Flavonoids as an Intervention for Alzheimer’s Disease: Progress and Hurdles Towards Defining a Mechanism of Action(1)

Attempts to develop a disease modifying intervention for Alzheimer’s disease (AD) through targeting amyloid β (Aβ) have so far been unsuccessful. There is, therefore, a need for novel therapeutics against alternative targets coupled with approaches which may be suitable for early and sustained use likely required for AD prevention. Numerous in vitro and in vivo studies have shown that flavonoids can act within processes and pathways relevant to AD, such as Aβ and tau pathology, increases in BDNF, inflammation, oxidative stress and neurogenesis. However, the therapeutic development of flavonoids has been hindered by an ongoing lack of clear mechanistic data that fully takes into consideration metabolism and bioavailability of flavonoids in vivo. With a focus on studies that incorporate these considerations into their experimental design, this review will evaluate the evidence for developing specific flavonoids as therapeutics for AD. Given the current lack of success of anti-Aβ targeting therapeutics, particular attention will be given to flavonoid-mediated regulation of tau phosphorylation and aggregation, where there is a comparable lack of study. Reflecting on this evidence, the obstacles that prevent therapeutic development of flavonoids will be examined. Finally, the significance of recent advances in flavonoid metabolomics, modifications and influence of the microbiome on the therapeutic capacity of flavonoids in AD are explored. By highlighting the potential of flavonoids to target multiple aspects of AD pathology, as well as considering the hurdles, this review aims to promote the efficient and effective identification of flavonoid-based approaches that have potential as therapeutic interventions for AD.