Flavonoid-Rich Foods, Dementia Risk, and Interactions With Genetic Risk, Hypertension, and Depression

Key Points Question What is the association of a flavonoid-rich diet with dementia risk among UK adults? Findings In this cohort study of 121 986 UK Biobank participants, those with the highest adherence to a flavonoid-rich diet, specifically intakes of tea, red wine, and berries, had a lower risk of dementia. Reductions were more pronounced in participants with a high genetic risk, hypertension, and depressive symptoms. Meaning These findings suggest that increasing daily consumption of flavonoid-rich foods may lower dementia risk, especially in populations at high risk.

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eMethods 2. Healthy Plant-Based Diet Index
The healthy plant-based diet index (hPDI), made up of 17 food groups: whole grains, fruits, vegetables, nuts, legumes and vegetarian protein alternatives, tea and coffee, fruit juices, refined grains, potatoes, sugarsweetened beverages, sweets and desserts, animal fat, dairy, eggs, fish or seafood, meat, and miscellaneous animal-derived foods, was derived.as previously described 1 eMethods 3. Genetic Risk Genotyping was assayed using the UK BiLEVE Axiom (Affymetrix) and the UK Biobank Axiom arrays (Applied Biosystems) 2 .Imputed genotypes were derived from the Haplotype Reference Consortium and UK10K haplotype resource using computationally efficient methods.The APOE single-nucleotide polymorphisms were directly genotyped by rs429358 and rs7412.A polygenic risk score (PRS) was constructed to capture an individual's load of common genetic variants associated with Alzheimer's diseaserelated genetic risk in UK Biobank; full details of the methods and the selected SNPs have previously been published 3 .This polygenic risk score was categorized into low (lowest quintile), intermediate (quintiles 2 to 4), and high (highest quintile) risk groups, a routinely used approach for modelling polygenic risk scores in UK Biobank studies 4 .

eMethods 4. Covariate Assessment
Participants completed a touchscreen questionnaire and a verbal interview conducted by trained staff and provided physical measurements and biological samples at baseline.At these assessments data were collected on age, sex, ethnicity, socioeconomic status, education, smoking status, sleep duration, physical activity, BMI, family history of dementia, post-menopausal status, number of self-reported medications and number of longterm health conditions.History of stroke was defined for participants with a primary or secondary diagnosis of stroke, identified from hospital records or death registries using ICD codes I60, I61, I63 and I64, prior to diagnosis of dementia or end of follow-up.Current depressive symptoms at baseline were measured based on the frequency of four items from the Patient Health Questionnaire: 1) depressed mood, 2) disinterest or absence of enthusiasm, 3) tenseness or restlessness, and 4) tiredness or lethargy, with one point awarded if participants reported symptoms in the previous two weeks.The subsequent depressive symptoms score ranged from 0 to 4 for each participant with depression defined for scores >2 5 .
Systolic blood pressure and diastolic blood pressure were measured twice by using a digital sphygmomanometer (Omron 705 IT; OMRON Healthcare Europe B.V.) with the participants at rest in the seated position for at least five minutes and a one-minute interval between measurements.Hypertension was defined if systolic blood pressure was >140 and/ or diastolic blood pressure >90 and/ or self-reported use of blood pressure medication.For participants, without these data (n=6874) we used a self-reported diagnosis by a medical professional.Proanthocyanidins are also included in the polymer subclass.Models adjusted for sex (male or female), socioeconomic status (Townsend Index, categorised as low [quintile 1], moderate [quintiles 2-4], high [quintile 5] deprivation), highest level of education (higher, vocational, upper Secondary, lower Secondary, none or unknown), ethnicity (White, Mixed, Asian, Black, Chinese, other group, not answered), current smoking status (yes or no), typical sleep duration (≤ 6 hours, 7-8 hours or > 8 hours, not answered), physical activity (total excess metabolic equivalents, in quintiles), BMI (kg/m 2 ), family history of dementia (yes or no), history of stroke (yes or no), post-menopausal status (yes, no, male or unknown), number of medications taken (1-3, 4-6, 7-9 or 10+), number of longterm health conditions (1-2, 3, 4, 5+), genetic kinship (at least one relative, no kinship, unknown), number of dietary assessments completed with plausible energy intakes (2, 3, 4 or 5), healthy plantbased diet index (score, in quintiles), alcohol intake not from red wine (g/d, in quintiles), energy intake (kcal/d, in quintiles) and fat intake (g/d, in quintiles) and stratified by region (London, North-West England, North-East England, Yorkshire, West Midlands, East Midlands, South-East England, South-West England, Scotland and Wales).P-interaction was calculated using all participants and refers to the interaction term between intake and indicator of genetic risk (high vs low) in the highest quintile of intake.
© Values are adjusted hazard ratios (95% CI). 1 flavodiet score was calculated by summing intakes (in servings per day) of tea (black and green), red wine, apples, berries, grapes, oranges, grapefruit, sweet peppers, onions, and dark chocolate. 2Proanthocyanidins are also included in the polymer subclass.Models adjusted for sex (male or female), socioeconomic status (Townsend Index, categorised as low [quintile 1], moderate [quintiles 2-4], high [quintile 5] deprivation), highest level of education (higher, vocational, upper Secondary, lower Secondary, none or unknown), ethnicity (White, Mixed, Asian, Black, Chinese, other group, not answered), current smoking status (yes or no), typical sleep duration (≤ 6 hours, 7-8 hours or > 8 hours, not answered), physical activity (total excess metabolic equivalents, in quintiles), BMI (kg/m 2 ), family history of dementia (yes or no), history of stroke (yes or no), post-menopausal status (yes, no, male or unknown), number of medications taken (1-3, 4-6, 7-9 or 10+), number of long-term health conditions (1-2, 3, 4, 5+), number of dietary assessments completed with plausible energy intakes (2, 3, 4 or 5), healthy plantbased diet index (score, in quintiles), alcohol intake not from red wine (g/d, in quintiles), energy intake (kcal/d, in quintiles) and fat intake (g/d, in quintiles) and stratified by region (London, North-West England, North-East England, Yorkshire, West Midlands, East Midlands, South-East England, South-West England, Scotland and Wales).P-interaction was calculated using all participants and refers to the interaction term between intake and indicator of hypertension (yes vs no) in the highest quintile of intake.
© ), family history of dementia (yes or no), history of stroke (yes or no), post-menopausal status (yes, no, male or unknown), number of medications taken (1-3, 4-6, 7-9 or 10+), number of long-term health conditions (1-2, 3, 4, 5+), number of dietary assessments completed with plausible energy intakes (2, 3, 4 or 5), healthy plantbased diet index (score, in quintiles), alcohol intake not from red wine (g/d, in quintiles), energy intake (kcal/d, in quintiles) and fat intake (g/d, in quintiles) and stratified by region (London, North-West England, North-East England, Yorkshire, West Midlands, East Midlands, South-East England, South-West England, Scotland and Wales).P-interaction was calculated using all participants and refers to the interaction term between intake and indicator of hypertension (yes vs no) in the highest quintile of intake.

eMethods 1 . 2 . 1 . 3 . 1 . 2 . 3 . 4 . 5 .
Flavonoid Subclasses eMethods Healthy Plant-Based Diet Index eMethods 3. Genetic Risk eMethods 4. Covariate Assessment eFigure Flowchart of Participants in the UK Biobank Study eFigure 2. Age-and Sex-Adjusted Kaplan-Meier Survival Curves in All Participants and Stratified by Subgroup in 121 986 Males and Females From the UK Biobank eFigure Risk of Dementia by the Number of Components Met of Tea Intake of ≥5 Servings/d, Red Wine Intake ≥1 Serving/d, and Berry Intake ≥0.5 Servings/d in 121 986 Males and Females From the UK Biobank eTable International Classification of Diseases Codes Used for Ascertainment of Dementia eTable Percent Contribution of Flavonoid-Rich Foods and the Flavodiet Score to Intake of Flavonoid Subclasses in 121 986 Males and Females From the UK Biobank eTable Baseline Characteristics by Inclusion Status in 502 411 Males and Females From the UK Biobank eTable Baseline Characteristics and Dietary Intakes by Dementia Diagnosis in 121 986 Males and Females From the UK Biobank eTable Estimated Hazard Ratios for LASSO Cox Regression Between Risk of Dementia and Flavodiet Score in 121 986 Males and Females From the UK Biobank eTable 6. Risk of Dementia by Quintiles of Flavodiet Score After Removing Each Food From the Final Score in 121 986 Males and Females From the UK Biobank eTable 7. Risk of Dementia by Quintiles of Flavodiet Score and Flavonoid Subclass Intake in 121 986 Males and Females From the UK Biobank, Stratified by Genetic Risk eTable 8. Risk of Dementia by Quintiles of Flavodiet Score and Flavonoid Subclass Intake in 121 105 Males and Females From the UK Biobank, Stratified by Depression Status eTable 9. Risk of Dementia by Quintiles of Flavodiet Score and Flavonoid Subclass Intake in 121 981 Males and Females From the UK Biobank, Stratified by Hypertension Status eTable 10.Risk of Dementia by Quintiles of Flavodiet Score and Flavonoid Subclass Intake in 61 719 Males and Females Aged More Than 60 Years From the UK Biobank eTable 11.Risk of Dementia by Quintiles of Flavodiet Score and Flavonoid Subclass Intake in 120 959 Males and Females With at Least 5 Years Follow-Up From the UK Biobank

eTable 12 .
Risk of Dementia by Quintiles of Flavodiet Score and Flavonoid Subclass Intake in 119 053 Males and Females With No Reported Stroke History From the UK Biobank eTable 13.Risk of Dementia by Quintiles of Flavodiet Score and Flavonoid Subclass Intake in 35 110 Males and Females At High Genetic Risk of Dementia Whose Reported Ethnicity Was White From the UK Biobank eTable 14.Risk of Dementia by Quintiles of Flavodiet Score and Flavonoid Subclass Intake in 121 986 Males and Females From the UK Biobank Adjusted for Individual Foods Associated With Dementia Risk) eTable 15.Risk of Dementia by Quintiles of Flavodiet Score and Flavonoid Subclass Intake in 53 101 Males and Females From the UK Biobank Living in High Areas of Deprivation or With Low Levels of Education eTable 16.Risk of Dementia by Quintiles of Flavodiet Score and Flavonoid Subclass Intake in 73 200 Males and Females From the UK Biobank With Low or Moderate Levels of Physical Activity

eTable 2. Percent Contribution of Flavonoid-Rich Foods and the Flavodiet Score to Intake of Flavonoid Subclasses in 121 986 Males and Females From the UK Biobank Food Servings/d Percentage contribution to flavonoid subclass intake Mean (SD) Flavanone Anthocyanin Flavan-3-ol Flavonol Flavone Polymer Proanthocyanidin 2 Total Flavonoid
2Proanthocyanidins are also included in the polymer subclass.

Estimated Hazard Ratios for LASSO Cox Regression Between Risk of Dementia and Flavodiet Score in 121 986 Males and Females From the UK Biobank
2Values are the post selection coefficients of the unstandardized variables calculated from LASSO Cox regression.2flavodiet sore was calculated by summing intakes (in servings per day) of tea (black and green), red wine, apples, berries, grapes, oranges, grapefruit, sweet peppers, onions, and dark chocolate, values relate to per quintile of the score.eTable 6.

Risk of Dementia by Quintiles of Flavodiet Score After Removing Each Food From the Final Score in 121 986 Males and Females From the UK Biobank
1ther group, not answered), current smoking status (yes or no), typical sleep duration (≤ 6 hours, 7-8 hours or > 8 hours, not answered), physical activity (total excess metabolic equivalents, in quintiles), BMI (kg/m 2 ), family history of dementia (yes or no), history of stroke (yes or no), post-menopausal status (yes, no, male or unknown), number of medications taken (1-3, 4-6, 7-9 or 10+), number of long-term health conditions (1-2, 3, 4, 5+), number of dietary assessments completed with plausible energy intakes (2, 3, 4 or 5), healthy plant-based diet index (score, in quintiles), alcohol intake not from red wine (g/d, in quintiles), energy intake (kcal/d, in quintiles) and fat intake (g/d, in quintiles) and stratified by region (London, North-West England, North-East England, Yorkshire, West Midlands, East Midlands, South-East England, South-West England, Scotland and Wales).HR (© 2024 Jennings A et al.JAMA Network Open.Values are adjusted hazard ratios (95% CI).Participants at high genetic risk were those in the highest quintile of PRS (n=2988), a carrier of the APOE ε4 genotype (n=12435) or both (n=20882)1flavodiet score was calculated by summing intakes (in servings per day) of tea (black and green), red wine, apples, berries, grapes, oranges, grapefruit, sweet peppers, onions, and dark chocolate.

Risk of Dementia by Quintiles of Flavodiet Score and Flavonoid Subclass Intake in 121 105 Males and Females From the UK Biobank, Stratified by Depression Status
2024 Jennings A et al.JAMA Network Open.eTable 8. © 2024 Jennings A et al.JAMA Network Open.

Risk of Dementia by Quintiles of Flavodiet Score and Flavonoid Subclass Intake in 121 981 Males and Females From the UK Biobank, Stratified by Hypertension Status
2024 Jennings A et al.JAMA Network Open.

Risk of Dementia by Quintiles of Flavodiet Score and Flavonoid Subclass Intake in 61 719 Males and Females Aged More Than 60 Years From the UK Biobank
2024 Jennings A et al.JAMA Network Open.eTable 10.