Myeloid neoplasm with histiocytosis and spleen tyrosine kinase fusion responds to fostamatinib.

Not available.

Friendship Bench Intervention to Address Depression and Improve HIV Care Engagement Among Adolescents Living with HIV in Malawi: Study Protocol for a Pilot Randomized Controlled Trial.

Background: Adolescents in Sub-Saharan Africa are disproportionately affected by the HIV epidemic. Comorbid depression is prevalent among adolescents living with HIV (ALWH) and poses numerous challenges to HIV care engagement and retainment. We present a pilot trial designed to investigate feasibility, fidelity, and acceptability of an adapted and an enhanced Friendship Bench intervention (henceforth: AFB and EFB) in reducing depression and improving engagement in HIV care among ALWH in Malawi. Methods: Design:: Participants will be randomized to one of three conditions: the Friendship Bench intervention adapted for ALWH (AFB, n=35), the Friendship Bench intervention enhanced with peer support (EFB, n=35), or standard of care (SOC, n=35). Recruitment is planned for early 2024 in four clinics in Malawi.Participants:: Eligibility criteria (1) aged 13-19; (2) diagnosed with HIV (vertically or horizontally); (3) scored ≥ 13 on the self-reported Beck's Depression Inventory (BDI-II); (4) living in the clinic's catchment area with intention to remain for at least 1 year; and (5) willing to provide informed consent.Interventions:: AFB includes 6 counseling sessions facilitated by young, trained non-professional counselors. EFB consists of AFB plus integration of peer support group sessions to facilitate engagement in HIV care. SOC for mental health in public facilities in Malawi includes options for basic supportive counseling, medication, referral to mental health clinics or psychiatric units at tertiary care hospitals for more severe cases.Outcomes:: The primary outcomes are feasibility, acceptability, and fidelity of the AFB and EFB assessed at 6 months and 12 months and compared across 3 arms. The secondary outcome is to assess preliminary effectiveness of the interventions in reducing depressive symptoms and improving HIV viral suppression at 6 months and 12 months. Discussion: This pilot study will provide insights into youth-friendly adaptations of the Friendship Bench model for ALWH in Malawi and the value of adding group peer support for HIV care engagement. The information gathered in this study will lead to a R01 application to test our adapted intervention in a large-scale cluster randomized controlled trial to improve depression and engagement in HIV care among ALWH.

Phase separation of polyubiquitinated proteins in UBQLN2 condensates controls substrate fate.

Ubiquitination is one of the most common post-translational modifications in eukaryotic cells. Depending on the architecture of polyubiquitin chains, substrate proteins can meet different cellular fates, but our understanding of how chain linkage controls protein fate remains limited. UBL-UBA shuttle proteins, such as UBQLN2, bind to ubiquitinated proteins and to the proteasome or other protein quality control machinery elements and play a role in substrate fate determination. Under physiological conditions, UBQLN2 forms biomolecular condensates through phase separation, a physicochemical phenomenon in which multivalent interactions drive the formation of a macromolecule-rich dense phase. Ubiquitin and polyubiquitin chains modulate UBQLN2's phase separation in a linkage-dependent manner, suggesting a possible link to substrate fate determination, but polyubiquitinated substrates have not been examined directly. Using sedimentation assays and microscopy we show that polyubiquitinated substrates induce UBQLN2 phase separation and incorporate into the resulting condensates. This substrate effect is strongest with K63-linked substrates, intermediate with mixed-linkage substrates, and weakest with K48-linked substrates. Proteasomes can be recruited to these condensates, but proteasome activity towards K63-linked and mixed linkage substrates is inhibited in condensates. Substrates are also protected from deubiquitinases by UBQLN2-induced phase separation. Our results imply that phase separation can act as a regulatory switch that controls the fate of ubiquitinated substrates in a chain-linkage dependent manner, thus serving as an interpreter of the ubiquitin code.

Pathogenic mutations in UBQLN2 exhibit diverse aggregation propensity and neurotoxicity.

The ubiquitin-adaptor protein UBQLN2 promotes degradation of several aggregate-prone proteins implicated in neurodegenerative diseases. Missense UBQLN2 mutations also cause X-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previously we demonstrated that the liquid-like properties of UBQLN2 molecular assemblies are altered by a specific pathogenic mutation, P506T, and that the propensity of UBQLN2 to aggregate correlated with neurotoxicity. Here, we systematically assess the effects of multiple, spatially distinct ALS/FTD-linked missense mutations on UBQLN2 aggregation propensity, neurotoxicity, phase separation, and autophagic flux. In contrast to what we observed for the P506T mutation, no other tested pathogenic mutant exhibited a clear correlation between aggregation propensity and neurotoxicity. These results emphasize the unique nature of pathogenic UBQLN2 mutations and argue against a generalizable link between aggregation propensity and neurodegeneration in UBQLN2-linked ALS/FTD.

Neurodesk: an accessible, flexible and portable data analysis environment for reproducible neuroimaging.

Neuroimaging research requires purpose-built analysis software, which is challenging to install and may produce different results across computing environments. The community-oriented, open-source Neurodesk platform ( https://www.neurodesk.org/ ) harnesses a comprehensive and growing suite of neuroimaging software containers. Neurodesk includes a browser-accessible virtual desktop, command-line interface and computational notebook compatibility, allowing for accessible, flexible, portable and fully reproducible neuroimaging analysis on personal workstations, high-performance computers and the cloud.

Short disordered termini and proline-rich domain are major regulators of UBQLN1/2/4 phase separation.

Highly homologous ubiquitin-binding shuttle proteins UBQLN1, UBQLN2, and UBQLN4 differ in both their specific protein quality control functions and their propensities to localize to stress-induced condensates, cellular aggregates, and aggresomes. We previously showed that UBQLN2 phase separates in vitro, and that the phase separation propensities of UBQLN2 deletion constructs correlate with their ability to form condensates in cells. Here, we demonstrated that full-length UBQLN1, UBQLN2, and UBQLN4 exhibit distinct phase behaviors in vitro. Strikingly, UBQLN4 phase separates at a much lower saturation concentration than UBQLN1. However, neither UBQLN1 nor UBQLN4 phase separates with a strong temperature dependence, unlike UBQLN2. We determined that the temperature-dependent phase behavior of UBQLN2 stems from its unique proline-rich region, which is absent in the other UBQLNs. We found that the short N-terminal disordered regions of UBQLN1, UBQLN2, and UBQLN4 inhibit UBQLN phase separation via electrostatics interactions. Charge variants of the N-terminal regions exhibit altered phase behaviors. Consistent with the sensitivity of UBQLN phase separation to the composition of the N-terminal regions, epitope tags placed on the N-termini of the UBQLNs tune phase separation. Overall, our in vitro results have important implications for studies of UBQLNs in cells, including the identification of phase separation as a potential mechanism to distinguish the cellular roles of UBQLNs and the need to apply caution when using epitope tags to prevent experimental artifacts.

Polyubiquitin ligand-induced phase transitions are optimized by spacing between ubiquitin units.

Biomolecular condensates form via multivalent interactions among key macromolecules and are regulated through ligand binding and/or posttranslational modifications. One such modification is ubiquitination, the covalent addition of ubiquitin (Ub) or polyubiquitin chains to target macromolecules. Specific interactions between polyubiquitin chains and partner proteins, including hHR23B, NEMO, and UBQLN2, regulate condensate assembly or disassembly. Here, we used a library of designed polyubiquitin hubs and UBQLN2 as model systems for determining the driving forces of ligand-mediated phase transitions. Perturbations to either the UBQLN2-binding surface of Ub or the spacing between Ub units reduce the ability of hubs to modulate UBQLN2 phase behavior. By developing an analytical model based on polyphasic linkage principles that accurately described the effects of different hubs on UBQLN2 phase separation, we determined that introduction of Ub to UBQLN2 condensates incurs a significant inclusion energetic penalty. This penalty antagonizes the ability of polyUb hubs to scaffold multiple UBQLN2 molecules and cooperatively amplify phase separation. The extent to which polyubiquitin hubs promote UBQLN2 phase separation is encoded in the spacings between Ub units. This spacing is modulated by chains of different linkages and designed chains of different architectures, thus illustrating how the ubiquitin code regulates functionality via the emergent properties of the condensate. The spacing in naturally occurring linear polyubiquitin chains is already optimized to promote phase separation with UBQLN2. We expect our findings to extend to other condensates, emphasizing the importance of ligand properties, including concentration, valency, affinity, and spacing between binding sites in studies and designs of condensates.

Short N-terminal disordered regions and the proline-rich domain are major regulators of phase transitions for full-length UBQLN1, UBQLN2 and UBQLN4.

Highly homologous ubiquitin-binding shuttle proteins UBQLN1, UBQLN2 and UBQLN4 differ in both their specific protein quality control functions and their propensities to localize to stress-induced condensates, cellular aggregates and aggresomes. We previously showed that UBQLN2 phase separates in vitro, and that the phase separation propensities of UBQLN2 deletion constructs correlate with their ability to form condensates in cells. Here, we demonstrated that full-length UBQLN1, UBQLN2 and UBQLN4 exhibit distinct phase behaviors in vitro. Strikingly, UBQLN4 phase separates at a much lower saturation concentration than UBQLN1. However, neither UBQLN1 nor UBQLN4 phase separates with a strong temperature dependence, unlike UBQLN2. We determined that the temperature-dependent phase behavior of UBQLN2 stems from its unique proline-rich (Pxx) region, which is absent in the other UBQLNs. We found that the short N-terminal disordered regions of UBQLN1, UBQLN2 and UBQLN4 inhibit UBQLN phase separation via electrostatics interactions. Charge variants of the N-terminal regions exhibit altered phase behaviors. Consistent with the sensitivity of UBQLN phase separation to the composition of the N-terminal regions, epitope tags placed on the N-termini of the UBQLNs tune phase separation. Overall, our in vitro results have important implications for studies of UBQLNs in cells, including the identification of phase separation as a potential mechanism to distinguish the cellular roles of UBQLNs, and the need to apply caution when using epitope tags to prevent experimental artifacts.

Ion Mobility Mass Spectrometry Unveils Global Protein Conformations in Response to Conditions that Promote and Reverse Liquid-Liquid Phase Separation.

Liquid-liquid phase separation (LLPS) is a process by which biomacromolecules, particularly proteins, condense into a dense phase that resembles liquid droplets. Dysregulation of LLPS is implicated in disease, yet the relationship between protein conformational changes and LLPS remains difficult to discern. This is due to the high flexibility and disordered nature of many proteins that phase separate under physiological conditions and their tendency to oligomerize. Here, we demonstrate that ion mobility mass spectrometry (IM-MS) overcomes these limitations. We used IM-MS to investigate the conformational states of full-length ubiquilin-2 (UBQLN2) protein, LLPS of which is driven by high-salt concentration and reversed by noncovalent interactions with ubiquitin (Ub). IM-MS revealed that UBQLN2 exists as a mixture of monomers and dimers and that increasing salt concentration causes the UBQLN2 dimers to undergo a subtle shift toward extended conformations. UBQLN2 binds to Ub in 2:1 and 2:2 UBQLN2/Ub complexes, which have compact geometries compared to free UBQLN2 dimers. Together, these results suggest that extended conformations of UBQLN2 are correlated with UBQLN2's ability to phase separate. Overall, delineating protein conformations that are implicit in LLPS will greatly increase understanding of the phase separation process, both in normal cell physiology and disease states.

We con-dense if we want to; We can't leave AZUL outside.

In this issue of Structure, Buel et al. (2023) combined NMR data with AlphaFold2 to map out the interaction between the AZUL domain of ubiquitin ligase E6AP and UBQLN1/2 UBA. The authors demonstrated that this interaction enhances the self-association of the helix neighboring UBA and enables E6AP to localize to UBQLN2 droplets.

Homobifunctional imidoester-modified zinc nano-spindle attenuated hyphae growth of Aspergillus against hypersensitivity responses.

Fungi cause various forms of invasive fungal disease (IFD), and fungal sensitization can contribute to the development of asthma, asthma severity, and other hypersensitivity diseases, such as atopic dermatitis (AD). In this study, we introduce a facile and controllable approach, using homobifunctional imidoester-modified zinc nano-spindle (HINS), for attenuating hyphae growth of fungi and reducing the hypersensitivity response complications in fungi-infected mice. To extend the study of the specificity and immune mechanisms, we used HINS-cultured Aspergillus extract (HI-AsE) and common agar-cultured Aspergillus extract (Con-AsE) as the refined mouse models. HINS composites within the safe concentration range inhibited the hyphae growth of fungi but also reduce the number of fungal pathogens. Through the evaluation of lung and skin tissues from the mice, asthma pathogenesis (lung) and the hypersensitivity response (skin) to invasive aspergillosis were least severe in HI-AsE-infected mice. Therefore, HINS composites attenuate asthma and the hypersensitivity response to invasive aspergillosis.

Neurodesk: An accessible, flexible, and portable data analysis environment for reproducible neuroimaging.

Neuroimaging data analysis often requires purpose-built software, which can be challenging to install and may produce different results across computing environments. Beyond being a roadblock to neuroscientists, these issues of accessibility and portability can hamper the reproducibility of neuroimaging data analysis pipelines. Here, we introduce the Neurodesk platform, which harnesses software containers to support a comprehensive and growing suite of neuroimaging software (https://www.neurodesk.org/). Neurodesk includes a browser-accessible virtual desktop environment and a command line interface, mediating access to containerized neuroimaging software libraries on various computing platforms, including personal and high-performance computers, cloud computing and Jupyter Notebooks. This community-oriented, open-source platform enables a paradigm shift for neuroimaging data analysis, allowing for accessible, flexible, fully reproducible, and portable data analysis pipelines.

Decoding optimal ligand design for multicomponent condensates.

Biomolecular condensates form via multivalent interactions among key macromolecules and are regulated through ligand binding and/or post-translational modifications. One such modification is ubiquitination, the covalent addition of ubiquitin (Ub) or polyubiquitin chains to target macromolecules for various cellular processes. Specific interactions between polyubiquitin chains and partner proteins, including hHR23B, NEMO, and UBQLN2, regulate condensate assembly or disassembly. Here, we used a library of designed polyubiquitin hubs and UBQLN2 as model systems for determining the driving forces of ligand-mediated phase transitions. Perturbations to the UBQLN2-binding surface of Ub or deviations from the optimal spacing between Ub units reduce the ability of hubs to modulate UBQLN2 phase behavior. By developing an analytical model that accurately described the effects of different hubs on UBQLN2 phase diagrams, we determined that introduction of Ub to UBQLN2 condensates incurs a significant inclusion energetic penalty. This penalty antagonizes the ability of polyUb hubs to scaffold multiple UBQLN2 molecules and cooperatively amplify phase separation. Importantly, the extent to which polyubiquitin hubs can promote UBQLN2 phase separation are encoded in the spacings between Ub units as found for naturally-occurring chains of different linkages and designed chains of different architectures, thus illustrating how the ubiquitin code regulates functionality via the emergent properties of the condensate. We expect our findings to extend to other condensates necessitating the consideration of ligand properties, including concentration, valency, affinity, and spacing between binding sites in studies and designs of condensates.

Magnetic transferrin nanoparticles (MTNs) assay as a novel isolation approach for exosomal biomarkers in neurological diseases.

BACKGROUND: Brain-derived exosomes released into the blood are considered a liquid biopsy to investigate the pathophysiological state, reflecting the aberrant heterogeneous pathways of pathological progression of the brain in neurological diseases. Brain-derived blood exosomes provide promising prospects for the diagnosis of neurological diseases, with exciting possibilities for the early and sensitive diagnosis of such diseases. However, the capability of traditional exosome isolation assays to specifically isolate blood exosomes and to characterize the brain-derived blood exosomal proteins by high-throughput proteomics for clinical specimens from patients with neurological diseases cannot be assured. We report a magnetic transferrin nanoparticles (MTNs) assay, which combined transferrin and magnetic nanoparticles to isolate brain-derived blood exosomes from clinical samples. METHODS: The principle of the MTNs assay is a ligand-receptor interaction through transferrin on MTNs and transferrin receptor on exosomes, and electrostatic interaction via positively charged MTNs and negatively charged exosomes to isolate brain-derived blood exosomes. In addition, the MTNs assay is simple and rapid (< 35 min) and does not require any large instrument. We confirmed that the MTNs assay accurately and efficiently isolated exosomes from serum samples of humans with neurodegenerative diseases, such as dementia, Parkinson's disease (PD), and multiple sclerosis (MS). Moreover, we isolated exosomes from serum samples of 30 patients with three distinct neurodegenerative diseases and performed unbiased proteomic analysis to explore the pilot value of brain-derived blood protein profiles as biomarkers. RESULTS: Using comparative statistical analysis, we found 21 candidate protein biomarkers that were significantly different among three groups of neurodegenerative diseases. CONCLUSION: The MTNs assay is a convenient approach for the specific and affordable isolation of extracellular vesicles from body fluids for minimally-invasive diagnosis of neurological diseases.

Hot-Spot-Specific Probe (HSSP) for Rapid and Accurate Detection of KRAS Mutations in Colorectal Cancer.

Detection of oncogene mutations has significance for early diagnosis, customized treatment, treatment progression, and drug resistance monitoring. Here, we introduce a rapid, sensitive, and specific mutation detection assay based on the hot-spot-specific probe (HSSP), with improved clinical utility compared to conventional technologies. We designed HSSP to recognize KRAS mutations in the DNA of colorectal cancer tissues (HSSP-G12D (GGT→GAT) and HSSP-G13D (GGC→GAC)) by integration with real-time PCR. During the PCR analysis, HSSP attaches to the target mutation sequence for interference with the amplification. Then, we determine the mutation detection efficiency by calculating the difference in the cycle threshold (Ct) values between HSSP-G12D and HSSP-G13D. The limit of detection to detect KRAS mutations (G12D and G13D) was 5-10% of the mutant allele in wild-type populations. This is superior to the conventional methods (≥30% mutant allele). In addition, this technology takes a short time (less than 1.5 h), and the cost of one sample is as low as USD 2. We verified clinical utility using 69 tissue samples from colorectal cancer patients. The clinical sensitivity and specificity of the HSSP assay were higher (84% for G12D and 92% for G13D) compared to the direct sequencing assay (80%). Therefore, HSSP, in combination with real-time PCR, provides a rapid, highly sensitive, specific, and low-cost assay for detecting cancer-related mutations. Compared to the gold standard methods such as NGS, this technique shows the possibility of the field application of rapid mutation detection and may be useful in a variety of applications, such as customized treatment and cancer monitoring.

Effects of Ti-doping amount and annealing temperature on electrochromic performance of sol-gel derived WO3.

Fine control of structural and morphological features in electrochromic materials is of paramount importance for realizing practical electrochromic devices (ECDs), which can dynamically adjust indoor light and temperature of buildings. To this end, herein we investigate impacts of two variants such as Ti-doping amount and the annealing temperature on physical and chemical properties of sol-gel derived electrochromic WO3 films. We use a wide range of titanium coupling agents (TCAs) as Ti-dopants ranging from 0 wt% to 20 wt% and vary the annealing temperature between 200 °C and 400 °C with 50 °C interval. Both variants greatly influence the physical properties of the resulting WO3 films, resulting in different crystallinities and morphologies. Through complementary analytical techniques, we find that the WO3 film featuring an amorphous phase with nano-porous morphology enhances the electrochemical and electrochromic performances. The specific TCA used in this study helps stabilize the amorphous WO3 structure and generate the nano-pores during the following thermal treatment via its thermal decomposition. As a result, the WO3 film having an optimal 8 wt% TCA annealed at 300 °C shows a high optical density of 73.78% in visible light (400-780 nm), rapid switching speed (t c = 5.12 s and t b = 4.74 s), and high coloration efficiency of 52.58 cm2 C-1 along with a superior cyclic stability. Thus, understanding a structure-property relationship is of paramount importance in engineering the advanced electrochromic WO3 for use in practical ECDs and other optoelectronic applications.

Mechanistic insights into enhancement or inhibition of phase separation by different polyubiquitin chains.

Ubiquitin-binding shuttle UBQLN2 mediates crosstalk between proteasomal degradation and autophagy, likely via interactions with K48- and K63-linked polyubiquitin chains, respectively. UBQLN2 comprises self-associating regions that drive its homotypic liquid-liquid phase separation (LLPS). Specific interactions between one of these regions and ubiquitin inhibit UBQLN2 LLPS. Here, we show that, unlike ubiquitin, the effects of multivalent polyubiquitin chains on UBQLN2 LLPS are highly dependent on chain types. Specifically, K11-Ub4 and K48-Ub4 chains generally inhibit UBQLN2 LLPS, whereas K63-Ub4, M1-Ub4 chains, and a designed tetrameric ubiquitin construct significantly enhance LLPS. We demonstrate that these opposing effects stem from differences in chain conformations but not in affinities between chains and UBQLN2. Chains with extended conformations and increased accessibility to the ubiquitin-binding surface promote UBQLN2 LLPS by enabling a switch between homotypic to partially heterotypic LLPS that is driven by both UBQLN2 self-interactions and interactions between multiple UBQLN2 units with each polyubiquitin chain. Our study provides mechanistic insights into how the structural and conformational properties of polyubiquitin chains contribute to heterotypic LLPS with ubiquitin-binding shuttles and adaptors.

Chimeric nanocomposites for the rapid and simple isolation of urinary extracellular vesicles.

Cancer cell-derived extracellular vesicles (EVs) are promising biomarkers for cancer diagnosis and prognosis. However, the lack of rapid and sensitive isolation techniques to obtain EVs from clinical samples at a sufficiently high yield limits their practicability. Chimeric nanocomposites of lactoferrin conjugated 2,2-bis(methylol)propionic acid dendrimer-modified magnetic nanoparticles (LF-bis-MPA-MNPs) are fabricated and used for simple and sensitive EV isolation from various biological samples via a combination of electrostatic interaction, physically absorption, and biorecognition between the surfaces of the EVs and the LF-bis-MPA-MNPs. The speed, efficiency, recovery rate, and purity of EV isolation by the LF-bis-MPA-MNPs are superior to those obtained by using established methods. The relative expressions of exosomal microRNAs (miRNAs) from isolated EVs in cancerous cell-derived exosomes are verified as significantly higher than those from noncancerous ones. Finally, the chimeric nanocomposites are used to assess urinary exosomal miRNAs from urine specimens from 20 prostate cancer (PCa), 10 benign prostatic hyperplasia (BPH), patients and 10 healthy controls. Significant up-regulation of miR-21 and miR-346 and down-regulation of miR-23a and miR-122-5p occurs in both groups compared to healthy controls. LF-bis-MPA-MNPs provide a rapid, simple, and high yield method for human excreta analysis in clinical applications.

O, N-doped porous biochar by air oxidation for enhancing heavy metal removal: The role of O, N functional groups.

Oxygen- and nitrogen-doped porous oxidized biochar (O,N-doped OBC) was fabricated in this study. Biochar (BC) can be enriched in surface functional groups (O and N) and the porosity can be improved by a simple, convenient and green procedure. BC was oxidized at 200 °C in an air atmosphere with quality control via oxidation time changes. As the oxidation time increased, the O and N contents and porosity of the materials improved. After 1.5 h of oxidation, the O and N contents of O,N-doped OBC-1.5 were 54.4% and 3.9%, higher than those of BC, which were 33.4% and 1.8%, respectively. The specific surface area and pore volume of O,N-doped OBC-1.5 were 88.5 m2 g-1 and 0.07 cm3 g-1, respectively, which were greater than those of BC. The improved surface functionality and porosity resulted in an increased heavy metal removal efficiency. As a result, the maximum adsorption capacity of Cu(II) by O,N-doped OBC was 23.32 mg L-1, which was twofold higher than that of pristine BC. Additionally, for a multiple ion solution, O,N-doped OBC-1.5 showed a greater adsorption behavior toward Cu(II) than Zn(II) and Ni(II). In a batch experiment, the concentration of Cu(II) decreased 92.3% after 90 min. In a filtration experiment, the O,N-doped OBC-based filter achieved a Cu(II) removal capacity of 12.90 mg g-1 and breakthrough time after 250 min. Importantly, the chemical mechanism was mainly governed by monolayer adsorption of Cu(II) onto a homogeneous surface of O,N-doped OBC-1.5. Surface complexation and electrostatic attraction were considered to be the chemical mechanisms governing the adsorption process.

Genetic analysis of Vietnamese patients with early-onset Alzheimer's disease.

Purpose of the study: Alzheimer's disease (AD) is the most common type of dementia and its prevalence is rapidly increasing worldwide. Early-onset Alzheimer's disease (EOAD) constitutes of patients with age of onset earlier than 65 year-old and is known to be associated with genetic mutations. In this study, we reported the first genetic analysis of Vietnamese patients with EOAD.Materials and methods: We analyzed targeted sequencing data obtained from a cohort of 51 Vietnamese EOAD patients to identify pathogenic variants in twenty nine well-characterized neurodengerative genes.Results: We identified four missense mutations in APP/PSEN1 genes from six individuals, which accounts for 11.8% of all tested cases. Three of these mutations were previously reported as pathogenic and one mutation in the APP gene was newly identified and might be specific for Vietnamese patients. Our study also found eight individuals carrying homozygous APOE ε4 allele, the main risk factor gene for late-onset AD.Conclusions: Our findings showed that mutation rate in APP/PSEN genes in Vietnamese EOAD patients is consistent with that in other ethnic groups. Although further functional studies are required to validate the pathogenesis of the new mutations, our study demonstrated the necessity of genetic screening for EOAD patients as well as additional genetic data collection in Vietnamese population.