Dietary Pattern,Diet Quality,and Dementia: A Systematic Review and Meta-Analysis of Prospective Cohort Studies

Abstract

Background:

Diet is an important lifestyle factor that may prevent or slow the onset and progression of neurodegeneration. Some, but not all, recent studies have suggested that adherence to a healthy dietary pattern may be associated with reduced risk of dementia.

Objective:

In this meta-analysis, we systematically examined the associations between overall dietary patterns, assessed a priori and a posteriori, and risk of dementia.

Methods:

We systematically searched PubMed, Web of Science, and the Cumulative Index for Nursing and Allied Health databases from January 1, 1981 to September 11, 2019. Prospective studies published in English were included. Random-effects model was used to calculate the pooled risk ratios and 95% confidence intervals (CIs).

Results:

Sixteen research articles were identified in the systematic review and 12 research articles including 66,930 participants were further included for the meta-analysis. Adherence to high diet quality or a healthy dietary pattern was significantly associated with lower risk of overall dementia (pooled risk ratio = 0.82; 95% CI: 0.70, 0.95; n = 12) and Alzheimer’s disease (pooled risk ratio = 0.61; 95% CI: 0.47, 0.79; n = 6) relative to those with low diet quality or an unhealthy dietary pattern. Subgroup analyses stratified by age, sex, follow-up duration, diet quality assessment approach, study location, and study quality generated similar results.

Conclusion:

Adherence to a healthy dietary pattern was associated with lower risk of overall dementia. Further randomized controlled trials are needed to provide additional evidence about the role of a healthy diet on the development and progression of dementia.

Keywords

Alzheimer’s disease dementia diet quality dietary pattern

INTRODUCTION

As worldwide life expectancy continues to increase, so may the prevalence of age-related neurodegenerative disorders [1, 2]. Using the United States as an example, the prevalence of Alzheimer’s disease (the most common cause of dementia) is increasing and 1 in 10 people age 65 and over currently has Alzheimer’s dementia [3, 4]. Furthermore, the World Health Organization (WHO) in 2015 estimated that around 47 million people globally had dementia [1].

Due to the growing prevalence of dementia and associated comorbidity, researchers are seeking to identify efficient and practical approaches that prevent or slow the progression of dementia. Diet is a modifiable lifestyle factor that may delay the onset of dementia with a favorable public health impact. More importantly, the dietary pattern and diet quality that reflect overall eating habits provide a better understanding of the impact of diet on chronic disease outcomes compared with individual foods and nutrients [5 –7].

Several systematic reviews and meta-analyses examined the relationships between dietary patterns and cognitive function and found that greater adherence to a healthy dietary pattern, the Mediterranean diet in particular, was associated with better global cognition in older adults [8], slower cognitive decline [9 –13], and lower risk of dementia and Alzheimer’s disease [9 , 11–14]. However, there are a number of limitations in the existing research literatures that must be highlighted. The use of the Mediterranean diet score, which is an a priori measure of diet quality, may limit the comparability and reproducibility among studies conducted in regions outside of the Mediterranean that have different dietary practices. In addition, most previous meta-analyses on this topic have focused on cognitive function, which may introduce bias and reduced sensitivity in comparison with clinically diagnosed disease outcomes [15]. In a recent review examining three diet quality indices, including the Mediterranean diet, Dietary approaches to Stop Hypertension (DASH) diet, and the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, and risk of Alzheimer’s disease and dementia, 9 longitudinal studies were included; however, studies assessing dementia outcome were relatively limited and studies using a posteriori diet assessment approaches and a priori methods except the three above-mentioned diet quality indices were not included in this review [16]. Interestingly, a recently-published prospective study with 24.8 years of follow-up and repeated diet quality assessments observed that midlife diet quality was not associated with risk of dementia [17]. This finding further highlighted the importance of follow-up time, which has not been examined in previous meta-analyses [8 , 14]. Finally, to the best of our knowledge, there are very few systematic reviews and meta-analyses of prospective cohort studies that specifically examine the role of overall dietary pattern and clinically diagnosed dementia.

Our aim for this systematic review and meta-analysis was to extract evidence from existing prospective cohort studies to generate summary observations regarding the associations between overall dietary pattern and diet quality, derived from both a priori and a posteriori methods, and risk of overall dementia.

METHODS

Search strategy

We systematically searched in the PubMed, Web of Science, and the Cumulative Index for Nursing and Allied Health (CINAHL) databases from January 1, 1981 to September 11, 2019. Search terms related to dietary pattern and diet quality in controlled vocabulary (in PubMed and CINAHL) as well as text words were used. The same approach was used with search terms related to dementia and Alzheimer’s disease. Detailed search terms for the three databases with results can be found in Supplementary Table 1.

Eligibility criteria

Study selection was guided by the inclusion and exclusion criteria listed in Supplementary Table 2. Only prospective studies published from January 1, 1981 to September 11, 2019 in English as a primary research article in a peer-reviewed journal were included in our systematic review and meta-analysis. Inclusion criteria were related to dietary exposure and the outcome measures as detailed in Supplementary Table 2. Studies where the exposure assessed was overall dietary patterns or diet quality using either an a priori or a posteriori approach were eligible. Studies where analyses focused on a single nutrient or selected dietary components were ineligible for this systematic review and meta-analysis. Diet assessment approaches were utilized to assist in determining whether the exposure was overall dietary patterns or diet quality [18]. Examples of eligible studies included studies using a priori (e.g., the Healthy Eating Index) or a posteriori approaches (e.g., principal component analysis). In addition, eligible studies must have outcome(s) of diagnosed dementia or Alzheimer’s disease. Studies with cognitive decline or cognitive functions outcomes were excluded in our current study because the objective was to extract and pool evidence on diet quality or dietary pattern and risk of diagnosed dementia among prospective cohort studies. There was no age limit and studies with all age groups were included if they met eligibility requirements as stated above.

For the meta-analysis, only studies using diet quality or dietary pattern scores grouped as categorical variable(s) that used the lowest diet quality or dietary pattern score group as the reference were included. In order to address potential overrepresentation of the same cohort [19 –22], only the study with the most dementia cases and the longest follow-up period was included in the meta-analysis when the same cohort was used in more than one published analysis. One study that used diet quality or dietary pattern score as a continuous variable [23] was excluded from the meta-analysis to calculate pooled risk ratio, but this study was included in the systematic review.

Study selection process, data extraction, and quality assessment

Study selection and the coding process were managed using Rayyan online software. Study selection was conducted by one reviewer (YL) and verified by a second reviewer (MN). Data extraction for each included study was conducted by one reviewer (YL) and verified by the other reviewer (MN). Extracted data included study characteristics, cohort description, participant characteristics, covariates, dietary assessment, outcome assessment, statistical methods, and primary results. Quality of all included studies was assessed using the Newcastle-Ottawa Scale [24]. Quality assessment ranged from 0 to 9 stars with 7 stars or higher representing good study quality [24].

Statistical analyses

For the meta-analysis, Stata/SE software version 15.1 (StataCorp, College Station, TX) was utilized to pool results from all included studies and conduct statistical analyses. To increase cohort size and statistical power, studies with dementia and Alzheimer’s disease outcomes were combined as overall dementia. However, we also reported pooled results for Alzheimer’s disease specifically (n = 6). For a study including more than one follow-up risk ratio [17], three risk ratios were pooled as one overall risk ratio for this study. Pooled risk ratios and 95% confidence intervals (CIs) between two dietary pattern scores or diet quality categories (the highest versus the lowest) were calculated with the lowest dietary pattern score or diet quality group as reference using random effects models in generic inverse variance method. Heterogeneity among studies was examined by Q statistics and I² index with 25%, 50%, and 75% representing low, moderate, and high heterogeneity [25]. In order to address potential publication bias and small study bias, we generated funnel plots of log (risk ratio) against the standard error and visually inspected for potential bias. We also conducted the Egger test to examine potential small study effects.

Subgroup analyses were conducted for dementia, based on diet assessment approach (a priori; a posteriori), follow-up period (<10.6 years versus ≥10.6 years; based on the median follow-up period), age (<a median of 72.9 years; ≥a median of 72.9 years), sex proportion (<50% women; ≥50% women), country (United States; other countries), and study quality (<7 Newcastle-Ottawa Scale stars; ≥7 Newcastle-Ottawa Scale stars). Meta-regression was conducted to examine whether potential sources of heterogeneity among included studies are associated with certain study characteristics in sensitivity analyses [26]. In our bubble plot examining the relationship between follow-up time and risk of overall dementia, all follow-up risk ratios within the studies were included in the meta-regression resulting in 14 risk ratios shown in the plot (Supplementary Figure 1).

RESULTS

A total of 608 studies were identified based on our search strategy and 16 studies met our inclusion criteria for the systematic review (Fig. 1). For the meta-analysis, we further excluded 4 studies due to using the same cohort (n = 3) [20 –22] or using diet quality or dietary pattern score as a continuous variable (n = 1) [23], leaving a total of 12 studies in the meta-analysis.

Fig. 1

Flow diagram of study selection process. A total of 608 studies were identified through three electronic databases. After title, abstract, and full-text review, 16 studies met the inclusion criteria and were included in the systematic review and 12 studies were included in the meta-analysis. (CINAHL: Cumulative Index for Nursing and Allied Health).

Characteristics of studies

Among the 16 studies included in the systematic review (Fig. 1 and Table 1), 4 reported results on both Alzheimer’s disease and dementia [27 –30], 7 examined dementia only [17 , 31–35], and 5 studies examined Alzheimer’s disease only [19–22 , 36]. Follow-up periods for the included studies ranged from 2.2 to 41 years [17 , 27–36] (Table 1). Furthermore, 12 studies utilized a priori diet approaches [19 , 33–36], 2 studies assessed dietary pattern or diet quality using a posteriori methods [20, 29], and 2 studies applied both a priori and a posteriori approaches [17, 32]. Characteristics and quality assessment of included studies are shown in Table 1.

Dementia and Alzheimer’s disease

In our systematic review of diet quality, dietary pattern, and dementia (excluding studies of Alzheimer’s disease only), a total of 11 studies were included and 4 of them showed statistically significant associations between adherence to high diet quality or a healthy dietary pattern and lower risk of having dementia (Table 1). Studies using the Mediterranean diet score to assess overall diet quality were consistent in finding no significant association between adherence to the Mediterranean diet and risk of developing dementia [17 , 35]. Among prospective studies using diet quality assessments other than the Mediterranean diet score, results were inconsistent. Notably, one study that included 8,225 participants with a mean baseline age of 50.2 years found that three separate measurements of midlife diet quality, assessed by the Alternate Heathy Eating Index (AHEI) and the Mediterranean diet score, were not associated with risk of incident dementia after a median 24.8 years of follow-up [17]. Of the 2 prospective studies using a posteriori dietary evaluation, both suggested that better adherence to the Japanese dietary pattern was associated with lower risk of dementia [29, 32].

Table 1

Characteristics of included studies examining the associations between dietary pattern, diet quality, and overall dementia

Author (y)		Study characteristics		Mean/median age (y); sex (% female)	Dietary assessment		Adjusted covariates	Outcome assessment		Results	Study quality
	Cohort (country)	Design (follow-up periods, y)	Sample size		Diet assessment method	Evaluation of dietary pattern or diet quality		Outcome of interest	Diagnosis of outcome
Scarmeas et al. (2006) [22]	Washington Heights-Inwood Columbia Aging Project (WHICAP) 1992 and 1999 (USA)	Prospective (mean: 4 y)	2,258	77.2; 68.0%	61-item version of Willett’s semiquantitative food frequency questionnaire	a priori; Mediterranean diet score (ranged from 0 to 9)	Cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, smoking, comorbidity index, and BMI	AD	The criteria of the NINCDS-ADRDA	Compared with individuals in the lowest Mediterranean score group, those in the highest group had lower risk of AD (adjusted HR = 0.60; 95% CI: 0.42, 0.87)	7
Scarmeas et al. (2009) [19]	WHICAP 1992 and 1999 (USA)	Prospective (mean: 5.4 y)	1,880	77.2; 69.0%	61-item version of Willett’s semiquantitative food frequency questionnaire	a priori; Mediterranean diet score (ranged from 0 to 9)	Cohort, age, sex, ethnicity, education, apolipoprotein E ɛ4 allele, caloric intake, BMI, smoking, depression, leisure activities, comorbidity index, baseline Clinical Dementia Rating score, and time between first dietary and first physical activity assessment	AD	The criteria of the NINCDS-ADRDA	Individuals who had the highest adherence to the Mediterranean diet had lower risk of developing AD (adjusted HR = 0.60; 95% CI: 0.42, 0.87) compared with those having the lowest adherence	7
Feart et al. (2009) [27]	Three-City Cohort (France)	Prospective (median: 4.1 y)	1,410	75.9; 62.6%	Validated food frequency questionnaire and 24-hour dietary recall	a priori; Mediterranean diet score (ranged from 0 to 9)	Sex, education, marital status, total energy intake, practice of physical exercise, taking 5 medications/d or more, Center for Epidemiological Studies-Depression Scale score, apolipoprotein E genotype, BMI, hypertension, hypercholesterolemia, diabetes, tobacco use, and stroke	Dementia and AD	Dementia: DSM-IV; AD: The criteria of the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition)	(1) Adherence to the Mediterranean diet was not associated with risk of dementia (High compared with low adherence: adjusted HR = 1.12; 95% CI: 0.60, 2.10); (2) Adherence to the Mediterranean diet was not associated with risk of AD (High compared with low adherence: adjusted HR = 0.86; 95% CI: 0.39, 1.88)	7
Gu et al. (2010) [20]	WHICAP 1992 and 1999 (USA)	Prospective (mean: 3.9 y)	2,148	77.2; 68.0%	61-item version of Willett’s semiquantitative food frequency questionnaire	a posteriori; dietary pattern scores generated by reduced rank regression	Recruitment cohort, age, education, ethnicity, sex, smoking status, BMI, caloric intake, comorbidity index, and apolipoprotein E ɛ4 genotype	AD	The criteria of the NINCDS-ADRDA	Compared with individuals having low adherence to the identified dietary pattern, those who had high adherence had lower risk of developing AD (adjusted HR = 0.62; 95% CI: 0.43, 0.89)	7
Roberts et al. (2010) [31]	The Mayo Clinic Study of Aging (USA)	Prospective (median: 2.2 y)	1,141	80.1; 48%	The modified Block 1995 Revision of the Health Habits and History Questionnaire including 103 food items and 25 beverages	a priori; Mediterranean diet score (ranged from 0 to 9)	not reported	Dementia	DSM-IV	No significant risk reduction in the middle (HR = 0.79; 95% CI: 0.51, 1.21) or high (HR = 0.75; 95% CI: 0.46, 1.21) adherence to the Mediterranean diet group was observed compared with low adherence	5
Gu et al. (2010) [21]	WHICAP II (USA)	Prospective (mean: 3.8 y)	1,219	76.6; 66.6%	61-item version of Willett’s semiquantitative food frequency questionnaire	a priori; Mediterranean diet score (ranged from 0 to 9)	Age, gender, education, race, hsCRP, fasting insulin, and adiponectin	AD	The criteria of the NINCDS-ADRDA	Better adherence to the Mediterranean diet was associated with lower risk of developing AD (p-trend=0.04)	6
Eskelinen et al. (2011) [28]	The Cardiovascular risk factors, Aging and Dementia (CAIDE) study (Finland)	Prospective (mean: 14 y)	385	57; 61.7%	Questionnaire consisting of 20 qualitative or frequency-based questions	a priori; Healthy-diet index (ranged from 0 to 17)	Age, sex, education, follow-up time, community of residence, the apolipoprotein E ɛ4 carrier status, midlife systolic blood pressure, serum total cholesterol, BMI, the presence of late-life myocardial infarction/stroke/diabetes mellitus, and midlife leisure-time physical activity and smoking status	Dementia and AD	Dementia: DSM-IV; AD: The criteria of the NINCDS-ADRDA	(1) Compared with individuals with low adherence to healthy-diet index at midlife, those having high adherence had lower risk of dementia (adjusted OR = 0.12; 95% CI: 0.02, 0.85); (2) Compared with individuals with low adherence to healthy-diet index at midlife, those having high adherence had lower risk of AD (adjusted OR = 0.08; 95% CI: 0.01, 0.89)	6
Ozawa et al. (2013) [29]	The Hisayama Study (Japan)	Prospective (median: 15 y)	1,006	68.5; 57%	Validated 70-item semiquantitative food frequency questionnaire	a posteriori; dietary pattern scores generated by reduced rank regression	Age, sex, education, diabetes, hypertension, total cholesterol, history of stroke, BMI, smoking habits, exercise, and energy intake	Dementia and AD	Dementia: DSM-III; AD: The criteria of the NINCDS-ADRDA	(1) Individuals in the highest dietary pattern score quartile had lower risk of developing all-cause dementia compared with those in the lowest quartile (adjusted HR = 0.66; 95% CI: 0.46, 0.95); (2) No significant risk reduction of AD was observed among individuals in the highest dietary pattern score quartile compared with those in the lowest quartile (adjusted HR = 0.65; 95% CI: 0.40, 1.06)	8
Morris et al. (2015) [36]	The Rush Memory and Aging Project (MAP) (USA)	Prospective (mean: 4.5 y)	923	81.2; 75.7%	Validated semiquantitative food frequency questionnaire	a priori; Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet score (ranged from 0 to 15), DASH diet score (ranged from 0 to 10), and the Mediterranean diet score (ranged from 0 to 55)	Age, sex, education, apolipoprotein E ɛ4 (any), participation in cognitively stimulating activities, physical activity, total energy intake, and cardiovascular conditions	AD	The criteria of the NINCDS-ADRDA	MIND diet: Participants in the highest score tertile had lower risk of AD compared with the lowest score tertile (adjusted HR = 0.48; 95% CI: 0.29, 0.79)	7
										DASH diet: Participants in the highest score tertile had lower risk of AD compared with the lowest score tertile (adjusted HR = 0.60; 95% CI: 0.37, 0.96)
										The Mediterranean diet: Participants in the highest score tertile had lower risk of AD compared with the lowest score tertile (adjusted HR = 0.49; 95% CI: 0.29, 0.85)
Olsson et al. (2015) [30]	The Uppsala longitudinal study (Sweden)	Prospective (mean: 12 y)	1,138	71; 0%	Seven-day food record based on a validated precoded menu book	a priori; Healthy diet indicator (ranged from 0 to 8), modified Mediterranean diet score (ranged from 0 to 8), and Low-Carbohydrate High-Protein Score (ranged from 2 to 20)	Energy intake, education, apolipoprotein E ɛ4, living alone, smoking, physical activity	Dementia and AD	Dementia: DSM-IV; AD: The criteria of the NINCDS-ADRDA	Healthy diet indicator: (1) No significant association between high adherence and risk of all-type dementia compared with low adherence was observed (adjusted HR = 0.95; 95% CI: 0.46, 1.99); (2) No significant association between high adherence and risk of AD compared with low adherence was observed (adjusted HR = 0.99; 95% CI: 0.39, 2.53)	7
										Modified Mediterranean diet: (1) No significant association between high adherence and risk of all-type dementia compared with low adherence was observed (adjusted HR = 0.85; 95% CI: 0.44, 1.62); (2) No significant association between high adherence and risk of AD compared with low adherence was observed (adjusted HR = 0.99; 95% CI: 0.44, 2.26)
										Low-Carbohydrate High-Protein: (1) No significant association between high adherence and risk of all-type dementia compared with low adherence was observed (adjusted HR = 1.59; 95% CI: 0.85, 2.96); (2) No significant association between high adherence and risk of AD compared with low adherence was observed (adjusted HR = 1.60; 95% CI: 0.74, 3.44)
Tomata et al. (2016) [32]	The Ohsaki Cohort 2006 Study (Japan)	Prospective (mean: 5.7 y)	14,402	73.9; 55.2%	Validated 39-item food frequency questionnaire	a priori and a posteriori; dietary pattern scores generated by principal component analysis and the Japanese diet index score (ranged from 0 to 9) generated by confirmatory factor analysis	Age, sex, history of disease, education level, smoking, alcohol drinking, BMI, psychological distress score, time spent walking, motor function score, cognitive function score, number of remaining teeth, and energy as well as protein intake	Dementia	The criteria of the long-term care insurance system used in Japan	Japanese pattern score: Participants in the highest quartile had lower risk of dementia compared with those in the lowest quartile (adjusted HR = 0.80; 95% CI: 0.66, 0.97)	7
										Animal food pattern score: No significant association between the highest quartile and risk of dementia compared with the lowest quartile was observed (adjusted HR = 1.12; 95% CI: 0.92, 1.36)
										High dairy pattern score: No significant association between the highest quartile and risk of dementia compared with the lowest quartile was observed (adjusted HR = 0.97; 95% CI: 0.83, 1.15)
										Japanese diet index: Participants in the highest quartile had lower risk of dementia compared with those in the lowest quartile (adjusted HR = 0.79; 95% CI: 0.66, 0.95)
Haring et al. (2016) [33]	The Women’s Health Initiative Memory Study (WHIMS) (USA)	Prospective (median: 9.1 y)	6,425	72; 100%	Self-administered the Women’s Health Initiative food frequency questionnaire	a priori; alternate Mediterranean diet score (ranged from 0 to 9), the HEI-2010 (ranged from 0 to 100), the alternate HEI-2010 (ranged from 0 to 110), and the DASH diet score (ranged from 8 to 40)	Age, race, education level, Women’s Health Initiative Hormone Trial randomization assignment, baseline Modified Mini-Mental State Examination level, smoking status, physical activity, diabetes status, hypertension status, body mass index, family income, depression, history of cardiovascular disease, and total energy intake	Dementia	DSM-IV	Alternate Mediterranean diet: No significant association between the highest quintile and risk of probable dementia compared with the lowest quintile was observed (adjusted HR = 1.13; 95% CI: 0.79, 1.63)	6
										HEI-2010: Better adherence to the HEI-2010 was associated with higher risk of developing probable dementia (adjusted HR for the highest versus the lowest quintile = 1.60; 95% CI: 1.10, 2.33)
										AHEI-2010: No significant association between the highest quintile and risk of probable dementia compared with the lowest quintile was observed (adjusted HR = 1.01; 95% CI: 0.71, 1.46)
										DASH diet: No significant association between the highest quintile and risk of probable dementia compared with the lowest quintile was observed (adjusted HR = 1.28; 95% CI: 0.86, 1.91)
Voortman et al. (2017) [23]	The Rotterdam Study (The Netherlands)	Prospective (median: 13.5 y)	9,701	64.1; 58.1%	Validated 170- and 389-item food frequency questionnaires	a priori; adherence to the Dutch dietary guidelines (ranged from 0 to 14)	Cohort, age at dietary assessment, sex, smoking status, educational level, employment status, total energy intake, physical activity, and body mass index	Dementia	Cambridge Examination for Mental Disorders in the Elderly	Better adherence to the Dutch dietary guidelines was not associated with risk of dementia (adjusted HR for every additional adhered component = 1.01; 95% CI: 0.98, 1.05)	8
Larsson et al. (2018) [34]	National Research Infrasturcture SIMPLER (Sweden)	Prospective (mean: 12.6 y)	28,775	83.2; 46.6%	Validated 96-item food frequency questionnaire	a priori; modified DASH diet score (ranged from 7 to 35) and modified Mediterranean diet score (ranged from 8 to 40)	Age, sex, education, body mass index, and history of hypertension, hypercholesterolemia, diabetes, and sleep duration	Dementia	The Swedish National Patient Register	Modified DASH diet: No significant association was observed between overall diet quality and risk of dementia (adjusted HR for the highest versus the lowest quartile = 0.96; 95% CI: 0.87, 1.05)	7
										Modified Mediterranean diet: No significant association was observed between overall diet quality and risk of dementia (adjusted HR for the highest versus the lowest quartile = 1.12; 95% CI: 0.96, 1.31)
Hosking et al. (2019) [35]	Personality and Total Health (PATH) Through Life study (Australia)	Prospective (mean: 12 y)	1,220	62.5; 51%	The Commonwealth Scientific and Industrial Research Organization semi-quantitative food frequency questionnaire	a priori; Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet score	MIND diet score, energy intake, age, sex, APOE 4 status, education, mental activity, physical activity, smoking status, depression, diabetes, body mass index, hypertension, heart disease, and stroke	Dementia	National Institute of Neurological Disorders criteria	Adherence to the MIND diet was associated with lower risk of dementia (adjusted OR = 0.72; 95% CI: 0.54, 0.95)	8
Akbaraly et al. (2019) [17]	The Whitehall II study (UK)	Prospective (median: 24.8 y)	8,225	50.2; 30.9%	127-item food frequency questionnaire	a priori and a posteriori; alternate Heathy Eating Index (ranged from 0 to 110) and dietary pattern scores generated by principal component analysis	Age, sex, race/ethnicity, total energy intake, education level, occupational position, marital status, smoking status, physical activity level, alcohol consumption, hypertension, type 2 diabetes, body mass index, dyslipidemia, depressive symptoms, coronary heart disease or stroke, and use of any cardiovascular disease medication	Dementia	International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes F00, F01, F02, F03, F05.1, G30, and G31.0	AHEI: Midlife diet quality was not significantly associated with subsequent risk for dementia (adjusted HRs ranged from 0.73; 95% CI: 0.51, 1.05 to 0.95; 95% CI: 0.67, 1.35)	8
										Healthy food dietary pattern score: No significant association was observed between midlife diet quality and subsequent risk of dementia (adjusted HRs ranged from 0.70; 95% CI: 0.47, 1.05 to 0.97; 95% CI: 0.73, 1.30)
										Western-type dietary pattern score: No significant association was observed between midlife diet quality and subsequent risk of dementia (adjusted HRs ranged from 0.80; 95% CI: 0.50, 1.28 to 1.00; 95% CI: 0.70, 1.43)

AD, Alzheimer’s disease; HEI, Healthy Eating Index; DASH, Dietary Approaches to Stop Hypertension; MIND, Mediterranean-DASH Intervention for Neurodegenerative Delay; DSM, The criteria of the Diagnostic and Statistical Manual of Mental Disorders; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association.

There were 9 studies that examined Alzheimer’s disease that are included in our systematic review and 6 of them showed statistically significant inverse associations between diet quality and risk of Alzheimer’s disease (Table 1). Some studies found that high diet quality, as assessed by the Mediterranean diet score [19 , 22], healthy-diet index [28], and the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet score [36], was associated with lower risk of developing Alzheimer’s disease. However, some studies found that better diet quality, assessed by the Mediterranean diet score [27] and the healthy diet indicator [30], were not associated with risk of incident Alzheimer’s disease. Among studies determining the relationship between dietary pattern scores and risk of Alzheimer’s disease, results were also inconsistent [20, 29].

Our meta-analysis among 12 studies of dementia including Alzheimer’s disease showed a significant association between adherence to a high quality diet or a healthy dietary pattern and lower risk of dementia (pooled risk ratio = 0.82; 95% CI: 0.70, 0.95) compared with those with low diet quality or an unhealthy dietary pattern (Fig. 2A) [17 , 27–36]. Similar association was observed in our sensitivity analysis restricting to studies that used the most common diagnosed criteria for dementia and Alzheimer’s disease (pooled risk ratio = 0.78, 95% CI: 0.62, 0.99). Meta-regression conducted to examine whether potential bias resulted from certain study characteristics including diet assessment method, follow-up length, age, sex proportion, country, and study quality did not show any statistically significant impact (Table 2). Funnel plot analysis that examined potential publication bias did not suggest the presence of publication or small study biases (Fig. 3). We did not observe significant associations between follow-up period and risk of overall dementia (Supplementary Figure 1). Similarly, in our meta-analysis restricted to 6 studies that examined Alzheimer’s disease only, we observed a significant association between having high diet quality or a healthy dietary pattern and lower risk of Alzheimer’s disease (pooled risk ratio = 0.61; 95% CI: 0.47, 0.79) compared with having low diet quality or an unhealthy dietary pattern (Fig. 2B) [19 , 36].

Fig. 2

The association between diet quality or dietary pattern and risk of (A) overall dementia (n = 12) and (B) Alzheimer’s disease (n = 6) (risk ratio for the highest versus the lowest diet quality or dietary pattern category) (95% CI: confidence interval).

Table 2

Dietary pattern, diet quality, and overall dementia: subgroup analyses

Study characteristics (reference)	Cohort (n)	Participants (n)	Risk ratio (95% CI)	p for heterogeneity
Diet assessment				0.66
a priori [17 , 33–36]	10	51,522	0.83 (0.69, 1.01)
a posteriori [29, 32]	2	15,408	0.77 (0.65, 0.91) ^**
Follow-up period				0.88
<10.6 y [19 , 36]	6	26,181	0.82 (0.60, 1.13)
≥10.6 y [17 , 34]	6	40,749	0.83 (0.69, 0.98) ^*
Age				0.59
<72.9 y [17 , 35]	6	18,399	0.86 (0.63, 1.17)
≥72.9 y [19 , 36]	6	48,531	0.78 (0.63, 0.96) ^*
Sex proportion, % female				0.51
<50% [17 , 34]	4	39,279	0.94 (0.86, 1.02)
≥50% [19 , 36]	8	27,651	0.76 (0.58, 0.99) ^*
Country				0.88
United States [19 , 36]	4	10,369	0.78 (0.45, 1.33)
Other countries [17 , 35]	8	56,561	0.84 (0.73, 0.96) ^*
Study quality				0.30
<7 Newcastle-Ottawa Scale stars [28 , 33]	3	7,951	0.79 (0.33, 1.91)
≥7 Newcastle-Ottawa Scale stars [17 , 34–36]	9	58,979	0.79 (0.69, 0.91) ^**

^*p < 0.05; ^**p < 0.01.

Fig. 3

Funnel plot with pseudo 95% confidence limits examining potential publication bias between diet quality or dietary pattern and risk of dementia (p-value from the egger test = 0.14).

DISCUSSION

In our systematic review and meta-analysis on the relationships between dietary pattern, diet quality, and overall dementia, we reviewed 16 prospective studies and conducted a meta-analysis using 12 of these studies. Although mixed results were generated from these individual studies, the pooled results suggested that better adherence to a healthy dietary pattern or having high diet quality was significantly associated with lower risk of overall dementia and Alzheimer’s disease.

Earlier studies that examined the association between diet and health outcomes usually used single nutrient or selected multiple nutrient approaches. For example, nutrients such as polyunsaturated fatty acids, monounsaturated fatty acids, and antioxidants have been found to be protective factors while saturated fatty acids and trans-fatty acids are thought to be risk factors for dementia [37, 38]. However, methodological limitations have directed more recent studies toward focusing on the impact of overall dietary patterns or diet quality on health outcomes because dietary pattern analysis reflects the study of “real-world” eating patterns of many different populations that may be an ideal way to address potential nutrient interactions and collinearity that usually occurs using a single nutrient approach [6 , 40]. One of the most-studied examples is the Mediterranean diet, which has been associated with lower risk of all-cause mortality, cardiovascular disease and related mortality, cancer and related mortality, cognitive decline, and improved lipid profiles [14 , 41–43].

Dementia is one of the degenerative brain diseases, which often has a long preclinical phase that ultimately impacts quality of life and increases the toll on public health [4, 44]. The most distinguishing pathological feature of Alzheimer’s dementia (the most common type of dementia) is the buildup of amyloid plaque and tau tangles in the brain that can lead to neuron death and impaired cognitive functions [45]. Oxidative stress is believed to play a role in the pathogenesis of Alzheimer’s disease [46 –48]. The majority of healthy dietary patterns are high in fruits and vegetables, legumes, and whole grains and low in processed and red meats. These foods in combination may protect against the development of dementia [47, 49], particularly because of their synergistic role in reducing oxidative stress and chronic inflammation [50 –53]. Food components that are rich in n-3 fatty acids may have a protective role in development of Alzheimer’s disease by reversing age-related synaptic plasticity changes and maintaining cognitive performance [49, 54]. However, some prospective cohort studies and recent meta-analyses of prospective cohort studies only demonstrated significant positive association between dietary saturated fatty acids consumption and risk of dementia and Alzheimer’s disease while mixed results were observed for dietary intakes of unsaturated fatty acids [38 , 55–57]. The results from our meta-analysis are consistent with the hypothesis that adherence to high diet quality or a healthy dietary pattern is associated with lower risk of developing overall dementia. These findings may further support the importance of understanding the relationships of overall diet quality and dietary pattern and risk of dementia.

Diet quality and dietary pattern analyses have frequently been used to study the relationships between overall dietary intake and health outcomes and to strengthen the importance of healthy dietary patterns with diverse food components. However, several limitations exist in a priori and a posteriori approaches that may hinder the reproducibility and interpretation of results across studies. Taking diet quality index scores as an example, most of the diet quality indices were created based on a well-established healthy dietary pattern, such as the Mediterranean diet, the Dietary Guidelines for Americans, and the DASH diet. These diet quality indices were mainly developed in the western countries and may not be appropriately applied in countries with different ethnic groups [6 , 58]. Meanwhile, dietary patterns identified empirically in a specific cohort may have restricted application in other cohorts [6 , 58]. In our meta-analysis of 12 studies using a priori or a posteriori diet assessments, we observed that high diet quality or a healthy dietary pattern was significantly associated with a lower pooled risk ratio of overall dementia. Studies using a priori and a posteriori diet assessments generated similar results. Our results may thus provide preliminary pooled evidence on the beneficial role of adherence to a high-quality diet or a healthy dietary pattern.

Besides dietary pattern evaluation, other methodological issues, such as addressing possible reverse causality and determination of potential confounding factors, have been widely discussed in observational studies investigating dietary patterns, diet quality, and dementia. The length of follow-up varied appreciably across the reviewed prospective cohort studies. Because the process and progress of age-related neurological changes remain unclear, studies with a short period of follow-up may lead to reverse causality since individuals with underlying neurodegenerative disorders may have already had changes in their dietary patterns. A recent study examining the 12-year trajectories of diet quality score among participants with and without dementia at the end of follow-up observed that diet quality scores were significantly associated with risk of developing dementia at year 10, but no significant association was observed in the first 9 years of follow-up [17]. However, we did not observe any significant association between length of follow-up period and risk of overall dementia in our meta-analysis. Likewise, our subgroup analysis did not suggest any significant heterogeneity among studies with follow-up period <10.6 years or ≥10.6 years. More prospective studies with longer follow-up and repeated diet assessments during follow-up are needed to better understand the relationships between follow-up period and risk of dementia. Furthermore, potential residual confounding effects by un-identified risk factors and possible mediation effects may also limit resolution of the associations between dietary pattern and risk of dementia.

Our systematic review and meta-analysis updated the recently-published review conducted by van den Brink et al. [16] and we further included 7 additional longitudinal studies for overall dementia including Alzheimer’s disease by conducting systematic literature searches in three electronic databases. There are several strengths of our systematic review and meta-analysis. First, we assessed overall diet quality or dietary pattern and only included studies with diagnosed dementia including Alzheimer’s disease outcomes. However, there are some limitations that should be considered when interpreting our study results. Although we conducted systematic literature searches, a relatively small number of studies met our inclusion criteria. To address this concern, we combined dementia and Alzheimer’s disease studies into overall dementia outcome in our meta-analysis since Alzheimer’s dementia is the most common type of dementia. However, we recognize that dementia includes a broad spectrum of disorders and associated etiologies. Pooling dementia and Alzheimer’s disease into overall dementia may underestimate other subtypes of dementia. In addition, heterogeneity in follow-up length, diet assessment, age, and sex proportion of participants, and country of study location across included studies also need to be considered. We therefore conducted subgroup analyses to examine the impact of heterogeneity and minimize the bias when interpreting our meta-analysis. Furthermore, studies using different diet quality or dietary pattern assessments were included in our meta-analysis which may result in difficulty in comparing and interpreting the results. However, we recognize that most of the healthy dietary patterns or high-quality diets do share some similarities, such as high intake of fruits and vegetables and low intake of saturated fats, which may help address this concern.

In conclusion, our meta-analysis showed that adherence to a high-quality diet or a healthy dietary pattern may provide protective effects on risk of overall dementia. Though studies using overall dietary pattern as a predictor of incident dementia are still limited, overall dietary patterns, as compared to single nutrient components, offer an approach that is more representative of how people actually eat and also encompass the complex interactions between nutrients. In view of the limitations related to dietary evaluation and methodological issues discussed above, more large-scale observational studies are warranted to better understand the association between overall dietary patterns and risk of dementia. In addition, randomized controlled trials are also needed to explore causal relationships and to further provide evidence-based dietary recommendations for the general public to prevent many chronic diseases such as dementia, and improve overall health status and quality of life.

Footnotes

ACKNOWLEDGMENTS

This study is funded by the United States Department of Agriculture, Agricultural Research Service agreement 8050-51530-012-01A.

Authors’ disclosures available online ().

The supplementary material is available in the electronic version of this article: .

References

Prince

, Wimo

, Guerchet

, Ali

, Wu

, Prina

(2015) World Alzheimer Report 2015. The global impact of dementia an analysis of prevalence, incidence, cost and trends. Alzheimer’s Disease International, London.

Prince

, Ali

, Guerchet

, Prina

, Albanese

, Wu

(2016) Recent global trends in the prevalence and incidence of dementia, and survival with dementia. Alzheimers Res Ther 8, 23.

Alzheimer’s Association (2017) 2017 Alzheimer’s disease facts and figures. Alzheimers Dement 13, 325–373.

Alzheimer’s Association (2019) 2019 Alzheimer’s disease facts and figures. Alzheimers Dement 15, 321–387.

Jacques

, Tucker

(2001) Are dietary patterns useful for understanding the role of diet in chronic disease? Am J Clin Nutr 73, 1–2.

(2002) Dietary pattern analysis: A new direction in nutritional epidemiology. Curr Opin Lipidol 13, 3–9.

Tapsell

, Neale

, Satija

, Hu

(2016) Foods, nutrients, and dietary patterns: Interconnections and implications for dietary guidelines. Adv Nutr 7, 445–454.

Loughrey

, Lavecchia

, Brennan

, Lawlor

, Kelly

(2017) The impact of the Mediterranean diet on the cognitive functioning of healthy older adults: A systematic review and meta-analysis. Adv Nutr 8, 571–586.

van de Rest

, Berendsen

, Haveman-Nies

, de Groot

(2015) Dietary patterns, cognitive decline, and dementia: A systematic review. Adv Nutr 6, 154–168.

10.

Lourida

, Soni

, Thompson-Coon

, Purandare

, Lang

, Ukoumunne

, Llewellyn

(2013) Mediterranean diet, cognitive function, and dementia: A systematic review. Epidemiology 24, 479–489.

11.

, Scarmeas

(2011) Dietary patterns in Alzheimer’s disease and cognitive aging. Curr Alzheimer Res 8, 510–519.

12.

Singh

, Parsaik

, Mielke

, Erwin

, Knopman

, Petersen

, Roberts

(2014) Association of mediterranean diet with mild cognitive impairment and Alzheimer’s disease: A systematic review and meta-analysis. J Alzheimers Dis 39, 271–282.

13.

Petersson

, Philippou

(2016) Mediterranean diet, cognitive function, and dementia: A systematic review of the evidence. Adv Nutr 7, 889–904.

14.

Sofi

, Abbate

, Gensini

, Casini

(2010) Accruing evidence on benefits of adherence to the Mediterranean diet on health: An updated systematic review and meta-analysis. Am J Clin Nutr 92, 1189–1196.

15.

Devenney

, Hodges

(2017) The Mini-Mental State Examination: Pitfalls and limitations. Pract Neurol 17, 79–80.

16.

van den Brink

, Brouwer-Brolsma

, Berendsen

AAM

, van de Rest

(2019) The Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets are associated with less cognitive decline and a lower risk of Alzheimer’s disease-a review. Adv Nutr 10, 1040–1065.

17.

Akbaraly

, Singh-Manoux

, Dugravot

, Brunner

, Kivimaki

, Sabia

(2019) Association of midlife diet with subsequent risk for dementia. JAMA 321, 957–968.

18.

Tucker

(2010) Dietary patterns, approaches, and multicultural perspective. Appl Physiol Nutr Metab 35, 211–218.

19.

Scarmeas

, Luchsinger

, Schupf

, Brickman

, Cosentino

, Tang

, Stern

(2009) Physical activity, diet, and risk of Alzheimer disease. JAMA 302, 627–637.

20.

, Nieves

, Stern

, Luchsinger

, Scarmeas

(2010) Food combination and Alzheimer disease risk: A protective diet. Arch Neurol 67, 699–706.

21.

, Luchsinger

, Stern

, Scarmeas

(2010) Mediterranean diet, inflammatory and metabolic biomarkers, and risk of Alzheimer’s disease. J Alzheimers Dis 22, 483–492.

22.

Scarmeas

, Stern

, Tang

, Mayeux

, Luchsinger

(2006) Mediterranean diet and risk for Alzheimer’s disease. Ann Neurol 59, 912–921.

23.

Voortman

, Kiefte-de Jong

, Ikram

, Stricker

, van Rooij

FJA

, Lahousse

, Tiemeier

, Brusselle

, Franco

, Schoufour

(2017) Adherence to the 2015 Dutch dietary guidelines and risk of non-communicable diseases and mortality in the Rotterdam Study. Eur J Epidemiol 32, 993–1005.

24.

GA Wells BS, D O’Connell, J Peterson, V Welch, M Losos, P Tugwell The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Ottawa Hospital Research Institute.

25.

Higgins

, Thompson

, Deeks

, Altman

(2003) Measuring inconsistency in meta-analyses. BMJ 327, 557–560.

26.

Harbord

, Higgins

JPT

(2008) Meta-regression in Stata. Stata J 8, 493–519.

27.

Feart

, Samieri

, Rondeau

, Amieva

, Portet

, Dartigues

, Scarmeas

, Barberger-Gateau

(2009) Adherence to a Mediterranean diet, cognitive decline, and risk of dementia. JAMA 302, 638–648.

28.

Eskelinen

, Ngandu

, Tuomilehto

, Soininen

, Kivipelto

(2011) Midlife healthy-diet index and late-life dementia and Alzheimer’s disease. Dement Geriatr Cogn Dis Extra 1, 103–112.

29.

Ozawa

, Ninomiya

, Ohara

, Doi

, Uchida

, Shirota

, Yonemoto

, Kitazono

, Kiyohara

, (2013) Dietary patterns and risk of dementia in an elderly Japanese population: The Hisayama Study. Am J Clin Nutr 97, 1076–1082.

30.

Olsson

, Karlstrom

, Kilander

, Byberg

, Cederholm

, Sjogren

(2015) Dietary patterns and cognitive dysfunction in a 12-year follow-up study of 70 year old men. J Alzheimers Dis 43, 109–119.

31.

Roberts

, Geda

, Cerhan

, Knopman

, Cha

, Christianson

, Pankratz

, Ivnik

, Boeve

, O’Connor

, Petersen

(2010) Vegetables, unsaturated fats, moderate alcohol intake, and mild cognitive impairment. Dement Geriatr Cogn Disord 29, 413–423.

32.

Tomata

, Sugiyama

, Kaiho

, Honkura

, Watanabe

, Zhang

, Sugawara

, Tsuji

(2016) Dietary patterns and incident dementia in elderly Japanese: The Ohsaki Cohort 2006 Study. J Gerontol A Biol Sci Med Sci 71, 1322–1328.

33.

Haring

, Wu

, Mossavar-Rahmani

, Snetselaar

, Brunner

, Wallace

, Neuhouser

, Wassertheil-Smoller

(2016) No association between dietary patterns and risk for cognitive decline in older women with 9-year follow-up: Data from the Women’s Health Initiative Memory Study. J Acad Nutr Diet 116, 921–930 e921.

34.

Larsson

, Wolk

(2018) The role of lifestyle factors and sleep duration for late-onset dementia: A cohort study. J Alzheimers Dis 66, 579–586.

35.

Hosking

, Eramudugolla

, Cherbuin

, Anstey

(2019) MIND not Mediterranean diet related to 12-year incidence of cognitive impairment in an Australian longitudinal cohort study. Alzheimers Dement 15, 581–589.

36.

Morris

, Tangney

, Wang

, Sacks

, Bennett

, Aggarwal

(2015) MIND diet associated with reduced incidence of Alzheimer’s disease. Alzheimers Dement 11, 1007–1014.

37.

Creegan

, Hunt

, McManus

, Rainey-Smith

(2015) Diet, nutrients and metabolism: Cogs in the wheel driving Alzheimer’s disease pathology? Br J Nutr 113, 1499–1517.

38.

Morris

, Evans

, Bienias

, Tangney

, Bennett

, Aggarwal

, Schneider

, Wilson

(2003) Dietary fats and the risk of incident Alzheimer disease. Arch Neurol 60, 194–200.

39.

Jacobs

Jr , Steffen

(2003) Nutrients, foods, and dietary patterns as exposures in research: A framework for food synergy. Am J Clin Nutr 78, 508S–513S.

40.

Alles

, Samieri

, Feart

, Jutand

, Laurin

, Barberger-Gateau

(2012) Dietary patterns: A novel approach to examine the link between nutrition and cognitive function in older individuals. Nutr Res Rev 25, 207–222.

41.

Martinez-Gonzalez

, Bes-Rastrollo

, Serra-Majem

, Lairon

, Estruch

, Trichopoulou

(2009) Mediterranean food pattern and the primary prevention of chronic disease: Recent developments. Nutr Rev 67(Suppl 1), S111–116.

42.

Trichopoulou

, Kouris-Blazos

, Wahlqvist

, Gnardellis

, Lagiou

, Polychronopoulos

, Vassilakou

, Lipworth

, Trichopoulos

(1995) Diet and overall survival in elderly people. BMJ 311, 1457–1460.

43.

Trichopoulou

, Costacou

, Bamia

, Trichopoulos

(2003) Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med 348, 2599–2608.

44.

Wolters

, Adams

HHH

, Bos

, Licher

, Ikram

(2018) Three decades of dementia research: Insights from one small community of indomitable Rotterdammers. J Alzheimers Dis 64, S145–S159.

45.

Bloom

(2014) Amyloid-beta and tau: The trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71, 505–508.

46.

Barnham

, Masters

, Bush

(2004) Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 3, 205–214.

47.

Rao

, Balachandran

(2002) Role of oxidative stress and antioxidants in neurodegenerative diseases. Nutr Neurosci 5, 291–309.

48.

Niedzielska

, Smaga

, Gawlik

, Moniczewski

, Stankowicz

, Pera

, Filip

(2016) Oxidative stress in neurodegenerative diseases. Mol Neurobiol 53, 4094–4125.

49.

Dohrmann

, Putnik

, Bursac Kovacevic

, Simal-Gandara

, Lorenzo

, Barba

(2019) Japanese, Mediterranean and Argentinean diets and their potential roles in neurodegenerative diseases. Food Res Int 120, 464–477.

50.

Panza

, Solfrizzi

, Colacicco

, D’Introno

, Capurso

, Torres

, Del Parigi

, Capurso

(2004) Mediterranean diet and cognitive decline. Public Health Nutr 7, 959–963.

51.

Widmer

, Flammer

, Lerman

(2015) The Mediterranean diet, its components, and cardiovascular disease. Am J Med 128, 229–238.

52.

Willett

, Sacks

, Trichopoulou

, Drescher

, Ferro-Luzzi

, Helsing

, Trichopoulos

(1995) Mediterranean diet pyramid: A cultural model for healthy eating. Am J Clin Nutr 61, 1402S–1406S.

53.

Simonetto

, Infante

, Sacco

, Rundek

, Della-Morte

(2019) A novel anti-inflammatory role of omega-3 PUFAs in prevention and treatment of atherosclerosis and vascular cognitive impairment and dementia. Nutrients 11, 2279.

54.

(2010) Mechanisms of n-3 fatty acid-mediated development and maintenance of learning memory performance. J Nutr Biochem 21, 364–373.

55.

Ruan

, Tang

, Guo

, Li

(2018) Dietary fat intake and risk of Alzheimer’s disease and dementia: A meta-analysis of cohort studies. Curr Alzheimer Res 15, 869–876.

56.

Cao

, Li

, Han

, Tayie

, Yao

, Huang

, Ai

, Liu

, Hu

, Xu

(2019) Dietary fat intake and cognitive function among older populations: A systematic review and meta-analysis. J Prev Alzheimers Dis 6, 204–211.

57.

Kalmijn

, Launer

, Ott

, Witteman

, Hofman

, Breteler

(1997) Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol 42, 776–782.

58.

Moeller

, Reedy

, Millen

, Dixon

, Newby

, Tucker

, Krebs-Smith

, Guenther

(2007) Dietary patterns: Challenges and opportunities in dietary patterns research an Experimental Biology workshop, April 1, 2006. J Am Diet Assoc 107, 1233–1239.