Intended for healthcare professionals

CCBYNC Open access

Rapid response to:


Modifiable pathways in Alzheimer’s disease: Mendelian randomisation analysis

BMJ 2017; 359 doi: (Published 07 December 2017) Cite this as: BMJ 2017;359:j5375

Rapid Response:

Dietary risk factors for Alzheimer's disease are well known

The recent Mendelian randomization (MR) analysis by Larsson et al.1 did not find evidence that dietary factors other than coffee consumption were associated with risk of Alzheimer's disease (AD). The MR analysis for determining risk factors for various health outcomes is a relatively new approach. The basic assumption is that genetic variations in personal response to risk factors can help identify risk factors unaffected by confounding factors. As it is a new approach, it is important to validate the approach by comparing its results with those of other approaches.

There are several approaches used to evaluate the role of diet in the risk of AD. The approaches include ecological studies, observational studies, studies of brain biomarkers of AD with respect to diet, and studies of mechanisms. Results from each of these approaches are examined here.

There have been several multi-country ecological studies of national dietary supply and prevalence of AD. The first one identified total fat and total energy supply as important risk factors with fish and cereals as risk reduction factors.2 One examined the increase in AD rates in Japan following the nutrition transition to the Western diet. Rates rose from 1% in 1985 to 7% in 2008, lagging the nutrition transition by 20-25 years.3 A more recent study examined the correlation of AD prevalence with respect to macro elements of national dietary supply five to 15 years prior to the prevalence data. For the ten countries, dietary meat supply with or without other animal products other than milk five years prior to the prevalence data, the regression coefficient was 0.94 or 0.95 (P<0.001) while that for cereals was -0.56 (P=0.10).4 The Mediterranean diet, characterized by the diet of Cyprus in the early 1960s, was associated with half the maximum AD prevalence.

The first paper linking meat consumption to risk of AD was an observational study from the Adventist Health Study. "The matched subjects who ate meat (including poultry and fish) were more than twice as likely to become demented as their vegetarian counterparts (relative risk 2.18, p = 0.065) and the discrepancy was further widened (relative risk 2.99, p = 0.048) when past meat consumption was taken into account.".5 In the U.S., about two-thirds of dementia is AD. A prospective study in Illinois found that fish consumption once a week was associated with a 60% reduction in risk of developing AD.6 Another prospective study found a significantly reduced risk of AD in a prospective study of the MIND diet, a hybrid Mediterranean-Dietary Approaches to Stop Hypertension diet.7 The foods associated with risk reduction were whole grains, green leafy and other vegetables, berries, fish, poultry, beans, nuts, while the foods associated with risk were red meats and products, fast/fried food, butter and margarine, cheese, and pastries/sweets. The hazard rate for those with a MIND diet score of 8.5--12.5 was 0.47 (0.30, 0.73) compared to those with a MIND diet score of 2.5--6.5.

It is also possible to study brain biomarkers of AD with respect to dietary pattern. A study in Ohio involving 71 persons with AD and 71 controls used a food-frequency questionnaire and determined: "The AD dietary pattern, FACTOR AD was characterized by a high intake of meat, butter, high-fat dairy products, eggs, and refined sugar, whereas the other pattern, (FACTOR C) was characterized by a high intake of grains and vegetables.".8 In another study involving 49 cognitively normal individuals, "The identified nutrient combination was associated with higher intake of vegetables, fruit, whole grains, fish and legumes, and lower intake of high-fat dairies, meat and sweets.".9

The mechanisms linking animal product consumption to risk of AD include those related to cholesterol,10 trace metals,2 and advanced glycation end products (AGEs).11
Copper, iron and zinc are elevated in the senile plaques of people with AD, where they could increase the formation of free radicals.12 "With elimination of meat and increased intake of phytate-containing legumes and whole grains, the absorption of both iron and zinc is lower with vegetarian than with nonvegetarian, diets.".13 Neurons are extremely sensitive to attacks by destructive free radicals.14 AGEs, which are formed in cooking meat at high dry temperatures such as bar-b-que or by aging cheese, or through the Millard reaction between glucose and proteins in the body. AGEs generate free radicals and increase inflammation.15 In combination with copper and sugars, AGEs also contribute to neurological dysfunction.16

There is also evidence that higher 25-hydroxyvitamin D concentrations are associated with lower risk of developing AD,17,18 in agreement with the results of Ref. 1.

Thus, the fact that the MR analysis by Larsson et al.1 did not find any significant risk of AD related to diet is surprising given the strong support for the role of diet in influencing risk of AD found by several other approaches.

1. Larsson SC, Traylor M, Malik R, Dichgans M, Burgess S, Markus HS; CoSTREAM Consortium, on behalf of the International Genomics of Alzheimer’s Project. Modifiable pathways in Alzheimer's disease: Mendelian randomisation analysis. BMJ. 2017;359:j5375.
2. Grant WB. Dietary links to Alzheimer's disease. Alz Dis Rev 1997;2:42-55
3. Grant WB. Trends in diet and Alzheimer’s disease during the nutrition transition in Japan and developing countries. J Alz Dis. 2014;38:611¬20.
4. Grant WB. Using Multicountry ecological and observational studies to determine dietary risk factors for Alzheimer’s disease. J Am Coll Nutr, 2016;35:476–89.
5. Giem P, Beeson WL, Fraser GE: The incidence of dementia and intake of animal products: preliminary findings from the Adventist Health Study. Neuroepidemiology 12:28–36, 1993.
6. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Wilson RS, Aggarwal N, Schneider J. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol. 2003;60:940¬6.
7. Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, Aggarwal NT. MIND diet associated with reduced incidence of Alzheimer's disease. Alzheimers Dement. 2015;11:1007¬14.
8. Gustaw-Rothenberg K. Dietary patterns associated with Alzheimer's disease: population based study. Int J Environ Res Public Health. 2009;6:1335¬40.
9. Mosconi L, Murray J, Davies M, Williams S, Pirraglia E, Spector N, Tsui WH, Li Y, Butler T, Osorio RS, Glodzik L, Vallabhajosula S, McHugh P, Marmar CR, de Leon MJ. Nutrient intake and brain biomarkers of Alzheimer's disease in at-risk cognitively normal individuals: a cross-sectional neuroimaging pilot study. BMJ Open. 2014;4:e004850.
10. Czuba E, Steliga A, Lietzau G, Kowiański P. Cholesterol as a modifying agent of the neurovascular unit structure and function under physiological and pathological conditions. Metab Brain Dis. 2017;32:935¬48.
11. Perrone L, Grant WB. Observational and ecological studies of dietary advanced glycation end products in national diets and Alzheimer’s disease incidence and prevalence. J Alz Dis. 2015;45:965–79.
12. Cheignon C, Tomas M, Bonnefont-Rousselot D, Faller P, Hureau C, Collin F. Oxidative stress and the amyloid beta peptide in Alzheimer's disease. Redox Biol. 2018;14:450¬64.
13. Hunt JR. Bioavailability of iron, zinc, and other trace minerals from vegetarian diets. Am J Clin Nutr. 2003;78:633S¬9S.
14. Christen Y. Oxidative stress and Alzheimer disease. Am J Clin Nutr. 2000;71:621S¬9S.
15. Ajith TA, Vinodkumar P. Advanced Glycation End Products: Association with the pathogenesis of diseases and the current therapeutic advances. Curr Clin Pharmacol. 2016;11:118¬27.
16, Fica-Contreras SM, Shuster SO, Durfee ND, Bowe GJK, Henning NJ, Hill SA, Vrla GD, Stillman DR, Suralik KM, Sandwick RK, Choi S. Glycation of Lys-16 and Arg-5 in amyloid-β and the presence of Cu2+ play a major role in the oxidative stress mechanism of Alzheimer's disease. J Biol Inorg Chem. 2017;22:1211¬22.
17. Littlejohns TJ, Henley WE, Lang IA, Annweiler C, Beauchet O, Chaves PH, Fried L, Kestenbaum BR, Kuller LH, Langa KM, Lopez OL, Kos K, Soni M, Llewellyn DJ. Vitamin D and the risk of dementia and Alzheimer disease. Neurology. 2014;83:920¬8.
18. Feart C, Helmer C, Merle B, Herrmann FR, Annweiler C, Dartigues JF, Delcourt C, Samieri C. Associations of lower vitamin D concentrations with cognitive decline and long-term risk of dementia and Alzheimer's disease in older adults. Alzheimers Dement. 2017;13:1207¬16.

Competing interests: No competing interests

10 December 2017
William B. Grant
Independent Researcher
Sunlight, Nutrition and Health Research Center
PO Box 641603, San Francisco, CA 94164-1603