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Drug Development.
Alzheimers Dement
December 2024
University of Kentucky Sanders-Brown Center on Aging, Lexington, KY, USA.
Background: The presence of multiple comorbid pathologic features in late-onset dementia has been well documented across cohort studies that incorporate autopsy evaluation. It is likely that such mixed pathology potentially confounds the results of interventional trials that are designed to target a solitary pathophysiologic mechanism in Alzheimer's disease and related dementias (ADRD).
Method: The UK ADRC autopsy database was screened for participants who had previously engaged in therapeutic interventional trials for Alzheimer's disease, vascular cognitive impairment, dementia, and/or ADRD prevention trials from 2005 to the present.
Drug Development.
Alzheimers Dement
December 2024
The University of Texas Health Science Center at Houston, Houston, TX, USA.
Background: Developing drugs for treating Alzheimer's disease (AD) has been extremely challenging and costly due to limited knowledge on underlying biological mechanisms and therapeutic targets. Repurposing drugs or their combination has shown potential in accelerating drug development due to the reduced drug toxicity while targeting multiple pathologies.
Method: To address the challenge in AD drug development, we developed a multi-task machine learning pipeline to integrate a comprehensive knowledge graph on biological/pharmacological interactions and multi-level evidence on drug efficacy, to identify repurposable drugs and their combination candidates RESULT: Using the drug embedding from the heterogeneous graph representation model, we ranked drug candidates based on evidence from post-treatment transcriptomic patterns, mechanistic efficacy in preclinical models, population-based treatment effect, and Phase 2/3 clinical trials.
Drug Development.
Alzheimers Dement
December 2024
NYU Grossman School of Medicine, New York, NY, USA; NYU, New York City, NY, USA.
Background: Astrocytes, a major glial cell in the central nervous system (CNS), can become reactive in response to inflammation or injury, and release toxic factors that kill specific subtypes of neurons. Over the past several decades, many groups report that reactive astrocytes are present in the brains of patients with Alzheimer's disease, as well as several other neurodegenerative diseases. In addition, reactive astrocyte sub-types most associated with these diseases are now reported to be present during CNS cancers of several types.
View Article and Find Full Text PDFDrug Development.
Alzheimers Dement
December 2024
National Institute on Aging, NIH, Baltimore, MD, USA.
Background: Epidemiological studies report an elevated risk of neurodegenerative disorders, particularly Parkinson's disease (PD), in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed incretin mimetics or dipeptidyl peptidase 4 inhibitors (DPP-4Is). Incretin mimetic repurposing appears promising in human PD and Alzheimer's disease (AD) clinical trials. DPP-4Is are yet to be evaluated in PD or AD human studies.
View Article and Find Full Text PDFDrug Development.
Alzheimers Dement
December 2024
Merry Life Biomedical Company, Ltd., Tainan City, Taiwan, Taiwan.
Background: Alzheimer's disease (AD) is complex in pathogenesis and related to aging biology, especially in late-onset AD. We identified a novel synthetic curcumin analog TML-6 through the platform of 6 biomarkers of anti-aging, anti-inflammation, and anti-Aβ as the potential AD drug candidate. TML-6 exhibits multi-target effects on AD pathogenesis, including the activation of NrF-2, the regulation of autophagic machinery through mTOR, the inhibition of APP synthesis and reduction of Aβ, the upregulation of ApoE, and the inhibition of microglial activation.
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