Calculation of Synergy to Discover the Multitarget Potential of Novel Combinations of Betanin, Betaine, and Quercetin against Alzheimer’s Disease

Alzheimer’s disease (AD) is a rising pandemic that is estimated to affect up to 139 million people in 2050 along with other dementias. The failure of using mono-target therapy against Alzheimer’s has shifted the focus towards multi-target approaches. Phytocompounds have complex chemical structures that enable them to target multiple pathways of disease. Our previous studies and studies from several other groups have emphasized the use of individual phytocompounds like Quercetin, Betanin, and Betaine for the treatment and management of AD. So, we hypothesized about a combinatorial therapy approach by making dual combinations of Quercetin, Betanin, and Betaine. We tested the antioxidant, anti-inflammatory, and anti-acetylcholinesterase potential of the individual compounds, as well as dual combinations, by performing in vitro assays. We then performed an enzyme (AChE) kinetics analysis to identify the mechanism of inhibition employed by each compound against AChE. From the results obtained, we calculated the drug–drug interaction-like synergy between these drug combinations by using mathematical models of their synergy. In this way, we were able to find combinations with higher antioxidant, anti-inflammatory, and anti-AChE activity, even when the dose was reduced. We then performed network pharmacology-based identification of multiple gene and pathway targets for our compounds in humans against AD. We conclude that these combinations have excellent multi-target potential and should be further tested in AD models to better understand their effects on AD pathology.