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Targeting impaired nutrient sensing with repurposed drugs to prevent or treat age-related dementia: a systematic review

D. Heard (1), T. Rego (1), C. Tuttle (2), N. Lautenschlager (1, 3) and A. Maier (2, 4)

  1. North West Mental Health, Melbourne Health, Melbourne, Victoria, Australia

  2. @AgeMelbourne, Department of Medicine and Aged Care, University of Melbourne, Melbourne, Victoria, Australia

  3. Academic Unit for Psychiatry of Old Age, Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia

  4. @AgeAmsterdam, Department of Human Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, The Netherlands

Background

Dementia is a debilitating disease that affects 5-8% of the older population. Recently, the impairment of nutrient sensing pathways has been implicated in the pathogenesis of the dementias and is considered a viable therapeutic target to treat this illness. There are currently several available FDA approved therapeutics used to manage chronic disease that modulate nutrient sensing pathways (e.g. metformin). Thus, rather than developing new therapeutics, repurposing currently available therapeutics to treat the dementias may significantly improve patient outcomes. In this review we aimed to collate all current evidence of the efficacy of using available ‘modulation of nutrient sensing’ therapeutics to manage dementia.


Methods

PubMed, Embase and Web of Science databases were searched from inception until 2nd April 2019. Key search terms focused on available therapeutics such as ‘metformin’, ‘GLP1’, ‘insulin’ and the dementias including ‘Alzheimer’s disease’ and ‘Parkinson’s disease’. Studies were included in this review if an interventional design and a cognitive outcome was reported.


Results

Preliminary analysis of the data identifies 19 different ‘modulation of nutrient sensing pathway’ therapeutics (11 in animal trials, 2 in human trial and 6 in both animal and human trials), currently being trialed in dementia models. GLP-1 agonists, glitazones, intranasal insulin, metformin, growth hormone secretagogues and growth hormone have been trialed in both human and animal models. However; while GLP-1 agonists and glitazones have positive influences on cognition in animal models this has not been replicated in human studies. The current evidence for the efficacy of metformin in improving cognitive outcomes is inconclusive. However, the growth hormone secretagogues have significant benefits on cognition in both animal and human dementia trials.


Conclusion

Not all currently available FDA approved therapeutics that target the nutrient sensing pathways may be effective in managing the dementias. However, there is evidence that some therapeutics, such as the growth hormone secretagogues, may have a significant positive impact on cognition and patient outcomes.