Apolipoprotein E

2.6 APOE, DIETARY CHOLESTEROL AND CHOLINE INTAKE AND

double ε4 alleles (208). The risk of onset also depends on race for unknown reasons. Whites have a greater ε4-related risk than Blacks (209).

The impact of the APOE4 on the associations between dietary intakes and cognitive outcomes have been investigated in at least 34 studies during the last two decades (Table 19). The investigated dietary intakes have been widespread covering topics from micronutrient intakes to macronutrient intakes and from certain foods to entire food patterns.

Thus, studies concerning a single topic are few and conclusions on the impact of the APOE4 cannot reliably be made. In general, the role of APOE4 in the relationships between dietary intakes and cognitive outcomes is inconsistent.

Both APOE4 carriers and noncarriers seem to have beneficial and adverse health impacts from certain dietary intakes, but most of the findings are based on observational studies (Table 19). Although APOE4 is linked to higher risk of dementia and cardiovascular diseases, having APOE4 does not always seem to have logical influences on the

relationships between unhealthy diet and cognitive outcomes. For example, in the intervention study by Hanson et al. (212), the APOE4 carriers (APOE4+) had higher memory scores after eating a meal high in saturated fat and glycemic index than APOE4 non-carrier (APOE4-)

participants. However, cognitive performance directly after a meal may not represent long term cognitive performance if a certain diet is maintained for months or years. All in all, more studies are needed to clarify the role of APOE in the diet-related dementia outcomes.

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Table 19. Summary of the studies of the impact of the APOE4 on the associations between dietary intakes and cognitive outcomes. ReferenceStudy design Study populationObjectiveThe impact of the APOE4 phenotype Zhang et al. 2021 (122) Prospective cohort study 493 888 UK participants Association between meat consumption and risk of incident dementia

Each 50 g/d increase of unprocessed red meat lowered the risk of incident all-cause dementia and AD among APOE4+ Zhang et al. 2021 (157) Prospective cohort study 3029 Chinese participants

Association between dietary protein intake and cognitive decline

Higher dietary protein intake and daily fish intake associated with slower cognitive decline among APOE4+. Fish intake was more beneficial for female APOE4+ Gentreau et al. 2020 (213) Prospective cohort study 2539 French participants

Association between high glycemic load meals and cognitive decline

Afternoon snack with high glycemic load associated with cognitive decline among APOE4+ Gentreau et al. 2020 (214) Prospective cohort study 2777 French participants

Association between refined carbohydrate-rich diet and the risk of dementia and AD

Afternoon snack with high glycemic load associated with higher risk of dementia and AD among APOE4+ Holland et al. 2020 (215) Prospective cohort study 921 US participants

Associations between dietary flavonol intakes and ADNone Keenan et al. 2020 (216) Cross-sectional study 7756 US participants Association between adherence to the alternative Mediterranean diet and cognitive function

None Table 19 continues

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Table 19. (continued) Summary of the studies of the impact of the APOE4 on the associations between dietary intakes and cognitive outcomes. ReferenceStudy design Study populationObjectiveThe impact of the APOE4 phenotype Klinedinst et al. 2020 (173) Prospective cohort study 1787 UK participants

Association between total diet and long-term cognitionWeekly cheese intake was associated with better fluid intelligence (FI) among APOE4+ and daily vegetable consumption with worse FI among APOE4-. Adding salt in foods was associated with worse FI among APOE4+ Oleson et al. 2020 (217) Cross-sectional study 122 US participants Association between dietary polyunsaturated fat and cognitive function

Higher polyunsaturated fat intake was associated with better memory performance among APOE4- Yuan et al. 2020 (218) Prospective cohort study 49 493 US women

Association between long- term carotenoid intake and subjective cognitive function

Higher carotenoid intake was associated with lower risk of moderate or poor subjective cognitive function among APOE4+ homozygotes Zhao et al. 2020 (219) Prospective cohort study 1759 US participants

Association between vitamin D intake and dementiaHigher dietary vitamin D intake was associated with lower risk of dementia among APOE4- Agarwal et al. 2019 (220) Prospective cohort study 925 US participants

Association between strawberry intake and ADHigher anthocyanidins intake was associated with lower risk of AD among APOE4- Prinelli et al. 2019 (181) Prospective cohort study 2250 Swedish participants Association between nutrient patterns and cognitive decline Plant- and animal-derived nutrient patterns were associated with slower cognitive decline among APOE4+ compared to dairy pattern Table 19 continues

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Table 19. (continued) Summary of the studies of the impact of the APOE4 on the associations between dietary intakes and cognitive outcomes. ReferenceStudy design Study populationObjectiveThe impact of the APOE4 phenotype Berendsen et al. 2018 (221) Prospective cohort study 16 058 US women Association between adherence to a MIND and cognitive function and cognitive decline

None Samieri et al. 2018 (203) Meta-analysis 23 688 French and US participants

Association between fish intake and cognitive declineNone Gardener et al. 2017 (222) Cross-sectional study 666 Australian participants Association between carbohydrate intake and cognitive performance

Higher carbohydrate intake was associated with lower verbal memory performance among APOE4- and lower attention performance among APOE4+ Morris et al. 2016 (223) Cross-sectional study 286 US participants

Association between seafood intake and brain neuropathologies

At least one seafood meal per week or higher long-chain n-3 fatty acid intake was associated with less AD pathology among APOE4+ van de Rest et al. 2016 (200)

Prospective cohort study 915 US participants Associations between seafood intake, long-chain n-3 fatty acids intake and cognitive function Higher seafood, long-chain n-3 fatty acid, and α-linolenic acid intakes were associated with slower cognitive decline among APOE4+ Table 19 continues

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Table 19. (continued) Summary of the studies of the impact of the APOE4 on the associations between dietary intakes and cognitive outcomes. ReferenceStudy design Study populationObjectiveThe impact of the APOE4 phenotype Zhang et al. 2016 (136) Meta-analysis 181 580 participants Associations between fish and polyunsaturated fatty acid intakes and cognitive impairment risk

Higher DHA intake was associated with lower risk of cognitive impairment among APOE4+ Gardener 2015 (224) Prospective cohort study 527 Australian participants

Associations between dietary patterns and cognitive change

Higher adherence to Australian-style Mediterranean diet was associated with better cognitive performance among APOE4+. Higher adherence to western diet was associated with higher cognitive decline among APOE4- Hanson et al. 2015 (212) Intervention 46 US participants

To assess effects of meals high in SFA and high GI vs. low SFA and low GI on cognitive outcomes

APOE4- had lower memory scores after high SFA and GI meals, whereas APOE4+ had higher scores after the same meal Danthiir et al. 2014 (196) Cross-sectional study 390 Australian participants

Associations between fish intake and cognitive functionNone Geda et al. 2013 (225) Case-control study 1233 US participants

Association between dietary caloric intake and MCI High caloric intake was associated with more increased odds of MCI among APOE4+, although the risk was also increased among APOE4- Table 19 continues

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Table 19. (continued) Summary of the studies of the impact of the APOE4 on the associations between dietary intakes and cognitive outcomes. ReferenceStudy design Study populationObjectiveThe impact of the APOE4 phenotype Martínez- Lapiscina et al. 2013 (226) RCT 285 Spanish participants To compare the effects of two Mediterranean diets on cognition

None Eskelinen et al. 2009 (227) Prospective cohort study 1409 Finnish participants

Associations between coffee/tea drinking and dementia/AD risk.

Coffee drinkers had a lower risk of dementia, but it was even more beneficial among APOE4+ than APOE4- Eskelinen et al. 2008 (228) Prospective cohort study 1449 Finnish participants

Association between fat intake and cognitive performance

Total fat intake was associated with higher risk of MCI among APOE4- and saturated fat intake with higher risk of MCI among APOE4+ Barberger- Gateau et al. 2007 (123)

Prospective cohort study 8085 French participants Association between dietary patterns and risk of dementia/AD

Weekly fish intake associated with lower dementia and AD risks among APOE4- and regular n-6 rich oil intake with higher risks among APOE4- Luchsinger et al. 2007 (229) Prospective cohort study 965 US participants

Associations between folate, vitamin B6, and vitamin B12 intakes and AD

None Salerno- Kennedy et al. 2007 (230)

Cross-sectional study 44 Irish participants Associations between nutrient intakes and cognitive performance

None Table 19 continues

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Table 19. (continued) Summary of the studies of the impact of the APOE4 on the associations between dietary intakes and cognitive outcomes. ReferenceStudy design Study populationObjectiveThe impact of the APOE4 phenotype Morris et al. 2006 (231) Prospective cohort study 1041 US participants Associations between folate, vitamin B12, and vitamin B6 intakes and the risk of AD

None Scarmeas et al. 2006 (232) Case-control study 1984 US participants

Association between the Mediterranean diet and ADNone Huang et al. 2005 (129) Prospective cohort study 2233 US participants Associations between lean/fatty fish and dementia/ AD/vascular dementia

Higher tuna/other fish intake was associated with lower risk of dementia among APOE4- Laurin et al. 2004 (233) Prospective cohort study 2459 Japanese-US participants

Associations between dietary antioxidants intake and dementia

None Luchsinger et al. 2003 (234) Prospective cohort study 980 US participants

Associations between antioxidant intakes and ADNone Table 19 continues

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Table 19. (continued) Summary of the studies of the impact of the APOE4 on the associations between dietary intakes and cognitive outcomes. ReferenceStudy design Study populationObjectiveThe impact of the APOE4 phenotype Luchsinger et al. 2002 (235) Prospective cohort study 980 US participants

Association between energy intake and ADHigher energy and fat intakes were associated with higher risk of AD among APOE4+ AD, Alzheimer’s disease; APOE4+; apolipoprotein E ε4 carriers; APOE4-; apolipoprotein E ε4 non-carriers; DHA, docosahexaenoic acid; FI, fluid intelligence; GI, glycemic index; MCI, mild cognitive impairment; MIND, Mediterranean-DASH Intervention for Neurodegenerative Delay diet; SFA, saturated fat; UK, the United Kingdom; US, the United States