Abstract
Healthy lifestyles are promising targets for prevention of cognitive aging, yet the optimal time windows for interventions remain unclear. We selected a case-control sample nested within the ...Nurses’ Health Study (starting year 1976, mean age = 51 years), including 14,956 women aged ≥70 years who were free of both stroke and cognitive impairment at enrollment in a cognitive substudy (1995–2001). Cases (n = 1,496) were women with the 10% worst slopes of cognitive decline, and controls (n = 7,478) were those with slopes better than the median. We compared the trajectories of body mass index (weight (kg)/height (m)2), alternate Mediterranean diet (A-MeDi) score, and physical activity between groups, from midlife through 1 year preceding the cognitive substudy. In midlife, cases had higher body mass index than controls (mean difference (MD) = 0.59 units, 95% confidence interval (CI): 0.39, 0.80), lower physical activity (MD = –1.41 metabolic equivalent of task–hours/week, 95% CI: –2.07, –0.71), and worse A-MeDi scores (MD = –0.16 points, 95% CI: –0.26, –0.06). From midlife through later life, compared with controls, cases had consistently lower A-MeDi scores but a deceleration of weight gain and a faster decrease in physical activity. In conclusion, maintaining a healthy lifestyle since midlife may help reduce cognitive decline in aging. At older ages, both deceleration of weight gain and a decrease in physical activity may reflect early signs of cognitive impairment.
Understanding which aspects of diet and lifestyle may predispose to the development of Alzheimer’s disease and identifying populations vulnerable to prevention by lifestyle modification is a critical ...asset for precision prevention. However, diet is a complex exposure that is extremely challenging to evaluate using questionnaires in human populations, and inherent measurement error in self‐reported dietary intake data has certainly hampered our way to study properly the impact of nutrition on brain health in epidemiological studies.
Measuring markers of nutritional exposure in biological matrices represents a unique way to monitor nutrition and dietary intakes. Candidate biomarkers have been complemented recently by a comprehensive investigation in biological matrices of the chemicals derived from foods after digestion and metabolism, the so‐called food metabolome, that has started to reveal novel dietary biomarkers. High‐throughput metabolomics now enable the measurement of markers of food exposures in biological matrices with unprecedented depth, while capturing the heterogeneity in the response to dietary bioactives from diet across individuals and populations. Thus biomarkers are critical for precision nutrition, as they reflect nutritional status, a product of intakes and of endogenous metabolism, itself linked to many factors, including personal genetic background and microbiome.
This “Perspectives” presentation will overview a few recent exploratory studies on signatures of healthy diets and brain health in the food metabolome as examples to discuss challenges and opportunities for further developments. We will also address opportunities of development of multi‐biomarker panels combining self‐reported nutritional intake data with biomarker data from biofluids (blood and urine) to improve assessment of healthy dietary patterns as preventive approaches in dementia.
The main objective of this study was to evaluate the association of the insomnia-anxiety comorbidity with incident type 2 diabetes (T2D) in a large prospective cohort. We selected adults without ...diabetes at baseline from the French NutriNet-Santé cohort who had completed the trait anxiety subscale of the Spielberger State-Trait Anxiety Inventory (STAI-T, 2013-2016) and a sleep questionnaire (2014); insomnia was defined according to established criteria. Using multivariable Cox models, we compared T2D risk across 4 groups: no insomnia or anxiety (reference), insomnia alone, anxiety alone (STAI-T ≥ 40), and comorbid anxiety and insomnia. Among 35,014 participants (mean baseline age: 52.4 ± 14.0 years; 76% women), 378 (1.1%) developed T2D over a mean follow-up of 5.9 ± 2.1 years. Overall, 28.5% of the sample had anxiety alone, 7.5%-insomnia alone, and 12.5%-both disorders. In the fully-adjusted model, a higher T2D risk was associated with anxiety-insomnia comorbidity (HR = 1.40; 95% CI 1.01, 1.94), but not with each disorder separately, compared to the group without insomnia or anxiety. The findings supported a positive association between anxiety-insomnia comorbidity and incident T2D among general-population adults. Future research using clinical diagnoses of mental disorders could confirm the findings and guide diabetes prevention programs.
Recent evidence suggests that a high glycemic load (GL) diet is a risk factor for dementia, especially among apolipoprotein E ε4 allele (
) carriers, while its association with cognitive decline is ...poorly known. Here, we investigated the association of high-GL meals with cognitive decline in older adults during a 12-year follow-up, according to their
carrier status. We used random-effect models and data from 2539 elderly participants from the Three-City study who completed a food frequency questionnaire (FFQ) to longitudinally assess the association of GL with changes in different cognitive domains (verbal fluency, visual memory, attention, visual motor processing speed, episodic memory). In
carriers, afternoon snack with high GL was significantly associated with cognitive decline in visual memory, episodic memory, and global cognition compared with
non-carriers. This study suggests a detrimental association between a high-GL diet and cognitive decline. The promotion of a low GL diet as a target to prevent cognitive decline in high-risk populations deserves more research.
Background
There is substantial inter‐individual variability in the metabolic and neurobiological responses to diet. Deciphering such heterogeneity ‐ the foundation of precision medicine ‐ may help ...refine nutritional interventions for the prevention of dementia. The development of high‐throughput technologies applied to biological matrices has fostered characterization of the molecular architecture underpinning such heterogeneity across individuals, allowing to refine knowledge on how specific elements of the food matrix may impact pathways leading to dementia. Moreover, a critical step in precision medicine is to interrogate effect modification by some biological modulators that may define individualized vulnerability profiles.
Method
We will review recent epidemiological and clinical studies leveraging biomarkers, genomics and microbiomics for the identification of molecular pathways underlying the effect of nutrition on brain health and of factors of heterogeneity in metabolism and efficacy (eg, baseline nutritional status, host genome and the microbiome).
Result
Recent advances in omics (proteomics, metabolomics, nutrigenomics, epigenetics and transcriptomics) have started reveal both neurobiological pathways that may be corrected by appropriate diet as well as potential novel diet‐related targets for preventive interventions. Moreover, observational studies and randomized controlled trials have suggested that nutrient supplementation may specifically benefit individuals with baseline nutrient deficiencies. Emerging studies also suggest gene‐by‐environment interactions in dementia, as well as a strong influence of the microbiota as a key mediator and/or modulator on the way nutrients are absorbed and metabolized and how they exert biological effects on the brain along the so‐called gut brain axis.
Conclusion
A precision medicine approach of nutrition and brain health needs to be expanded, from observational epidemiology to clinical research through basic science. Given the heterogeneity of nutritional behaviors across cultures, this will necessitate cross‐cohort collaborative projects to identify robust nutritional exposures that determine neurobiological changes leading to dementia. The multiple dimensions of nutrition will have to be captured through repeated behavioral, environmental and biological measures, both reliable and valid in cross‐cultural populations. Measurement of genomic variation and of the individual microbiome have started to develop in epidemiological studies and should be expanded. Most promising strategies will be validated in preclinical models and in appropriately powered clinical trials.
Abstract
Background
Optimal nutrition may prevent dementia; several nutrients have been associated with dementia risk, yet randomized controlled trials (RCT) testing the efficacy of nutrient ...supplementation for the prevention of dementia have remained largely disappointing so far. One of the reasons for the inability of RCT to demonstrate the efficacy of nutrient supplementation may be their failure to take into account basal nutritional status (as supplementation may benefit only people with nutrient deficiency). Epidemiology is a unique tool to understand and define the basal nutritional deficiencies that may primarily deserve correction with (multi)‐nutrient supplementation. We leveraged the large prospective French Three‐City (3C) cohort study, with multiple nutrient biomarkers measured at study entry and 17 years of follow‐up for the incidence of dementia, to define a micro‐nutritional biological status (MNBS) score that is associated with subsequent dementia risk.
Method
We included n=666 participants from the 3C study not demented and with blood measurements of 22 nutrients (12 fatty acids, 6 carotenoids, vitamin D, 2 forms of vitamin E, and vitamin A) at baseline, who were followed for up to 17 years for incidence of dementia. To construct our MNBS score, we: (1) defined the primary nutrients of interest, based on both literature review and 3C data; (2) defined plasma concentration thresholds, based on both existing thresholds (eg, existing recommendations, as for vitamin D) and 3C data (modeling each individual nutrient with dementia risk using Cox models with penalized splines); (3) computing a summary MNBS score and estimating its multivariable association with dementia risk.
Result
Our MNBS score included 3 nutrient groups significantly associated with dementia risk in our cohort: 25(OH)D; EPA+DHA; total carotenoids. Each component was divided into 3 biological levels (low, 0 point; intermediate, 1 point; high, 2 points), and the total score ranged from 0 to 6 points (Figure 1). Each increase of 1 point of the score was associated with a 20% reduction of dementia risk (p=0.002) (Figure 2).
Conclusion
A biological score assessing micro‐nutritional status globally is strongly associated with dementia risk. B vitamins may increase the predictive performance of the score and will be incorporated shortly.
Background
Optimal nutrition may prevent dementia; several nutrients have been associated with dementia risk, yet randomized controlled trials (RCT) testing the efficacy of nutrient supplementation ...for the prevention of dementia have remained largely disappointing so far. One of the reasons for the inability of RCT to demonstrate the efficacy of nutrient supplementation may be their failure to take into account basal nutritional status (as supplementation may benefit only people with nutrient deficiency). Epidemiology is a unique tool to understand and define the basal nutritional deficiencies that may primarily deserve correction with (multi)‐nutrient supplementation. We leveraged the large prospective French Three‐City (3C) cohort study, with multiple nutrient biomarkers measured at study entry and 17 years of follow‐up for the incidence of dementia, to define a micro‐nutritional biological status (MNBS) score that is associated with subsequent dementia risk.
Method
We included n=666 participants from the 3C study not demented and with blood measurements of 22 nutrients (12 fatty acids, 6 carotenoids, vitamin D, 2 forms of vitamin E, and vitamin A) at baseline, who were followed for up to 17 years for incidence of dementia. To construct our MNBS score, we: (1) defined the primary nutrients of interest, based on both literature review and 3C data; (2) defined plasma concentration thresholds, based on both existing thresholds (eg, existing recommendations, as for vitamin D) and 3C data (modeling each individual nutrient with dementia risk using Cox models with penalized splines); (3) computing a summary MNBS score and estimating its multivariable association with dementia risk.
Result
Our MNBS score included 3 nutrient groups significantly associated with dementia risk in our cohort: 25(OH)D; EPA+DHA; total carotenoids. Each component was divided into 3 biological levels (low, 0 point; intermediate, 1 point; high, 2 points), and the total score ranged from 0 to 6 points (Figure 1). Each increase of 1 point of the score was associated with a 20% reduction of dementia risk (p=0.002) (Figure 2).
Conclusion
A biological score assessing micro‐nutritional status globally is strongly associated with dementia risk. B vitamins may increase the predictive performance of the score and will be incorporated shortly.
Nutrition constitutes an interesting approach for the prevention of age-related brain disorders. The objective of this review was to examine the most recent evidence on the association between ...adherence to a Mediterranean diet (MeDi) and cognitive health among elderly individuals.
Based on available epidemiological studies, two meta-analyses published in 2013 have underlined a protective effect of a greater MeDi adherence on cognitive health, including a reduced risk of Alzheimer's disease and cognitive impairment. Since then, six additional studies, from longitudinal cohorts or post-hoc analyses of randomized controlled trials conducted in the USA and Europe, have been published and provided mixed results. Potential reasons for such discrepancies include methodological limitations inherent to observational studies, and interactions between diet, environmental factors, such as those enhancing cognitive reserve, chronic diseases, and genetic factors.
Overall, available evidence suggests that the MeDi might exert a long-term beneficial effect on brain functioning. However, more high-powered observational studies with long-term follow-up for cognition and randomized controlled trials assessing the impact of shifting to a MeDi on cognitive functions are still needed in various populations.
Vascular risk factors have been proposed as important targets for the prevention of dementia. As lipid fractions represent easily modifiable targets, we examined the longitudinal relationship of ...baseline lipid fractions with 13-y incident dementia and its subtypes (Alzheimer disease AD and mixed or vascular dementia) in older community-dwelling persons.
Non-institutionalized persons aged 65+ y (n = 9,294) were recruited for the Three-City Study (3C Study), a population-based cohort study from the electoral rolls of the cities of Dijon, Bordeaux, and Montpellier, France, between March 1999 and March 2001. Follow-up examinations were performed every 2 y after the baseline assessment. The final study sample comprised 7,470 participants from the 3C Study (mean age ± standard deviation SD 73.8 ± 5.3 y, 61.0% women) who were prospectively followed up for up to 13 y. Fasting lipid fractions (triglycerides TGs, high-density lipoprotein cholesterol HDL-C, low-density lipoprotein cholesterol LDL-C, total cholesterol TC) were studied as continuous variables, and results are reported per SD increase of each lipid fraction. Incident dementia and its subtypes were studied as censored variables using Cox models with age as time scale. Analyses were adjusted for sex, study center, and educational level, as well as vascular risk factors and apolipoprotein E (APOE) ε4 genotype. We corrected for multiple testing, yielding a significance threshold of 0.0169. p-Values above the significance threshold but less than 0.05 were considered nominally significant. During a mean (± SD) follow-up period of 7.9 ± 3.6 y, 779 participants developed incident dementia (n = 532 AD and n = 154 mixed or vascular dementia). Higher LDL-C and TC concentrations at baseline were associated with an increased risk of AD (hazard ratio HR per SD increase = 1.13 95% CI 1.04-1.22, p = 0.0045, and HR = 1.12 1.03-1.22, p = 0.0072, respectively). These associations were largely unchanged after adjustment for vascular risk factors and were attenuated after adjustment for APOEε4 (HR per SD increase = 1.12 1.03-1.23, p = 0.0110, and HR = 1.12 1.02-1.23, p = 0.0171, respectively). Higher TG concentrations at baseline were associated with an increased risk of all dementia (HR per SD increase = 1.11 1.03-1.19, p = 0.0044) and mixed or vascular dementia (HR = 1.21 1.04-1.41, p = 0.0163). However, these associations disappeared after adjusting for vascular risk factors (HR = 1.07 0.98-1.17, p = 0.1374, and HR = 1.17 0.96-1.42, p = 0.1206, respectively). Main limitations of the study include interval censoring of incident dementia cases, potential selective survival bias, and the fact that variation in lipid concentrations during follow-up could not be accounted for in the analyses.
In a large population-based sample of older community-dwelling persons with up to 13 y of follow-up, we observed that higher LDL-C and TC concentrations were associated with an increased risk of AD. This result was independent of vascular risk factors and was attenuated after adjustment for APOEε4 carrier status. TG and HDL-C concentrations were not associated with risk of incident dementia or its subtypes after accounting for vascular risk factors.
PDF
