Repurposing drugs for Alzheimer´s disease using a reverse translational approach - PROJECT SUMMARY Age is the major risk factor for Alzheimer´s disease (AD), and as the world’s population is becoming older it is increasingly prevalent. There are many commonalities between aging and AD, both on the molecular and systems level. There is also ample evidence, in particular from work in animal models, that a broad spectrum of aging-preventive interventions that confer longevity have the ability to alleviate diverse aspects of AD pathology, such as Aβ and tau aggregation. These pathologies lead to severe neurodegeneration and occurrence of clinical symptoms such as memory loss, mood swings and changes in personality. No disease-modifying treatments exist, only medications that relieve the symptoms temporarily. To find treatments that prevent disease progression, testing drugs that have already been approved for other indications – a strategy referred to as drug repurposing – may be useful. A major benefit of drug repurposing is that it speeds up drug development and reduces the risks for patients, since these drugs have already passed safety assessment in humans. Thus, we propose a data-driven approach to search among drugs used for other age-related conditions and identify some that can be repurposed for the prevention of AD. Towards this approach, we will investigate the effect of the 20 most commonly used drug classes among 65+ year-olds in Sweden (>200 substances also approved for use in the U.S.) on biological aging and AD in a series of epidemiological analyses. We will use deeply phenotyped longitudinal cohort data to see how drug treatment changes biological aging trajectories, as well as apply Mendelian Randomizations to mimic the modulation on drug targets using large-scale genotyping data and emulated target trials in the Swedish Prescribed Drug Register linked to a quality register on dementia. Following this, the individual substances within the 2-3 most promising drug classes will be screened in vitro in human cellular models of AD and in vivo in C. elegans models of aging and of human Aβ and tau aggregation and toxicity. Top candidates will be tested in established and most relevant AD mouse models and in models of accelerated aging. Taken together, our approach to discover new drugs for AD prevention by screening already approved substances bears great benefits. The fact that much of the testing happens in silico and that the screening focuses only on drugs that are already approved for use in patients makes our approach faster and more cost- effective than conventional de novo compound screens.
