Dementia Linked To Inferior Nutrient Intake
Overview
While observational research indicates that nutrition may play a protective role in brain aging, intervention studies have yet to provide conclusive evidence. This gap between observational and interventional research may be due to the failure to consider interactions between different nutrients.
Researchers developed a nutrient status index to quantify the number of suboptimal statuses of omega-3 fatty acids, homocysteine, and vitamin D, with a range from 0 to 3. This index was then used to analyze its association with dementia incidence in participants aged 50 and older from the Framingham Heart Study Offspring cohort.
79 out of 968 participants developed dementia in 15.5 median follow-up years. Each point increase in the nutrient status index was linked to a 50% higher risk of dementia (hazard ratio [HR] = 1.50; 95% confidence interval [CI] = 1.16, 1.96). Participants with three high-risk statuses had a fourfold increase in dementia risk compared to those with no high-risk status (HR = 4.68; 95% CI = 1.69, 12.94).
The study found that concurrent nutrient deficiencies significantly contribute to dementia risk. These findings suggest that optimizing nutritional status could potentially reduce the risk of dementia, emphasizing the need for further research into multiple-nutrient approaches. Specifically, the study focused on the combined suboptimal statuses of omega-3 polyunsaturated fatty acids, homocysteine, and vitamin D, revealing that the associated risk of dementia was greater than that posed by other factors such as diabetes and apolipoprotein E ε4 carrier status. Future research should investigate whether improving these nutrient statuses can effectively reduce the risk of dementia.
Introduction
The increasing prevalence of dementia due to an aging population, along with its significant social and economic impacts, underscores the need for preventive strategies in the absence of curative treatments. Research has suggested that various nutritional factors, such as omega-3 polyunsaturated fatty acids (n-3 PUFAs), B vitamins, vitamin D, antioxidants, and polyphenols, may influence brain aging due to their antioxidant, anti-inflammatory, and vascular health benefits. Epidemiological studies support these findings; however, clinical trials focusing on single-nutrient supplementation have largely been unsuccessful.
One reason for the lack of efficacy in these trials may be the interaction of nutrients within multifactorial processes, where the absence of one nutrient can limit the benefits of others. Additionally, most clinical trials do not account for participants’ baseline nutrient statuses, which is crucial since only those with deficiencies are likely to benefit from supplementation. This is illustrated by secondary analyses of the VITACOG trial, where B-vitamin supplementation’s impact on brain atrophy was influenced by initial homocysteine levels.
To advance our understanding, it is essential to explore the cumulative effects of multiple nutrients and baseline nutrient statuses on brain aging. Currently, the literature on this subject is sparse, with only two longitudinal studies indicating that combined deficiencies in n-3 PUFAs, B vitamins, and vitamin D correlate with faster cognitive decline and a higher risk of dementia. More research is needed to investigate these interactions, particularly the combined impact of B vitamins, vitamin D, and n-3 PUFAs on dementia incidence. To address this, we developed a nutrient status index incorporating homocysteine (indicative of B6, B12, and folate status), vitamin D, and n-3 PUFAs, and examined its association with dementia incidence in the Framingham Heart Study (FHS) Offspring cohort, a prospective community-based study.
Method
The Framingham Heart Study (FHS) is a prospective community-based cohort study initiated in 1948 to investigate factors contributing to cardiovascular disease among residents of Framingham, Massachusetts. The Original cohort was established in 1948, and the Offspring cohort, including children of the Original cohort and their spouses, was established in 1971, enrolling 5124 participants. These participants have undergone ten examination cycles approximately every four years. This study focuses on participants aged 50 and older, free of dementia, with available biomarker data on homocysteine, 25-hydroxyvitamin D, and n-3 PUFAs, with the baseline set at exam 7. Of the 5124 Offspring cohort participants, 1525 had data on all three biomarkers and were free of dementia. After excluding 557 participants due to age or missing covariate data, 968 participants were included in the analysis.
Laboratory measurements were performed on fasting serum, plasma, and red blood cell samples collected and stored at −80°C. Plasma homocysteine levels were measured using high-performance liquid chromatography, serum 25-hydroxyvitamin D levels by radioimmunoassay, and red blood cell fatty acid composition by gas chromatography at exam 8. Despite the time gap between exams 7 and 8, the red blood cell fatty acid composition remains a reliable indicator of n-3 PUFA status due to its stability over time.
The study aimed to determine the incidence of all-cause dementia through December 2018, using diagnostic procedures previously detailed. Participants flagged for cognitive decline underwent neuropsychological examinations, and dementia diagnoses were confirmed by consensus between neurologists and neuropsychologists, based on DSM-IV criteria. Covariates were collected at baseline, including age, sex, education, smoking status, APOE genotype, physical activity, alcohol consumption, hypertension, diabetes, and depression.
A nutrient status index was constructed, indicating high-risk statuses for homocysteine, vitamin D, and n-3 PUFAs based on plausible mechanisms of action in preventing dementia. Cut-offs for high-risk levels were determined through visualizing dose-response relationships. Homocysteine levels ≥8 μmol/L, vitamin D levels ≤15 ng/mL, and an omega-3 index ≤5% were classified as high risk. The index ranged from 0 to 3, summing the number of high-risk statuses.
The study highlighted the association between suboptimal levels of these critical nutrients and increased dementia risk. Each additional suboptimal nutrient status heightened this risk, with a four-fold increase observed in participants with suboptimal levels for all three nutrients compared to those with optimal levels. These findings underscore the potential of multi-nutrient strategies in dementia prevention, suggesting future research into personalized supplementation or dietary interventions.
Statistical Analysis
To compare baseline characteristics, participants were categorized based on the number of high-risk nutrient statuses. Chi-squared tests were utilized for the categorical variables, while Kruskal–Wallis or ANOVA tests were utilized for the continuous variables.
For the main analysis, the study investigated the longitudinal association between the nutrient status index and the incidence of dementia. Multivariate-adjusted Cox proportional hazard models were employed, incorporating delayed entry and using age as the time scale. The models analyzed the nutrient status index both categorically and continuously. Model 1 adjusted for age, sex, education, and APOE ε4 carrier status, while Model 2 also included adjustments for physical activity, smoking, alcohol intake, hypertension, diabetes, and depression. The proportional hazard assumption was confirmed. The results are expressed as adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). These HRs indicate the dementia risk difference for those with a high-risk status (categorical) and the change in dementia risk per unit increase in the nutrient status index (continuous).
A sensitivity analysis assessed the robustness of the nutrient status index. This involved adjusting cut-offs by 10%, using cut-offs from a previous study, altering the definition of omega-3 PUFA status to include docosapentaenoic acid (DPA), and changing the age cut-off to ≥60 years. These adjusted indices were then associated with dementia incidence similarly to the primary analysis. The study also examined whether sex or APOE ε4 carrier status modified the association by testing for interactions with these variables.
A p-value of < 0.05 was considered statistically significant for the main analyses, and a p-value of < 0.10 was deemed significant for interaction tests. All analyses were conducted using RStudio version 1.1.463.
Result
The study characterized 968 participants with an average age of 61.4 years, 48% of whom were male. Approximately 22% carried at least one APOE ε4 allele. Participants’ nutrient status index, ranging from 0 to 3, indicated that 40% had one high-risk nutrient status. Those with more high-risk statuses tended to be male, had higher average body mass index, and were more likely smokers.
Over a median follow-up of 15.5 years, 79 participants developed dementia. Adjusted for multiple variables, the study found that each point increase in the nutrient status index was associated with a 50% higher risk of dementia. Specifically, those with three high-risk statuses had a fourfold increased risk compared to those without any high-risk status.
Sensitivity analyses confirmed the robustness of these findings across variations in nutrient cutoffs and study populations. Interaction analyses revealed that APOE ε4 carrier status significantly influenced the association between the nutrient status index and dementia incidence, with carriers showing a stronger positive association.
Comparing effect sizes, the study noted that the risk of dementia associated with the nutrient status index was substantial, similar to the risks posed by well-established factors such as smoking and diabetes. Specifically, the risk associated with the nutrient status index in APOE ε4 carriers was notable (HR = 2.05 per point increase), contrasting with non-carriers where the association was weaker and non-significant.
In conclusion, the study underscores the significant association between poor nutrient status and increased dementia risk, particularly pronounced in APOE ε4 carriers. These findings emphasize the potential role of dietary interventions in mitigating dementia risk, highlighting avenues for further research and public health strategies.
Conclusion
In their study, researchers developed a nutrient status index to assess the impact of nutrient deficiencies on dementia risk. They found that individuals with higher index scores, indicating suboptimal levels of homocysteine (a marker of B vitamins), vitamin D, and n-3 polyunsaturated fatty acids (PUFAs), faced an elevated risk of developing dementia compared to those with lower scores. Remarkably, having suboptimal levels of all three nutrients was associated with a four-fold increase in dementia risk. This effect size is considerable compared to other known risk factors for dementia such as smoking or diabetes.
The study also highlighted the role of APOE ε4 genotype, indicating that the association between nutrient status index and dementia risk was predominantly observed in carriers of this genetic variant. The findings underscored the substantial impact of combined nutrient deficiencies, suggesting that optimizing nutritional status could potentially mitigate dementia risk. Previous research has similarly shown associations between multiple-nutrient deficiencies and cognitive decline, though variations in study methodologies and nutrient cut-offs complicate direct comparisons.
The biological plausibility of these findings is supported by the diverse roles nutrients play in brain health. For instance, vitamin D helps regulate calcium homeostasis and reduce oxidative stress, while n-3 PUFAs possess anti-inflammatory properties crucial for neuronal health. Elevated homocysteine levels, on the other hand, negatively affect vascular function and may exacerbate neurodegenerative processes.
Looking ahead, the study calls for further research to refine optimal nutrient thresholds specific to different populations and explore potential synergistic effects among nutrients. This could inform future clinical trials aimed at assessing the impact of nutrient supplementation or dietary interventions on dementia prevention. Additionally, investigations into interactions between nutrient status and genetic factors like APOE ε4 genotype are warranted to better understand personalized approaches to dementia risk management.
In conclusion, the study underscores the significance of nutrient status as a modifiable risk factor for dementia. It advocates for tailored nutritional strategies to potentially reduce dementia incidence, emphasizing the importance of ongoing research in this field to optimize preventive measures.
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