Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Авг. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Язык: Английский

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DeepDrug as an expert guided and AI driven drug repurposing methodology for selecting the lead combination of drugs for Alzheimer’s disease

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 15, 2025

Язык: Английский

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Systematic characterization of multi-omics landscape between gut microbial metabolites and GPCRome in Alzheimer’s disease

Cell Reports, Год журнала: 2024, Номер 43(5), С. 114128 - 114128

Опубликована: Апрель 21, 2024

Shifts in the magnitude and nature of gut microbial metabolites have been implicated Alzheimer's disease (AD), but host receptors that sense respond to these are largely unknown. Here, we develop a systems biology framework integrates machine learning multi-omics identify molecular relationships with non-olfactory G-protein-coupled (termed "GPCRome"). We evaluate 1.09 million metabolite-protein pairs connecting 408 human GPCRs 335 metabolites. Using genetics-derived Mendelian randomization integrative analyses brain transcriptomic proteomic profiles, orphan (i.e., GPR84) as potential drug targets AD triacanthine experimentally activates GPR84. demonstrate phenethylamine agmatine significantly reduce tau hyperphosphorylation (p-tau181 p-tau205) patient induced pluripotent stem cell-derived neurons. This study demonstrates uncover GPCR microbiota other complex diseases if broadly applied.

Язык: Английский

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A network-based systems genetics framework identifies pathobiology and drug repurposing in Parkinson’s disease

npj Parkinson s Disease, Год журнала: 2025, Номер 11(1)

Опубликована: Янв. 22, 2025

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. However, current treatments only manage symptoms and lack ability to slow or prevent progression. We utilized a systems genetics approach identify potential risk genes repurposable drugs for PD. First, we leveraged non-coding genome-wide association studies (GWAS) loci effects on five types of brain-specific quantitative trait (xQTLs, including expression, protein, splicing, methylation histone acetylation) under protein–protein interactome (PPI) network. then prioritized 175 PD likely (pdRGs), such as SNCA, CTSB, LRRK2, DGKQ, CD44, which are enriched in druggable targets differentially expressed across multiple human cell types. Integrating network proximity-based drug repurposing patient electronic health record (EHR) data observations, identified Simvastatin being significantly associated with reduced incidence (hazard ratio (HR) = 0.91 fall outcome, 95% confidence interval (CI): 0.87–0.94; HR 0.88 dementia CI: 0.86–0.89) after adjusting 267 covariates. In summary, our network-based framework identifies other diseases if broadly applied.

Язык: Английский

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Utilization of precision medicine digital twins for drug discovery in Alzheimer's disease

Neurotherapeutics, Год журнала: 2025, Номер unknown, С. e00553 - e00553

Опубликована: Фев. 1, 2025

Alzheimer's disease (AD) presents significant challenges in drug discovery and development due to its complex poorly understood pathology etiology. Digital twins (DTs) are recently developed virtual real-time representations of physical entities that enable rapid assessment the bidirectional interaction between domains. With recent advances artificial intelligence (AI) growing accumulation multi-omics clinical data, application DTs healthcare is gaining traction. twin technology, form multiscale models patients or organ systems, can track health status real time with continuous feedback, thereby driving model updates enhance decision-making. Here, we posit an additional role for discovery, particular utility diseases like AD. In this review, discuss salient AD development, including comorbidities, difficulty early diagnosis, current high failure rate trials. We also review potential applications predicting progression, discovering biomarkers, identifying new targets opportunities repurposing, facilitating trials, advancing precision medicine. Despite hurdles area, such as integration standardization dynamic medical data issues security privacy, represent a promising approach revolutionizing

Язык: Английский

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Artificial Intelligence for Drug Discovery: An Update and Future Prospects

Seminars in Nuclear Medicine, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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Harnessing omics data for drug discovery and development in ovarian aging

Human Reproduction Update, Год журнала: 2025, Номер unknown

Опубликована: Фев. 20, 2025

Ovarian aging occurs earlier than the of many other organs and has a lasting impact on women's overall health well-being. However, effective interventions to slow ovarian remain limited, primarily due an incomplete understanding underlying molecular mechanisms drug targets. Recent advances in omics data resources, combined with innovative computational tools, are offering deeper insight into complexities aging, paving way for new opportunities discovery development. This review aims synthesize expanding multi-omics data, spanning genome, transcriptome, proteome, metabolome, microbiome, related from both tissue-level single-cell perspectives. We will specially explore how analysis these emerging datasets can be leveraged identify novel targets guide therapeutic strategies slowing reversing aging. conducted comprehensive literature search PubMed database using range relevant keywords: age at natural menopause, premature insufficiency (POI), diminished reserve (DOR), genomics, transcriptomics, epigenomics, DNA methylation, RNA modification, histone proteomics, metabolomics, lipidomics, single-cell, genome-wide association studies (GWAS), whole-exome sequencing, phenome-wide (PheWAS), Mendelian randomization (MR), epigenetic target, machine learning, artificial intelligence (AI), deep multi-omics. The was restricted English-language articles published up September 2024. Multi-omics have uncovered key driving including damage repair deficiencies, inflammatory immune responses, mitochondrial dysfunction, cell death. By integrating researchers critical regulatory factors across various biological levels, leading potential Notable examples include genetic such as BRCA2 TERT, like Tet FTO, metabolic sirtuins CD38+, protein BIN2 PDGF-BB, transcription FOXP1. advent cutting-edge technologies, especially technologies spatial provided valuable insights guiding treatment decisions become powerful tool aimed mitigating or As technology advances, integration AI models holds more accurately predict candidate convergence offers promising avenues personalized medicine precision therapies, tailored Not applicable.

Язык: Английский

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Glutamate: Molecular Mechanisms and Signaling Pathway in Alzheimer’s Disease, a Potential Therapeutic Target

Molecules, Год журнала: 2024, Номер 29(23), С. 5744 - 5744

Опубликована: Дек. 5, 2024

Gamma-glutamate is an important excitatory neurotransmitter in the central nervous system (CNS), which plays role transmitting synapses, plasticity, and other brain activities. Nevertheless, alterations glutamatergic signaling pathway are now accepted as a element Alzheimer's disease (AD) pathophysiology. One of most prevalent types dementia older adults AD, progressive neurodegenerative illness brought on by persistent decline cognitive function. Since AD has been shown to be multifactorial, variety pharmaceutical targets may used treat condition. N-methyl-D-aspartic acid receptor (NMDAR) antagonists acetylcholinesterase inhibitors (AChEIs) two drug classes that Food Drug Administration authorized for treatment AD. The AChEIs approved galantamine, donepezil, rivastigmine. However, memantine only non-competitive NMDAR antagonist This review aims outline involvement glutamate (GLU) at molecular level pathways associated with demonstrate target therapeutic potential its receptor. We will also consider opinion leading authorities working this area, drawback existing strategies, direction further investigation.

Язык: Английский

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A Deep Subgrouping Framework for Precision Drug Repurposing via Emulating Clinical Trials on Real-world Patient Data

Опубликована: Апрель 4, 2025

Drug repurposing identifies new therapeutic uses for existing drugs, reducing the time and costs compared to traditional de novo drug discovery. Most studies using real-world patient data often treat entire population as homogeneous, ignoring heterogeneity of treatment responses across subgroups. This approach may overlook promising drugs that benefit specific subgroups but lack notable effects population, potentially limiting number repurposable candidates identified. To address this, we introduce STEDR, a novel framework integrates subgroup analysis with effect estimation. Our first by emulating multiple clinical trials on then characterizes learning subgroup-specific effects. We deploy \model Alzheimer's Disease (AD), condition few approved known in responses. emulate over one thousand medications large-scale database covering 8 million patients, identifying 14 beneficial AD characterized Experiments demonstrate STEDR's superior capability approaches. Additionally, our method can characterize clinically relevant associated important AD-related risk factors, paving way precision repurposing.

Язык: Английский

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How to advance the pharmacological management of cognitive impairment in Parkinson's disease

Journal of Parkinson s Disease, Год журнала: 2025, Номер unknown

Опубликована: Фев. 2, 2025

Cognitive impairment is a common non-motor symptom in people with Parkinson's disease (PD) and associated to poor clinical outcomes. Currently, rivastigmine the only approved medication for PD dementia, there are no treatments available mild cognitive impairment. To advance pharmacological management of PD, it essential optimize trial design. This includes refining outcome measures, ensuring longer study durations, incorporating PD-specific assessments. Biomarkers offer valuable opportunities screening, stratification, enrichment, monitoring trials, increasing likelihood detecting treatment effects. Additionally, adopting patient-centered approaches that prioritize inclusivity can enhance validity address current lack diversity studies. Digital assessments promising tool improving participation enabling longitudinal monitoring, especially underrepresented mobility-challenged populations. By tackling these challenges, this review outlines strategies advancing PD. It emphasizes need precise, inclusive, biomarker-driven trials accelerate drug development.

Язык: Английский

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