**5. Prevention of cognitive decline through lifestyle interventions**

There is increasing evidence that diet rich in flavonoid or supplements might delay the initiation of and/or slow the progression of cognitive decline related to aging and Alzheimer's diseases (AD). Among existing dietary patterns, adherence to a Mediterranean diet is associated with less cognitive decline, dementia, or AD [64, 65]. For example, a meta-analysis showed that greater adherence to a Mediterranean-style dietary pattern during older adulthood was associated with a lower risk of developing several different health outcomes such as CVD, neurodegenerative disorders, cancer, and overall mortality [66].

With regard to AD, the consumption of food rich in flavonoids such as red wine, fruit juice, and vegetables has been shown to delay the onset of AD [17, 67]. This is in accordance with previous studies linking high consumption of flavonoids to decline related to aging and dementia [19, 68]. A number of studies using animal models of AD have begun to investigate the possible mechanisms involved in these effects. For example, oral administration of the green tea flavonoid EGCG for 6 months to mice overexpressing the Swedish mutation of APP (Tg2576) reduced amyloid β (Aβ) pathology as well as improving cognition [69], and similarly longterm green tea catechin administration improved spatial learning and memory in senescence-prone mice [70]. Furthermore, feeding APP+PS1 double-transgenic mice blueberry from 4 months of age prevented deficits in Y-maze performance at 12 months, without altering the Aβ burden [71]. The myricetin and morin are successful to inhibit the β-sheet of Aβ oligomers. Apigenin, a flavone, and quercetin, a flavonol, have shown promising results with animal model of AD, and quercetin has shown to be benefit to early-stage AD patients [72].

The mechanism underlying these changes is not clear but might be linked to increase α-secretase activity [73] reported in vitro and in vivo after i.p. injection of EGCG [42, 74] or due to disruption of cAbl/Fe65 interactions [75]. Gallic acid and catechin-rich grape seed polyphenolic extract (GSPE) administered for 5 months to Tg2576 mice inhibited cognitive deterioration coincident with reduced levels of

*Flavonoids as Modulators of Synaptic Plasticity: Implications for the Development of Novel… DOI: http://dx.doi.org/10.5772/intechopen.84164*

soluble high-molecular-weight oligomers of Aβ [76]. Moreover, GSPE also inhibits tau fibrillization, promotes the loss of preformed tau aggregates, and disrupts paired helical filaments [77–80]. EGCG seems to have broadly similar effects. (−)-Epicatechin and hesperetin hold the potential to inhibit the development of tau pathology through an alternative mechanism relating to their ability to enhance Akt phosphorylation, thereby inhibiting GSK3β-induced tau hyperphosphorylation [55, 56]. Overall, this supports the claim that orally active flavonoids could have the utility in AD beyond anti-Aβ actions. The challenge ahead is to determine if flavonoids have efficacy in individuals affected by dementia.
