Introduction
The number of people living with dementia is increasing worldwide due to the aging of the population [
1]. With a total of 46 million people living with dementia worldwide in 2015, this number is estimated to increase to 131.5 million by 2050 [
2]. As no effective treatment for dementia exists, research on modifiable risk factors is critically important to derive health recommendations and preventive interventions. A healthy lifestyle has been suggested to be one of the modifiable risk factors for cognitive decline and dementia, and prevention studies, therefore, increasingly focus on lifestyle and cognition [
3].
Nutrition is one of the lifestyle factors that could prevent or delay cognitive decline and dementia [
4,
5]. It has been suggested that specific foods (e.g., e.g., fatty fish [
6‐
10], red wine [
6‐
8]) are positively associated with cognition, but this is not consistently reported [
11]. Moreover, foods are usually not consumed in isolation. A dietary pattern comprises the intake of multiple foods and nutrients in combination. Also, investigating dietary patterns may be more informative for public health purposes, such as the development of food-based dietary guidelines. It has, therefore, been suggested that relationships between food intake and cognition should be evaluated by taking into account dietary patterns, rather than the intake of single food or nutrients [
12].
Several dietary patterns have been established, such as the Mediterranean diet and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet [
13]. The Mediterranean diet comprises a high intake of whole grains, fruits, vegetables, fish and oils, while limiting the intake of fat, salt, alcohol, dairy and meat [
14]. Adherence to the Mediterranean diet has been associated with a lower risk for cognitive decline, dementia, and AD [
13]. The MIND diet is a modified hybrid of the Dietary Approach to Systolic Hypertension diet (DASH, aiming to reduce blood pressure) and Mediterranean diet, reflecting the most compelling scientific evidence on foods and nutrients that protect the brain [
15,
16]. Compared to the Mediterranean diet, the MIND diet was defined to encourage healthy brain aging, e.g., e.g., promoting the intake of berries and green leafy vegetables, while limiting the intake of animal-based and highly saturated fat foods. Adherence to the MIND diet was found to be associated with lower incidence of AD [
16], cognitive decline [
13,
15,
17,
18] and subjective memory complaints [
19].
The relationships between greater adherence to these diets and better cognition, slower cognitive decline and decreased risk for dementia could not always be replicated (e.g., e.g., [
20‐
22]). Methodological challenges such as the sensitivity of outcome measures, the most sensitive time periods in life course and the true adherence of cultural diverse populations to the predefined diets might have contributed to these inconsistent findings [
23]. A complementary strategy for the analysis of dietary patterns is a bottom-up approach, using data-driven methodologies to identify underlying dietary patterns of the specific population under study [
24]. For example, a Japanese study found that a dietary pattern characterized by high intake of soybean products, vegetables and dairy products and a low intake of rice was associated with reduced risk for dementia [
25]. In a Swedish sample, the ‘prudent’ pattern, characterized by vegetables, fruit, oil and fish, was associated with less decline in MMSE [
26] and in an American sample, a pattern characterized by higher intakes of amongst others salad dressing, several vegetables, fruit, nuts, fish and poultry, and a lower intake of high-fat dairy products, red meat, organ meat, and butter was associated with lower risk for AD [
27].
Most studies on cognition and diet have been conducted in general population-based samples and could lead to primary prevention recommendations. However, studies in individuals at increased risk for AD, e.g., e.g., subjects who report or show symptoms of cognitive decline [
28,
29] may be particularly informative. These samples are expected to include more subjects with AD pathology, which could be counteracted by certain nutrients or diets, to be leveraged for secondary prevention. A recent study in memory-clinic patients with subjective cognitive decline (SCD), a group known to be at increased risk for AD [
28], found a positive association between the ‘high-Veggy’ dietary pattern, characterized by fruit, vegetables, fish, and fibers, with global cognition using a data-driven approach [
30].
We aimed to cross-sectionally investigate the associations between dietary patterns and cognition in a memory clinic-based sample of German elderly free of dementia. More specifically, the association between adherence to the Mediterranean diet, MIND diet and data-derived dietary patterns and memory, language, executive functions, working memory and visuospatial functions was investigated.
Results
Participants were on average 69.4 ± 5.6 years old, included 202 (52%) females, had a MMSE score of 29.1 ± 1.2 and had completed 14 (median; IQR 12–17) years of education. Descriptive statistics are listed in Table
1. The average Mediterranean diet score was 4.5 ± 1.9 (max. 9) and the average MIND diet score was 6.4 ± 1.4 (max. 15). MD and MIND scores were moderately correlated (
r = 0.37) and did not differ between subgroups (SCD, REL, MCI, CON).
Age (years) | 69.4 ± 5.6 |
Sex female n (%) | 202 (51.9) |
Education (years)b | 14.0 (IQR: 12.0–17.0) |
ApoE4-carrier n (%)a | 107 (27.9) |
BMI (kg/m2) | 25.9 ± 3.7 |
Smoking status n (%)b | |
Never smoked | 192 (49.4) |
Former smokers | 165 (42.4) |
Current smokers | 32 (8.2) |
Physical activity scoreb | 358.4 ± 142.4 |
Total daily energy intake (kcal/day) | 2315.4 ± 746.5 |
Cognitive status n (%) | |
Cognitively normal | 329 (85) |
MCI | 60 (15) |
MMSE total score, max. 30 | 29.1 ± 1.2 |
Mediterranean diet, max. 9 | 4.5 ± 1.9 |
MIND diet, max. 15 | 6.4 ± 1.4 |
First, associations of cognition with the Mediterranean and MIND diet scores were investigated (Table
2). Using model 1, we found associations between higher Mediterranean diet score and better memory (
p = 0.003) and language (
p = 0.017). In addition, higher MIND diet score was associated with better memory (
p = 0.046). In the fully adjusted model, the associations of greater adherence to both the Mediterranean and MIND diet with better memory remained (
p = 0.004 and
p = 0.029, respectively), whereas the associations with language fell short of significance (Mediterranean
p = 0.051, MIND
p = 0.053). After the exclusion of subjects with MCI, associations of higher Mediterranean and MIND diet score with language became significant (Model 2:
p = 0.031 and
p = 0.027, respectively), while the association between MIND and memory was lost (
p = 0.290).
Table 2
Mediterranean and MIND diet scores on cognitive outcomes
Memory | | | |
Model 1 | Total | 0.051 [0.048 to 0.053]* | 0.042 [0.001 to 0.082]* |
Model 2 | Total | 0.049 [0.014 to 0.085]* | 0.045 [0.003 to 0.087]* |
Model 2 | CN | 0.037 [0.009 to 0.064]* | 0.019 [− 0.014 to 0.051] |
Language | | | |
Model 1 | Total | 0.040 [0.023 to 0.057]* | 0.036 [− 0.003 to 0.076] |
Model 2 | Total | 0.033 [− 0.002 to 0.067] | 0.039 [− 0.002 to 0.079] |
Model 2 | CN | 0.030 [0.003 to 0.058]* | 0.037 [0.004 to 0.069]* |
Executive functioning | | | |
Model 1 | Total | 0.018 [0.001 to 0.036] | 0.013 [− 0.028 to 0.055] |
Model 2 | Total | 0.013 [− 0.023 to 0.050] | 0.014 [− 0.029 to 0.057] |
Model 2 | CN | 0.014 [− 0.016 to 0.044] | 0.014 [− 0.022 to 0.049] |
Working memory | | | |
Model 1 | Total | 0.025 [0.006 to 0.043] | .028 [− 0.014 to 0.070] |
Model 2 | Total | 0.022 [− 0.017 to 0.060] | .031 [− 0.014 to 0.076] |
Model 2 | CN | 0.025 [− 0.011 to 0.060] | .031 [− 0.011 to 0.073] |
Visuospatial functioning | | | |
Model 1 | Total | 0.002 [− 0.014 to 0.017] | .014 [− 0.021 to 0.049] |
Model 2 | Total | − 0.010 [− 0.042 to 0.022] | .014 [− 0.024 to 0.052] |
Model 2 | CN | − 0.006 [− 0.035 to 0.023] | .026 [− 0.008 to 0.059] |
Subsequently, with the use of PCA, we identified six data-derived dietary patterns, explaining 44% of the variance. We named the dietary patterns (1) ‘Warm meal’, (2) ‘Vegetables’, (3) ‘Cereals and nuts’, (4) ‘Alcoholic beverages’, (5) ‘Bread meal’ and 6) ‘Snacks’ based on the highest intake of the dietary pattern contents (Supplementary table 5: loading of food groups on PCA factors).
Groups did not differ regarding these patterns, except that subjects with MCI had lower scores for the ‘Alcoholic beverages’ component.
Table
3 presents the associations of the PCA-based dietary patterns with the cognitive domains. Higher ‘Alcoholic beverages’ dietary pattern score was associated with higher scores on all domains except for visuospatial functioning in all models. Specifically, we found that a higher ‘Alcoholic beverages’ dietary pattern score was related to better memory (
p = 0.001), language (
p = 0.001), executive functioning (
p = 0.001) and working memory (
p < 0.001). In addition, higher ‘Cereals and Nuts’ dietary pattern score was associated with better language (
p = 0.041), but only in the fully adjusted model (Model 3). Using model 1, we found an association between higher adherence to the ‘Vegetables’ pattern and better memory (
p = 0.039), which lost significance in models 2 (
p = 0.059) and 3 (
p = 0.080).
Table 3
Data-derived dietary patterns and cognitive outcomes
Memory | Model 1 | Total | − 0.023 [− 0.081 to 0.036] | 0.060 [0.003 to 0.118]* | 0.024 [− 0.036 to 0.084] | 0.095 [0.034 to 0.156]* | − 0.009 [− 0.067 to 0.048] | 0.015 [− 0.043 to 0.074] |
| Model 2 | Total | − 0.029 [− 0.094 to 0.035] | 0.058 [− 0.002 to 0.119] | 00.035 [− 0.028 to 0.097] | 0.093 [0.031 to 0.154]* | − 0.020 [− 0.084 to 0.045] | 0.004 [− 0.062 to 0.071] |
| Model 3 | Total | 0.021 [− 0.057 to 0.098] | 0.057 [− 0.007 to 0.121] | 0.061 [− 0.005 to 0.127] | 0.108 [0.042 to 0.175]* | .000 [− 0.035 to 0.036] | 0.046 [− 0.033 to 0.125] |
| Model 3 | CN | 0.047 [− 0.013 to 0.107] | 0.045 [− 0.005 to 0.096] | 0.055 [.002 to 0.109]* | 0.071 [0.018 to 0.124]* | .044 [− 0.009 to 0.098] | .051 [− 0.011 to 0.114] |
Language | Model 1 | Total | − 0.016 [− 0.072 to 0.040] | 0.052 [− 0.003 to 0.108] | 0.051 [− 0.007 to 0.109] | 0.104 [0.046 to 0.162]* | .019 [− 0.037 to 0.074] | − 0.003 [− 0.060 to 0.053] |
| Model 2 | Total | − 0.027 [− 0.090 to 0.035] | 0.040 [− 0.019 to 0.098] | 0.046 [− 0.014 to 0.106] | 0.099 [0.040 to 0.158]* | 0.002 [− 0.060 to 0.064] | − 0.029 [− 0.093 to 0.035] |
| Model 3 | Total | 0.010 [− 0.064 to 0.085] | 0.035 [− 0.027 to 0.096] | 00.067 [0.003 to 0.131]* | 0.110 [0.046 to 0.174]* | .010 [− 0.057 to 0.077] | 0.009 [− 0.068 to 0.085] |
| Model 3 | CN | − 0.005 [− 0.065 to 0.055] | .044 [− 0.006 to 0.094] | 0.052 [− 0.001 to 0.105] | 0.054 [0.001 to 0.107]* | .044 [− 0.009 to 0.097] | 0.002 [− 0.060 to 0.065] |
Exec. function | Model 1 | Total | − 0.016 [− 0.075 to 0.043] | 0.021 [− 0.037 to 0.080] | 0.027 [− 0.034 to 0.088] | 0.102 [0.041 to 0.163]* | − 0.001 [− 0.058 to 0.057] | − 0.007 [− 0.066 to 0.052] |
| Model 2 | Total | − 0.024 [− 0.090 to 0.043] | 0.010 [− 0.052 to 0.072] | 0.029 [− 0.035 to 0.093] | 0.104 [0.042 to 0.167]* | − 0.016 [− 0.082 to 0.050] | − 0.022 [− 0.089 to 0.046] |
| Model 3 | Total | 0.000 [− 0.079 to 0.079] | − 0.003 [− 0.068 to 0.063] | 0.048 [− 0.020 to 0.116] | 0.113 [0.045 to 0.181]* | − 0.020 [− 0.092 to 0.051] | − 0.001 [− 0.082 to 0.080] |
| Model 3 | CN | − 0.011 [− 0.077 to 0.001] | 0.021 [− 0.077 to 0.056] | 0.031 [− 0.028 to 0.090] | 0.056 [− 0.002 to 0.115] | .027 [− 0.032 to 0.086] | 0.009 [− 0.060 to 0.077] |
Working mem | Model 1 | Total | − 0.037 [− 0.099 to 0.025] | 0.018 [− 0.043 to 0.079] | 0.052 [− 0.012 to 0.116] | 0.122 [0.058 to 0.185]* | − 0.010 [− 0.071 to 0.051] | − 0.007 [− 0.070 to 0.055] |
| Model 2 | Total | − 0.045 [− 0.114 to 0.025] | 0.005 [− 0.060 to 0.070] | 0.048 [− 0.019 to 0.115] | 0.122 [0.056 to 0.187]* | − 0.023 [− 0.092 to 0.046] | − 0.019 [− 0.090 to 0.052] |
| Model 3 | Total | − 0.019 [− 0.100 to 0.063] | − 0.014 [− 0.083 to 0.054] | 0.067 [− 0.004 to 0.138] | 0.132 [0.061 to 0.202]* | − 0.034 [− 0.108 to 0.041] | − 0.003 [− 0.087 to 0.081] |
| Model 3 | CN | − 0.035 [− 0.112 to 0.043] | 0.008 [− 0.057 to 0.073] | 0.067 [− 0.001 to 0.136] | 0.088 [0.019 to 0.156]* | .011 [− 0.058 to 0.080] | .009 [− 0.071 to 0.088] |
Visuosp. Func | Model 1 | Total | 0.023 [− 0.029 to 0.075] | 0.024 [− 0.027 to 0.075] | 0.033 [− 0.021 to 0.087] | 00.024 [− 0.031 to 0.078] | − 0.009 [− 0.060 to 0.042] | .004 [− 0.049 to 0.056] |
| Model 2 | Total | 0.015 [− 0.043 to 0.073] | 0.009 [− 0.045 to 0.063] | 0.029 [− 0.027 to 0.085] | 0.023 [− 0.032 to 0.079] | − 0.044 [− 0.102 to 0.013] | − 0.021 [− 0.080 to 0.038] |
| Model 3 | Total | 0.012 [− 0.058 to 0.082] | − 0.003 [− 0.061 to 0.054] | 0.032 [− 0.028 to 0.092] | 0.031 [− 0.029 to 0.091] | − 0.046 [− 0.109 to 0.017] | − 0.015 [− 0.087 to 0.057] |
| Model 3 | CN | 0.000 [− 0.062 to 0.062] | 0.009 [− 0.043 to 0.062] | 0.029 [− 0.026 to 0.84] | − 0.001 [− 0.056 to 0.054] | − 0.020 [− 0.076 to 0.035] | − 0.012 [− 0.015 to 0.010] |
After the exclusion of subjects with MCI, analyses were repeated using the fully adjusted model (Model 3). Higher adherence to the ‘Alcoholic beverages’ dietary pattern remained associated with better memory (p = 0.009), language (p = 0.045) and working memory (p = 0.012). The association with executive functions, however, attenuated and became non-significant (p = 0.060). Also, the association between the ‘Cereals and Nuts’ dietary pattern and better language attenuated in the cognitive unimpaired and became non-significant (p = 0.055). However, we did find an association between higher adherence to the ‘Cereals and Nuts’ dietary pattern and better memory (p = 0.042) in the cognitively normals.
Discussion
In this study, we found that higher adherence to the Mediterranean diet or the MIND diet was associated with aspects of cognition in an elderly sample free of dementia, enriched with individuals at increased risk for AD. More specifically, higher adherence to MD and MIND was associated with better memory, and exclusion of MCI subjects revealed that Mediterranean and MIND diet were related to language in the unimpaired group. In addition, an empirical dietary pattern mainly characterized by intake of alcohol was associated with several cognitive domain scores. Although exclusion of MCI subjects attenuated the associations with this component, most remained significant.
These results are in line with population-based studies, which observed a positive association between adherence to the Mediterranean diet [
43‐
46], or MIND diet and cognitive decline or dementia [
15,
16,
18,
20]. While not all cross-sectional [
21,
22] and longitudinal [
47‐
49] studies did replicate these findings, a meta-analysis on the Mediterranean diet and a systematic review of the MIND diet support that greater adherence to these diets are positively associated with cognitive functioning, cognitive decline and AD [
13,
50,
51]. Extending the evidence from these population-based studies, we here show that higher adherence to the Mediterranean diet and MIND diet are also associated with cognitive outcomes in a sample enriched with subjects who are either clinically or genetically at increased risk for AD.
The associations between the dietary patterns and cognition were most pronounced for memory and language. This has also been observed in some other studies [
52,
53] and may be mediated by dietary effects on mediotemporal atrophy [
53] or on cerebral amyloid pathology [
54], which first affects memory function. Our language tasks assessed mainly verbal fluency performance. Verbal fluency was shown to be affected in individuals with amnestic MCI and cognitive complaints (e.g., [
55]) and it relies on storage and retrieval of verbal information from semantic memory. As our sample was enriched for AD risk, and memory and language are affected early in the course of AD, it is tempting to speculate that the apparent specificity of the diet–cognition associations which we observed stems from protective effects of MEDI and MIND diets which mitigate early cognitive effects of AD. This hypothesis will need to be examined with biomarker data in DELCODE and other deeply phenotyped samples.
Regarding confounders, it is not likely that the associations that were found were driven by cardiovascular risk factors, because further adjustment for these diseases (data not shown) did not change the betas of the associations. After exclusion of individuals with cognitive impairment, some associations attenuated in significance or effect size. Analyses in larger samples are needed to investigate whether these changes indeed indicate different associations in different subgroups, or whether they were due to statistical power loss.
Longitudinal and imaging analyses in DELCODE will allow us to address sub-group analysis as well as the biological correlates of different dietary patterns.
A methodological issue with predefined dietary patterns is that they may not well represent the typical diet in many countries. We, therefore, supplemented the analysis with a data-driven approach. Two of the six data-derived dietary patterns also revealed a positive association with better cognition, PCA pattern 4 ‘Alcoholic beverages’ (being related to with better functioning in several domains), and PCA pattern 3 ‘Cereals and Nuts’ (being related to language in the total group and with memory in the cognitively normal group).
Our findings with respect to alcohol intake suggest a possibly beneficial effect of mild to moderate alcohol consumption for cognition, as has been described before in longitudinal studies [
56‐
59]. Whereas light to moderate alcohol consumption might be beneficial for cognitive health, high alcohol intake or abuse of alcohol has been shown to be detrimental for brain function due to a U-shaped dose–response relationship [
60,
61]. The majority of our sample had a moderate ethanol intake (total group mean 18.8 ± 24.4 g/day) which is in accordance with the alcohol guidelines of the Mediterranean diet (84% of females < 25 g/day, 88% of males < 50 g/day). Subjects with MCI had lower scores for PCA component 4, but the total amount of alcohol intake per day was not different, suggesting that all components of PCA4 contribute to the observed association and not solely the total alcohol intake. To rule out reversed causation, we excluded MCI patients and nearly all associations remained significant after exclusion. Thus, subjects worried about their memory for good reasons (i.e., subjects with MCI) may reduce their alcohol intake, but the observed associations between the “alcoholic beverages” component and cognition unlikely result from this change. It would be interesting for future studies to look into foods that often accompany alcohol intake, such as fish meals, that might also contribute to the observed positive association. Fruit was negatively loading on the ‘alcoholic beverages’ pattern. However, additional adjusting for fruit intake did not change the associations (data not shown).
Regarding the cereals and nuts, and bread meal pattern, we have found inconsistent results. Wholegrain and nuts are included in the Mediterranean diet and MIND guidelines, because their potential beneficial health effects can primarily be ascribed to fiber and phytonutrients [
62,
63]. However, the inconsistent findings of the present study are in line with previous studies that did not find a relationship between wholegrain and cognitive function or decline [
64,
65]. Results from studies that investigated nuts in relation to both outcomes have been mixed, as some found associations, while others did not [
48,
66‐
68].
The primary strength of this study involved the study population, as the study was conducted in a sample of elderly that were free of dementia, enriched with individuals at increased risk for AD. Results from the present study are a significant addition to the current literature, which is mainly based on population-based samples. Second, we used an extensive neuropsychological test battery to assess cognitive functioning, which is more sensitive to differences compared to measures of global cognitive functioning such as the MMSE. Third, we used a state-of-the-art psychometrics method to aggregate neuropsychological scores into cognitive domains scores. Fourth, we used a detailed food frequency questionnaire, providing information on the amount and frequency of nutrient and food intake, which was modified specifically for a German population, which enabled us to use a combination of both predefined and data-derived dietary patterns to assess adherence to dietary patterns in this study population.
This study has several limitations. The cross-sectional study design precludes conclusions about temporality of associations or causality. Longitudinal data will become available in DELCODE and will be used to study whether diet is associated with future cognitive decline. The analyzed sample consists of several subgroups, which we analyzed together as they did not differ regarding diet and—with the exception of MCI patients—performed within normal limits at neuropsychological testing. Individuals with amnestic MCI might have had difficulties in filling out the FFQ. However, all study participants had a study partner (e.g., spouse) to assist and we excluded questionnaires indicating an unrealistic nutritional intake. It has also been reported that FFQs from MCI patients are valid if a study partner is involved [
69]. We used a FFQ, which is subject to measurement error. To account for potential systematic measurement error, we adjusted the relationships under study for total energy intake [
70]. However, we acknowledge the possible presence of non-differential misclassification, which may have led to bias towards the null [
71]. Furthermore, while the subjects with SCD and with an AD relative may be at increased risk for having preclinical AD, they are generally healthy elderly research participants similar to those in the volunteer control group. Subgroup analyses (e.g., in subjects with Amyloid pathology) are planned once the complete sample and biomarker data will be available. All participants were German and mainly well educated, white individuals, limiting the generalizability of the findings to other countries or cultures. While our sample is heterogeneous in terms of recruitment, it represents a group of elderly which is enriched for AD-risk, but free of dementia. Importantly, our results align well with data from general population studies, suggesting that the association of diet with specific cognitive functions also holds true in risk-enriched populations, which is a prerequisite for considering nutritional intervention studies in such groups. As associations between diet and cognition are generally small, and the size of our sample was only moderate, we did not correct for multiple testing. While this limitation calls for a cautious interpretation, we note that the size and pattern of the associations found are consistent with much of the literature. Replication of our findings in other risk-enriched cohorts, the study of imaging and fluid neurodegeneration biomarkers in relation to diet, and longitudinal studies are needed to corroborate the present results. The current results add to current literature on diet and cognition as a sample including individuals with increased risk for AD was studied and an elaborate cognitive assessment has been used to construct sensitive cognitive outcome measures.
In this sample of German elderly free of dementia, Mediterranean diet and MIND diet were related to better memory and language, and two data-derived dietary patterns, one characterized by high intake of cereals and nuts and the other one by higher intake of alcoholic beverages were also related to better cognition.
The present study results would be consistent with a beneficial effect of some diets and dietary components on cognitive health. We consider it encouraging that associations previously found in population samples were also evident in our risk-enriched sample, which can be conceived as a target sample for prevention of cognitive decline, as subjects often are concerned about their cognitive health and motivated to change their lifestyle. It may not be “too late” for dietary changes to be effective in such populations.
In sum, the current results suggest that dietary intake is of importance in individuals free of dementia, ranging from cognitively healthy to MCI, and should be taken into account when designing interventions to delay cognitive decline.