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Drug Development.
Alzheimers Dement
December 2024
GSK R&D, Stevenage, Hertfordshire, United Kingdom.
Background: Genetic variants in GRN, the gene encoding progranulin, are causal for or are associated with the risk of multiple neurodegenerative diseases. Modulating progranulin has been considered as a therapeutic strategy for neurodegenerative diseases including Frontotemporal Dementia (FTD) and Alzheimer's Disease (AD). Here, we integrated genetics with proteomic data to determine the causal human evidence for the therapeutic benefit of modulating progranulin in AD.
View Article and Find Full Text PDFBackground: The autophagy lysosomal pathway (ALP) and the ubiquitin-proteasome system (UPS) are key proteostasis mechanisms in cells, which are dysfunctional in AD and linked to protein aggregation and neuronal death. Autophagy is over activated in Alzheimer's disease brain whereas UPS is severely impaired. Activating autophagy has received most attention, however recent evidence suggests that UPS can clear aggregate proteins and a potential therapeutic target for AD and protein misfolding diseases.
View Article and Find Full Text PDFBackground: Availability of amyloid modifying therapies will dramatically increase the need for disclosure of Alzheimer's disease (AD) related genetic and/or biomarker test results. The 21st Century Cares Act requires the immediate return of most medical test results, including AD biomarkers. A shortage of genetic counselors and dementia specialists already exists, thus driving the need for scalable methods to responsibly communicate test results.
View Article and Find Full Text PDFDrug 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
Centre for Addiction and Mental Health, Toronto, ON, Canada.
Background: Dysregulated GABA/somatostatin (SST) signaling has been implicated in psychiatric and neurodegenerative disorders. The inhibition of excitatory neurons by SST+ interneurons, particularly through α5-containing GABAA receptors (α5-GABAAR), plays a crucial role in mitigating cognitive functions. Previous research demonstrated that an α5-positive allosteric modulator (α5-PAM) mitigates working memory deficits and reverses neuronal atrophy in aged mice.
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