Understanding how diet modifies cognitive ageing represents the next frontiers for developing
prevention strategies. A key may rely on elucidating the exact combination of dietary bioactives
capable of modulating cognitive decline via brain plasticity, a major compensatory mechanism to
maintain cognitive function. Another important question is the sensitive population in which such
nutritional intervention should be undertaken. We hypothesize that (i) there exists a combination
of dietary bioactives capable of modulating cognition and brain plasticity, (ii) dietary modulation of
brain plasticity and cognition starts in early-life and occurs throughout life and (iii) exposure to
stress/genetic predisposition are vulnerability factors to consider. We propose a translational
project across nutrition, epidemiology, and neurosciences leveraging human data/serum samples
and mouse models and using innovative approaches of: (i) dietary exposure assessment (the
food metabolome), (ii) human brain plasticity (in vitro parabiosis to assess neurogenesis and
microglial function, lipidomics to assess neuronal integrity), and (iii) cognitive ageing modeling
(early-life stress mouse model).

D-CogPlast will start with a discovery stage in humans, aimed at identifying a set of dietary
bioactives from the food metabolome associated with cognitive decline, along with vulnerable
populations, in 200 individuals with accelerated cognitive decline over 13+ years against 200
individuals with preserved cognition. This will be further validated in 400 participants from a
separate cohort. The second stage will be to investigate the ability of the identified set of
bioactives predictive of cognitive decline to modulate brain plasticity and neuronal integrity. The
third stage will consist in a proof-of-principle dietary intervention with identified bioactives in a
mouse model of cognitive decline.

On completion of this proposal we will have (i) identified and validated an optimum combination of
dietary compounds providing protective effect against cognitive ageing and brain plasticity
alteration, (ii) identified vulnerable populations responding to the impact of diet on cognitive
decline, (iii) provided evidence of brain plasticity as targets of choice for bioactives intervention to
prevent/slowdown cognitive decline and (iv) provided a proof-of-principle life-long dietary
intervention for preventing/rescuing cognitive decline. It is expected that the bioactives identified
and validated will lead to dietary interventions and recommendations for cognitive decline
prevention.