The serum metabolome mediates the concert of diet, exercise, and neurogenesis, determining the risk for cognitive decline and dementia

Introduction: Diet and exercise influence the risk of cognitive decline (CD) and dementia through the food metabolome and exercise-triggered endogenous factors, which use the blood as a vehicle to communicate with the brain. These factors might act in concert with hippocampal neurogenesis (HN) to shape CD and dementia. Methods: Using an in vitro neurogenesis assay, we examined the effects of serum samples from a longitudinal cohort (n = 418) on proxy HN readouts and their association with future CD and dementia across a 12-year period. Results: Altered apoptosis and reduced hippocampal progenitor cell integrity were associated with exercise and diet and predicted subsequent CD and dementia. The effects of exercise and diet on CD specifically were mediated by apoptosis. Discussion: Diet and exercise might influence neurogenesis long before the onset of CD and dementia. Alterations in HN could signify the start of the pathological process and potentially represent biomarkers for CD and dementia

Personalized nutrition for dementia prevention

The role of nutrition has been investigated for decades under the assumption of one-size-fits-all. Yet there is heterogeneity in metabolic and neurobiological responses to diet. Thus a more personalized approach may better fit biological reality and have increased efficacy to prevent dementia. Personalized nutrition builds on the food exposome, defined as the history of diet-related exposures over the lifetime, and on its interactions with the genome and other biological characteristics (eg, metabolism, the microbiome) to shape health. We review current advances of personalized nutrition in dementia research. We discuss key questions, success milestones, and future roadmap from observational epidemiology to clinical studies through basic science. A personalized nutrition approach based on the best prescription for the most appropriate target population in the most relevant time-window has the potential to strengthen dementia-prevention efforts. © 2021 the Alzheimer's Associatio

Coffee polyphenols ameliorate early-life stress-induced cognitive deficits in male mice

Stress exposure during the sensitive period of early development has been shown to program the brain and increases the risk to develop cognitive deficits later in life. We have shown earlier that early-life stress (ES) leads to cognitive decline at an adult age, associated with changes in adult hippocampal neurogenesis and neuroinflammation. In particular, ES has been shown to affect neurogenesis rate and the survival of newborn cells later in life as well as microglia, modulating their response to immune or metabolic challenges later in life. Both of these processes possibly contribute to the ES-induced cognitive deficits. Emerging evidence by us and others indicates that early nutritional interventions can protect against these ES-induced effects through nutritional programming. Based on human metabolomics studies, we identified various coffee-related metabolites to be part of a protective molecular signature against cognitive decline in humans. Caffeic and chlorogenic acids are coffee-polyphenols and have been described to have potent anti-oxidant and anti-inflammatory actions. Therefore, we here aimed to test whether supplementing caffeic and chlorogenic acids to the early diet could also protect against ES-induced cognitive deficits. We induced ES via the limited nesting and bedding paradigm in mice from postnatal(P) day 2-9. On P2, mice received a diet to which 0.02% chlorogenic acid (5-O-caffeoylquinic acid) + 0.02% caffeic acid (3',4'-dihydroxycinnamic acid) were added, or a control diet up until P42. At 4 months of age, all mice were subjected to a behavioral test battery and their brains were stained for markers for microglia and neurogenesis. We found that coffee polyphenols supplemented early in life protected against ES-induced cognitive deficits, potentially this is mediated by the survival of neurons or microglia, but possibly other mechanisms not studied here are mediating the effects. This study provides additional support for the potential of early nutritional interventions and highlights polyphenols as nutrients that can protect against cognitive decline, in particular for vulnerable populations exposed to ES

Diet-Related Metabolites Associated with Cognitive Decline Revealed by Untargeted Metabolomics in a Prospective Cohort

SCOPE: Untargeted metabolomics may reveal preventive targets in cognitive aging, including within the food metabolome. METHODS AND RESULTS: A case-control study nested in the prospective Three-City study included participants aged >/=65 years and initially free of dementia. We contrasted 209 cases of cognitive decline and 209 controls (matched for age, gender and educational level) with slower cognitive decline over up to 12 years. This article is protected by copyright. All rights reserved Using a bootstrap-enhanced LASSO regression on the baseline serum metabolomes analyzed with LC-QTOF, we identified a signature of 22 metabolites associated with subsequent cognitive decline. The signature included three coffee metabolites, a biomarker of citrus intake, a cocoa metabolite, two metabolites putatively derived from fish and wine, three medium-chain acylcarnitines, glycodeoxycholic acid, lysoPC(18:3), trimethyllysine, glucose, cortisol, creatinine and arginine. Adding the 22 metabolites to a reference predictive model for cognitive decline (conditioned on age, gender and education and including ApoE-epsilon4, diabetes, BMI and number of medications) substantially increased the predictive performance: cross-validated Area Under the Receiver Operating Curve = 75% [95% CI 70-80%] compared to 62% [95% CI 56-67%]. CONCLUSIONS: Our untargeted metabolomics study supports a protective role of specific foods (e.g., coffee, cocoa, fish) and various alterations in the endogenous metabolism responsive to diet in cognitive aging