the method includes depleting the patient's population of endogenous microglia before providing the patient with the composition (e.g., the one or more nucleic acid molecules). Microglia can be depleted using, for example, an agent selected from the group consisting of busulfan, PLX3397, PLX647, PLX5622, treosulfan, and clodronate liposomes; radiation therapy; or a combination thereof.

[0060] In some embodiments, before providing the composition (e.g., the one or more nucleic acid molecules) to a patient, the endogenous expression of one or more of the proteins is disrupted in the cells administered to the patient.For example, the endogenous expression of one or more proteins can be disrupted in the cells administered to the patient by contacting the cells with a nuclease that catalyzes the cleavage of the endogenous gene encoding one of the proteins.The nuclease can be a clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein, such as CRISPR-associated protein 9 (Cas9), or the CRISPR-associated protein is particularly CRISPR-associated protein 12a (Cas12a).In some embodiments, the nuclease is a transcription activator-like effector nuclease, a meganuclease, or a zinc finger nuclease.

[0061] Additionally or alternatively, endogenous expression of one or more proteins can be disrupted in cells administered to a patient by contacting the cells with an inhibitory RNA molecule, e.g., an siRNA, shRNA, or miRNA, that is specific for (e.g., fused to) and suppresses expression of a gene encoding one of the proteins.

[0062] In some embodiments, endogenous expression of one or more of the proteins is disrupted in a patient before providing the patient with the composition (e.g., the one or more nucleic acid molecules). For example, in some embodiments, endogenous expression of one or more of the proteins is disrupted in a population of neurons in a patient before providing the patient with the composition (e.g., the one or more nucleic acid molecules). Endogenous expression of one or more of the proteins can be disrupted by contacting cells with an inhibitory RNA molecule, e.g., siRNA, shRNA, or miRNA, that is specific to (e.g., fused to) and suppresses the expression of a gene encoding one of the proteins.

[0063] In a fifth aspect, the present disclosure provides a method for the detection of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, Pharmaceutical compositions are provided comprising a population of cells that together comprise one or more nucleic acids encoding one or more proteins selected from ZNF224 and AP2A2, e.g., one or more proteins selected from PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1.

[0064] In some embodiments of the foregoing aspects, the cells are selected from the group consisting of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSR A, HS3ST1, ZNF224, and AP2A2, together with one or more nucleic acids encoding two or more proteins selected from, for example, PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1.For example, the cells may express three, four, five, six, seven, eight, or nine of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, and AP2A2. , 10, 11, 12, 13, 14, 15, 17, 18, 19, 20, or more, for example, one or more nucleic acids encoding three, four, five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 17, 18, 19, 20, or more of PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1.

[0065] In some embodiments of the foregoing aspects, the cells express between 2 and 20 of the proteins, e.g., proteins APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTH 2-19, 2-18, 2-17, 2-16, 2-15, 2-14, 2-13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-20, 3-19, 3-18, 3-17, 3-16, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-20, 4-19, 4-18, 4-17, 4-16, 4-15, 4-1 4, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 5-20, 5-19, 5-18, 5-17, 5-16, 5-15, 5-14, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 6-20, 6-19, 6-18, 6-17, 6-16, 6-15, 6-14, 6-13, 6-12, 6-11, 6-10, 6-9, 6-8, 7-20, 7-19, 7-18, 7-17, 7-16, 7-15, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 8-20, 8-19, 8-18, 8-17, 8-1 6, 8-15, 8-14, 8-13, 8-12, 8-11, 8-10, 9-20, 9-19, 9-18, 9-17, 9-16, 9-15, 9-14, 9-13, 9-12, 9-11, 10-20, 10-19, 10-18, 10-17, 10-16, 10-15, 10-14, 1 0-13, 10-12, 11-20, 11-19, 11-18, 11-17, 11-16, 11-15, 11-14, 11-13, 12-20, 12-19, 12-18, 12-17, 12-16, 12-15, 12-14, 13-20, 13-19, 13-18, 13-17,13-16, 13-15, 14-20, 14-19, 14-18, 14-17, 14-16, 15-20, 15-19, 15-18, 15-17, 16-20, 16-19, 16-18, 17-20, 17-19, or 18-20 species (e.g., proteins PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPP 2-19, 2-18, 2-17, 2-16, 2-15, 2-14, 2-13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-20, 3-19, 3-18, 3-17, 3-16, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-20, 4-19, 4-18, 4-17, 4-16, 4-15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4 ~7, 4~6, 5~20, 5~19, 5~18, 5~17, 5~16, 5~15, 5~14, 5~13, 5~12, 5~11, 5~10, 5~9, 5~8, 5~7, 6~20, 6~19, 6~18, 6~17, 6~16, 6~15, 6~14, 6~13, 6~12, 6~11, 6-10, 6-9, 6-8, 7-20, 7-19, 7-18, 7-17, 7-16, 7-15, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 8-20, 8-19, 8-18, 8-17, 8-16, 8-15, 8-14, 8-13, 8-12, 8-11, 8-1 0, 9-20, 9-19, 9-18, 9-17, 9-16, 9-15, 9-14, 9-13, 9-12, 9-11, 10-20, 10-19, 10-18, 10-17, 10-16, 10-15, 10-14, 10-13, 10-12, 11-20, 11-19, 11-18, 1 1-17, 11-16, 11-15, 11-14, 11-13, 12-20, 12-19, 12-18, 12-17, 12-16, 12-15, 12-14, 13-20, 13-19, 13-18, 13-17, 13-16, 13-15, 14-20, 14-19, 14-18,In some embodiments, the proteins comprise a panel of proteins described in Table 1 herein.

[0066] In a sixth aspect, the present disclosure provides a method for the detection of FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM17 and one or more nucleic acids encoding one or more proteins selected from: 5, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD, e.g., one or more proteins selected from: FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2.

[0067] In some embodiments of the foregoing aspects, the cells express any of the following: FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, T The nucleic acid sequence includes one or more nucleic acids encoding two or more proteins selected from MEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD, together with one or more nucleic acids encoding two or more proteins selected from FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2. For example, cells include FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SY NJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, R The nucleic acid sequence may include one or more nucleic acids encoding three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, seventeen, eighteen, nineteen, twenty, or more of IT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD, together with one or more nucleic acids encoding three, four, five, six, seven, eight, nine, or more of FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2.

[0068] In some embodiments of the foregoing aspects, the cells express between 2 and 20 of the proteins, e.g., proteins FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, , DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD. , 3-9, 3-8, 3-7, 3-6, 3-5, 4-20, 4-19, 4-18, 4-17, 4-16, 4-15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 5-20, 5-19, 5-18, 5-17, 5-16, 5-15, 5-1 4, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 6-20, 6-19, 6-18, 6-17, 6-16, 6-15, 6-14, 6-13, 6-12, 6-11, 6-10, 6-9, 6-8, 7-20, 7-19, 7-18, 7-17, 7-16, 7-1 5, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 8-20, 8-19, 8-18, 8-17, 8-16, 8-15, 8-14, 8-13, 8-12, 8-11, 8-10, 9-20, 9-19, 9-18, 9-17, 9-16, 9-15, 9-14, 9-13 , 9-12, 9-11, 10-20, 10-19, 10-18, 10-17, 10-16, 10-15, 10-14, 10-13, 10-12, 11-20, 11-19, 11-18, 11-17, 11-16, 11-15, 11-14, 11-13, 12-20, 12-19,12-18, 12-17, 12-16, 12-15, 12-14, 13-20, 13-19, 13-18, 13-17, 13-16, 13-15, 14-20, 14-19, 14-18, 14-17, 14-16, 15-20, 15-19, 15-18, 15-17, 16-20, 16-19, 16-18, 17-20, 17-19, or 18-20 species (e.g., protein FCGR2A, SCAF11, DNAJC13) , GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2 (2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-10, 4-9, 4-8, 4-7, 4-6, 5-10, 5-9, 5-8, 5-7, 6-10, 6-9, 6-8, 7-10, 7-9, or 8-10 of these proteins. In some embodiments, the proteins comprise a panel described in Table 2 herein.

[0069] In a seventh aspect, the present disclosure provides a population of cells that together comprise one or more nucleic acids encoding one or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT, e.g., one or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF.

[0070] In some embodiments of the foregoing aspects, the cell comprises one or more nucleic acids encoding two or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT, together with one or more nucleic acids encoding two or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF. For example, the cell may contain one or more nucleic acids encoding three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more of HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT, together, e.g., three, four, five, six, or more of HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF.

[0071] In some embodiments of the foregoing aspects, the cells express between 2 and 15 of the proteins, e.g., between 2 and 14, 2 and 13, 2 and 12, or 3 of proteins HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT. 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 5-15, 5-14, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 6-15, 6-14, 6-13 , 6-12, 6-11, 6-10, 6-9, 6-8, 7-15, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 8-15, 8-14, 8-13, 8-12, 8-11, 8-10, 9-15, 9-14, 9-13, 9-12, 9-11, 10-15, 10-14, 10-13, 10-12, 11-15, 11-14, 11-13, 12-15, or 12-14 species, for example, HLA-DRA, HLA - one or more nucleic acids encoding two or more proteins selected from HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF (e.g., 2-6, 2-5, 2-4, 3-6, 3-5, 4-10, or 4-6 of the proteins HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF together). In some embodiments, the proteins comprise a panel described in Table 3 herein.

[0072] In an eighth aspect, the present disclosure provides a method for the detection of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, SCAF 11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L 2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B , DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ , STX1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.

[0073] In some embodiments of the foregoing aspects, the cells are selected from the group consisting of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2 A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, R AB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2 , DGKQ, STX1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT, together with one or more nucleic acids encoding two or more of the proteins selected from the group consisting of:For example, cells may express APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FR MD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, SCAF11, HLA-DQ B1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYN J1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1 , TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, The nucleic acids may together comprise one or more nucleic acids encoding three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more of ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.

[0074] In some embodiments of the foregoing aspects, the cells express between 2 and 15 of the proteins, e.g., the proteins APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1, L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, I NPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKD K, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MA Among PTs, 2-14, 2-13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 5-15, 5-14, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 6-15, 6-14, 6-13, 6-12, 6-11, 6-10, 6-9, 6-8, 7-15, 7-14, 7-13, 7-12,In some embodiments, the protein comprises one or more nucleic acids encoding 7-11, 7-10, 7-9, 8-15, 8-14, 8-13, 8-12, 8-11, 8-10, 9-15, 9-14, 9-13, 9-12, 9-11, 10-15, 10-14, 10-13, 10-12, 11-15, 11-14, 11-13, 12-15, or 12-14 species together. In some embodiments, the protein comprises a panel described in Table 4 herein. In some embodiments of any of the foregoing aspects, the population of cells is a homogeneous population of cells. In some embodiments, the population of cells is a heterogeneous population of cells. In some embodiments, the cells are embryonic stem cells or derived cells. In some embodiments, the cells are pluripotent cells. In some embodiments, the pluripotent cells are ESCs. In some embodiments, the pluripotent cells are iPSCs. In some embodiments, the cells are CD34+ cells. In some embodiments, the cells are pluripotent cells. In some embodiments, the pluripotent cells are CD34+ cells. In some embodiments, the CD34+ cells are hematopoietic stem cells. In some embodiments, the CD34+ cells are myeloid progenitor cells. In some embodiments, the cells are blood lineage progenitor cells (BLPCs). In some embodiments, the BLPCs are monocytes. In some embodiments, the cells are macrophages. In some embodiments, the cells are microglial progenitor cells. In some embodiments, the cells are microglia.

[0075] In some embodiments of any of the foregoing aspects, the composition is formulated for systemic administration to a patient. In some embodiments, the composition is formulated for intravenous injection to a patient. In some embodiments, the composition is formulated for direct administration to the central nervous system of a patient (e.g., a mammalian patient, e.g., a human patient). In some embodiments, the composition is formulated for direct administration to the CSF of a patient. In some embodiments, the composition is formulated for ICV injection, intrathecal injection, stereotactic injection, intraparenchymal injection, or a combination thereof, to a patient.

[0076] In some embodiments of any of the foregoing aspects, the composition is formulated for systemic administration and direct administration into the central nervous system of a patient (e.g., a mammalian patient, such as a human patient). In some embodiments, the composition is formulated for intravenous injection and direct administration into the CSF of a patient. In some embodiments, the composition is formulated for intravenous injection and ICV injection, intrathecal injection, stereotactic injection, intraparenchymal injection, or a combination thereof into a patient.

[0077] In some embodiments of any of the preceding aspects, the cells are autologous cells. In some embodiments, the cells are allogeneic cells.

[0078] In some embodiments of any of the foregoing aspects, the cell comprises a transgene encoding one or more of the proteins operably linked to a ubiquitous promoter. In some embodiments, the ubiquitous promoter is an elongation factor 1-alpha promoter or a phosphoglycerate kinase 1 promoter. The cell may comprise a transgene encoding one or more of the proteins operably linked to a cell lineage-specific promoter, such as a PGRN promoter, a CD11b promoter, a CD68 promoter, a C-X3-C motif chemokine receptor 1 promoter, an allograft inflammatory factor 1 promoter, a purinergic receptor P2Y12 promoter, a transmembrane protein 119 promoter, or a colony-stimulating factor 1 receptor promoter. In some embodiments, the cell comprises a transgene encoding one or more of the proteins operably linked to a synthetic promoter.

[0079] In some embodiments of any of the foregoing aspects, one or more of the proteins further comprises an Rb domain of ApoE. The Rb domain may include, for example, a portion of ApoE having an amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105. In some embodiments, the Rb domain comprises a region having at least 70% sequence identity to the amino acid sequence of residues 159-167 of SEQ ID NO: 105 (e.g., a region having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 100% sequence identity).

[0080] In some embodiments of any of the aforementioned aspects, the cell comprises a transgene encoding one or more of the proteins and comprising an miRNA targeting sequence within its 3'-UTR, e.g., an miR-126 targeting sequence.

[0081] In a ninth aspect, the present disclosure provides a method for the detection of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3S The present invention provides a pharmaceutical composition comprising a population of viral vectors that together encode one or more proteins selected from T1, ZNF224, and AP2A2, e.g., one or more proteins selected from PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1.

[0082] In some embodiments of the foregoing aspects, the viral vector is selected from the group consisting of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP , TRIP4, MSRA, HS3ST1, ZNF224, and AP2A2, for example, two or more proteins selected from PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1 together.For example, the viral vector may encode three or four of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, and AP2A2. , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20 or more of, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20 or more of PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1 together may be encoded.

[0083] In some embodiments of the foregoing aspects, the viral vector can be capable of expressing between 2 and 20 of the proteins, e.g., proteins APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL1, SPPL2, SPPL3, SPPL4, SPPL5, SPPL6, SPPL7, SPPL8, SPPL9, SPPL10, SPPL11, SPPL12, SPPL13, SPPL14, SPPL15, SPPL16, SPPL17, SPPL18, SPPL19, SPPL20, SPPL21, SPPL22, SPPL23, SPPL24, SPPL25, SPPL26, SPPL27, SPPL28, SPPL29, SPPL29, SPPL29, SPPL21, SPPL22, SPPL25, SPPL26, SPPL28, SPPL29 ... 2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, and AP2A2, 2-19, 2-18, 2-17, 2-16, 2-15, 2-14, 2-13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-20, 3-19, 3-18, 3-17, 3-16, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-20, 4-19, 4-18, 4-17, 4-16, 4- 15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 5-20, 5-19, 5-18, 5-17, 5-16, 5-15, 5-14, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 6-20, 6-19, 6-18 , 6-17, 6-16, 6-15, 6-14, 6-13, 6-12, 6-11, 6-10, 6-9, 6-8, 7-20, 7-19, 7-18, 7-17, 7-16, 7-15, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 8-20, 8-19, 8-18, 8- 17, 8-16, 8-15, 8-14, 8-13, 8-12, 8-11, 8-10, 9-20, 9-19, 9-18, 9-17, 9-16, 9-15, 9-14, 9-13, 9-12, 9-11, 10-20, 10-19, 10-18, 10-17, 10-16, 10-15, 1 0-14, 10-13, 10-12, 11-20, 11-19, 11-18, 11-17, 11-16, 11-15, 11-14, 11-13, 12-20, 12-19, 12-18, 12-17, 12-16, 12-15, 12-14, 13-20, 13-19, 13-18,13-17, 13-16, 13-15, 14-20, 14-19, 14-18, 14-17, 14-16, 15-20, 15-19, 15-18, 15-17, 16-20, 16-19, 16-18, 17-20, 17-19, or 18-20 species (e.g., proteins PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD 2-19, 2-18, 2-17, 2-16, 2-15, 2-14, 2-13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-20, 3-19, 3-18, 3-17, 3-16, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-20, 4-19, 4-18, 4-17, 4-16, 4-15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9 of 4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1 , 4-8, 4-7, 4-6, 5-20, 5-19, 5-18, 5-17, 5-16, 5-15, 5-14, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 6-20, 6-19, 6-18, 6-17, 6-16, 6-15, 6-14, 6-13, 6-12 , 6-11, 6-10, 6-9, 6-8, 7-20, 7-19, 7-18, 7-17, 7-16, 7-15, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 8-20, 8-19, 8-18, 8-17, 8-16, 8-15, 8-14, 8-13, 8-12, 8- 11, 8-10, 9-20, 9-19, 9-18, 9-17, 9-16, 9-15, 9-14, 9-13, 9-12, 9-11, 10-20, 10-19, 10-18, 10-17, 10-16, 10-15, 10-14, 10-13, 10-12, 11-20, 11-19, 1 1-18, 11-17, 11-16, 11-15, 11-14, 11-13, 12-20, 12-19, 12-18, 12-17, 12-16, 12-15, 12-14, 13-20, 13-19, 13-18, 13-17, 13-16, 13-15, 14-20, 14-19,In some embodiments, the proteins together encode a panel of nucleotides (e.g., nucleotides 14-18, 14-17, 14-16, 15-20, 15-19, 15-18, 15-17, 16-20, 16-19, 16-18, 17-20, 17-19, or 18-20). In some embodiments, the proteins comprise a panel set forth in Table 1 herein.

[0084] In a tenth aspect, the present disclosure provides a method for the treatment of cancer, comprising administering to a patient a therapeutically effective amount of at least one of FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TM A population of viral vectors is provided that together encode one or more proteins selected from EM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD, for example, one or more proteins selected from FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2.

[0085] In some embodiments of the foregoing aspects, the viral vector is selected from the group consisting of FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC and two or more proteins selected from the group consisting of 6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD, for example, two or more proteins selected from the group consisting of FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2. For example, viral vectors can be used to express FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BS Three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, seventeen, eighteen, nineteen, twenty or more of T1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD, for example, three, four, five, six, seven, eight, nine or more of FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2, may be encoded together.

[0086] In some embodiments of the foregoing aspects, the viral vector contains 2 to 20 of the proteins, e.g., proteins FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, R 2-19, 2-18, 2-17, 2-16, 2-15, 2-14, 2-13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-20, 3-19, 3-18, 3-17, 3-16, 3-15, 3-14, 3-13, 3-12, 3-11 of AB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD , 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-20, 4-19, 4-18, 4-17, 4-16, 4-15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 5-20, 5-19, 5-18, 5-17, 5-16, 5- 15, 5-14, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 6-20, 6-19, 6-18, 6-17, 6-16, 6-15, 6-14, 6-13, 6-12, 6-11, 6-10, 6-9, 6-8, 7-20, 7-19, 7-18, 7-17, 7- 16, 7-15, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 8-20, 8-19, 8-18, 8-17, 8-16, 8-15, 8-14, 8-13, 8-12, 8-11, 8-10, 9-20, 9-19, 9-18, 9-17, 9-16, 9-15, 9-1 4, 9-13, 9-12, 9-11, 10-20, 10-19, 10-18, 10-17, 10-16, 10-15, 10-14, 10-13, 10-12, 11-20, 11-19, 11-18, 11-17, 11-16, 11-15, 11-14, 11-13, 12-20,12-19, 12-18, 12-17, 12-16, 12-15, 12-14, 13-20, 13-19, 13-18, 13-17, 13-16, 13-15, 14-20, 14-19, 14-18, 14-17, 14-16, 15-20, 15-19, 15-18, 15-17, 16-20, 16-19, 16-18, 17-20, 17-19, or 18-20 species (e.g., protein FCGR2A, SCAF1 In some embodiments, the proteins together encode 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-10, 4-9, 4-8, 4-7, 4-6, 5-10, 5-9, 5-8, 5-7, 6-10, 6-9, 6-8, 7-10, 7-9, or 8-10 of: 1, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2. In some embodiments, the proteins comprise a panel set forth in Table 2 herein.

[0087] In an eleventh aspect, the present disclosure provides a population of viral vectors that together encode one or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT, e.g., one or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF.

[0088] In some embodiments of the foregoing aspects, the viral vector encodes two or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT, e.g., two or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF together. For example, the viral vector may encode three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more of HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT, e.g., three, four, five, six, or more of HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF together.

[0089] In some embodiments of the foregoing aspects, the viral vector encodes between 2 and 15 of the proteins, e.g., between 2 and 14, 2 to 3 of proteins HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT. 13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 5-15, 5-14, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 6-15, 6-14, 6-13, 6-12, 6-11, 6-10, 6-9, 6-8, 7-15, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 8-15, 8-14, 8-13, 8-12, 8-11, 8-10, 9-15, 9-14, 9-13, 9-12, 9-11, 10-15, 10-14, 10-13, 10-12, 11-15, 11-14, 11-13, 12-15, or 12-14 species, e.g. In some embodiments, the proteins together encode two or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF (e.g., 2-6, 2-5, 2-4, 3-6, 3-5, 4-10, or 4-6 of the proteins HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF). In some embodiments, the proteins comprise a panel described in Table 3 herein.

[0090] In a twelfth aspect, the present disclosure provides a method for the detection of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG 2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, S CAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SI PA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RA B39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2 , DGKQ, STX1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.

[0091] In some embodiments of the foregoing aspects, the viral vector is selected from the group consisting of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CL U, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP 2A2, FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP 25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BC KDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, I Two or more proteins selected from TGA8, ATP13A2, DGKQ, STX1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT are jointly encoded.For example, viral vectors can be used to express any of the following: APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, SCAF 11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2 , MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, D NAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, S Three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or more of TX1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT may be encoded together.

[0092] In some embodiments of the foregoing aspects, the viral vector comprises 2 to 15 of the proteins, e.g., proteins APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL1, SPPL2, SPPL3, SPPL4, SPPL5, SPPL6, SPPL7, SPPL8, SPPL9, SPPL10, SPPL11, SPPL12, SPPL13, SPPL14, SPPL15, SPPL16, SPPL17, SPPL18, SPPL19, SPPL20, SPPL21, SPPL22, SPPL23, SPPL24, SPPL25, SPPL26, SPPL27, SPPL28, SPPL29, SPPL29, SPPL29, SPPL21, SPPL22, SPPL25, SPPL26, SPPL28, SPPL29 ... 2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO 7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, S REBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1 B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, B TNL2 and MAPT, 2-14, 2-13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 5-15, 5-14, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 6-15, 6-14, 6-13, 6-12, 6-11, 6-10, 6-9, 6-8, 7-15, 7-14,In some embodiments, the proteins comprise a panel of 7-13, 7-12, 7-11, 7-10, 7-9, 8-15, 8-14, 8-13, 8-12, 8-11, 8-10, 9-15, 9-14, 9-13, 9-12, 9-11, 10-15, 10-14, 10-13, 10-12, 11-15, 11-14, 11-13, 12-15, or 12-14.

[0093] In some embodiments of any of the foregoing aspects, the viral vector comprises an AAV, adenovirus, parvovirus, coronavirus, rhabdovirus, paramyxovirus, picornavirus, alphavirus, herpesvirus, poxvirus, and / or retroviridae virus. In some embodiments, the viral vector is a retroviridae virus vector, such as a lentiviral vector, an alpharetroviral vector, or a gammaretroviral vector. In some embodiments, the retroviridae virus vector comprises a central polypurine tract, a woodchuck hepatitis virus posttranscriptional regulatory element, a 5'-LTR, an HIV signal sequence, an HIV Psi signal 5'-splice site, a delta-GAG element, a 3'-splice site, and a 3'-self-inactivating LTR. In some embodiments, the viral vector is an AAV selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, and AAVrh74. In some embodiments, the viral vector is a pseudotyped viral vector, e.g., a pseudotyped viral vector selected from the group consisting of a pseudotyped AAV, a pseudotyped adenovirus, a pseudotyped parvovirus, a pseudotyped coronavirus, a pseudotyped rhabdovirus, a pseudotyped paramyxovirus, a pseudotyped picornavirus, a pseudotyped alphavirus, a pseudotyped herpesvirus, a pseudotyped poxvirus, and a pseudotyped retroviridae virus.

[0094] In some embodiments of any of the foregoing aspects, the composition is formulated for systemic administration to a patient. In some embodiments, the composition is formulated for intravenous injection to a patient. In some embodiments, the composition is formulated for direct administration to a patient's central nervous system. In some embodiments, the composition is formulated for direct administration to a patient's CSF. In some embodiments, the composition is formulated for ICV injection, intrathecal injection, stereotactic injection, intraparenchymal injection, or a combination thereof, to a patient. In some embodiments of any of the foregoing aspects, the composition is formulated for systemic administration and direct administration to a patient's (e.g., a mammalian patient, such as a human patient) central nervous system. In some embodiments, the composition is formulated for intravenous injection and direct administration to a patient's CSF. In some embodiments, the composition is formulated for intravenous injection and ICV injection, intrathecal injection, stereotactic injection, intraparenchymal injection, or a combination thereof, to a patient.

[0095] In some embodiments, the patient has been diagnosed with an NCD. In some embodiments, the NCD is a severe NCD. In some embodiments, the severe NCD interferes with the patient's independence and / or normal daily functioning (e.g., social, occupational, or academic functioning, personal hygiene, grooming, dressing, toilet hygiene, functional mobility (e.g., ability to walk, get in and out of bed), and self-feeding). In some embodiments, a severe NCD is associated with a score achieved by the patient on a cognitive test that is at least two standard deviations away from the mean score of a reference population. In some embodiments, the NCD is a mild NCD. In some embodiments, a mild NCD does not interfere with the patient's independence and / or normal daily functioning. In some embodiments, a mild NCD is associated with a score achieved by the patient on a cognitive test that is at least one to two standard deviations away from the mean score of a reference population. In some embodiments, the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE. In some embodiments, the NCD is associated with impairments in one or more of complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition. In some embodiments, the NCD is not due to delirium or another psychiatric disorder (e.g., schizophrenia, bipolar disorder, or major depression). In some embodiments, the reference population is the general population. In some embodiments, the reference population is selected based on the patient's age, medical history, education, socioeconomic status, and lifestyle. In some embodiments, the NCD is Alzheimer's disease. In some embodiments, the NCD is a movement disorder. In some embodiments, the movement disorder is Parkinson's disease. In some embodiments, the NCD is a frontotemporal NCD. In some embodiments, the frontotemporal NCD is FTLD. In some embodiments, the FTLD is behavioral disorder frontotemporal dementia. In some embodiments, the FTLD is semantic dementia. In some embodiments, the FTLD is progressive incompetent aphasia.

[0096] In some embodiments, one or more of the viral vectors comprise a transgene encoding one or more of the proteins operably linked to a ubiquitous promoter. The ubiquitous promoter may be, for example, the elongation factor 1-alpha promoter or the phosphoglycerate kinase 1 promoter. In some embodiments, one or more of the viral vectors comprise a transgene encoding one or more of the proteins operably linked to a cell lineage-specific promoter, such as the PGRN promoter, the CD11b promoter, the CD68 promoter, the C-X3-C motif chemokine receptor 1 promoter, the allograft inflammatory factor 1 promoter, the purinergic receptor P2Y12 promoter, the transmembrane protein 119 promoter, or the colony-stimulating factor 1 receptor promoter. In some embodiments, one or more of the viral vectors comprise a transgene encoding one or more of the proteins operably linked to a synthetic promoter.

[0097] In some embodiments of any of the foregoing aspects, one or more of the proteins further comprises an Rb domain of ApoE. The Rb domain may include a portion of ApoE, such as a portion having an amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105. In some embodiments, the Rb domain comprises a region having at least 70% sequence identity to the amino acid sequence of residues 159-167 of SEQ ID NO: 105 (e.g., a region having at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 100% sequence identity).

[0098] In some embodiments, one or more of the viral vectors comprise a transgene encoding one or more of the proteins, and the transgene may further comprise, for example, an miRNA targeting sequence in its 3'-UTR. In some embodiments, the miRNA targeting sequence is a miR-126 targeting sequence.

[0099] In an additional aspect, the disclosure features a kit including the pharmaceutical composition of the fifth or ninth aspect above. The kit may further include a package insert instructing a user of the kit to administer the pharmaceutical composition to a patient (e.g., a mammalian patient, such as a human patient (e.g., an adult patient)) having an NCD. In some embodiments, the patient (e.g., a human) has been diagnosed with an NCD. In some embodiments, the NCD is a severe NCD. In some embodiments, a severe NCD interferes with the patient's independence and / or normal daily functioning (e.g., social, occupational, or academic functioning, personal hygiene, grooming, dressing, toilet hygiene, functional mobility (e.g., ability to walk, get in and out of bed), and self-feeding). In some embodiments, a severe NCD is associated with a score achieved by the patient on a cognitive test that is at least two standard deviations away from the mean score of a reference population. In some embodiments, the NCD is a mild NCD. In some embodiments, a mild NCD does not interfere with the patient's independence and / or normal daily functioning. In some embodiments, mild NCD is associated with a score achieved by the patient on a cognitive test that is at least 1-2 standard deviations away from the mean score of a reference population. In some embodiments, the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE. In some embodiments, the NCD is associated with impairments in one or more of complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition. In some embodiments, the NCD is not due to delirium or another psychiatric disorder (e.g., schizophrenia, bipolar disorder, or major depression). In some embodiments, the reference population is the general population. In some embodiments, the reference population is selected based on the patient's age, medical history, education, socioeconomic status, and lifestyle. In some embodiments, the NCD is Alzheimer's disease.

[0100] In another aspect, the disclosure features a kit including the pharmaceutical composition of the sixth or tenth aspect above. The kit may further include a package insert instructing a user of the kit to administer the pharmaceutical composition to a patient (e.g., a mammalian patient, such as a human patient (e.g., an adult patient)) having an NCD. In some embodiments, the patient (e.g., a human) has been diagnosed with an NCD. In some embodiments, the NCD is a severe NCD. In some embodiments, a severe NCD interferes with the patient's independence and / or normal daily functioning (e.g., social, occupational, or academic functioning, personal hygiene, grooming, dressing, toilet hygiene, functional mobility (e.g., ability to walk, get in and out of bed), and self-feeding). In some embodiments, a severe NCD is associated with a score achieved by the patient on a cognitive test that is at least two standard deviations away from the mean score of a reference population. In some embodiments, the NCD is a mild NCD. In some embodiments, a mild NCD does not interfere with the patient's independence and / or normal daily functioning. In some embodiments, a mild NCD is associated with a score achieved by the patient on a cognitive test that is at least 1-2 standard deviations away from the mean score of a reference population. In some embodiments, the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE. In some embodiments, the NCD is associated with impairments in one or more of complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition. In some embodiments, the NCD is not due to delirium or another psychiatric disorder (e.g., schizophrenia, bipolar disorder, or major depression). In some embodiments, the reference population is the general population. In some embodiments, the reference population is selected based on the patient's age, medical history, education, socioeconomic status, and lifestyle. In some embodiments, the NCD is a movement disorder. In some embodiments, the movement disorder is Parkinson's disease.

[0101] In a further aspect, the disclosure features a kit including the pharmaceutical composition of the seventh or eleventh aspect above. The kit may further include a package insert instructing a user of the kit to administer the pharmaceutical composition to a patient (e.g., a mammalian patient, such as a human patient (e.g., an adult patient)) having an NCD. In some embodiments, the patient (e.g., a human) has been diagnosed with an NCD. In some embodiments, the NCD is a severe NCD. In some embodiments, a severe NCD interferes with the patient's independence and / or normal daily functioning (e.g., social, occupational, or academic functioning, personal hygiene, grooming, dressing, toilet hygiene, functional mobility (e.g., ability to walk, getting in and out of bed), and self-feeding). In some embodiments, a severe NCD is associated with a score obtained by the patient on a cognitive test that is at least two standard deviations away from the mean score of a reference population. In some embodiments, the NCD is a mild NCD. In some embodiments, a mild NCD does not interfere with the patient's independence and / or normal daily functioning. In some embodiments, mild NCD is associated with a score achieved by the patient on a cognitive test that is at least 1-2 standard deviations away from the mean score of a reference population. In some embodiments, the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE. In some embodiments, the NCD is associated with impairment in one or more of complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition. In some embodiments, the NCD is not due to delirium or another psychiatric disorder (e.g., schizophrenia, bipolar disorder, or major depression). In some embodiments, the reference population is the general population. In some embodiments, the reference population is selected based on the patient's age, medical history, education, socioeconomic status, and lifestyle. In some embodiments, the NCD is frontotemporal NCD. In some embodiments, the frontotemporal NCD is FTLD. In some embodiments, the FTLD is behavioral disorder frontotemporal dementia. In some embodiments, the FTLD is semantic dementia. In some embodiments, the FTLD is progressive incompetent aphasia.

[0102] In a further aspect, the disclosure features a kit including the pharmaceutical composition of the eighth or twelfth aspect above. The kit may further include a package insert instructing a user of the kit to administer the pharmaceutical composition to a patient (e.g., a mammalian patient, such as a human patient (e.g., an adult patient)) having an NCD. In some embodiments, the patient (e.g., a human) has been diagnosed with an NCD. In some embodiments, the NCD is a severe NCD. In some embodiments, a severe NCD interferes with the patient's independence and / or normal daily functioning (e.g., social, occupational, or academic functioning, personal hygiene, grooming, dressing, toilet hygiene, functional mobility (e.g., ability to walk, getting in and out of bed), and self-feeding). In some embodiments, a severe NCD is associated with a score achieved by the patient on a cognitive test that is at least two standard deviations away from the mean score of a reference population. In some embodiments, the NCD is a mild NCD. In some embodiments, a mild NCD does not interfere with the patient's independence and / or normal daily functioning. In some embodiments, a mild NCD is associated with a score achieved by the patient on a cognitive test that is at least 1-2 standard deviations away from the mean score of a reference population. In some embodiments, the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE. In some embodiments, the NCD is associated with impairments in one or more of complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition. In some embodiments, the NCD is not due to delirium or another psychiatric disorder (e.g., schizophrenia, bipolar disorder, or major depression). In some embodiments, the reference population is the general population. In some embodiments, the reference population is selected based on the patient's age, medical history, education, socioeconomic status, and lifestyle. In some embodiments, the NCD is Alzheimer's disease. In some embodiments, the NCD is a movement disorder. In some embodiments, the movement disorder is Parkinson's disease. In some embodiments, the NCD is a frontotemporal NCD. In some embodiments, the frontotemporal NCD is FTLD. In some embodiments, the FTLD is behavioral disorder frontotemporal dementia.In some embodiments, the FTLD is semantic dementia. In some embodiments, the FTLD is progressive incompetent aphasia.

[0103] Additional embodiments of the present invention are provided in the paragraphs listed below.

[0104] E1. 1. A method of treating a patient diagnosed with a neurocognitive disorder (NCD), comprising providing said patient with one or more agents that collectively increase the expression and / or activity of two or more proteins selected from APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, and AP2A2.

[0105] E2. The method of E1, wherein the protein is selected from PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1; and optionally, the protein comprises a panel described in Table 1.

[0106] E3. The method according to E1 or E2, wherein said NCD is a severe NCD.

[0107] E4. The method of E3, wherein said severe NCD interferes with the patient's independence and / or normal daily functioning.

[0108] E5. The method of E3 or E4, wherein said severe NCD is associated with a score obtained by the patient on a cognitive test that is at least 2 standard deviations away from the mean score of a reference population.

[0109] E6. The method according to E1 or E2, wherein said NCD is a mild NCD.

[0110] E7. The method of E6, wherein said mild NCD does not interfere with the patient's independence and / or normal daily functioning.

[0111] E8. The method of E6 or E7, wherein said mild NCD is associated with a score obtained by the patient on a cognitive test that is at least 1-2 standard deviations away from the mean score of a reference population.

[0112] E9. The method of E5 or E8, wherein the reference population is the general population.

[0113] E10. The method of E5, E8, or E9, wherein the cognitive test is selected from the group consisting of the Eight-item Informant Interview to Differentiate Aging and Dementia (AD8), Annual Wellness Visit (AWV), General Practitioner Assessment of Cognition (GPCOG), Health Risk Assessment (HRA), Memory Impairment Screen (MIS), Mini Mental Status Exam (MMSE), Montreal Cognitive Assessment (MoCA), St. Louis University Mental Status Exam (SLUMS), and Short Informant Questionnaire on Cognitive Decline in the Elderly (Short IQCODE).

[0114] E11. The method of any one of E1-E10, wherein said NCD is associated with impairment in one or more of complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition.

[0115] E12. The method of any one of E1 to E11, wherein said NCD is not due to delirium or other psychiatric disorder.

[0116] E13. The method according to any one of E1 to E12, wherein said NCD is Alzheimer's disease.

[0117] E14. 1. A method of treating a patient diagnosed with an NCD, comprising administering to the patient one or more of the following: FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK 1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD.

[0118] E15. The method of E14, wherein said protein is selected from FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2, and optionally said protein comprises a panel listed in Table 2.

[0119] E16. The method according to E14 or E15, wherein said NCD is a severe NCD.

[0120] E17. The method of E16, wherein said severe NCD interferes with the patient's independence and / or normal daily functioning.

[0121] E18. The method of E16 or E17, wherein said severe NCD is associated with a score obtained by the patient on a cognitive test that is at least 2 standard deviations away from the mean score of a reference population.

[0122] E19. The method according to claim 14 or 15, wherein said NCD is a mild NCD.

[0123] E20. The method of E19, wherein said mild NCD does not interfere with the patient's independence and / or normal daily functioning.

[0124] E21. The method of E19 or E20, wherein said mild NCD is associated with a score obtained by the patient on a cognitive test that is at least 1-2 standard deviations away from the mean score of a reference population.

[0125] E22. The method of any one of E18 and E21, wherein said reference population is the general population.

[0126] E23. The method of E18, E21, or E22, wherein the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE.

[0127] E24. A method according to any one of E14 to E23, wherein said NCD is associated with impairment in one or more of complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition.

[0128] E25. The method according to any one of E14 to E24, wherein said NCD is not due to delirium or other psychiatric disorder.

[0129] E26. The method according to any one of E14 to E25, wherein said NCD is a movement disorder.

[0130] E27. The method of E26, wherein said movement disorder is Parkinson's disease.

[0131] E28. 1. A method of treating a patient diagnosed with an NCD, comprising providing said patient with one or more agents that collectively increase the expression and / or activity of two or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.

[0132] E29. The method of E28, wherein the protein is selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF, and optionally the protein comprises a panel listed in Table 3.

[0133] E30. The method of E28 or E29, wherein said NCD is a severe NCD.

[0134] E31. The method of E30, wherein said severe NCD interferes with the patient's independence and / or normal daily functioning.

[0135] E32. The method of E30 or E31, wherein said severe NCD is associated with a score obtained by the patient on a cognitive test that is at least 2 standard deviations away from the mean score of a reference population.

[0136] E33. The method of E28 or E29, wherein said NCD is a mild NCD.

[0137] E34. The method of E33, wherein said mild NCD does not interfere with the patient's independence and / or normal daily functioning.

[0138] E35. The method of E33 or E34, wherein said mild NCD is associated with a score obtained by the patient on a cognitive test that is at least 1-2 standard deviations away from the mean score of a reference population.

[0139] E36. The method of E32 or E35, wherein said reference population is the general population.

[0140] E37. The method of E32, E35, or E36, wherein the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE.

[0141] E38. The method of any one of E28 to E37, wherein said NCD is associated with impairment in one or more of complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition.

[0142] E39. The method of any one of E28 to E38, wherein the NCD is not due to delirium or other psychiatric disorder.

[0143] E40. The method according to any one of E28 to E39, wherein said NCD is a frontotemporal NCD.

[0144] E41. The method of E40, wherein said frontotemporal NCD is frontotemporal lobar degeneration (FTLD).

[0145] E42. The method of E40, wherein said FTLD is behavioral abnormality frontotemporal dementia.

[0146] E43. The method of E40, wherein said FTLD is semantic dementia.

[0147] E44. The method of E40, wherein said FTLD is progressive incompetent aphasia.

[0148] E45. The method of any one of E1 to E44, wherein said one or more agents collectively increase expression and / or activity of three or more of said proteins.

[0149] E46. The method of E45, wherein said one or more agents collectively increase the expression and / or activity of four or more of said proteins.

[0150] E47. The method of E46, wherein said one or more agents collectively increase the expression and / or activity of five or more of said proteins.

[0151] E48. The method of any one of E1 to E13, wherein said one or more agents collectively increase the expression and / or activity of 5 to 20 of said proteins.

[0152] E49. The method of E48, wherein said one or more agents collectively increase the expression and / or activity of 8 to 18 of said proteins.

[0153] E50. The method of E49, wherein said one or more agents collectively increase the expression and / or activity of 10-15 of said proteins.

[0154] E51. The method according to any one of E14 to E27, wherein said one or more agents collectively increase the expression and / or activity of 3 to 10 of said proteins.

[0155] E52. The method of E51, wherein said one or more agents collectively increase the expression and / or activity of 4 to 8 of said proteins.

[0156] E53. The method of E52, wherein said one or more agents collectively increase the expression and / or activity of 5 to 7 of said proteins.

[0157] E54. The method of any one of E28 to E44, wherein said one or more agents collectively increase the expression and / or activity of 2 to 7 of said proteins.

[0158] E55. The method of E54, wherein said one or more agents collectively increase the expression and / or activity of 3 to 6 of said proteins.

[0159] E56. The method of E55, wherein said one or more agents collectively increase the expression and / or activity of four or five of said proteins.

[0160] E57. The method of any one of E1-E56, wherein the one or more agents comprise (i) one or more nucleic acid molecules that collectively encode the two or more proteins, (ii) one or more interfering RNA molecules that collectively increase the expression and / or activity of the two or more proteins, (iii) one or more nucleic acid molecules encoding the one or more interfering RNA molecules, (iv) two or more of the proteins, and / or (v) one or more small molecules that collectively increase the expression and / or activity of the two or more proteins.

[0161] E58. The method of E57, wherein the one or more interfering RNA molecules comprise short interfering RNA (siRNA), short hairpin RNA (shRNA), and / or microRNA (miRNA).

[0162] E59. The method of E57, wherein said one or more agents comprise one or more nucleic acid molecules that collectively encode said two or more proteins.

[0163] E60. The method of E59, wherein said one or more nucleic acid molecules collectively encode three or more of said proteins.

[0164] E61. The method of E60, wherein said one or more nucleic acid molecules collectively encode four or more of said proteins.

[0165] E62. The method of E61, wherein said one or more nucleic acid molecules collectively encode five or more of said proteins.

[0166] E63. The method of any one of E1-E13, wherein said one or more agents comprise one or more nucleic acid molecules collectively encoding 5 to 20 of said proteins.

[0167] E64. The method of E63, wherein said one or more nucleic acid molecules collectively encode 8 to 18 of said proteins.

[0168] E65. The method according to E64, wherein said one or more nucleic acid molecules collectively encode 10 to 15 of said proteins.

[0169] E66. The method of any one of E14 to E27, wherein said one or more agents comprise one or more nucleic acid molecules collectively encoding 3 to 10 of said proteins.

[0170] E67. The method of E66, wherein said one or more nucleic acid molecules collectively encode 4 to 8 of said proteins.

[0171] E68. The method of E67, wherein said one or more nucleic acid molecules collectively encode 5 to 7 of said proteins.

[0172] E69. The method of any one of E28 to E44, wherein said one or more agents comprise one or more nucleic acid molecules collectively encoding two to seven of said proteins.

[0173] E70. The method of E69, wherein said one or more nucleic acid molecules collectively encode 3 to 6 of said proteins.

[0174] E71. The method of E70, wherein said one or more nucleic acid molecules collectively encode four or five of said proteins.

[0175] E72. The method of any one of E59 to E71, wherein the one or more nucleic acid molecules are provided to the patient by administering to the patient a composition comprising a population of cells that together comprise nucleic acids encoding the proteins.

[0176] E73. The method of E72, wherein the population is a homogeneous population of cells comprising the nucleic acid encoding the protein.

[0177] E74. The method of E72, wherein the population is a heterogeneous population of cells that together comprise nucleic acids encoding the protein.

[0178] E75. The method according to any one of E72 to E74, wherein the cells are ESCs.

[0179] E76. The method according to any one of E72 to E74, wherein the cells are iPSCs.

[0180] E77. The method according to any one of E72 to E74, wherein the cells are CD34+ cells.

[0181] E78. The method of E77, wherein the CD34+ cells are HSCs.

[0182] E79. The method of E77, wherein the CD34+ cells are MPCs.

[0183] E80. The method of any one of E72 to E79, wherein said composition is administered systemically to said patient.

[0184] E81. The method of E80, wherein said composition is administered to said patient by intravenous injection.

[0185] E82. The method of any one of E72 to E79, wherein said composition is administered directly into the central nervous system of said patient.

[0186] E83. The method of E72, wherein said composition is administered directly into the cerebrospinal fluid (CSF) of said patient.

[0187] E84. The method of E72 or 83, wherein the composition is administered to the patient by intracerebroventricular (ICV) injection, intrathecal injection, stereotactic injection, intraparenchymal injection, or a combination thereof.

[0188] E85. The method of any one of E72 to E79, wherein said composition is administered to said patient systemically and directly into said patient's central nervous system.

[0189] E86. The method of E85, wherein said composition is administered to said patient by intravenous injection and directly into said patient's CSF.

[0190] E87. The method of E85, wherein the composition is administered to the patient by intravenous injection, and by ICV injection, intrathecal injection, stereotactic injection, intraparenchymal injection, or a combination thereof.

[0191] E88. The method according to any one of E72 to E85, wherein said cells are autologous cells.

[0192] E89. The method according to any one of E72 to E85, wherein said cells are allogeneic cells.

[0193] E90. The method of any one of E72 to E89, wherein said cells are transduced ex vivo to express said protein.

[0194] E91. The method of E90, wherein the cells are transduced with a viral vector selected from the group consisting of adeno-associated virus (AAV), adenovirus, parvovirus, coronavirus, rhabdovirus, paramyxovirus, picornavirus, alphavirus, herpesvirus, poxvirus, and retroviridae virus.

[0195] E92. The method according to E91, wherein the viral vector is a retroviridae viral vector.

[0196] E93. The method according to E92, wherein the Retroviridae viral vector is a lentiviral vector.

[0197] E94. The method according to E92, wherein the Retroviridae viral vector is an alpharetroviral vector.

[0198] E95. The method according to E94, wherein said Retroviridae viral vector is a gamma retroviral vector.

[0199] E96. The method of any one of E92 to E95, wherein the Retroviridae viral vector comprises a central polypurine tract, a woodchuck hepatitis virus post-transcriptional regulatory element, a 5'-LTR, an HIV signal sequence, an HIV Psi signal 5'-splice site, a delta-GAG element, a 3'-splice site, and a 3'-self-inactivating LTR.

[0200] E97. The method of E91, wherein the viral vector is an AAV selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, and AAVrh74.

[0201] E98. The method according to any one of E91 to E97, wherein the viral vector is a pseudotyped viral vector.

[0202] E99. The method of E98, wherein the pseudotyped viral vector is selected from the group consisting of pseudotyped AAV, pseudotyped adenovirus, pseudotyped parvovirus, pseudotyped coronavirus, pseudotyped rhabdovirus, pseudotyped paramyxovirus, pseudotyped picornavirus, pseudotyped alphavirus, pseudotyped herpesvirus, pseudotyped poxvirus, and pseudotyped retroviridae viruses.

[0203] E100. The method of any one of E72 to E99, wherein said cells are transfected ex vivo to express said protein.

[0204] E101. The method of E100, wherein the cells are transfected using: a) an agent selected from the group consisting of cationic polymers, diethylaminoethyl-dextran, polyethyleneimine, cationic lipids, liposomes, calcium phosphate, activated dendrimers, and magnetic beads; or b) a technique selected from the group consisting of electroporation, nucleofection, squeeze-poration, sonoporation, optical transfection, magnetofection, and impalefection.

[0205] E102. The method described in any one of E59 to E71, wherein the one or more nucleic acid molecules are provided to the patient by administering to the patient one or more viral vectors that together comprise the one or more nucleic acid molecules.

[0206] E103. The method of E102, wherein the patient is administered multiple viral vectors that together comprise the one or more nucleic acid molecules.

[0207] E104. The method of E102, wherein the patient is administered a plurality of viral vectors each individually comprising the one or more nucleic acid molecules.

[0208] E105. The method according to any one of E102 to E104, wherein the one or more viral vectors are administered systemically to the patient.

[0209] E106. The method of E105, wherein said one or more viral vectors are administered to said patient by intravenous injection.

[0210] E107. The method according to any one of E102 to E104, wherein the one or more viral vectors are administered directly into the central nervous system of the patient.

[0211] E108. The method of E107, wherein the one or more viral vectors are administered directly into the patient's CSF.

[0212] E109. The method of E107 or 108, wherein the one or more viral vectors are administered to the patient by ICV injection, intrathecal injection, stereotactic injection, intraparenchymal injection, or a combination thereof.

[0213] E110. The method according to any one of E102 to E104, wherein the one or more viral vectors are administered to the patient systemically and directly into the patient's central nervous system.

[0214] E111. The method of E110, wherein said one or more viral vectors are administered to said patient by intravenous injection and directly into said patient's CSF.

[0215] E112. The method of E111, wherein said one or more viral vectors are administered to said patient by intravenous injection, and by ICV injection, intrathecal injection, stereotactic injection, intraparenchymal injection, or a combination thereof.

[0216] E113. The method of any one of E102 to E112, wherein the one or more viral vectors comprise a viral vector selected from the group consisting of AAV, adenovirus, parvovirus, coronavirus, rhabdovirus, paramyxovirus, picornavirus, alphavirus, herpesvirus, poxvirus, and retroviridae virus.

[0217] E114. The method according to E113, wherein the viral vector is a retroviridae viral vector.

[0218] E115. The method according to E113, wherein the Retroviridae viral vector is a lentiviral vector.

[0219] E116. The method of E113, wherein said Retroviridae viral vector is an alpharetroviral vector.

[0220] E117. The method according to E113, wherein said Retroviridae viral vector is a gamma retroviral vector.

[0221] E118. The method of any one of E113 to E117, wherein the Retroviridae viral vector comprises a central polypurine tract, a woodchuck hepatitis virus post-transcriptional regulatory element, a 5'-LTR, an HIV signal sequence, an HIV Psi signal 5'-splice site, a delta-GAG element, a 3'-splice site, and a 3'-self-inactivating LTR.

[0222] E119. The method of E113, wherein the viral vector is an AAV selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, and AAVrh74.

[0223] E120. The method according to any one of E113 to E119, wherein the viral vector is a pseudotyped viral vector.

[0224] E121. The method of E120, wherein the pseudotyped viral vector is selected from the group consisting of pseudotyped AAV, pseudotyped adenovirus, pseudotyped parvovirus, pseudotyped coronavirus, pseudotyped rhabdovirus, pseudotyped paramyxovirus, pseudotyped picornavirus, pseudotyped alphavirus, pseudotyped herpesvirus, pseudotyped poxvirus, and pseudotyped retroviridae viruses.

[0225] E122. The method of any one of E59 to E121, wherein one or more of the nucleic acid molecules comprises a transgene encoding one or more of the proteins operably linked to a ubiquitous promoter.

[0226] E123. The method of E122, wherein the ubiquitous promoter is selected from the group consisting of elongation factor 1-alpha promoter and phosphoglycerate kinase 1 promoter.

[0227] E124. The method of any one of E59 to E123, wherein one or more of said nucleic acid molecules comprises a transgene encoding one or more of said proteins operably linked to a cell lineage-specific promoter.

[0228] E125. The method of E124, wherein the cell lineage-specific promoter is selected from the group consisting of PGRN promoter, CD11b promoter, CD68 promoter, C-X3-C motif chemokine receptor 1 promoter, allograft inflammatory factor 1 promoter, purinergic receptor P2Y12 promoter, transmembrane protein 119 promoter, and colony-stimulating factor 1 receptor promoter.

[0229] E126. The method of any one of E59 to E125, wherein one or more of the nucleic acid molecules comprises a transgene encoding one or more of the proteins operably linked to a synthetic promoter.

[0230] E127. The method of any one of E59 to E126, wherein one or more of said proteins further comprises the receptor binding (Rb) domain of apolipoprotein E (ApoE).

[0231] E128. The method of E127, wherein the Rb domain comprises a portion of ApoE having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO:105.

[0232] E129. The method of E127 or E128, wherein the Rb domain comprises a region having at least 70% sequence identity to the amino acid sequence of residues 159 to 167 of SEQ ID NO:105.

[0233] E130. The method of any one of E59 to E129, wherein said one or more nucleic acid molecules comprise a microRNA (miRNA) targeting sequence in the 3'-UTR.

[0234] E131. The method of E130, wherein the miRNA targeting sequence is a miR-126 targeting sequence.

[0235] E132. The method of any one of E59 to E131, wherein providing said one or more nucleic acid molecules to said patient causes said protein to penetrate the blood-brain barrier of said patient.

[0236] E133. The method of any one of E59 to E132, wherein the endogenous microglia population in said patient has been ablated prior to providing said one or more nucleic acid molecules to said patient.

[0237] E134. The method of any one of E59 to E132, comprising removing a population of endogenous microglia in said patient prior to providing said one or more nucleic acid molecules to said patient.

[0238] E135. The method of E133 or E134, wherein the microglia are ablated using an agent selected from the group consisting of busulfan, PLX3397, PLX647, PLX5622, treosulfan, and clodronate liposomes, radiation therapy, or a combination thereof.

[0239] E136. The method of any one of E72 to E101 or E122 to E135, wherein endogenous expression of one or more of said proteins is disrupted in said cells prior to providing said one or more nucleic acid molecules to said patient.

[0240] E137. The method of any one of E59 to E136, wherein endogenous expression of one or more of said proteins is disrupted in said patient prior to providing said one or more nucleic acid molecules to said patient.

[0241] E138. The method of E137, wherein endogenous expression of one or more of said proteins is disrupted in a population of neurons in said patient prior to providing said one or more nucleic acid molecules to said patient.

[0242] E139. The method of E136, wherein said endogenous expression is disrupted by contacting said cell with a nuclease that catalyzes cleavage of an endogenous gene encoding one of said proteins.

[0243] E140. The method of E139, wherein the nuclease is a clustered regularly interspaced short palindromic repeats (CRISPR) associated protein.

[0244] E141. The method of E140, wherein the CRISPR-associated protein is CRISPR-associated protein 9 (Cas9).

[0245] E142. The method of E140, wherein the CRISPR-associated protein is CRISPR-associated protein 12a (Cas12a).

[0246] E143. The method of E139, wherein the nuclease is a transcription activator-like effector nuclease, a meganuclease, or a zinc finger nuclease.

[0247] E144. The method of any one of E136 to E140, wherein endogenous expression of one or more of said proteins is disrupted by administering an inhibitory RNA molecule to said cell, said patient, or said population of neurons.

[0248] E145. The method of E144, wherein the inhibitory RNA molecule is an siRNA, shRNA, or miRNA.

[0249] E146. The method of any one of E1 to E145, wherein the patient is a human.

[0250] E147. 1. A pharmaceutical composition comprising a population of cells which together contain nucleic acids encoding two or more proteins selected from APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, and AP2A2.

[0251] E148. The pharmaceutical composition of E147, wherein the protein is selected from PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1.

[0252] E149. FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP2 5, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, B A pharmaceutical composition comprising a population of cells that together contain nucleic acids encoding two or more proteins selected from CKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD.

[0253] E150. The pharmaceutical composition of E149, wherein the protein is selected from FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2.

[0254] E151. A pharmaceutical composition comprising a population of cells that together contain nucleic acids encoding two or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.

[0255] E152. The pharmaceutical composition of E151, wherein the protein is selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF.

[0256] E153. The pharmaceutical composition of any one of E147 to E152, wherein the cell comprises nucleic acids encoding three or more of the proteins together.

[0257] E154. The pharmaceutical composition of E153, wherein said cell comprises nucleic acids encoding four or more of said proteins together.

[0258] E155. The pharmaceutical composition of E154, wherein said cells together comprise nucleic acids encoding five or more of said proteins.

[0259] E156. The pharmaceutical composition of E147 or E148, wherein the cells together comprise nucleic acids encoding 5 to 20 of the proteins.

[0260] E157. The pharmaceutical composition of E156, wherein the cells together comprise nucleic acids encoding 8 to 18 of the proteins.

[0261] E158. The pharmaceutical composition of E157, wherein the cells together comprise nucleic acids encoding 10 to 15 of the proteins.

[0262] E159. The pharmaceutical composition of E149 or E150, wherein the cells together comprise nucleic acids encoding 3 to 10 of the proteins.

[0263] E160. The pharmaceutical composition of E159, wherein the cells together comprise nucleic acids encoding 4 to 8 of the proteins.

[0264] E161. The pharmaceutical composition of E160, wherein the cells together comprise nucleic acids encoding 5 to 7 of the proteins.

[0265] E162. The pharmaceutical composition of E151 or E152, wherein the cells together comprise nucleic acids encoding 2 to 7 of the proteins.

[0266] E163. The pharmaceutical composition of E162, wherein the cells together comprise nucleic acids encoding 3 to 6 of the proteins.

[0267] E164. The pharmaceutical composition of E163, wherein the cells comprise nucleic acids encoding four or five of the proteins together.

[0268] E165. The pharmaceutical composition according to any one of E147 to E164, wherein the population is a homogeneous population of cells comprising a nucleic acid encoding the protein.

[0269] E166. The pharmaceutical composition of any one of E147 to E164, wherein the population is a heterogeneous population of cells that together comprise the nucleic acid encoding the protein.

[0270] E167. The pharmaceutical composition according to any one of E147 to E166, wherein the cells are ESCs.

[0271] E168. The pharmaceutical composition according to any one of E147 to E166, wherein the cells are iPSCs.

[0272] E169. The pharmaceutical composition of any one of E147 to E166, wherein the cells are CD34+ cells.

[0273] E170. The pharmaceutical composition of E169, wherein the CD34+ cells are HSCs.

[0274] E171. The pharmaceutical composition of E169, wherein the CD34+ cells are MPCs.

[0275] E172. The pharmaceutical composition of any one of E147 to E171, formulated for systemic administration to a human patient.

[0276] E173. The pharmaceutical composition of E172, wherein the patient has been diagnosed with an NCD.

[0277] E174. The pharmaceutical composition according to E173, wherein said NCD is a severe NCD.

[0278] E175. The pharmaceutical composition according to E174, wherein said severe NCD interferes with the patient's independence and / or normal daily functioning.

[0279] E176. The pharmaceutical composition of E174 or E175, wherein said severe NCD is associated with a score obtained by the patient on a cognitive test that is at least 2 standard deviations away from the mean score of a reference population.

[0280] E177. The pharmaceutical composition according to E173, wherein said NCD is a mild NCD.

[0281] E178. The pharmaceutical composition according to E177, wherein said mild NCD does not interfere with the patient's independence and / or normal daily functioning.

[0282] E179. The pharmaceutical composition of E177 or E178, wherein said mild NCD is associated with a score obtained by the patient on a cognitive test that is at least 1-2 standard deviations away from the mean score of a reference population.

[0283] E180. The pharmaceutical composition of E177 or E179, wherein said reference population is the general population.

[0284] E181. The pharmaceutical composition of E176, E179, or E180, wherein the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE.

[0285] E182. The pharmaceutical composition according to any one of E173 to E181, wherein said NCD is Alzheimer's disease.

[0286] E183. The pharmaceutical composition according to any one of E173 to E181, wherein said NCD is a movement disorder.

[0287] E184. The pharmaceutical composition according to E183, wherein said movement disorder is Parkinson's disease.

[0288] E185. The pharmaceutical composition according to any one of E173 to E181, wherein said NCD is a frontotemporal NCD.

[0289] E186. The pharmaceutical composition of E185, wherein the frontotemporal NCD is FTLD.

[0290] E187. The pharmaceutical composition described in E186, wherein the FTLD is behavioral abnormality frontotemporal dementia.

[0291] E188. The pharmaceutical composition described in E186, wherein the FTLD is semantic dementia.

[0292] E189. The pharmaceutical composition described in E186, wherein said FTLD is progressive incompetent aphasia.

[0293] E190. The pharmaceutical composition of any one of E147 to E189, formulated for intravenous injection into said human patient.

[0294] E191. The pharmaceutical composition of any one of E147 to E189, formulated for direct administration to the central nervous system of a human patient.

[0295] E192. The pharmaceutical composition of E191, which is formulated for administration directly to the CSF of the human patient.

[0296] E193. The pharmaceutical composition of E191 or E192, wherein the pharmaceutical composition is formulated for ICV injection, intrathecal injection, stereotactic injection, intraparenchymal injection, or a combination thereof, into the human patient.

[0297] E194. The pharmaceutical composition of any one of E147 to E189, formulated for systemic administration and for direct administration into the central nervous system of a human patient.

[0298] E195. The pharmaceutical composition of E194, formulated for intravenous injection and direct administration into the CSF of said human patient.

[0299] E196. The pharmaceutical composition of E195, formulated for intravenous and ICV injection, intrathecal injection, stereotactic injection, intraparenchymal injection, or a combination thereof, into the human patient.

[0300] E197. The pharmaceutical composition according to any one of E147 to E196, wherein the cells are autologous cells.

[0301] E198. The pharmaceutical composition of any one of E147 to E196, wherein the cells are allogeneic cells.

[0302] E199. The pharmaceutical composition of any one of E147 to E198, wherein the cells comprise a transgene encoding one or more of said proteins operably linked to a ubiquitous promoter.

[0303] E200. The pharmaceutical composition of E199, wherein the ubiquitous promoter is selected from the group consisting of elongation factor 1-alpha promoter and phosphoglycerate kinase 1 promoter.

[0304] E201. A pharmaceutical composition described in any one of E147 to E200, wherein the cells comprise a transgene encoding one or more of said proteins operably linked to a cell lineage-specific promoter.

[0305] E202. The pharmaceutical composition of E201, wherein the cell lineage-specific promoter is selected from the group consisting of PGRN promoter, CD11b promoter, CD68 promoter, C-X3-C motif chemokine receptor 1 promoter, allograft inflammatory factor 1 promoter, purinergic receptor P2Y12 promoter, transmembrane protein 119 promoter, and colony-stimulating factor 1 receptor promoter.

[0306] E203. A pharmaceutical composition described in any one of E147 to E202, wherein the cells comprise a transgene encoding one or more of the proteins operably linked to a synthetic promoter.

[0307] E204. The pharmaceutical composition of any one of E147 to E203, wherein one or more of the proteins further comprises the Rb domain of ApoE.

[0308] E205. The pharmaceutical composition of E204, wherein the Rb domain comprises a portion of ApoE having an amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO:105.

[0309] E206. The pharmaceutical composition of E204 or E205, wherein the Rb domain comprises a region having at least 70% sequence identity to the amino acid sequence of residues 159 to 167 of SEQ ID NO:105.

[0310] E207. The pharmaceutical composition described in any one of E147 to E206, wherein the one or more nucleic acid molecules comprise an miRNA targeting sequence in the 3'-UTR.

[0311] E208. The pharmaceutical composition described in E207, wherein the miRNA targeting sequence is a miR-126 targeting sequence.

[0312] E209. A pharmaceutical composition comprising a population of viral vectors that together encode two or more proteins selected from APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, and AP2A2.

[0313] E210. The pharmaceutical composition of E209, wherein the protein is selected from PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1.

[0314] E211. FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP2 5, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, B A pharmaceutical composition comprising a population of viral vectors that together encode two or more proteins selected from CKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD.

[0315] E212. The pharmaceutical composition of E211, wherein the protein is selected from FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2.

[0316] E213. A pharmaceutical composition comprising a population of viral vectors that together encode two or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.

[0317] E214. The pharmaceutical composition of E213, wherein the protein is selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF.

[0318] E215. The pharmaceutical composition according to any one of E209 to E214, wherein the viral vector encodes three or more of the proteins together.

[0319] E216. The pharmaceutical composition of E215, wherein the viral vector encodes four or more of the proteins together.

[0320] E217. The pharmaceutical composition of E216, wherein the viral vector encodes five or more of the proteins together.

[0321] E218. The pharmaceutical composition of E209 or E210, wherein the viral vector encodes 5 to 20 of the proteins together.

[0322] E219. The pharmaceutical composition described in E218, wherein the viral vector encodes 8 to 18 of the proteins together.

[0323] E220. The pharmaceutical composition of E219, wherein the viral vector encodes 10 to 15 of the proteins together.

[0324] E221. The pharmaceutical composition of E211 or E212, wherein the viral vector encodes 3 to 10 of the proteins together.

[0325] E222. The pharmaceutical composition of E221, wherein the viral vector encodes 4 to 8 of the proteins together.

[0326] E223. The pharmaceutical composition of E222, wherein the viral vector encodes 5 to 7 of the proteins together.

[0327] E224. The pharmaceutical composition of E213 or E214, wherein the viral vector encodes two to seven of the proteins together.

[0328] E225. The pharmaceutical composition according to E224, wherein the viral vector encodes 3 to 6 of the proteins together.

[0329] E226. The pharmaceutical composition of E225, wherein the viral vector encodes four or five of the proteins together.

[0330] E227. The pharmaceutical composition of any one of E209 to E226, wherein the viral vector comprises an AAV, adenovirus, parvovirus, coronavirus, rhabdovirus, paramyxovirus, picornavirus, alphavirus, herpesvirus, poxvirus, and / or retroviridae virus.

[0331] E228. The pharmaceutical composition according to E227, wherein the viral vector comprises a retroviridae viral vector.

[0332] E229. The pharmaceutical composition according to E228, wherein the retroviridae viral vector is a lentiviral vector.

[0333] E230. The pharmaceutical composition according to E228, wherein the Retroviridae viral vector is an alpharetroviral vector.

[0334] E231. The pharmaceutical composition according to E228, wherein the Retroviridae viral vector is a gamma retroviral vector.

[0335] E232. The pharmaceutical composition described in any one of E228 to E231, wherein the Retroviridae viral vector comprises a central polypurine tract, a woodchuck hepatitis virus post-transcriptional regulatory element, a 5'-LTR, an HIV signal sequence, an HIV Psi signal 5'-splice site, a delta-GAG element, a 3'-splice site, and a 3'-self-inactivating LTR.

[0336] E233. The pharmaceutical composition described in E232, wherein the viral vector is an AAV selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, and AAVrh74.

[0337] E234. The pharmaceutical composition according to any one of E209 to E233, wherein the viral vector comprises a pseudotyped viral vector.

[0338] E235. The pharmaceutical composition of E234, wherein the pseudotyped viral vector is selected from the group consisting of pseudotyped AAV, pseudotyped adenovirus, pseudotyped parvovirus, pseudotyped coronavirus, pseudotyped rhabdovirus, pseudotyped paramyxovirus, pseudotyped picornavirus, pseudotyped alphavirus, pseudotyped herpesvirus, pseudotyped poxvirus, and pseudotyped retroviridae viruses.

[0339] E236. The pharmaceutical composition of any one of E209 to E235, formulated for systemic administration to a human patient.

[0340] E237. The pharmaceutical composition of E236, formulated for intravenous injection into said human patient.

[0341] E238. The pharmaceutical composition of any one of E209 to E235, formulated for direct administration to the central nervous system of a human patient.

[0342] E239. The pharmaceutical composition of E238, which is formulated for administration directly to the CSF of the human patient.

[0343] E240. The pharmaceutical composition of E238 or E239, formulated for ICV injection, intrathecal injection, stereotactic injection, intraparenchymal injection, or a combination thereof, into the human patient.

[0344] E241. The pharmaceutical composition of any one of E209 to E235, formulated for systemic administration and for direct administration into the central nervous system of a human patient.

[0345] E242. The pharmaceutical composition of E241, formulated for intravenous injection and direct administration into the CSF of said human patient.

[0346] E243. The pharmaceutical composition of E242, formulated for intravenous and ICV injection, intrathecal injection, stereotactic injection, intraparenchymal injection, or combinations thereof, into the human patient.

[0347] E244. A pharmaceutical composition described in any one of E209 to E243, wherein one or more of the viral vectors comprises an introduced gene encoding one or more of the proteins operably linked to a ubiquitous promoter.

[0348] E245. The pharmaceutical composition according to E244, wherein said ubiquitous promoter is selected from the group consisting of elongation factor 1-alpha promoter and phosphoglycerate kinase 1 promoter.

[0349] E246. A pharmaceutical composition described in any one of E209 to E243, wherein one or more of the viral vectors comprises a transgene encoding one or more of the proteins operably linked to a cell lineage-specific promoter.

[0350] E247. The pharmaceutical composition of E246, wherein the cell lineage-specific promoter is selected from the group consisting of PGRN promoter, CD11b promoter, CD68 promoter, C-X3-C motif chemokine receptor 1 promoter, allograft inflammatory factor 1 promoter, purinergic receptor P2Y12 promoter, transmembrane protein 119 promoter, and colony-stimulating factor 1 receptor promoter.

[0351] E248. A pharmaceutical composition described in any one of E209 to E243, wherein one or more of the viral vectors comprises an introduced gene encoding one or more of the proteins operably linked to a synthetic promoter.

[0352] E249. The pharmaceutical composition of any one of E209 to E248, wherein one or more of the proteins further comprises the Rb domain of ApoE.

[0353] E250. The pharmaceutical composition of E249, wherein the Rb domain comprises a portion of ApoE having an amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO:105.

[0354] E251. The pharmaceutical composition of E249 or E250, wherein the Rb domain comprises a region having at least 70% sequence identity to the amino acid sequence of residues 159 to 167 of SEQ ID NO:105.

[0355] E252. A pharmaceutical composition described in any one of E209 to E251, wherein one or more of the viral vectors comprises a transgene encoding one or more of the proteins, and the transgene further encodes an miRNA targeting sequence in its 3'-UTR.

[0356] E253. The pharmaceutical composition described in E252, wherein the miRNA targeting sequence is a miR-126 targeting sequence.

[0357] E254. A kit comprising the pharmaceutical composition of any one of E209, E210, E215-E220, and E227-E253, further comprising a package insert instructing a user of the kit to administer the pharmaceutical composition to a human patient with an NCD.

[0358] E255. The kit according to E254, wherein the NCD is a severe NCD.

[0359] E256. The kit of E255, wherein the severe NCD interferes with the patient's independence and / or normal daily functioning.

[0360] E257. The kit of E255 or E256, wherein said severe NCD is associated with a score obtained by the patient on a cognitive test that is at least 2 standard deviations away from the mean score of a reference population.

[0361] E258. The kit according to E254, wherein the NCD is a mild NCD.

[0362] E259. The kit of E256, wherein said mild NCD does not interfere with the patient's independence and / or normal daily functioning.

[0363] E260. The kit of E258 or E259, wherein said mild NCD is associated with a score obtained by the patient on a cognitive test that is at least 1-2 standard deviations away from the mean score of a reference population.

[0364] E261. The kit of E257 or E260, wherein the reference population is a general population.

[0365] E262. The kit of E257, E260, or E261, wherein the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE.

[0366] E263. The kit according to any one of E254 to E262, wherein the NCD is Alzheimer's disease.

[0367] E264. A kit comprising the pharmaceutical composition of any one of E211, E212, E221-E226, and E227-E253, further comprising a package insert instructing a user of the kit to administer the pharmaceutical composition to a human patient with an NCD.

[0368] E265. The kit according to E264, wherein the NCD is a movement disorder.

[0369] E266. The kit according to E265, wherein the movement disorder is Parkinson's disease.

[0370] E267. A kit comprising the pharmaceutical composition of any one of E213, E214, E224-E226, and E227-E253, further comprising a package insert instructing a user of the kit to administer the pharmaceutical composition to a human patient with an NCD.

[0371] E268. The kit according to E267, wherein the NCD is a severe NCD.

[0372] E269. The kit of E268, wherein the severe NCD interferes with the patient's independence and / or normal daily functioning.

[0373] E270. The kit of E268 or E269, wherein the severe NCD is associated with a score obtained by the patient on a cognitive test that is at least 2 standard deviations away from the mean score of a reference population.

[0374] E271. The kit according to E268, wherein the NCD is a mild NCD.

[0375] E272. The kit of E271, wherein said mild NCD does not interfere with the patient's independence and / or normal daily functioning.

[0376] E273. The kit of E271 or E272, wherein the mild NCD is associated with a score obtained by the patient on a cognitive test that is at least 1-2 standard deviations away from the mean score of a reference population.

[0377] E274. The kit of E270 or E273, wherein the reference population is a general population.

[0378] E275. The kit of E270, E273, or E274, wherein the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE.

[0379] E276. The kit according to any one of E267 to E275, wherein the NCD is a frontotemporal NCD.

[0380] E277. The kit of E276, wherein the frontotemporal NCD is FTLD.

[0381] E278. The kit described in E277, wherein the FTLD is frontotemporal dementia with behavioral abnormalities.

[0382] E279. The kit described in E277, wherein the FTLD is semantic dementia.

[0383] E280. The kit described in E277, wherein the FTLD is progressive incompetent aphasia.

[0384] E281. 1. A method of treating a patient diagnosed with an NCD, comprising administering to the patient one or more of: APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCG R2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIP A1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, D NAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, The method comprises supplying one or more agents that collectively increase the expression and / or activity of two or more proteins selected from NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.

[0385] E282. The method according to E281, wherein said NCD is a severe NCD.

[0386] E283. The method of E282, wherein said severe NCD interferes with the patient's independence and / or normal daily functioning.

[0387] E284. The method of E282 or E283, wherein said severe NCD is associated with a score obtained by the patient on a cognitive test that is at least 2 standard deviations away from the mean score of a reference population.

[0388] E285. The method according to E281, wherein said NCD is a mild NCD.

[0389] E286. The method according to E285, wherein said mild NCD does not interfere with the patient's independence and / or normal daily functioning.

[0390] E287. The method of E285 or E286, wherein said mild NCD is associated with a score obtained by the patient on a cognitive test that is at least 1-2 standard deviations away from the mean score of a reference population.

[0391] E288. The method of E284 or E287, wherein the reference population is the general population.

[0392] E289. The method of E284, E287, or E288, wherein the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, Short IQCODE.

[0393] E290. The method of any one of E281 to E289, wherein said NCD is associated with impairment in one or more of complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition.

[0394] E291. The method of any one of E281 to E290, wherein the NCD is not due to delirium or other psychiatric disorder.

[0395] E292. The method of any one of E281 to E291, wherein said NCD is Alzheimer's disease.

[0396] E293. The method of any one of E281 to E291, wherein said NCD is a movement disorder.

[0397] E294. The method of any one of E293, wherein said movement disorder is Parkinson's disease.

[0398] E295. The method according to any one of E281 to E291, wherein said NCD is a frontotemporal NCD.

[0399] E296. The method of E295, wherein said frontotemporal NCD is FTLD.

[0400] E297. The method according to any one of E1 to E150, wherein the cell is a pluripotent cell (e.g., ESC, iPSC), a pluripotent cell (e.g., a CD34+ cell, such as an HSC or MPC), a BLPC, a monocyte, a macrophage, a microglial progenitor cell, or a microglia.

[0401] E298. The method of any one of E1 to E146, wherein said transgene is capable of being expressed in macrophages or microglial cells.

[0402] E299. APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP , PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD 4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, SCAF11, HLA-D QB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC 1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJ C6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, ST A pharmaceutical composition comprising a population of cells that together contain nucleic acids encoding two or more proteins selected from X1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.

[0403] E300. APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP , PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD 4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, SCAF11, HLA-D QB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC 1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJ C6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, ST A pharmaceutical composition comprising a population of viral vectors that together encode two or more proteins selected from X1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.

[0404] E301. A kit comprising the pharmaceutical composition of any one of E227 or E299, further comprising a package insert instructing a user of the kit to administer the pharmaceutical composition to a human patient with an NCD.

[0405] E302. The kit according to E301, wherein said NCD is a severe NCD.

[0406] E303. The kit of E302, wherein the severe NCD interferes with the patient's independence and / or normal daily functioning.

[0407] E304. The kit of E302 or E303, wherein said severe NCD is associated with a score obtained by the patient on a cognitive test that is at least 2 standard deviations away from the mean score of a reference population.

[0408] E305. The kit according to E301, wherein said NCD is a mild NCD.

[0409] E306. The kit of E305, wherein said mild NCD does not interfere with the patient's independence and / or normal daily functioning.

[0410] E307. The kit of E305 or E306, wherein said mild NCD is associated with a score obtained by the patient on a cognitive test that is at least 1-2 standard deviations away from the mean score of a reference population.

[0411] E308. The kit of E304 or E307, wherein the reference population is a general population.

[0412] E309. The kit of E304, E307, or E308, wherein the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE.

[0413] E310. The kit according to any one of E301 to E309, wherein the NCD is Alzheimer's disease.

[0414] E311. The kit according to any one of E301 to E309, wherein the NCD is a movement disorder.

[0415] E312. The kit according to E311, wherein the movement disorder is Parkinson's disease.

[0416] E313. The kit according to any one of E301 to E309, wherein the NCD is a frontotemporal NCD.

[0417] E314. The kit of E313, wherein the frontotemporal NCD is FTLD.

[0418] E315. The kit described in E314, wherein the FTLD is frontotemporal dementia with behavioral abnormalities.

[0419] E316. The kit of E314, wherein the FTLD is semantic dementia.

[0420] E317. The kit of E314, wherein the FTLD is progressive incompetent aphasia. [Brief explanation of the drawings]

[0421] [Figure 1] Western blot showing the expression of human triggering receptor expressed on myeloid cells 2 (TREM2) protein in mouse macrophages transduced with a lentiviral vector encoding TREM2. Cell lysates were generated from RAW mouse macrophage cells transduced with the MND.TREM2 viral vector (MND.TREM2), the MND.green fluorescent protein (GFP) viral vector (MND.GFP), or non-transduced control (NTC) cells at a multiplicity of infection (MOI) of 10, 50, 100, or 200. TREM2 expression was assessed using an antibody raised against human TREM2 (Figure 1). [Figure 2]Western blot showing human TREM2 protein expression in mouse microglia transduced with a lentiviral vector encoding TREM2. Cell lysates were generated from primary mouse microglia that were either non-transduced (NT) or transduced with the MND.TREM2 viral vector (MND-TREM2) or the MND.GFP viral vector (MND-GFP). TREM2 expression was assessed using an antibody raised against human TREM2 (Figure 2). [Figure 3] Western blots showing human TREM2 protein expression in lineage-negative (Lin-) cells transduced with a lentiviral vector encoding TREM2. Cell lysates from Lin- mouse cells transduced with the MND.TREM2 viral vector (LentiTREM2) or the MND.GFP viral vector. TREM2 expression was assessed using an antibody raised against human TREM2 (Figure 3). [Figure 4A] This is a series of plots showing the transduction of human cells with a lentiviral vector containing a transgene encoding the human progranulin (PGRN) protein. Cell lysates were generated from human 239T cells transduced with lentiviral vectors encoding PGRN (MND.GRN) or green fluorescent protein (GFP; MND.GFP) at a multiplicity of infection (MOI) of 10, 50, 100, or 200. A separate set of control cells was not transduced (NTC). PGRN levels were quantified relative to actin using densitometry. [Figure 4B] Western blot analysis using an antibody raised against human PGRN demonstrated stable PGRN expression in 239T cells, with maximal expression observed at an MOI of 200. All groups showed statistically significant differences except for NTC cells and GFP cells at an MOI of 10. Statistical analysis was performed using ANOVA. [Figure 5]Figure 5 is a Western blot showing the expression of human PGRN in mouse lineage negative (Lin-) cells transduced with a lentiviral vector containing a transgene encoding human PGRN (i.e., the MND.GRN vector). Analysis of conditioned medium generated from untransduced (-) or transduced (+) Lin- mouse cells with the MND.GRN lentiviral vector using a Western blot with an antibody raised against human PGRN demonstrated the release of human PGRN protein into the growth medium by the transduced cells (Figure 5). [Figure 6] Western blots showing that immortalized cell lines transduced with lentiviral vectors containing a transgene encoding human PGRN are N-linked glycosylated. Cell lysates were generated from human 239T cell lines that were untransduced (NT1, NT2, NT3, and NT4) or transduced with lentiviral vectors encoding human PGRN produced in four independent rounds of transduction (MND.GRN-1, MND.GRN-2, MND.GRN-3, and MND.GRN-4). Cell lysates were enzymatically digested with either EndoH (E.) or PNGase (P.) enzymes or heated (H.) and analyzed by Western blot using an antibody raised against human progranulin. Enzymatic digestion with EndoH and PNGase demonstrates that the human PGRN protein produced by the transduced cells is N-linked glycosylated (Figure 6). DETAILED DESCRIPTION OF THE INVENTION

[0422] definition As used herein, the terms "remove," "removing," "removal," and the like refer to the depletion of one or more cells in a population of cells in vivo or ex vivo. In some embodiments of the present disclosure, it may be desirable to remove endogenous cells within a patient (e.g., a patient undergoing treatment for a disease described herein, e.g., a neurocognitive disorder (NCD; e.g., Alzheimer's disease, Parkinson's disease, or frontotemporal lobar dementia (FTLD))) before administering a therapeutic composition, e.g., a therapeutic population of cells, to the patient. This may be advantageous, for example, to provide newly administered cells with an environment in which they can engraft. Removal of a population of endogenous cells can be performed in a manner that selectively targets specific cell types, for example, using antibody-drug conjugates that bind to antigens expressed on the target cells and subsequently cause death of the target cells. Additionally or alternatively, removal can be performed in a non-specific manner using cytotoxins that do not focus on a particular cell type but instead may exert their cytotoxic effects on a variety of different cells. Exemplary agents that can be used to ablate endogenous cell populations in a patient, such as endogenous microglia or microglia precursor cell populations in a patient receiving therapy for the treatment of an NCD, include busulfan, PLX3397, PLX647, PLX5622, treosulfan, clodronate liposomes, and combinations thereof. Examples of ablation include depletion of at least 5% (e.g., at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more) of cells in a population of cells in vivo or in vitro. Quantification of cell numbers in a sample of cells can be performed using various cell counting techniques, such as by using a counting chamber, a Coulter counter, flow cytometry, or other cell counting methods known in the art.

[0423] As used herein in the context of a protein of interest, the term "activity" refers to the biological functionality associated with the wild-type form of that protein. For example, in the context of an enzyme, the term "activity" refers to the ability of the protein to carry out substrate turnover to yield the product of a corresponding chemical reaction. For example, substrate turnover assays known in the art can be used to detect and quantify the activity level of an enzyme. As another example, in the context of a membrane-bound receptor, the term "activity" can refer to signal transduction initiated by the receptor, for example, upon binding to its cognate ligand. For example, the activity level of a receptor involved in a signal transduction pathway can be detected and quantified by observing an increase in the outcome of receptor signaling, e.g., an increase in transcription of one or more genes (which can be detected, for example, using polymerase chain reaction techniques known in the art).

[0424] As used herein, the terms "administering," "administration," and the like refer to providing a patient directly by any effective route with a therapeutic agent (e.g., a population of cells, e.g., cells (e.g., pluripotent cells (e.g., embryonic stem cells (ESCs) or induced pluripotent stem cells (ISPCs)), pluripotent cells (e.g., CD34+ cells, such as, e.g., hematopoietic stem cells (HSCs) or myeloid progenitor cells (MPCs)), blood lineage progenitor cells (BLPCs; e.g., monocytes), macrophages, microglial progenitor cells, or microglia) comprising a nucleic acid (e.g., a nucleic acid expressible in macrophages or microglia) encoding one or more proteins described herein. Exemplary routes of administration are described herein and include systemic routes, such as intravenous injection, as well as routes of administration directly into the patient's central nervous system, such as by intraventricular injection, intrathecal injection, and stereotactic injection, among others.

[0425] As used herein, the term "allogeneic" refers to cells, tissues, nucleic acid molecules, or other materials obtained or derived from a different patient of the same species. For example, in the context of a population of cells expressing one or more proteins described herein, allogeneic cells include those (i) obtained from a patient who has not received treatment and then (ii) transduced or transfected with a vector that directs the expression of one or more desired proteins. The phrase "directing expression" refers to the inclusion of one or more polynucleotides that encode the protein or proteins to be expressed. The polynucleotides may contain additional sequence motifs that enhance expression of the protein of interest.

[0426] As used herein, the term "autologous" refers to cells, tissues, nucleic acid molecules, or other materials obtained or derived from an individual's own cells, tissues, nucleic acid molecules, etc. For example, in the context of a population of cells expressing one or more proteins described herein, autologous cells include those obtained from a patient undergoing treatment and then transduced or transfected with a vector that directs the expression of one or more proteins of interest.

[0427] As used herein, the term "ApoE" refers to apolipoprotein E, a member of a class of proteins involved in lipid transport. Apolipoprotein E is a fat-binding protein (apolipoprotein) that is part of chylomicrons and intermediate-density lipoproteins (IDLs), which are essential for the normal processing (catabolism) of triglyceride-rich lipoproteins. ApoE is encoded by the APOE gene. The term "ApoE" also refers to variants of wild-type ApoE protein, e.g., proteins having at least 70% identity (e.g., at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to the amino acid sequence of wild-type ApoE set forth in SEQ ID NO: 105.

[0428] As used herein, the term "blood lineage progenitor cell" or "BLPC" refers to any cell (e.g., mammalian cell) that can differentiate into one or more (e.g., two, three, four, five, or more) types of hematopoietic (i.e., blood) cells. BLPCs can differentiate into red blood cells, white blood cells (e.g., granulocytes (e.g., basophils, eosinophils, neutrophils, and mast cells) or agranulocytes (e.g., lymphocytes and monocytes)), or platelets. BLPCs can also include differentiated blood cells (e.g., monocytes) that can further differentiate into another blood cell type (e.g., macrophages).

[0429] As used herein, the term "cell type" refers to a group of cells that share a statistically distinguishable phenotype based on gene expression data. For example, cells of a common cell type may share similar structural and / or functional characteristics, such as similar gene activation patterns and antigen presentation profiles. Cells of a common cell type may include those isolated from a common tissue (e.g., epithelial, nervous, connective, or muscle tissue) and / or those isolated from a common organ, tissue system, blood vessel, or other structure and / or region of the body.

[0430] As used herein, "codon optimization" refers to the process of modifying a nucleic acid sequence according to the principle that the frequency of synonymous codons (e.g., codons encoding the same amino acid) in coding DNA is biased across different species. Such codon degeneracy allows the same polypeptide to be encoded by a variety of nucleotide sequences. Sequences modified in this manner are referred to herein as "codon optimization." This process may be performed on any of the sequences described herein to enhance expression or stability. Codon optimization can be performed, for example, in the manner described in U.S. Patent Nos. 7,561,972, 7,561,973, and 7,888,112, each of which is incorporated herein by reference in its entirety. The sequence surrounding the translation start site can be converted to a consensus Kozak sequence according to known methods. See, for example, Kozak et al., Nucleic Acids Res. 15: 8125-48 (1987), incorporated herein by reference in its entirety. Multiple stop codons can be incorporated.

[0431] As used herein, the term "cognitive testing" refers to a test that can be administered by a skilled professional to assess the cognitive abilities of humans and other animals. Cognitive testing can be used to assess inductive reasoning skills, IQ, cognitive development, memory, knowledge organization, metacognition, thinking, and mental time measurement. Cognitive testing can be used to assess a patient's performance across multiple cognitive domains, including, but not limited to, executive function, learning and memory, language, perceptual-motor function, and social cognition. Examples of cognitive tests include, but are not limited to, the Eight-item Informant Interview to Differentiate Aging and Dementia (AD8), Annual Wellness Visit (AWV), General Practitioner Assessment of Cognition (GPCOG), Health Risk Assessment (HRA), Memory Impairment Screen (MIS), Mini Mental Status Exam (MMSE), Montreal Cognitive Assessment (MoCA), St. Louis University Mental Status Exam (SLUMS), and Short Informant Questionnaire on Cognitive Decline in the Elderly (Short IQCODE). Those skilled in the art will recognize that other cognitive tests known in the art can also be used to assess cognitive function in patients.

[0432] As used herein, the term "complex attention" refers to a cognitive function that describes a patient's (e.g., a human patient's) ability to hold information in memory for short periods of time and manipulate that information (e.g., mental arithmetic). Dysfunctions in complex attention can result in difficulty concentrating on conversations, difficulty blocking out unwanted information, problems with prospective memory (e.g., remembering something for later), and inefficient memory for new information.

[0433] As used herein, the terms "conditioning" and "conditioning" refer to a process by which a patient is prepared to receive a graft containing a population of cells (e.g., a population of cells, such as CD34+ cells, hematopoietic stem cells, or myeloid progenitor cells). Such procedures promote engraftment of the cell graft, for example, by selectively depleting endogenous cells (e.g., endogenous CD34+ cells, hematopoietic stem cells, myeloid progenitor cells, or microglia, among others), thereby creating voids that are filled by the exogenous cell graft. According to the methods described herein, a patient can be pretreated for a cell transplant procedure by administering to the patient one or more agents capable of eliminating endogenous cells (e.g., CD34+ cells, hematopoietic stem cells, myeloid progenitor cells, or microglia, among others), endogenous microglia, and / or hematopoietic stem or progenitor cells, such as busulfan, treosulfan, PLX3397, PLX647, PLX5622, and clodronate liposomes, radiation therapy, or a combination thereof. Transplant conditioning treatments that can be used in conjunction with the compositions and methods of the present disclosure can be myeloablative or non-myeloablative. Other cell-depleting agents and methods known in the art (e.g., antibody-drug conjugates) can also be used.

[0434] As used herein, the terms "conservative mutation," "conservative substitution," "conservative amino acid substitution," and the like refer to the replacement of one or more amino acids with one or more different amino acids that exhibit similar physicochemical properties, such as polarity, electrostatic charge, and steric bulk, which are summarized in Table 5 below for each of the 20 naturally occurring amino acids. [Table 5]

[0435] It can be seen from this table that conservative amino acid families include: (i) G, A, V, L, and I; (ii) D and E; (iii) C, S, and T; (iv) H, K, and R; (v) N and Q; and (vi) F, Y, and W. Thus, a conservative variation or substitution is one that substitutes one amino acid for a member of the same amino acid family (e.g., Thr for Ser, Arg for Lys).

[0436] As used herein, the term "delirium or other psychiatric disorder" refers to a condition, such as delirium (i.e., a syndrome involving impairments in attention, consciousness, and cognition that develops over a short period of time (e.g., hours to days)) or another disorder of the mind (e.g., schizophrenia, bipolar disorder, and major depression), that is distinct from a neurocognitive disorder and does not exhibit cognitive impairment as a core symptom. For example, a condition, such as delirium or another psychiatric disorder, may differ from an NCD in that cognitive impairment may be a symptom associated with the disease but is not a core feature of the disease. Delirium or another psychiatric disorder may differ from an NCD in terms of time to onset (e.g., hours to days for delirium versus months to years for NCD), etiology (e.g., substance-induced delirium), duration of symptoms (e.g., delirium may last days to hours, while NCDs can last for years), and resolution (e.g., delirium may resolve completely, while NCDs often do not).

[0437] As used herein in the context of a gene of interest, the term "disrupt" refers to preventing the formation of a functional gene product. A gene product is considered functional in the present disclosure if it fulfills its normal (wild-type) function(s). Disruption of a gene prevents expression of a functional factor (e.g., protein) encoded by the gene and can be achieved, for example, by inserting, deleting, or substituting one or more bases in the sequence encoded by the gene and / or in the promoter and / or operator required for expression of the gene in the patient. A disrupted gene may be disrupted, for example, by removing at least a portion of the gene from the patient's genome, modifying the gene to prevent expression of the functional factor (e.g., protein) encoded by the gene, by interfering RNA, or by expression of a dominant-negative factor by an exogenous gene. Materials and methods for genetically modifying cells to disrupt expression of one or more genes are described in detail, for example, in US 8,518,701; US ​​9,499,808; and US 2012 / 0222143, the disclosures of each of which are incorporated herein by reference in their entirety (in case of conflict, the present specification takes precedence).

[0438] As used herein, when used in reference to a therapeutic composition, such as a composition, vector construct, viral vector, or cell described herein, the terms "effective amount," "therapeutically effective amount," and the like, refer to an amount sufficient to produce a beneficial or desired result, e.g., a clinical outcome, when administered to a patient, including a mammal, e.g., a human. For example, in the context of treating an NCD described herein, these terms refer to an amount of a composition sufficient to achieve a therapeutic response compared to the response obtained when the composition, vector construct, viral vector, or cell is not administered. The amount of a given composition described herein that corresponds to such an amount may vary depending on various factors, such as the given agent, pharmaceutical formulation, route of administration, type of disease or disorder, patient identity (e.g., age, sex, weight), or recipient being treated. An "effective amount," "therapeutically effective amount," and the like, of a composition, such as a vector construct, viral vector, or cell, of the present disclosure also includes an amount that produces a beneficial or desired result in a patient compared to a control.

[0439] As used herein, the terms "embryonic stem cell" and "ES cell" refer to embryo-derived, totipotent, or pluripotent stem cells derived from the inner cell mass of a blastocyst that can be maintained in in vitro culture under appropriate conditions. ES cells can differentiate into cells of any of the three vertebrate germ layers, e.g., endoderm, ectoderm, and mesoderm. ES cells are also characterized by their ability to proliferate indefinitely under appropriate in vitro culture conditions. ES cells are described, for example, in Thomson et al., Science 282:1145 (1998), the disclosure of which relates to the structure and functionality of embryonic stem cells and is incorporated herein by reference.

[0440] As used herein, the term "endogenous" describes a molecule (e.g., a polypeptide, nucleic acid, or cofactor) that is naturally found in a particular organism (e.g., a human) or in a particular location within an organism (e.g., an organ, tissue, or cell, such as a human cell).

[0441] As used herein, the terms "engraft" and "engraftment" refer to the process of repopulating tissues with hematopoietic stem and progenitor cells (such cells either produced endogenously within the body or transplanted using any of the administration methods described herein). The terms encompass all events relating to or leading to engraftment, such as tissue homing of cells and colonization of cells within a tissue of interest.

[0442] As used herein, the term "executive function" refers to a set of cognitive functions that facilitate cognitive control of behavior in a patient (e.g., a human). Executive functions include, for example, selection and monitoring of goal-directed behavior, attention control, cognitive inhibition, inhibitory control, working memory, and cognitive flexibility. While individuals normally acquire or perfect executive functions throughout life, this process can be derailed by the development of an NCD in a patient, which can adversely affect executive function.

[0443] As used herein, the term "express" refers to one or more of the following events: (1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of the RNA transcript (e.g., by splicing, editing, 5' capping, and / or 3' end processing); (3) translation of the RNA into a polypeptide or protein; and (4) post-translational modification of the polypeptide or protein. In the context of a gene encoding a protein product, terms such as "gene expression" are used interchangeably with terms such as "protein expression." Expression of a gene or protein of interest in a patient can be determined, for example, by detecting, in a sample obtained from the patient, an increase in the amount or concentration of mRNA encoding the corresponding protein (e.g., assessed using RNA detection procedures described herein or known in the art, such as quantitative polymerase chain reaction (qPCR) and RNA-seq techniques), an increase in the amount or concentration of the corresponding protein (e.g., assessed using protein detection methods described herein or known in the art, such as enzyme-linked immunosorbent assay (ELISA), among others), and / or an increase in the activity of the corresponding protein (e.g., in the case of an enzyme, assessed using enzyme activity assays described herein or known in the art). As used herein, a cell is deemed to "express" a gene or protein of interest if one or more, or all, of the above events can be detected in the cell or the medium in which the cell resides.For example, a gene or protein of interest is determined to be "expressed" by a cell or population of cells if it is possible to detect (i) production of a corresponding RNA transcript, e.g., an mRNA template, by the cell or population of cells (e.g., using the RNA detection procedures described herein); (ii) processing of the RNA transcript (e.g., splicing, editing, 5' cap formation, and / or 3' end processing, e.g., using the RNA detection procedures described herein); (iii) translation of the RNA template into a protein product (e.g., using the protein detection procedures described herein); and / or (iv) post-translational modification of the protein product (e.g., using the protein detection procedures described herein).

[0444] As used herein, the term "exogenous" describes a molecule (e.g., a polypeptide, nucleic acid, or cofactor) that is not naturally found in a particular organism (e.g., a human) or in a particular location within an organism (e.g., an organ, tissue, or cell, such as a human cell). Exogenous materials include those provided to an organism or culture extracted from an organism from an external source.

[0445] As used herein, the term "functional potential" in relation to cells such as hematopoietic stem cells refers to functional properties of stem cells, including: 1) pluripotency (referring to the ability to differentiate into multiple different blood cell lineages, including, but not limited to, granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), erythrocytes (e.g., reticulocytes, red blood cells), platelets (e.g., megakaryoblasts, platelet-producing megakaryocytes, platelets), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B cells, and T cells)); 2) self-renewal (referring to the ability of stem cells to give rise to daughter cells that have the same potential as the mother cell and that can arise repeatedly throughout an individual's lifetime without this potential being exhausted); and 3) the ability of stem cells or their progeny, when reintroduced into a transplant recipient, to home into the stem cell niche and re-establish productive, sustained cell growth and differentiation.

[0446] As used herein, the term "general population" refers to the entire population of individuals with particular characteristics of interest (e.g., age, medical history, education, socioeconomic status, or lifestyle, among others). Alternatively, the term "general population" can refer to a subset of the entire population of individuals with particular characteristics of interest, such as, for example, a random sample with a specified sample size. In the methods disclosed herein, the general population can serve as a practical standard (e.g., a reference population) against which measured variables can be compared. For example, patients diagnosed with a disorder can be evaluated for cognition using a cognitive test disclosed herein, and the scores obtained by the patients on the test can be compared with the performance of individuals in the general population (e.g., the entire general population or a random sample of the general population) on the same test. The size of the random sample of the general population can be determined by a skilled artisan using methods well known in the art. For example, a skilled artisan can perform a power analysis before collecting data (e.g., before administering a cognitive test to patients) to determine the minimum sample size required to detect a statistically significant effect with a desired level of confidence.

[0447] As used herein, the terms "hematopoietic stem cells" and "HSCs" refer to immature blood cells that have the ability to self-renew and differentiate into mature blood cells of various cell lineages, including, but not limited to, granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), erythrocytes (e.g., reticulocytes, red blood cells), platelets (e.g., megakaryoblasts, platelet-producing megakaryocytes, platelets), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B cells, and T cells). It is known in the art that such cells may or may not contain CD34+ cells. CD34+ cells are immature cells that express the CD34 cell surface marker. In humans, CD34+ cells are thought to include a subpopulation of cells with the stem cell properties defined above, while in mice, HSCs are CD34-. In addition, HSCs are also referred to as long-term repopulating HSCs (LT-HSCs) and short-term repopulating HSCs (ST-HSCs). LT-HSCs and ST-HSCs are distinguished based on functional potential and expression of cell surface markers. For example, human HSCs are CD34+, CD38-, CD45RA-, CD90+, CD49F+, and lin- (negative for mature cell lineage markers including CD2, CD3, CD4, CD7, CD8, CD10, CD11B, CD19, CD20, CD56, and CD235A). In mice, bone marrow LT-HSCs are CD34-, SCA-1+, C-kit+, CD135-, Slamf1 / CD150+, CD48-, and lin- (negative for mature lineage markers such as Ter119, CD11b, Gr1, CD3, CD4, CD8, B220, and IL-7ra), whereas ST-HSCs are CD34+, SCA-1+, C-kit+, CD135-, Slamf1 / CD150+, and lin- (negative for mature lineage markers including Ter119, CD11b, Gr1, CD3, CD4, CD8, B220, and IL-7ra). In addition, ST-HSCs are less quiescent (i.e., more active) and more proliferative than LT-HSCs under homeostatic conditions.However, LT-HSCs have a higher self-renewal capacity (i.e., they can survive throughout adulthood and be continuously transplanted through successive recipients), while ST-HSCs have a limited self-renewal capacity (i.e., they only survive for a limited period of time and do not have the ability to be continuously transplanted). Either of these HSCs can be used in any of the methods described herein. Optionally, ST-HSCs are useful because they are highly proliferative and can therefore generate differentiated progeny more quickly.

[0448] As used herein, the term "HLA-matched" refers to a donor-recipient pair in which there is no mismatch in any of the HLA antigens between the donor and recipient, such as a donor providing a hematopoietic stem cell graft to a recipient in need of hematopoietic stem cell transplantation therapy. HLA-matched (i.e., all six alleles matched) donor-recipient pairs have a lower risk of graft rejection because endogenous T cells and NK cells are less likely to recognize the foreign graft as foreign and therefore less likely to mount an immune response against the graft.

[0449] As used herein, the term "HLA-mismatched" refers to a donor-recipient pair in which at least one HLA antigen is mismatched between the donor and recipient, particularly with respect to HLA-A, HLA-B, HLA-C, and HLA-DR, such as a donor providing a hematopoietic stem cell graft to a recipient in need of hematopoietic stem cell transplantation therapy. In some embodiments, one haplotype is matched and the other is mismatched. HLA-mismatched donor-recipient pairs may be at higher risk of graft rejection compared to HLA-matched donor-recipient pairs because endogenous T cells and NK cells are more likely to recognize the foreign graft as foreign and, therefore, such T cells and NK cells are more likely to mount an immune response against the graft.

[0450] As used herein, the phrase "independence and / or normal daily functioning" refers to a patient's (e.g., human's) ability to successfully perform daily activities without the assistance of a caregiver or social worker. Non-limiting examples of activities that enable an individual to independently perform daily functions include, for example, social, occupational, or academic functioning, personal hygiene, grooming, dressing, toilet hygiene, functional mobility (e.g., the ability to walk, get in and out of bed), and self-feeding. Patients diagnosed with severe NCDs may have difficulty independently performing normal daily functions, while patients diagnosed with mild NCDs may not have difficulty independently performing normal daily functions.

[0451] As used herein, the terms "induced pluripotent stem cell," "iPS cell," and "iPSC" refer to pluripotent stem cells that can be derived directly from differentiated somatic cells. Human iPS cells can be generated by introducing a specific set of reprogramming factors into non-human cells, which may include, for example, Oct3 / 4, Sox family transcription factors (e.g., Sox1, Sox2, Sox3, Sox15), Myc family transcription factors (e.g., c-Myc, l-Myc, n-Myc), Krüppel-like family (KLF) transcription factors (e.g., KLF1, KLF2, KLF4, KLF5), and / or related transcription factors such as NANOG, LIN28, and / or Glis1. Human iPS cells can also be generated by, for example, the use of miRNAs, small molecules that mimic the action of transcription factors, or cell lineage specifiers. Human iPS cells are characterized by their ability to differentiate into cells of any of the three vertebrate germ layers, e.g., endoderm, ectoderm, or mesoderm. Human iPS cells are also characterized by their ability to proliferate indefinitely under appropriate in vitro culture conditions. Human iPS cells are described, for example, in Takahashi and Yamanaka, Cell 126:663 (2006), the disclosure of which is incorporated herein by reference as it relates to the structure and functionality of iPS cells.

[0452] As used herein, the term "IRES" refers to an internal ribosome entry site. Generally, the IRES sequence is a function that allows eukaryotic ribosomes to bind to mRNA transcripts and initiate translation without binding to the 5' cap end. The mRNA containing the IRES sequence generates two translation products, one of which starts from the 5' end of the mRNA, and the other from the internal translation mechanism mediated by the IRES.

[0453] As used herein, the phrase "learning and memory" refers to cognitive abilities that encompass the acquisition of skills or knowledge and the expression of acquired skills or knowledge (e.g., learning to say new words and speaking new words, respectively). "Learning and memory" can refer to two independent processes: 1) the acquisition of new skills or knowledge (i.e., learning); and 2) the processing, storage, and retrieval of learned skills or knowledge (i.e., memorization), which can differ in timescale (learning generally takes longer and requires more effort than memory retrieval or execution of learned skills) and neurobiological basis. Patients diagnosed with an NCD may have impaired learning and memory compared to healthy patients.

[0454] As used herein, the term "macrophage" refers to a type of white blood cell that engulfs and digests cellular debris, foreign substances, microorganisms, cancer cells, and anything else that does not have the types of proteins on its surface that are specific to healthy body cells, in a process called phagocytosis. Macrophages are found in essentially all tissues, where they patrol for potential pathogens using amoeboid movement. They take on various forms (variously named) throughout the body (e.g., histiocytes, Kupffer cells, alveolar macrophages, microglia, etc.), but all are part of the mononuclear phagocyte system. In addition to phagocytosis, they play an important role in nonspecific defense (innate immunity) and also help initiate specific defense mechanisms (adaptive immunity) by recruiting other immune cells, such as lymphocytes. For example, they are important as antigen presenters for T cells. In addition to increasing inflammation and stimulating the immune system, macrophages also play an important anti-inflammatory role and can dampen immune responses through the release of cytokines.

[0455] As used herein, the term "microglia" or "microglia" refers to a type of resident macrophage cell and glial cell found in the brain and spinal cord that serves as the mainstay of immune defense in the central nervous system. The primary functions of microglia include immunosurveillance, phagocytosis, extracellular signaling (e.g., production and release of cytokines, chemokines, prostaglandins, and reactive oxygen species), antigen presentation, and promoting tissue repair and regeneration.

[0456] As used herein, the term "microglial progenitor cells" refers to progenitor cells that give rise to microglial cells. Microglial progenitor cells arise in the yolk sac during a limited period of embryonic development, infiltrate the brain mesenchyme, and continuously renew themselves throughout life.

[0457] As used herein, the term "miRNA targeting sequence" refers to a nucleotide sequence located in the 3'-UTR of a target mRNA molecule that is hybridizable and complementary to a specific miRNA molecule (e.g., miR-126) and promotes RNA-induced silencing complex-dependent and Dicer-dependent mRNA destabilization and / or cleavage, thereby preventing expression of the mRNA transcript.

[0458] As used herein, the term "monocyte" refers to a type of white blood cell (i.e., leukocyte) that can differentiate into macrophages and myeloid-lineage dendritic cells. Monocytes constitute an important component of the vertebrate adaptive immune response. Three distinct types of monocytes are known to exist: classical monocytes (i.e., CD14++CD16-), characterized by strong expression of the CD14 cell surface receptor and no expression of CD16; non-classical monocytes (CD14+CD16++), which exhibit low levels of CD14 expression and co-expression of C16; and intermediate monocytes (CD14++CD16+), which exhibit high levels of CD14 expression and low levels of C16 expression. Monocytes perform a variety of functions that benefit the immune system, including phagocytosis, antigen presentation, and cytokine secretion.

[0459] As used herein, the term "pluripotent cell" refers to a cell that has the capacity to develop into multiple (e.g., 2, 3, 4, 5, or more) differentiated cell types, although not all. Non-limiting examples of pluripotent cells include cells of the hematopoietic lineage (e.g., granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), erythroid (e.g., reticulocytes, erythrocytes), platelets (e.g., megakaryoblasts, platelet-producing megakaryocytes, platelets), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B cells, and T cells). An example of a pluripotent cell is a CD34+ cell.

[0460] As used herein, the term "movement disorder" refers to a range of clinical disorders or conditions characterized by abnormal voluntary or involuntary muscle movements that are unrelated to muscle weakness, fatigue, or spasticity. Movement disorders may be accompanied by excessive movement (e.g., hyperkinetic movement disorders) or lack of movement (e.g., akinetic movement disorders). Non-limiting examples of symptoms associated with hyperkinetic movement disorders include dyskinesia. Examples of symptoms associated with akinetic movement disorders include akinesia, hypokinesia, bradykinesia, and rigidity. Movement disorders are often associated with disorders of the extrapyramidal motor control circuits of the basal ganglia and central nervous system. Non-limiting examples of movement disorders include parkinsonian disorders (e.g., Parkinson's disease, atypical parkinsonism, secondary parkinsonism, and functional parkinsonism), choreiform disorders, dystonic disorders, ataxic disorders, tremor-associated disorders, tic disorders, and myoclonic disorders.

[0461] As used herein, the term "mutation" refers to a change in the nucleotide sequence of a gene. Mutations in genes can occur naturally, for example, as a result of DNA replication errors, DNA repair, radiation, and exposure to carcinogens, or can be induced as a result of administering a transgene that expresses a mutated gene. A mutation may result in the substitution of a single amino acid in a peptide chain. An exemplary nomenclature used herein to describe mutations resulting from amino acid substitution uses the format "p.AnB," where "p" indicates a change at the protein level, "A" indicates the amino acid found in the wild-type variant of the protein, "n" indicates the number of the amino acid in the peptide chain, and "B" indicates the new amino acid resulting from the substitution. For example, a p.R47H mutation corresponds to a change in a given protein at amino acid 47, where arginine is replaced with histidine.

[0462] As used herein, the terms "myeloablative" or "bone marrow ablation" refer to conditioning regimens that substantially damage or destroy the hematopoietic system, typically by exposure to cytotoxic drugs (e.g., busulfan) or radiation. Myeloablative treatment includes complete bone marrow destruction brought about by high doses of cytotoxic agents or total body irradiation that destroy the hematopoietic system.

[0463] As used herein, the terms "non-myeloablative" or "myelosuppressive" refer to a conditioning regimen that does not eliminate substantially all hematopoietic cells of host origin.

[0464] As used herein, the term "neurocognitive disorder" or "NCD" refers to a group of clinical disorders or syndromes in which the primary clinical impairment is cognitive function, such as deficits in complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition. NCDs are characterized as acquired conditions, rather than developmental conditions. For example, NCDs are conditions in which disrupted cognition has not been evident since birth or very early childhood, thus requiring that cognitive function in NCDs decline from previously acquired levels. NCDs are distinguished from other disorders in which patients exhibit cognitive impairment, and NCDs include only disorders in which the core impairment is cognition. NCDs can be "severe NCDs" or "mild NCDs." Severe NCDs are characterized by significant cognitive decline that interferes with an individual's independence and / or normal daily functioning and is not due to delirium or other psychiatric disorders. Mild NCDs are characterized by moderate cognitive decline that does not interfere with an individual's independence and / or normal daily functioning and is not due to delirium or other psychiatric disorders. Severe and mild NCDs can also be distinguished based on quantitative cognitive testing of any one of the specific cognitive functions described above. For example, severe NCDs can be characterized by a score obtained on a cognitive test by a patient identified as having or at risk of developing an NCD that is more than two standard deviations away from the mean score of a reference population (e.g., the mean score of the general population) or that is in the third percentile of the distribution of scores in the reference population. Mild NCDs can be characterized by a score obtained on a cognitive test by a patient identified as having or at risk of developing an NCD that is one to two standard deviations away from the mean score of the reference population or that is between the third and sixteenth percentiles of the distribution of scores in the reference population. Non-limiting examples of cognitive tests that can be used to classify NCD patients as having either severe or mild NCD include the AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE. Additionally, NCD (e.g., severe or mild NCD) includes specific etiologies of NCD, such as Alzheimer's disease, Parkinson's disease, or frontotemporal lobar degeneration (FTLD).As used herein, the terms "NCD due to Alzheimer's disease," "NCD due to movement disorders," and "frontotemporal NCD" correspond to NCDs due to Alzheimer's disease, movement disorders (e.g., Parkinson's disease), and FTLD, respectively.

[0465] As used herein, the term "pluripotent cell" refers to a cell that has the potential to develop into more than one differentiated cell type, such as cell types of the hematopoietic lineage (e.g., granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), erythroid (e.g., reticulocytes, red blood cells), platelets (e.g., megakaryoblasts, platelet-producing megakaryocytes, platelets), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B cells, and T cells). Examples of pluripotent cells are ESCs and iPSCs.

[0466] As used herein, the term "plasmid" refers to an extrachromosomal circular double-stranded DNA molecule into which additional DNA segments can be ligated. A plasmid is a type of vector, a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. Certain plasmids are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial plasmids having a bacterial origin of replication and episomal mammalian plasmids). Other vectors (e.g., non-episomal mammalian vectors) may be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Certain plasmids are capable of directing the expression of genes to which they are operatively linked.

[0467] As used herein, the term "promoter" refers to a recognition site on DNA to which RNA polymerase binds. The polymerase drives transcription of the transgene. Exemplary promoters suitable for use in the compositions and methods described herein are described, for example, in Sandelin et al., Nature Reviews Genetics 8:424 (2007), the disclosure of which pertains to nucleic acid regulatory elements and is incorporated herein by reference. In addition, the term "promoter" can refer to synthetic promoters, which are regulatory DNA sequences that do not naturally occur in biological systems. Synthetic promoters contain portions of naturally occurring promoters in combination with non-naturally occurring polynucleotide sequences and can be optimized to express recombinant DNA using a variety of transgenes, vectors, and target cell types.

[0468] As used herein, a therapeutic agent is considered to be "provided" to a patient when the therapeutic agent is administered directly to the patient or when a substance that is processed or metabolized in vivo to endogenously produce the therapeutic agent is administered to the patient. For example, a protein (e.g., granulin) of the present disclosure can be provided to a patient, such as a patient with an NCD described herein, by directly administering the protein or by administering a substance (e.g., a progranulin gene or protein) that is processed or metabolized in vivo to endogenously produce the desired protein. Additional examples of "providing" a patient with a protein of interest include administering to the patient (i) a nucleic acid molecule encoding the protein of interest, (ii) a vector (e.g., a viral vector) containing such a nucleic acid molecule, (iii) a cell or population of cells containing such a vector or nucleic acid molecule, (iv) an interfering RNA molecule, such as an siRNA, shRNA, or miRNA molecule, that stimulates endogenous protein expression when administered to the patient, or (v) a protein precursor that is processed, for example, by one or more post-translational modifications to endogenously produce the desired protein.

[0469] "Percent sequence identity" with respect to a reference polynucleotide or polypeptide sequence is defined as the percentage of nucleic acids or amino acids in a candidate sequence that are identical to those in the reference polynucleotide or polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid and amino acid sequence identity can be accomplished in a variety of ways within the capabilities of those skilled in the art, for example, using publicly available computer software such as BLAST, BLAST-2, or Megalign software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms required to achieve maximum alignment over the entire length of the sequences being compared. For example, percent sequence identity values ​​can be generated using the sequence comparison computer program BLAST. As an example, the percent sequence identity of a given nucleic acid or amino acid sequence A to, with, or compared with a given nucleic acid or amino acid sequence B (alternatively, it can be expressed as a given nucleic acid or amino acid sequence A having a certain percent sequence identity to, with, or compared with a given nucleic acid or amino acid sequence B) is calculated as follows: Multiply by 100 (fraction X / Y) where X is the number of nucleotides or amino acids in a programmatic alignment of A and B that are scored as identical matches by a sequence alignment program (e.g., BLAST), and Y is the total number of nucleic acids in B. It will be understood that if the length of nucleic acid or amino acid sequence A is not equal to the length of nucleic acid or amino acid sequence B, then the percent sequence identity of A to B will not equal the percent sequence identity of B to A.

[0470] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable for contact with the tissues of a patient, such as a mammal (e.g., a human), without undue toxicity, irritation, allergic response, or other significant complication, commensurate with a reasonable benefit / risk ratio.

[0471] As used herein, an "ApoE-derived receptor-binding peptide (Rb)" is a portion of the ApoE protein that, when incorporated into a fusion protein, has the ability to translocate the protein across the blood-brain barrier (BBB) ​​to the brain. Thus, when engineered as a fusion construct, this method can function to selectively open the BBB to therapeutic agents (e.g., proteins described herein). Because such peptides utilize the Rb domain of ApoE rather than the entire ApoE protein, they can be readily conjugated to diagnostic or therapeutic agents without compromising or interfering with important biological functions of ApoE. An exemplary Rb domain that can be used in conjunction with the compositions and methods of the present disclosure is that found at the N-terminus of ApoE. For example, Rb domains useful in conjunction with the compositions and methods described herein include polypeptides having the amino acid sequence of residues 1-191 of SEQ ID NO:105, residues 25-185 of SEQ ID NO:105, residues 50-180 of SEQ ID NO:105, residues 75-175 of SEQ ID NO:105, residues 100-170 of SEQ ID NO:105, or residues 125-165 of SEQ ID NO:105, as well as polypeptides having at least one amino acid sequence similar to any of the foregoing sequences. and variants thereof, such as polypeptides having at least 70% sequence identity (e.g., at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity). An exemplary Rb domain useful in conjunction with the compositions and methods of the present disclosure is a region of ApoE having the amino acid sequence of residues 159-167 of SEQ ID NO: 105, as well as a domain having at least 70% sequence identity to this sequence (e.g., at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity).

[0472] As used herein, the term "regulatory sequence" includes promoters, enhancers, and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of antibody chain genes. Such regulatory sequences are described, for example, in Perdew et al., Regulation of Gene Expression (Humana Press, New York, NY, (2014)), which is incorporated herein by reference.

[0473] As used herein, the term "sample" refers to a specimen isolated from a patient (e.g., blood, blood components (e.g., serum or plasma), urine, saliva, amniotic fluid, cerebrospinal fluid, tissue (e.g., placenta or skin), pancreatic juice, chorionic villus samples, and cells).

[0474] As used herein, the term "signal peptide" refers to a short (usually 16-30 amino acids) peptide region that directs the translocation of a translated protein from the host cytoplasm to a lipid membrane for anchorage. Such signal peptides are generally positioned at the amino terminus of a newly translated protein. In some embodiments, the signal peptide is linked to the amino terminus. Typically, the signal peptide is cleaved during transit through the endoplasmic reticulum.

[0475] As used herein, the term "social cognition" refers to cognitive function encompassing a set of skills that determine how a patient (e.g., a human) processes, remembers, and adapts to information about other conspecific patients (e.g., other humans) and social situations. Non-limiting examples of social cognition include, for example, emotional responses to social stimuli, performance on theory-of-mind tasks, the ability to recognize faces, impulse control in social situations, and joint attention. Patients diagnosed with an NCD may exhibit impaired social cognition compared to healthy patients.

[0476] As used herein, the term "splice variant" refers to the transcription products (i.e., RNA) of a single gene that can be processed to produce different mRNA molecules as a result of the alternative inclusion or exclusion of specific exons (e.g., exon skipping) within the precursor mRNA. The proteins produced from translation of specific splice variants can differ in their structure and biological activity.

[0477] As used herein, the terms "stem cell" and "undifferentiated cell" refer to cells in an undifferentiated or partially differentiated state that have the developmental potential to differentiate into multiple cell types. Stem cells can proliferate to give rise to more such stem cells while maintaining their functional potential. Stem cells can divide asymmetrically, known as obligate asymmetric differentiation, in which one daughter cell retains the functional potential of the parent stem cell and the other daughter cell expresses a specific function, phenotype, and / or developmental potential that is somewhat different from that of the parent cell. The daughter cells themselves can be induced to proliferate while also retaining one or more cells with the developmental potential of the parent and to give rise to progeny that subsequently differentiate into one or more mature cell types. Differentiated cells may themselves be derived from pluripotent cells, such as from pluripotent cells. Alternatively, some stem cells in a population can divide symmetrically into two stem cells. Thus, the term "stem cell" refers to any subset of cells that, under certain circumstances, have the developmental potential to differentiate into a more specialized or differentiated phenotype and, under certain circumstances, retain the ability to proliferate without substantial differentiation. In some embodiments, the term stem cell generally refers to a naturally occurring parent cell whose descendants (progeny cells) specialize, often in different directions, by differentiation, acquiring entirely different characteristics, e.g., as occurs in the gradual diversification of embryonic cells and tissues. Some differentiated cells also have the ability to give rise to cells of greater developmental potential. Such ability may be natural or may be artificially induced by treatment with various factors. Cells that begin as stem cells can progress to a differentiated phenotype, but can also be "reverted" and then induced to re-express the stem cell phenotype, a term often referred to by those skilled in the art as "dedifferentiation" or "reprogramming" or "reverse differentiation."

[0478] As used herein, the term "transfection" refers to any of a wide variety of techniques commonly used to introduce exogenous DNA into prokaryotic or eukaryotic host cells, such as electroporation, lipofection, calcium phosphate precipitation, DEAE-dextran transfection, Nucleofection, squeeze-poration, sonoporation, optical transfection, Magnetofection, impalefection, etc.

[0479] As used herein, the term "transgene" refers to a recombinant nucleic acid (e.g., DNA or cDNA) that encodes a gene product (e.g., a gene product described herein). The gene product can be RNA, a peptide, or a protein. In addition to the coding region for the gene product, the transgene may include or be operably linked to one or more elements that facilitate or enhance expression, such as a promoter, enhancer(s), destabilization domain(s), response element(s), reporter element(s), insulator element(s), polyadenylation signal(s), and / or other functional elements. Embodiments of the present disclosure may utilize any known suitable promoter(s), enhancer(s), destabilization domain(s), response element(s), reporter element(s), insulator element(s), polyadenylation signal(s), and / or other functional elements.

[0480] As used herein, the terms "subject" or "patient" are used interchangeably and refer to a living organism (e.g., a mammal, such as a human) that has been diagnosed with and / or is being treated for a disease, such as an NCD described herein. For example, patients and subjects that can be treated using the compositions and methods of the present disclosure include those diagnosed with an NCD, as well as individuals at risk for developing one or more of these conditions. Diagnosis can be made by any method or technique known in the art. One of skill in the art will understand that patients to be treated in accordance with the present disclosure may have undergone standard testing or may have been identified as at risk by the presence of one or more risk factors associated with the disease or condition without testing.

[0481] As used herein in the context of multiple agents that perform a particular activity together or collectively, the terms "together" and "collectively" are used interchangeably to describe an event in which each agent individually may or may not achieve its intended function, but when combined, the agents achieve their intended function. By way of example, multiple nucleic acid molecules that encode a panel of proteins "together" or "collectively" may include constituent nucleic acid molecules that individually encode a single protein in the panel, but when combined, encode all of the proteins in the panel. Similarly, multiple agents that "together" or "collectively" increase the expression and / or activity of a panel of proteins may include constituent agents of the present disclosure, e.g., host cells, viral vectors, nucleic acid molecules, or small molecules, that individually increase the expression and / or activity of a single protein in the panel, but when combined, increase the expression and / or activity of all of the proteins in the panel.

[0482] As used herein, the terms "transduction" and "transducing" refer to the process of introducing a viral vector construct or a portion thereof into a cell and the subsequent expression in the cell of a transgene encoded by the vector construct or portion thereof.

[0483] As used herein, "treatment" or "treating" refers to an approach for obtaining beneficial or desired results, e.g., clinical results. Beneficial or desired results include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable; reduction in the extent of the disease or condition; stabilization of the disease, disorder, or condition status (i.e., not worsening); prevention of the progression of the disease or condition; delay or slowing of the progression of the disease or condition; improvement or palliation of the disease or condition; and remission (whether partial or complete). "Ameliorating" or "alleviating" a disease or condition means reducing the severity and / or undesirable clinical signs of the disease, disorder, or condition and / or slowing or prolonging the time course of progression compared to the severity or time course in the absence of treatment. "Treatment" can also mean prolonging survival compared to expected survival in the absence of treatment. Those in need of treatment include those already with the condition or disorder, as well as those susceptible to or at risk of developing the condition or disorder, or those in whom the condition or disorder is to be prevented.

[0484] As used herein in the context of cells, such as genetically modified cells (e.g., cells that have been transfected or transduced to express a desired gene or protein), the term "homogeneous population" refers to a homogeneous population that contains one or more proteins, e.g., APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, M a panel of proteins including one or more or all of S4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, and AP2A2 (e.g., PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, M a panel of proteins selected from S4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1), FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GB A panel of proteins including one or more, or all of: TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD (e.g., FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK,a panel of proteins including one or more or all of HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF; ... F), or a panel of proteins selected from APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1 , NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DN one or more of AJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT;"Homogeneous" refers to a population of cells, or their progeny, that have been modified ex vivo to contain nucleic acids encoding a panel of proteins, including, but not limited to, all of the desired proteins. For example, a population is considered to be a "homogeneous population" if at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or more (e.g., 100%) of the cells contain nucleic acids encoding the complete panel of desired proteins. Cells can be transfected to contain nucleic acids encoding the desired proteins using genetic engineering techniques described herein, including by viral transduction (e.g., using a Retroviridae virus, such as a lentivirus), as well as by cell transformation techniques including electroporation and calcium phosphate-mediated nucleic acid transfer, among other strategies described herein. Methods for determining transgene expression are described herein and known in the art, and include, for example, RNAseq and RT-PCR assays, which are used to quantify transgene expression at the RNA transcript level, and enzyme-linked immunosorbent assays (ELISAs), which are used to quantify transgene expression at the protein level.

[0485] As used herein in the context of cells, such as genetically modified cells (e.g., cells that have been transfected or transduced to express a desired gene or protein), the term "heterogeneous population" refers to a collection of cells, or their progeny, that have been modified ex vivo to collectively contain nucleic acids encoding one or more of a panel of proteins, such as the panel of proteins described above. A population is considered to be a "heterogeneous population" if it contains substantially no cells that individually contain nucleic acids encoding all of the proteins in the desired panel, but the cells combine to contain nucleic acids encoding all of the proteins in the desired panel. Methods for determining transgene expression are described herein and are known in the art, and include, for example, RNAseq and RT-PCT assays, which are used to quantify transgene expression at the RNA transcript level, and enzyme-linked immunosorbent assays (ELISAs), which are used to quantify transgene expression at the protein level.

[0486] As used herein, the term "vector" includes nucleic acid vectors, e.g., DNA vectors such as plasmids, RNA vectors, viruses, or other suitable replicons (e.g., viral vectors). Various vectors have been developed for delivering polynucleotides encoding exogenous proteins into prokaryotic or eukaryotic cells. Examples of such expression vectors are disclosed, for example, in WO 1994 / 011026, which is incorporated herein by reference, as it relates to vectors suitable for expressing genes of interest. Expression vectors suitable for use in the compositions and methods described herein contain polynucleotide sequences as well as additional sequence elements used, for example, for protein expression and / or integration of these polynucleotide sequences into the genome of mammalian cells. Vectors that can be used to express one or more proteins described herein include plasmids containing regulatory sequences that direct gene transcription, such as promoter and enhancer regions. In addition, vectors useful for expressing one or more proteins described herein may contain polynucleotide sequences that increase the translation rate of the corresponding gene(s) or improve the stability or nuclear export of mRNA resulting from gene transcription. Examples of such sequence elements include 5' and 3' untranslated regions, internal ribosome entry sites (IRES), and polyadenylation signal sites to direct efficient transcription of one or more genes carried by the expression vector. Expression vectors suitable for use in the compositions and methods described herein may also contain a polynucleotide encoding a marker for selecting cells containing such a vector. Examples of suitable markers are genes encoding resistance to antibiotics such as ampicillin, chloramphenicol, kanamycin, nourseothricin, or zeocin, among others.

[0487] As used herein, the terms "triggering receptor expressed on myeloid cells 2" and "TREM2" refer to a transmembrane glycoprotein that belongs to the immunoglobulin variable domain receptor family. Its gene is located on human chromosome 6p21.1. The terms "triggering receptor 2 expressed in myeloid cells" and "TREM2" also refer to splice variants resulting from alternative splicing of the TREM2 primary transcript, e.g., variant proteins having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or greater) to the amino acid sequence of the wild-type TREM2 peptide (e.g., SEQ ID NO: 103), or the wild-type TREM2 gene. "TREM2" refers to variants of wild-type TREM2 peptides and nucleic acids encoding same, including polynucleotides having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or greater) to the nucleic acid sequence (European Nucleotide Archive Reference Number (ENA) AF213457.1), provided that the encoded TREM2 isoform maintains the therapeutic function of wild-type TREM2. The terms "triggering receptor 2 expressed in myeloid cells" and "TREM2" can also refer to the TREM2 protein in which the native signal peptide is present. Furthermore, the terms "triggering receptor 2 expressed on myeloid cells" and "TREM2" can refer to all products of TREM2 proteolytic cleavage, including soluble TREM2 (sTREM2), TREM2 C-terminal fragment (CTF), TREM2 intracellular domain (TREM2-ICD), and TREM2-A β-like peptide (T2β).TREM2 cleavage occurs when the mature polypeptide translocates to the membrane after post-translational processing in the endoplasmic reticulum and is mediated by members of the disintegrin and metalloprotease (ADAM) family. The full-length TREM2 peptide is initially cleaved at the ectodomain to generate the extracellular sTREM2 peptide and the transmembrane TREM2-CTF, the latter of which can be further cleaved by the γ-secretase complex to generate the cytoplasmic TREM2-ICD and extracellular TREM-T2β peptide. The terms "triggering receptor 2 expressed in myeloid cells" and "TREM2" can refer to TREM2 proteins that do not contain a functional ectodomain cleavage site. The terms "triggering receptor 2 expressed in myeloid cells" and "TREM2" can also refer to TREM2 proteins that do not contain a functional intramembrane cleavage site within the TREM2-CTF. Additionally, the terms "triggering receptor 2 expressed on myeloid cells" and "TREM2" can refer to a "TREM2 fusion protein," which is a protein in which TREM2 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, "TREM2" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by those of skill in the art.

[0488] As used herein, the term "functional ectodomain cleavage site" when referring to a TREM2 ectodomain cleavage site refers to amino acid residues within the full-length TREM2 peptide that undergo proteolytic cleavage by an extracellular protease (e.g., a disintegrin and metalloprotease family) ectodomain to generate soluble TREM2 and even a TREM2 C-terminal fragment. For example, a TREM2 ectodomain cleavage site may be non-functional as a result of a mutation in the TREM2 gene that alters the amino acid sequence within the ectodomain cleavage site or affects the three-dimensional protein structure, such that the ectodomain cleavage site is sterically protected from proteolytic cleavage.

[0489] As used herein, the term "functional intramembrane cleavage site" when referring to a TREM2 C-terminal fragment intramembrane cleavage site refers to amino acid residues within the TREM2 C-terminal fragment that undergo proteolytic cleavage by the γ-secretase complex to generate the TREM2 intracellular domain and the TREM2-A β-like peptide. For example, the TREM2 C-terminal fragment intramembrane cleavage site may be non-functional as a result of a mutation in the TREM2 gene that alters the amino acid sequence within the intramembrane cleavage site or affects the three-dimensional protein structure, such that the intramembrane cleavage site is sterically protected from proteolytic cleavage.

[0490] As used herein, a patient suffering from "trigger receptor 2-expressed on myeloid cells-associated Alzheimer's disease (AD)" and "TREM2-associated Alzheimer's disease" is a patient who has been diagnosed with Alzheimer's disease and also contains a deleterious mutation in the endogenous TREM2 gene. More than 40 mutations have been reported in the human TREM2 gene, which have various effects on downstream signaling, trafficking, ligand binding, and cell surface expression. TREM2 mutations are discussed in Guerreiro et al., The New England Journal of Medicine 368:117-27 (2013); Jonsson et al., The New England Journal of Medicine 368:107-16 (2013); and Ulrich et al., Neuron Review 94:237-48 (2017), the disclosures of which are incorporated herein by reference as they relate to human TREM2 mutations in Alzheimer's disease.

[0491] As used herein, the terms "glucocerebrosidase" and "GBA" refer to the lysosomal enzyme responsible for the metabolism of glucocerebroside (also known as glucosylceramide) to glucose and ceramide. The gene is located on chromosome 1q21 and is also known as GBA1. The terms "glucocerebrosidase" and "GBA" refer to variants of the wild-type glucocerebrosidase enzyme and nucleic acids encoding same, e.g., variant proteins having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or greater) to the amino acid sequence of the wild-type GBA enzyme (e.g., SEQ ID NO: 104) or the wild-type GBA gene (e.g., ENA "GBA" also refers to a polynucleotide having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or greater) to the nucleic acid sequence of SEQ ID NO: 16328.1, provided that the encoded GBA analog maintains the therapeutic function of wild-type GBA. "GBA" can also refer to a GBA protein in which the native signal peptide is present. Alternatively, "GBA" can refer to a GBA protein in which the native signal peptide has been removed (e.g., the mature protein). GBA can also refer to the catalytic domain of GBA or a variant having at least 70% sequence identity to such domain (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or higher).In addition, the terms "glucocerebrosidase" and "GBA" can also refer to a "GBA fusion protein," which is a protein in which GBA is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, GBA can also refer to the lysosomal enzyme or the gene encoding this protein, as appropriate, as will be understood by those of skill in the art.

[0492] As used herein, a patient suffering from "GBA-associated Parkinson's disease" or "GBA-associated PD" is one who has been diagnosed with Parkinson's disease and also has a deleterious mutation in the GBA gene. Severe pathogenic mutations include c.84GGIns, IVS2+1G>A, p.V394L, p.D409H, p.L444P, and RecTL, which are associated with odds ratios of 9.92 to 21.29 for developing PD. Mild GBA mutations p.N370S and p.R496H are associated with odds ratios of 2.84 to 4.94 for developing PD. Mutation p.E326K has also been identified as a PD risk factor. GBA mutations are discussed in Barkhuizen et al., Neurochemistry International 93:6 (2016) and Sidransky and Lopez, Lancet Neurol. 11:986 (2012), the disclosures of which relate to human GBA mutations and are incorporated herein by reference.

[0493] As used herein, the terms "granulin" and "GRN" refer to peptide products resulting from cleavage of the precursor protein PGRN. GRN peptides are involved in a variety of biological functions, including development, immunity, cell survival and proliferation, and tumorigenesis. The full-length wild-type human PGRN peptide has 7.5 GRN domains (e.g., seven GRN domains, each approximately 60 amino acids long) and a 30-amino acid paragranulin (para-GRN) domain that can be individually cleaved by proteases. The terms "granulin" and "GRN" also refer to variants of wild-type human granulin peptide and nucleic acids encoding same, e.g., variant proteins having at least 70% sequence identity (e.g., at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or greater) to any of the amino acid sequences of the wild-type GRN peptide (e.g., SEQ ID NO: 106), provided that the encoded GRN variant maintains the therapeutic function of the wild-type GRN. The terms "granulin" and "GRN" can also refer to GRN proteins in which the native secretory signal peptide is present. Additionally, the terms "granulin" and "GRN" can refer to a "GRN fusion protein," which is a protein in which GRN is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "GRN" can refer to the protein or the gene encoding the protein, as appropriate, as will be understood by those of skill in the art.

[0494] As used herein, the terms "progranulin" and "PGRN" refer to the secreted trophic factor and precursor peptide for granulin. The gene is located on chromosome 17q21.31 and is also known as granulin precursor, proepithelin, PEPI, PC cell-derived growth factor, granulin-epithelin, CLN11, PCDFGF, GP88, GEP, granulin, and acrogranin. The terms "progranulin" and "PGRN" refer to variants of wild-type human PGRN peptide and nucleic acids encoding same, e.g., variants having at least 70% sequence identity (e.g., at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or higher) to the amino acid sequence of the wild-type PGRN peptide. The term "PGRN variant" also refers to a protein or polynucleotide having at least 70% sequence identity (e.g., at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or higher) to the nucleic acid sequence of the wild-type PGRN gene, provided that the encoded PGRN variant maintains the therapeutic function of wild-type PGRN. The terms "Progranulin" and "PGRN" can also refer to variants of PGRN having two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) granulin (GRN) domains. The terms "Progranulin" and "PGRN" can also refer to variants of PGRN having 2 to 16 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) GRN domains. The terms "Progranulin" and "PGRN" can also refer to the PGRN protein in which the native secretory signal peptide is present.In addition, the terms "progranulin" and "PGRN" can refer to a "PGRN fusion protein," which is a protein in which PGRN is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "PGRN" can refer to the protein or the gene encoding the protein, as appropriate, as will be understood by one of skill in the art.

[0495] As used herein, the terms "frontotemporal lobar degeneration" and "FTLD" refer to a complex clinical syndrome characterized by degeneration of brain tissue within the frontal and temporal lobes of the cerebral cortex. The terms "frontotemporal lobar degeneration" and "FTLD" can refer to any one of three clinically distinct variants of FTLD, including: 1) behavioral variant frontotemporal dementia (BVFTD), characterized by behavioral and personality changes, apathy, social withdrawal, perseverative behavior, attention deficits, loss of inhibition, and significant degeneration of the frontal lobe. In addition, BVFTD has a strong relationship with amyotrophic lateral sclerosis; 2) semantic dementia (SD), characterized by verbal amnesic aphasia, progressive loss of semantic knowledge of words, objects, and concepts, and significant degeneration of the anterior temporal lobe. Furthermore, the SD variant of FTLD exhibits flat affect, social deficits, perseverative behavior, and loss of inhibition; 3) progressive nonverbal aphasia (PNA) is characterized by motor impairments in speech production, reduced language expression, and significant degeneration of the perisylvian cortex. The histopathological profile of FTLD patients generally falls into one of three broad phenotypes, including those showing aggregation and deposition of (i) microtubule-associated tau protein inclusions; (ii) tau-negative, ubiquitin- and TAR DNA-binding protein 43 (TDP-43)-positive protein inclusions; or (iii) ubiquitin- and sarcoma fusion (FUS)-positive protein inclusions. A comprehensive description of the clinical symptoms and histopathology of FTLD is provided in Rabinovici and Miller, CNS Drugs 24:375-398 (2010), the disclosure of which is incorporated herein by reference in its entirety.

[0496] As used herein, patients suffering from "progranulin-associated FTLD" and "PGRN-associated FTLD" are patients who have been diagnosed with FTLD and also contain a deleterious mutation in the PGRN gene. More than 70 pathogenic mutations have been reported in the PGRN gene, the majority of which result in a premature stop codon and nonsense-mediated decay of truncated PGRN mRNA. PGRN mutations are described in Gijselinck et al., Human Mutation 29:1373-1386 (2012) and Pottier et al., Journal of Neurochemistry. 138:32-53 (2016), the disclosures of which relate to human PGRN mutations and are incorporated herein by reference.

[0497] As used herein, the term "APP" refers to the gene encoding the amyloid-beta A4 protein or the corresponding protein product. The terms "APP" and "amyloid-beta A4 protein" include wild-type forms of the APP gene or protein, as well as variants of the wild-type APP protein and the nucleic acid encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). Examples of such variants are proteins having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or higher) to any of the amino acid sequences of the wild-type APP protein (e.g., SEQ ID NO: 1), provided that the APP variant maintains the therapeutic function of wild-type APP. In addition, the terms "APP" and "amyloid-beta A4 protein" can also refer to an "APP fusion protein," which is a protein in which APP is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "APP" can refer to the protein or the gene encoding the protein, as appropriate, as will be understood by those of skill in the art.

[0498] As used herein, the term "PSEN1" refers to the gene encoding presenilin-1 or the corresponding protein product. The terms "PSEN1" and "presenilin-1" include wild-type forms of the PSEN1 gene or protein, as well as variants of the wild-type PSEN1 protein and nucleic acids encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). Examples of such variants are proteins having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type PSEN1 protein (e.g., SEQ ID NO: 2), provided that the PSEN1 variant maintains the therapeutic function of wild-type PSEN1. In addition, the terms "PSEN1" and "presenilin-1" can also refer to a "PSEN1 fusion protein," which is a protein in which PSEN1 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "PSEN1" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by one of skill in the art.

[0499] As used herein, the term "PSEN2" refers to the gene encoding presenilin-2 or the corresponding protein product. The terms "PSEN2" and "presenilin-2" include wild-type forms of the PSEN2 gene or protein, as well as variants of the wild-type PSEN2 protein and nucleic acids encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). Examples of such variants are proteins having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type PSEN2 protein (e.g., SEQ ID NO: 3), provided that the PSEN2 variant maintains the therapeutic function of wild-type PSEN2. In addition, the terms "PSEN2" and "presenilin-2" can also refer to a "PSEN2 fusion protein," which is a protein in which PSE21 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "PSEN2" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by one of skill in the art.

[0500] As used herein, the term "TOMM40" refers to a gene encoding a mitochondrial import receptor subunit TOM40 homolog, or the corresponding protein product. The terms "TOMM40" and "mitochondrial import receptor subunit TOM40 homolog" include wild-type forms of the TOMM40 gene or protein, as well as variants of the wild-type TOMM40 protein and nucleic acids encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). An example of such a variant is a protein having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or greater) to any of the amino acid sequences of the wild-type TOMM40 protein (e.g., SEQ ID NO: 4), provided that the TOMM40 variant maintains the therapeutic function of wild-type TOMM40. In addition, the terms "TOMM40" and "mitochondrial import receptor subunit TOM40 homolog" can also refer to a "TOMM40 fusion protein," which is a protein in which TOMM40 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "TOMM40" can refer to the protein or the gene encoding the protein, as appropriate, as will be understood by one of skill in the art.

[0501] As used herein, the term "GAB2" refers to the gene encoding GRB2-related binding protein 2 or the corresponding protein product. The terms "GAB2" and "GRB2-related binding protein 2" include wild-type forms of the GAB2 gene or protein, as well as variants of the wild-type GAB2 protein and the nucleic acid encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). An example of such a variant is a protein having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type GAB2 protein (e.g., SEQ ID NO: 5), provided that the GAB2 variant maintains the therapeutic function of wild-type GAB2. In addition, the terms "GAB2" and "GRB2-related binding protein 2" can also refer to a "GAB2 fusion protein," which is a protein in which GAB2 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "GAB2" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by one of skill in the art.

[0502] As used herein, the term "APOC1" refers to the gene encoding apolipoprotein C-1 or the corresponding protein product. The terms "APOC1" and "apolipoprotein C-1" include wild-type forms of the APOC1 gene or protein, as well as variants of the wild-type APOC1 protein and nucleic acids encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). An example of such a variant is a protein having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type APOC1 protein (e.g., SEQ ID NO: 6), provided that the APOC1 variant maintains the therapeutic function of wild-type APOC1. In addition, the terms "APOC1" and "apolipoprotein C-1" can also refer to an "APOC1 fusion protein," which is a protein in which APOC1 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "APOC1" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by one of skill in the art.

[0503] As used herein, the term "ABI3" refers to the gene encoding ABI gene family member 3 or the corresponding protein product. The terms "ABI3" and "ABI gene family member 3" include wild-type forms of the ABI3 gene or protein, as well as variants of the wild-type ABI3 protein and the nucleic acid encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). An example of such a variant is a protein having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type ABI3 protein (e.g., SEQ ID NO: 7), provided that the ABI3 variant maintains the therapeutic function of wild-type ABI3. In addition, the terms "ABI3" and "ABI gene family member 3" can also refer to an "ABI3 fusion protein," which is a protein in which ABI3 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "ABI3" can refer to either the protein or the gene encoding this protein, as appropriate, as will be understood by one of skill in the art.

[0504] As used herein, the term "BIN1" refers to the gene encoding myc-box-dependent interacting protein 1 or the corresponding protein product. The terms "BIN1" and "myc-box-dependent interacting protein 1" include wild-type forms of the BIN1 gene or protein, as well as variants of the wild-type BIN1 protein and nucleic acids encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). An example of such a variant is a protein having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type BIN1 protein (e.g., SEQ ID NO: 8), provided that the BIN1 variant maintains the therapeutic function of wild-type BIN1. In addition, the terms "BIN1" and "myc-box-dependent interacting protein 1" can also refer to a "BIN1 fusion protein," which is a protein in which BIN1 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "BIN1" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by those of skill in the art.

[0505] As used herein, the term "CR1" refers to the gene encoding complement receptor type 1 or the corresponding protein product. The terms "CR1" and "complement receptor type 1" include wild-type forms of the CR1 gene or protein, as well as variants of the wild-type CR1 protein and the nucleic acid encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). An example of such a variant is a protein having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type CR1 protein (e.g., SEQ ID NO: 9), provided that the CR1 variant maintains the therapeutic function of wild-type CR1. In addition, the terms "CR1" and "complement receptor type 1" can also refer to a "CR1 fusion protein," which is a protein in which CR1 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "CR1" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by one of skill in the art.

[0506] As used herein, the term "ABCA7" refers to the gene encoding ATP-binding cassette subfamily A member 7 or the corresponding protein product. The terms "ABCA7" and "ATP-binding cassette subfamily A member 7" include wild-type forms of the ABCA7 gene or protein, as well as variants of the wild-type CR1 protein and nucleic acids encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). An example of such a variant is a protein having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type ABCA7 protein (e.g., SEQ ID NO: 10), provided that the ABCA7 variant maintains the therapeutic function of wild-type ABCA7. In addition, the terms "ABCA7" and "ATP-binding cassette subfamily A member 7" can also refer to an "ABCA7 fusion protein," which is a protein in which ABCA7 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "ABCA7" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by those of skill in the art.

[0507] As used herein, the term "FERMT2" refers to the gene encoding Fermitin Family Homolog 2 or the corresponding protein product. The terms "FERMT2" and "Fermitin Family Homolog 2" include wild-type forms of the FERMT2 gene or protein, as well as variants of the wild-type FERMT2 protein and the nucleic acid encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). An example of such a variant is a protein having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or higher) to any of the amino acid sequences of the wild-type FERMT2 protein (e.g., SEQ ID NO: 11), provided that the FERMT2 variant maintains the therapeutic function of wild-type FERMT2. In addition, the terms "FERMT2" and "Fermitin family homolog 2" can also refer to a "FERMT2 fusion protein," which is a protein in which FERMT2 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "FERMT2" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by one of skill in the art.

[0508] As used herein, the term "HLA-DRB5" refers to the gene encoding the HLA class II histocompatibility antigen, DR beta 5 chain, or the corresponding protein product. The terms "HLA-DRB5" and "HLA class II histocompatibility antigen, DR beta 5 chain" include wild-type forms of the HLA-DRB5 gene or protein, as well as variants of the wild-type HLA-DRB5 protein and the nucleic acid encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). An example of such a variant is a protein having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type HLA-DRB5 protein (e.g., SEQ ID NO: 12), provided that the HLA-DRB5 variant maintains the therapeutic function of wild-type HLA-DRB5. In addition, the terms "HLA-DRB5" and "HLA class II histocompatibility antigen, DR beta 5 chain" can also refer to an "HLA-DRB5 fusion protein," which is a protein in which HLA-DRB5 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "HLA-DRB5" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by those skilled in the art.

[0509] As used herein, the term "HLA-DRB1" refers to the gene encoding the HLA class II histocompatibility antigen, DR beta 1 chain, or the corresponding protein product. The terms "HLA-DRB1" and "HLA class II histocompatibility antigen, DR beta 1 chain" include wild-type forms of the HLA-DRB1 gene or protein, as well as variants of the wild-type HLA-DRB1 protein and the nucleic acid encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). An example of such a variant is a protein having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type HLA-DRB1 protein (e.g., SEQ ID NO: 13), provided that the HLA-DRB1 variant maintains the therapeutic function of wild-type HLA-DRB1. In addition, the terms "HLA-DRB1" and "HLA class II histocompatibility antigen, DR beta 1 chain" can also refer to an "HLA-DRB1 fusion protein," which is a protein in which HLA-DRB1 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "HLA-DRB1" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by those skilled in the art.

[0510] As used herein, the term "CD2AP" refers to a gene encoding a CD2-related protein or the corresponding protein product. The terms "CD2AP" and "CD2-related protein" include wild-type forms of the CD2AP gene or protein, as well as variants of the wild-type CD2AP protein and the nucleic acid encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). Examples of such variants are proteins having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type CD2AP protein (e.g., SEQ ID NO: 14), provided that the CD2AP variant maintains the therapeutic function of wild-type CD2AP. In addition, the terms "CD2AP" and "CD2-related protein" can also refer to a "CD2AP fusion protein," which is a protein in which CD2AP is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "CD2AP" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by one of skill in the art.

[0511] As used herein, the term "PTK2B" refers to the gene encoding protein-tyrosine kinase 2-beta or the corresponding protein product. The terms "PTK2B" and "protein-tyrosine kinase 2-beta" include wild-type forms of the PTK2B gene or protein, as well as variants of the wild-type PTK2B protein and the nucleic acid encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). An example of such a variant is a protein having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or greater) to any of the amino acid sequences of the wild-type PTK2B protein (e.g., SEQ ID NO: 15), provided that the PTK2B variant maintains the therapeutic function of wild-type PTK2B. In addition, the terms "PTK2B" and "protein-tyrosine kinase 2-beta" can also refer to a "PTK2B fusion protein," which is a protein in which PTK2B is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "PTK2B" can refer to either the protein or the gene encoding this protein, as appropriate, as will be understood by one of skill in the art.

[0512] As used herein, the term "CELF1" refers to the gene encoding CUGBP Elav-like family member 1 or the corresponding protein product. The terms "CELF1" and "CUGBP Elav-like family member 1" include wild-type forms of the CELF1 gene or protein, as well as variants of the wild-type CELF1 protein and nucleic acids encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). An example of such a variant is a protein having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of a wild-type CELF1 protein (e.g., SEQ ID NO: 16), provided that the CELF1 variant maintains the therapeutic function of wild-type CELF1. In addition, the terms "CELF1" and "CUGBP Elav-like family member 1" can also refer to a "CELF1 fusion protein," which is a protein in which CELF1 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "CELF1" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by one of skill in the art.

[0513] As used herein, the term "INPP5D" refers to the gene encoding phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1, or the corresponding protein product. The terms "INPP5D" and "phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1" include wild-type forms of the INPP5D gene or protein, as well as variants of the wild-type INPP5D protein and nucleic acids encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). Examples of such variants are proteins having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type INPP5D protein (e.g., SEQ ID NO: 17), provided that the INPP5D variant maintains the therapeutic function of wild-type INPP5D. Additionally, "INPP5D" and "phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1" can also refer to the term "INPP5D fusion protein," which is a protein in which INPP5D is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "INPP5D" can refer to either the protein or the gene encoding this protein, as appropriate, as will be understood by those of skill in the art.

[0514] As used herein, the term "MEF2C" refers to the gene encoding muscle cell-specific enhancer factor 2C or the corresponding protein product. The terms "MEF2C" and "muscle cell-specific enhancer factor 2C" include wild-type forms of the MEF2C gene or protein, as well as variants of the wild-type MEF2C protein and nucleic acids encoding same (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). Examples of such variants are proteins having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type MEF2C protein (e.g., SEQ ID NO: 18), provided that the MEF2C variant maintains the therapeutic function of wild-type MEF2C. In addition, the terms "MEF2C" and "myocyte-specific enhancer factor 2C" can also refer to a "MEF2C fusion protein," which is a protein in which MEF2C is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having an amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "MEF2C" can refer to the protein or the gene encoding the protein, as appropriate, as will be understood by one of skill in the art.

[0515] As used herein, the term "ZCWPW1" refers to a gene encoding zinc finger CW-type PWWP domain protein 1 or the corresponding protein product. The terms "ZCWPW1" and "zinc finger CW-type PWWP domain protein 1" include wild-type forms of the ZCWPW1 gene or protein, as well as variants of the wild-type ZCWPW1 protein and nucleic acids encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). Examples of such variants are proteins having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type ZCWPW1 protein (e.g., SEQ ID NO: 19), provided that the ZCWPW1 variant maintains the therapeutic function of wild-type ZCWPW1. In addition, the terms "ZCWPW1" and "zinc finger CW-type PWWP domain protein 1" can also refer to a "ZCWPW1 fusion protein," which is a protein in which ZCWPW1 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "ZCWPW1" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by one of skill in the art.

[0516] As used herein, the term "CD33" refers to the gene encoding the myeloid cell surface antigen CD33 or the corresponding protein product. The terms "CD33" and "myeloid cell surface antigen CD33" include wild-type forms of the CD33 gene or protein, as well as variants of the wild-type CD33 protein and the nucleic acid encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). Examples of such variants are proteins having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type CD33 protein (e.g., SEQ ID NO: 20), provided that the CD33 variant maintains the therapeutic function of wild-type CD33. In addition, the terms "CD33" and "myeloid cell surface antigen CD33" can also refer to a "CD33 fusion protein," which is a protein in which CD33 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "CD33" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by one of skill in the art.

[0517] As used herein, the term "MS4A4A" refers to the gene encoding transmembrane 4-domain subfamily A member 4A or the corresponding protein product. The terms "MS4A4A" and "transmembrane 4-domain subfamily A member 4A" include wild-type forms of the MS4A4A gene or protein, as well as variants of the wild-type MS4A4A protein and nucleic acids encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). An example of such a variant is a protein having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type MS4A4A protein (e.g., SEQ ID NO: 21), provided that the MS4A4A variant maintains the therapeutic function of wild-type MS4A4A. In addition, the terms "MS4A4A" and "transmembrane 4-domain subfamily A member 4A" can also refer to an "MS4A4A fusion protein," which is a protein in which MS4A4A is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, "MS4A4A" can also refer to the protein or the gene encoding this protein, as appropriate, as will be understood by those of skill in the art.

[0518] As used herein, the term "RIN3" refers to the gene encoding Ras and Rab interactor 3 or the corresponding protein product. The terms "RIN3" and "Ras and Rab interactor 3" include wild-type forms of the RIN3 gene or protein, as well as variants of the wild-type RIN3 protein and the nucleic acid encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). An example of such a variant is a protein having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type RIN3 protein (e.g., SEQ ID NO: 22), provided that the RIN3 variant maintains the therapeutic function of wild-type RIN3. In addition, the terms "RIN3" and "Ras and Rab interactor 3" can also refer to a "RIN3 fusion protein," which is a protein in which RIN3 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "RIN3" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by one of skill in the art.

[0519] As used herein, the term "EPHA1" refers to the gene encoding Ephrin type-A receptor 1 or the corresponding protein product. The terms "EPHA1" and "Ephrin type-A receptor 1" include wild-type forms of the EPHA1 gene or protein, as well as variants of the wild-type EPHA1 protein and the nucleic acid encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). Examples of such variants are proteins having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type EPHA1 protein (e.g., SEQ ID NO: 23), provided that the EPHA1 variant maintains the therapeutic function of wild-type EPHA1. In addition, the terms "EPHA1" and "Ephrin type-A receptor 1" can also refer to an "EPHA1 fusion protein," which is a protein in which EPHA1 is operably linked to another polypeptide, half-life-modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "EPHA1" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by those of skill in the art.

[0520] As used herein, the term "PICALM" refers to a gene encoding a phosphatidylinositol-linked clathrin assembly protein or the corresponding protein product. The terms "PICALM" and "phosphatidylinositol-linked clathrin assembly protein" include wild-type forms of the PICALM gene or protein, as well as variants of the wild-type PICALM protein and the nucleic acid encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). An example of such a variant is a protein having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type PICALM protein (e.g., SEQ ID NO: 24), provided that the PICALM variant maintains the therapeutic function of wild-type PICALM. In addition, the terms "PICALM" and "phosphatidylinositol-linked clathrin assembly protein" can also refer to a "PICALM fusion protein," which is a protein in which PICALM is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "PICALM" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by one of skill in the art.

[0521] As used herein, the term "CASS4" refers to the gene encoding Cas scaffold protein family member 4 or the corresponding protein product. The terms "CASS4" and "Cas scaffold protein family member 4" include wild-type forms of the CASS4 gene or protein, as well as variants of the wild-type CASS4 protein and nucleic acids encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). Examples of such variants are proteins having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type CASS4 protein (e.g., SEQ ID NO: 25), provided that the CASS4 variant maintains the therapeutic function of wild-type CASS4. In addition, the terms "CASS4" and "Cas scaffold protein family member 4" can also refer to a "CASS4 fusion protein," which is a protein in which CASS4 is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "CASS4" can refer to the protein or the gene encoding this protein, as appropriate, as will be understood by those of skill in the art.

[0522] As used herein, the term "CLU" refers to the gene encoding clusterin or the corresponding protein product. The terms "CLU" and "clusterin" include wild-type forms of the CLU gene or protein, as well as variants of the wild-type CLU protein and the nucleic acid encoding it (e.g., splice variants, truncations, concatemers, and fusion constructs, among others). Examples of such variants are proteins having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity or more) to any of the amino acid sequences of the wild-type CLU protein (e.g., SEQ ID NO: 26), provided that the CLU variant maintains the therapeutic function of wild-type CLU. In addition, the terms "CLU" and "clusterin" can also refer to a "CLU fusion protein," which is a protein in which CLU is operably linked to another polypeptide, half-life modifying agent, or therapeutic agent, such as an ApoE Rb domain (e.g., an Rb domain having the amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO: 105). As used herein, the term "CLU" can refer to either the protein or the gene encoding this protein, as appropria...

Claims

1. 2. A method of treating a patient diagnosed with a neurocognitive disorder (NCD), comprising administering to the patient a combination of APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, E The method comprises supplying one or more agents that collectively increase the expression and / or activity of two or more proteins selected from PHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, and AP2A2.

2. 2. The method of claim 1, wherein the protein is selected from PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1, and optionally wherein the protein comprises a panel set forth in Table 1.

3. 2. A method of treating a patient diagnosed with an NCD, comprising administering to the patient: FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK 1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD.

4. 4. The method of claim 3, wherein said protein is selected from FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2, and optionally said protein comprises the panel set out in Table 2.

5. 1. A method of treating a patient diagnosed with an NCD comprising providing to the patient one or more agents that collectively increase expression and / or activity of two or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.

6. 6. The method of claim 5, wherein the protein is selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF, and optionally the protein comprises the panel set forth in Table 3.

7. 2. A method of treating a patient diagnosed with an NCD, comprising administering to the patient an antibody to one or more of the following: APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCG R2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIP A1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, D NAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, The method comprises providing one or more agents that collectively increase the expression and / or activity of two or more proteins selected from NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.

8. The method according to any one of claims 1 to 7, wherein the NCD is a severe NCD.

9. 10. The method of claim 8, wherein the severe NCD interferes with the patient's independence and / or normal daily functioning.

10. 10. The method of claim 8 or 9, wherein said severe NCD is associated with a score obtained by said patient on a cognitive test that is at least 2 standard deviations away from the mean score of a reference population.

11. The method of any one of claims 1 to 7, wherein the NCD is a mild NCD.

12. 12. The method of claim 11, wherein the mild NCD does not interfere with the patient's independence and / or normal daily functioning.

13. 13. The method of claim 11 or 12, wherein said mild NCD is associated with a score obtained by said patient on a cognitive test that is 1-2 standard deviations away from the mean score of a reference population.

14. The method of claim 10 or 13, wherein the reference population is the general population.

15. 15. The method of claim 10, 13, or 14, wherein the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE.

16. 16. The method of any one of claims 1-15, wherein the NCD is associated with impairment in one or more of complex attention, executive function, learning and memory, language, sensorimotor function, and social cognition.

17. 17. The method of any one of claims 1 to 16, wherein the NCD is not due to delirium or other psychiatric disorder.

18. 10. The method of any one of claims 1, 2 or 7, wherein the NCD is Alzheimer's disease.

19. 10. The method of any one of claims 3, 4, or 7, wherein the NCD is a movement disorder.

20. 19. The method of claim 18, wherein the movement disorder is Parkinson's disease.

21. The method of any one of claims 5 to 7, wherein the NCD is a frontotemporal NCD.

22. 22. The method of claim 21, wherein the frontotemporal NCD is frontotemporal lobar degeneration (FTLD).

23. 23. The method of claim 22, wherein the FTLD is behavioral abnormality frontotemporal dementia.

24. 23. The method of claim 22, wherein the FTLD is semantic dementia.

25. 23. The method of claim 22, wherein the FTLD is progressive non-verbal aphasia.

26. 26. The method of any one of claims 1 to 25, wherein said one or more agents collectively increase the expression and / or activity of three or more of said proteins, optionally said one or more agents collectively increase the expression and / or activity of four or more of said proteins, or optionally said one or more agents collectively increase the expression and / or activity of five or more of said proteins.

27. 19. The method of any one of claims 1, 2, or 7-18, wherein said one or more agents collectively increase the expression and / or activity of 5 to 20 of said proteins, optionally said one or more agents collectively increase the expression and / or activity of 8 to 18 of said proteins, or optionally said one or more agents collectively increase the expression and / or activity of 10 to 15 of said proteins.

28. 21. The method of any one of claims 3, 4, 7-17, 19, or 20, wherein said one or more agents collectively increase the expression and / or activity of 3 to 10 of said proteins, optionally said one or more agents collectively increase the expression and / or activity of 4 to 8 of said proteins, or optionally said one or more agents collectively increase the expression and / or activity of 5 to 7 of said proteins.

29. 26. The method of any one of claims 5-17, or 21-25, wherein said one or more agents collectively increase the expression and / or activity of 2 to 7 of said proteins, optionally said one or more agents collectively increase the expression and / or activity of 3 to 6 of said proteins, or optionally said one or more agents collectively increase the expression and / or activity of 4 or 5 of said proteins.

30. 30. The method of any one of claims 1 to 29, wherein the one or more agents comprise: (i) one or more nucleic acid molecules that collectively encode the two or more proteins; (ii) one or more interfering RNA molecules that collectively increase the expression and / or activity of the two or more proteins; (iii) one or more nucleic acid molecules encoding the one or more interfering RNA molecules; (iv) two or more of the proteins; and / or (v) one or more small molecules that collectively increase the expression and / or activity of the two or more proteins.

31. 30. The method of claim 29, wherein the one or more interfering RNA molecules comprise short interfering RNA (siRNA), short hairpin RNA (shRNA), and / or microRNA (miRNA).

32. 32. The method of any one of claims 1 to 31, wherein said one or more agents comprise one or more nucleic acid molecules that collectively encode said two or more proteins, optionally said one or more nucleic acid molecules collectively encode three or more of said proteins, optionally said one or more nucleic acid molecules collectively encode four or more of said proteins, or optionally said one or more nucleic acid molecules collectively encode five or more of said proteins.

33. 19. The method of any one of claims 1, 2, or 7-18, wherein said one or more agents comprise one or more nucleic acid molecules that collectively encode between 5 and 20 of said proteins, optionally said one or more nucleic acid molecules collectively encode between 8 and 18 of said proteins, or optionally said one or more nucleic acid molecules collectively encode between 10 and 15 of said proteins.

34. 21. The method of any one of claims 3, 4, 7-17, 19, or 20, wherein the one or more agents comprise one or more nucleic acid molecules that collectively encode between 3 and 10 of the proteins, optionally wherein the one or more nucleic acid molecules collectively encode between 4 and 8 of the proteins, optionally wherein the one or more nucleic acid molecules collectively encode between 5 and 7 of the proteins.

35. 26. The method of any one of claims 5-17, or 21-25, wherein said one or more agents comprise one or more nucleic acid molecules that collectively encode from 2 to 7 of said proteins, optionally said one or more nucleic acid molecules collectively encode from 3 to 6 of said proteins, optionally said one or more nucleic acid molecules collectively encode 4 or 5 of said proteins.

36. 36. The method of any one of claims 32 to 35, wherein the one or more nucleic acid molecules are provided to the patient by administering to the patient a composition comprising a population of cells which together comprise a nucleic acid encoding the protein.

37. 37. The method of claim 36, wherein the population is a homogenous population of cells that contain a nucleic acid encoding the protein or a heterogenous population of cells that together contain a nucleic acid encoding the protein.

38. 38. The method of claim 36 or 37, wherein the cell is a pluripotent or multipotent cell.

39. 39. The method of claim 38, wherein the pluripotent cells are CD34+ cells.

40. 40. The method of claim 39, wherein the CD34+ cells are HSCs or MPCs.

41. 39. The method of claim 38, wherein the pluripotent cells are ESCs or iPSCs.

42. 38. The method of claim 36 or 37, wherein the cell is a BLPC, a microglial progenitor cell, a monocyte, a macrophage, or a microglia.

43. 43. The method of claim 42, wherein the BLPCs are monocytes.

44. 44. The method of any one of claims 1-43, wherein the composition is administered to the subject by systemic administration, by direct administration to the subject's central nervous system, by direct administration to the subject's bone marrow, or by bone marrow transplantation comprising the composition.

45. The method of any one of claims 36 to 44, wherein the cells are autologous or allogeneic cells.

46. The method of any one of claims 36 to 45, wherein the cells are transfected or transduced ex vivo to express the protein.

47. 47. The method of claim 46, wherein the cells are transduced with a viral vector selected from the group consisting of adeno-associated virus (AAV), adenovirus, parvovirus, coronavirus, rhabdovirus, paramyxovirus, picornavirus, alphavirus, herpesvirus, poxvirus, and retroviridae viruses.

48. 47. The method of claim 46, wherein the cells are transfected using: a) an agent selected from the group consisting of cationic polymers, diethylaminoethyl-dextran, polyethyleneimine, cationic lipids, liposomes, calcium phosphate, activated dendrimers, and magnetic beads; or b) a technique selected from the group consisting of electroporation, Nucleofection, squeeze-poration, sonoporation, optical transfection, Magnetofection, and impalefection.

49. 36. The method of any one of claims 30 to 35, wherein the one or more nucleic acid molecules are provided to the patient by administering to the patient one or more viral vectors that together comprise the one or more nucleic acid molecules.

50. 50. The method of claim 49, wherein the patient is administered multiple viral vectors that together comprise the one or more nucleic acid molecules.

51. 50. The method of claim 49, wherein the patient is administered multiple viral vectors each individually comprising the one or more nucleic acid molecules.

52. 52. The method of any one of claims 49 to 51, wherein the one or more viral vectors are administered to the patient systemically or directly to the patient's central nervous system.

53. The method according to any one of claims 47 to 52, wherein the viral vector is a retroviridae viral vector.

54. 54. The method of claim 53, wherein the Retroviridae viral vector is a lentiviral vector, an alpharetroviral vector, or a gammaretroviral vector.

55. 55. The method of any one of claims 53 or 54, wherein the Retroviridae viral vector comprises a central polypurine tract, a woodchuck hepatitis virus post-transcriptional regulatory element, a 5'-LTR, an HIV signal sequence, an HIV Psi signal 5'-splice site, a delta-GAG element, a 3'-splice site, and a 3'-self-inactivating LTR.

56. 53. The method of any one of claims 47 to 52, wherein the viral vector is an AAV selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, and AAVrh74.

57. The method of any one of claims 47 to 56, wherein the viral vector is a pseudotyped viral vector.

58. 58. The method of claim 57, wherein the pseudotyped viral vector is selected from the group consisting of pseudotyped AAV, pseudotyped adenovirus, pseudotyped parvovirus, pseudotyped coronavirus, pseudotyped rhabdovirus, pseudotyped paramyxovirus, pseudotyped picornavirus, pseudotyped alphavirus, pseudotyped herpesvirus, pseudotyped poxvirus, and pseudotyped Retroviridae viruses.

59. 59. The method of any one of claims 30-58, wherein one or more of the nucleic acid molecules comprises a transgene encoding one or more of the proteins operably linked to a ubiquitous promoter, a cell lineage specific promoter, or a synthetic promoter.

60. 60. The method of claim 59, wherein the ubiquitous promoter is selected from the group consisting of elongation factor 1-alpha promoter and phosphoglycerate kinase 1 promoter.

61. 60. The method of claim 59, wherein the cell lineage specific promoter is selected from the group consisting of PGRN promoter, CD11b promoter, CD68 promoter, C-X3-C motif chemokine receptor 1 promoter, allograft inflammatory factor 1 promoter, purinergic receptor P2Y12 promoter, transmembrane protein 119 promoter, and colony stimulating factor 1 receptor promoter.

62. 62. The method of any one of claims 32-61, wherein one or more of the proteins further comprises the receptor binding (Rb) domain of apolipoprotein E (ApoE).

63. 63. The method of claim 62, wherein the Rb domain comprises a portion of ApoE having an amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO:

105.

64. The method of claim 62 or 63, wherein the Rb domain comprises a region having at least 70% sequence identity to the amino acid sequence of residues 159-167 of SEQ ID NO:

105.

65. 65. The method of any one of claims 30 to 64, wherein the one or more nucleic acid molecules comprise a microRNA (miRNA)-126 (miR-126) targeting sequence in the 3'-UTR.

66. 66. The method of any one of claims 30-65, wherein said protein penetrates the blood-brain barrier of said patient upon delivery of said one or more nucleic acid molecules to said patient.

67. 67. The method of any one of claims 30 to 66, wherein the endogenous microglia population is depleted in the patient prior to providing the one or more nucleic acid molecules to the patient.

68. 68. The method of any one of claims 30 to 67, comprising removing a population of endogenous microglia in said patient prior to providing said one or more nucleic acid molecules to said patient.

69. 69. The method of claim 67 or 68, wherein the microglia are ablated using an agent selected from the group consisting of busulfan, PLX3397, PLX647, PLX5622, treosulfan, and clodronate liposomes; by radiation therapy, or a combination thereof.

70. 70. The method of any one of claims 30-69, wherein endogenous expression of one or more of said proteins is disrupted in said cells, in said patient, or in a population of neurons in said patient prior to providing said one or more nucleic acid molecules to said patient.

71. 71. The method of claim 70, wherein the endogenous expression is disrupted by contacting the cell with a nuclease that catalyzes cleavage of an endogenous gene encoding one of the proteins.

72. 72. The method of claim 71, wherein the nuclease is a CRISPR-associated protein 9 (Cas9), a CRISPR-associated protein 12a (Cas12a), a transcription activator-like effector nuclease, a meganuclease, or a zinc finger nuclease.

73. 73. The method of any one of claims 70-72, wherein endogenous expression of one or more of said proteins is disrupted by administering an inhibitory RNA molecule to said cell, said patient, or said population of neurons.

74. The method of claim 73, wherein the inhibitory RNA molecule is an siRNA, shRNA, or miRNA.

75. APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB 5, HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, C A pharmaceutical composition comprising a population of cells that together contain nucleic acids encoding two or more proteins selected from ASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, and AP2A2.

76. 76. The pharmaceutical composition of claim 75, wherein the protein is selected from PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1.

77. FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP2 5, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, B A pharmaceutical composition comprising a population of cells that together contain nucleic acids encoding two or more proteins selected from CKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD.

78. 78. The pharmaceutical composition of claim 77, wherein the protein is selected from FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2.

79. A pharmaceutical composition comprising a population of cells that together contain nucleic acids encoding two or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.

80. 80. The pharmaceutical composition of claim 79, wherein the protein is selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF.

81. APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP , PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD 4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, SCAF11, HLA-D QB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC 1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJ C6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, ST 1. A pharmaceutical composition comprising a population of cells comprising, together, nucleic acids encoding two or more proteins selected from X1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.

82. 82. The pharmaceutical composition of any one of claims 75-81, wherein the cell comprises nucleic acids encoding three or more of said proteins together, optionally wherein the cell comprises nucleic acids encoding four or more of said proteins together, or optionally wherein the cell comprises nucleic acids encoding five or more of said proteins together.

83. 77. The pharmaceutical composition of claim 75 or 76, wherein the cells together comprise nucleic acids encoding from 5 to 20 of said proteins, optionally wherein the cells together comprise nucleic acids encoding from 8 to 18 of said proteins, or optionally wherein the cells together comprise nucleic acids encoding from 10 to 15 of said proteins.

84. 79. The pharmaceutical composition of claim 77 or 78, wherein the cells together comprise nucleic acids encoding 3 to 10 of the proteins, optionally the cells together comprise nucleic acids encoding 4 to 8 of the proteins, or optionally the cells together comprise nucleic acids encoding 5 to 7 of the proteins.

85. 81. The pharmaceutical composition of claim 79 or 80, wherein the cell comprises nucleic acids encoding from 2 to 7 of the proteins together, optionally the cell comprises nucleic acids encoding from 3 to 6 of the proteins together, optionally the cell comprises nucleic acids encoding 4 or 5 of the proteins together.

86. 86. The pharmaceutical composition of any one of claims 75 to 85, wherein the population is a homogenous population of cells or a heterogenous population of cells that comprises a nucleic acid encoding the protein.

87. The composition of any one of claims 75 to 86, wherein the cell is a pluripotent or multipotent cell.

88. The composition of claim 87, wherein the pluripotent cells are CD34+ cells.

89. The composition of claim 88, wherein the CD34+ cells are HSCs or MPCs.

90. 88. The composition of claim 87, wherein the pluripotent cells are ESCs or iPSCs.

91. The composition of any one of claims 75 to 86, wherein the cell is a BLPC, a microglial progenitor cell, a macrophage, or a microglia.

92. 92. The composition of claim 91, wherein the BLPC is a monocyte.

93. The pharmaceutical composition of any one of claims 75 to 92, wherein the cells are autologous or allogeneic cells.

94. 94. The pharmaceutical composition of any one of claims 75-93, wherein the cells comprise a transgene encoding one or more of said proteins operably linked to a ubiquitous promoter, a cell lineage-specific promoter, or a synthetic promoter.

95. 95. The pharmaceutical composition of claim 94, wherein the ubiquitous promoter is selected from the group consisting of elongation factor 1-alpha promoter and phosphoglycerate kinase 1 promoter.

96. 95. The pharmaceutical composition of claim 94, wherein the cell lineage specific promoter is selected from the group consisting of PGRN promoter, CD11b promoter, CD68 promoter, C-X3-C motif chemokine receptor 1 promoter, allograft inflammatory factor 1 promoter, purinergic receptor P2Y12 promoter, transmembrane protein 119 promoter, and colony stimulating factor 1 receptor promoter.

97. 97. The pharmaceutical composition of any one of claims 75 to 96, wherein one or more of said proteins further comprises the Rb domain of ApoE.

98. 98. The pharmaceutical composition of claim 97, wherein the Rb domain comprises a portion of ApoE having an amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO:

105.

99. The pharmaceutical composition of claim 97 or 98, wherein the Rb domain comprises a region having at least 70% sequence identity to the amino acid sequence of residues 159-167 of SEQ ID NO:

105.

100. APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5 , HLA-DRB1, CD2AP, PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CA A pharmaceutical composition comprising a population of viral vectors that together encode two or more proteins selected from SS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, and AP2A2.

101. 101. The pharmaceutical composition of claim 100, wherein the protein is selected from PSEN1, GAB2, APOC1, TREM2, ABI3, BIN1, HLA-DRB5, HLA-DRB1, CD2AP, PTK2B, INPP5D, MEF2C, CD33, MS4A4A, RIN3, PICALM, CASS4, SORL1, PLCG2, SCIMP, FRMD4A, SPPL2A, MTHFD1L, DISC1, TRIP4, and HS3ST1.

102. FCGR2A, SCAF11, HLA-DQB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP2 5, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, B A pharmaceutical composition comprising a population of viral vectors that together encode two or more proteins selected from CKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, and ACMSD.

103. 103. The pharmaceutical composition of claim 102, wherein the protein is selected from FCGR2A, SCAF11, DNAJC13, GCH1, LRRK2, GBA, GAK, FGF20, HLA-DQB1, and NOD2.

104. A pharmaceutical composition comprising a population of viral vectors that together encode two or more proteins selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.

105. The pharmaceutical composition of claim 104, wherein the protein is selected from HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TBK1, PSEN1, GRN, and CTSF.

106. APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP , PTK2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD 4A, SPPL2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, SCAF11, HLA-D QB1, NOD2, VPS1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC 1, SYNJ1, LRRK2, SNCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJ C6, SMPD1, TMEM175, STK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, ST 1. A pharmaceutical composition comprising a population of viral vectors which together encode two or more proteins selected from X1B, NUCKS1, ACMSD, HLA-DRA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT.

107. 107. The pharmaceutical composition of any one of claims 100-106, wherein the viral vector encodes three or more of the proteins together, optionally wherein the viral vector encodes four or more of the proteins together, optionally wherein the viral vector encodes five or more of the proteins together.

108. 107. The pharmaceutical composition of claim 100, 101 or 106, wherein the viral vector together encodes between 5 and 20 of the proteins, optionally wherein the viral vector together encodes between 8 and 18 of the proteins, optionally wherein the viral vector together encodes between 10 and 15 of the proteins.

109. 107. The pharmaceutical composition of claim 102, 103, or 106, wherein the viral vector encodes between 3 and 10 of the proteins together, optionally wherein the viral vector encodes between 4 and 8 of the proteins together, optionally wherein the viral vector encodes between 5 and 7 of the proteins together.

110. 107. The pharmaceutical composition of claim 104, 105, or 106, wherein the viral vector encodes between 2 and 7 of the proteins together, optionally wherein the viral vector encodes between 3 and 6 of the proteins together, optionally wherein the viral vector encodes 4 or 5 of the proteins together.

111. The pharmaceutical composition of any one of claims 100 to 110, wherein the viral vector comprises AAV, adenovirus, parvovirus, coronavirus, rhabdovirus, paramyxovirus, picornavirus, alphavirus, herpesvirus, poxvirus, and retroviridae virus.

112. The pharmaceutical composition of claim 111, wherein the viral vector is a retroviridae viral vector.

113. The composition of claim 112, wherein the Retroviridae viral vector is a lentiviral vector, an alpharetroviral vector, or a gammaretroviral vector.

114. The pharmaceutical composition of any one of claims 111 to 113, wherein the Retroviridae viral vector comprises a central polypurine tract, a woodchuck hepatitis virus post-transcriptional regulatory element, a 5'-LTR, an HIV signal sequence, an HIV Psi signal 5'-splice site, a delta-GAG element, a 3'-splice site, and a 3'-self-inactivating LTR.

115. The pharmaceutical composition of claim 111, wherein the viral vector is an AAV selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, and AAVrh74.

116. The pharmaceutical composition of any one of claims 100 to 115, wherein the viral vector is a pseudotyped viral vector.

117. The pharmaceutical composition of claim 116, wherein the pseudotyped viral vector is selected from the group consisting of pseudotyped AAV, pseudotyped adenovirus, pseudotyped parvovirus, pseudotyped coronavirus, pseudotyped rhabdovirus, pseudotyped paramyxovirus, pseudotyped picornavirus, pseudotyped alphavirus, pseudotyped herpesvirus, pseudotyped poxvirus, and pseudotyped retroviridae virus.

118. 118. The pharmaceutical composition of any one of claims 100-117, wherein one or more of said cellular viral vectors comprises a transgene encoding one or more of said proteins operably linked to a ubiquitous promoter, a cell lineage-specific promoter, or a synthetic promoter.

119. The pharmaceutical composition of claim 118, wherein the ubiquitous promoter is selected from the group consisting of elongation factor 1-alpha promoter and phosphoglycerate kinase 1 promoter.

120. The pharmaceutical composition of claim 118, wherein the cell lineage specific promoter is selected from the group consisting of PGRN promoter, CD11b promoter, CD68 promoter, C-X3-C motif chemokine receptor 1 promoter, allograft inflammatory factor 1 promoter, purinergic receptor P2Y12 promoter, transmembrane protein 119 promoter, and colony stimulating factor 1 receptor promoter.

121. 121. The pharmaceutical composition of any one of claims 100-120, wherein one or more of said proteins further comprises the Rb domain of ApoE.

122. 122. The pharmaceutical composition of claim 121, wherein the Rb domain comprises a portion of ApoE having an amino acid sequence of residues 25-185, 50-180, 75-175, 100-170, 125-160, or 130-150 of SEQ ID NO:

105.

123. The pharmaceutical composition of claim 121 or 122, wherein the Rb domain comprises a region having at least 70% sequence identity to the amino acid sequence of residues 159-167 of SEQ ID NO:

105.

124. The pharmaceutical composition of any one of claims 100 to 123, wherein one or more of said viral vectors comprises a transgene encoding one or more of said proteins, said transgene further encoding a miR-126 targeting sequence in the 3'-UTR.

125. 130. A kit comprising the pharmaceutical composition of any one of claims 100, 101, 108, or 111-124, further comprising a package insert instructing a user of the kit to administer the pharmaceutical composition to a human patient having an NCD.

126. 15. A kit comprising the pharmaceutical composition of any one of claims 102, 103, 109, or 111-124, further comprising a package insert instructing a user of the kit to administer the pharmaceutical composition to a human patient having an NCD.

127. 130. A kit comprising the pharmaceutical composition of any one of claims 104, 105, 111, or 111-124, further comprising a package insert instructing a user of the kit to administer the pharmaceutical composition to a human patient having an NCD.

128. APP, PSEN1, PSEN2, APOE, TOMM40, GAB2, APOC1, TREM2, ABI3, BIN1, CR1, ABCA7, FERMT2, HLA-DRB5, HLA-DRB1, CD2AP, PT K2B, CELF1, INPP5D, MEF2C, ZCWPW1, CD33, MS4A4A, RIN3, EPHA1, PICALM, CASS4, CLU, SORL1, PLCG2, SCIMP, FRMD4A, SPPL 2A, MTHFD1L, STK24, DISC1, MPZL1, SLC4A1AP, TRIP4, MSRA, HS3ST1, ZNF224, AP2A2, FCGR2A, SCAF11, HLA-DQB1, NOD2, VP S1, SCARB2, GPNMB, VPS35, FBXO7, PARK7, INPP5F, DNAJC13, GCH1, NMD3, USP25, RAB7L1, SIPA1L2, MCCC1, SYNJ1, LRRK2, S NCA, PTRHD1, PINK1, GBA, TMEM163, GAK, FGF20, DLG2, DDRGK1, SREBF, BCKDK, PARK2, RAB39B, DNAJC6, SMPD1, TMEM175, S TK39, BST1, MMP16, RIT2, FAM47E, CCDC62, TMEM229B, MAPT, SPPL2B, ITGA8, ATP13A2, DGKQ, STX1B, NUCKS1, ACMSD, HLA-D RA, HLA-DRB5, C9ORF72, SQSTM1, TARDBP, TBK1, VCP, PSEN1, FUS, CHMP2B, UBQLN2, CHCHD10, GRN, RAB38, CTSF, PSEN2, CYP27A1, BTNL2, and MAPT, and a package insert instructing a user of the kit to administer the pharmaceutical composition to a human patient having an NCD.

129. The kit of any one of claims 125 to 128, wherein the NCD is a severe NCD.

130. The kit of claim 129, wherein the severe NCD interferes with a patient's independence and / or normal daily functioning.

131. 131. The kit of claim 129 or 130, wherein the severe NCD is associated with a score obtained by the patient on a cognitive test that is at least 2 standard deviations away from the mean score of a reference population.

132. The kit of any one of claims 125 to 128, wherein the NCD is a mild NCD.

133. The kit of claim 132, wherein the mild NCD does not interfere with a patient's independence and / or normal daily functioning.

134. The kit of claim 132 or 133, wherein the mild NCD is associated with a score obtained by the patient on a cognitive test that is at least 1-2 standard deviations away from the mean score of a reference population.

135. 135. The kit of claim 131 or 134, wherein the reference population is the general population.

136. 136. The kit of claim 131, 134, or 135, wherein the cognitive test is selected from the group consisting of AD8, AWV, GPCOG, HRA, MIS, MMSE, MoCA, SLUMS, and Short IQCODE.

137. The kit of claim 125 or 128, wherein the NCD is Alzheimer's disease.

138. The kit of claim 126 or 128, wherein the NCD is a movement disorder.

139. 139. The kit of claim 138, wherein the movement disorder is Parkinson's disease.

140. 129. The kit of claim 127 or 128, wherein the NCD is a frontotemporal NCD.

141. 141. The kit of claim 140, wherein the frontotemporal NCD is FTLD.

142. The kit of claim 141, wherein the FTLD is frontotemporal dementia.

143. The kit of claim 141, wherein the FTLD is semantic dementia.

144. 142. The kit of claim 141, wherein the FTLD is progressive non-verbal aphasia.

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