• National Dementia Conference 2018

Dementia and diet: modifiable risk factors and dietary prevention

By Sarah Belton
Bachelor of Human Nutrition,
University of Canberra

Dementia is defined as an insidious and progressive neurodegenerative disease that slowly reduces memory, higher intellectual function, and cognitive performance in general. Dementia is an umbrella term used to describe a range of symptoms caused by structural and chemical alterations in the brain, closely linked to a number of physical diseases such as hypertension, obesity, Type 2 diabetes, and cardiovascular diseases. Alzheimer’s disease is the most prevalent of the dementias, closely followed by vascular dementia. Risk factors associated with dementia include both genetic and environmental elements. The following discussion will focus on the modifiable dietary risk factors associated with serum cholesterol and homocysteine, with recommendations for preventative strategies and dietary advice.

The most prominent structural change in the brain, that has been labelled the characteristic hallmark associated with Alzheimer’s, is the over accumulation of b-amyloid protein deposits in neurons and extracellular brain space (1-3). Normal b-amyloid protein levels facilitate in modulation of synaptic activity and neuronal growth (4). However, the consequence of b-amyloid protein accumulation and aggregation is the unregulated buildup of neuritic plaques, which in turn compromise the structural integrity of cerebral blood vessels, and hence the nutrient transport to essential brain tissues (5). Recent studies have examined the generation and regulation of these plaques, with conclusions directing responsibility largely to cholesterol levels (6-8). Although the relationship is supported by evidence, there are very few scientific conclusions that can explain the exact interaction between increased cholesterol levels and the enhanced formation of b-amyloid plaques in the brain. However, the impact that cholesterol claims over the b-amyloid metabolic pathway can be directly observed through both genetic and dietary connections (2).

Evidence has established a specific allele variant of the apolipoprotein gene that is essential for cholesterol synthesis and transport in the brain, as a major genetic risk factor for dementia and Alzheimer’s disease (9-12).This allele is presumed to be highly influential on the accelerated formation of b-amyloid plaques, although the direct interaction remains highly controversial (6, 13).

Despite the consistent support for their biological relationship, the specific mechanisms of dietary cholesterol and b-amyloid regulation remain elusive (7, 13-16). One possible hypothesis postulates that the secondary vascular effects of elevated serum cholesterol may have a negative effect on the cerebrovascular system, which would cause alterations to the mechanisms of cerebral cholesterol synthesis and transport, as well as b-amyloid regulation and clearance (17).

A diet high in saturated fat has been shown to elevate serum cholesterol levels (18). Over time, high serum cholesterol levels have been associated with cardiovascular disorders such as high blood pressure (18), blood clots, cholesterol plaques within blood vessels (19), and consequent changes in blood circulation. The resulting physiological effect of blood clots, plaques, and b-amyloid deposits within blood vessels and tissues involves altered or restricted blood flow throughout the body, in addition to reduced nutrient transport. Both of these factors result in limited delivery of important nutrients such as oxygen and glucose through the cerebrovascular system, therefore affecting cognitive function (20, 21).

High cholesterol has also been associated with obesity (22, 23) and Type 2 diabetes (1, 24), which are both known risk factors for the development of dementia (25, 26). Furthermore, high serum cholesterol profiles have been shown to encourage b-amyloid deposits within neurons and surrounding cerebral tissue, which lead to the hallmark clusters associated with dementia (27). Thus, it is reasonable to assume that individuals with a diet high in saturated fat are at high risk of developing cardiovascular diseases and cognitive decline (2, 17, 27).

In contrast to the effect of saturated fats, intake of polyunsaturated dietary fats can act as a protective measure against the above mentioned physiological implications and risk factors linked to elevated cholesterol levels (28, 29). Unsaturated fat derivatives are key components of the highly synaptic myelin sheaths located in the brain (30). They have important roles in maintaining the structural integrity of the neuronal membranes (31) and establishing fluidity of the synaptosomal membranes, hence monitoring the plasticity, speed and effectiveness of neuronal communication (28).

Polyunsaturated fats promote positive reactions within the vascular system such as anti-arrhythmic, anti-thrombotic, anti-atherogenic and anti-inflammatory effects (32). More specifically, omega 3 polyunsaturated fats lower blood pressure, serum triglyceride levels, and improve endothelial functioning (29). As previously discussed, the knowledge that these factors decrease cardiovascular disease risk implies that they will also indirectly decrease dementia risk (2, 27).These fats could also have a direct protective impact against dementia by limiting the synthesis of pro-inflammatory cytokines. Cytokines are considered a strong pathological component to Alzheimer’s disease and cognitive decline (32). As an additional cerebral benefit to maintaining neuronal membrane function, unsaturated fat derivatives may have a role in regulating amyloid precursor protein (APP), thus limiting b-amyloid production (29).

The initial report from the Italian Longitudinal Study on Ageing established a distinct connection between high polyunsaturated fat intake and a decrease in cognitive decline. After a median follow up time of 8.5 years there was still a significant linear correlation between unsaturated dietary fat consumption and cognitive performance (28). The importance of unsaturated dietary fats can be supported further by the substantial field of evidence that directly relates fish intake to increased cognitive function and performance during old age. Multiple studies have shown a 40-60% reduced risk of dementia and Alzheimer’s with a high fish, and hence high polyunsaturated fat, diet (33-35).

In addition to polyunsaturated fats, fruits and vegetables should be considered a determinant for a healthy and protective diet. These two low saturated fat food groups are recognised for the high amounts of antioxidant micronutrients that they provide, with the added benefit of synergistically improved bioavailability (36). Antioxidants have the ability to neutralise free radicals, and reduce oxidative stress, which is defined as an imbalance between oxidants and antioxidants. This imbalance is a pathogenic mediator for Alzheimer’s, responsible for damaged DNA, proteins and lipids in both the brain and peripheral tissues of sufferers (37). A diet high in antioxidants has been associated with a slower rate of cognitive decline, illustrating a strong inverse linear relationship (38).

Taking into account the last two dietary components discussed, the Mediterranean diet is considered one of the best preventative measures to lower the risk of both cardiovascular and cognitive diseases (35). The Mediterranean diet consists primarily of vegetables, fruits, nuts, legumes, and fish, with moderate intake of wine, and low intake of meat and dairy products (18). This diet displays great benefit to blood lipid concentrations, decreased oxidative stress, and the overall function of the vascular system (18, 39-41). It is worth noting for the following discussion that vitamins B6, B12, and folate are all included in the Mediterranean diet. Vitamin B6 and folate are found in legumes, bananas, nuts and leafy green vegetables (25), while B12 is found in animal products such as meat, eggs and dairy (25). These vitamins are important regulators responsible for preventing the second structural change of the brain tissue observed in dementia sufferers; the shrinkage of vulnerable cerebral regions that are critical to learning and memory (42, 43).

One of the key biological components that influences this progressive atrophy is homocysteine (Hcy), a toxic by-product of amino acid metabolism (44). Total plasma Hcy concentrations are regulated and monitored by B vitamins. However, a deficiency in these essential nutrients can lead to high levels of Hcy in circulation, which may be responsible for various pathological changes in the brain including vascular damage, oxidative stress, promotion of apoptosis, and an increased generation and accumulation of b-amyloid plaques (45-47). In relation to atrophy of the brain, elevated Hcy levels have been held accountable for the reduction in hippocampal volume (48), total brain volume (49), medial temporal lobe volume, (44, 43, 48), and the ventrile-to-brain ratios (50), observed in dementia sufferers, although the causal pathway has yet to be defined. Further evidence regarding the detrimental side effects associated with the unregulated biomarker include carotid, coronary and cerebral atherosclerosis, thrombosis, stroke, cardiovascular mortality (27) and cognitive diseases (51-53).

The concept that this modifiable risk factor could be prevented by vitamin B intake has raised some promising research, although most of the longitudinal research does not have a sufficient number of participants. Regarding B6, B12, and folate, studies have been controversial but the general consensus appears to be that B6 and folate demonstrate a linear correlation between plasma concentrations and higher memory or cognitive performance tests (52, 53, 42). B12 however poses difficulty for research in the sense that serum concentrations do not accurately reflect the intracellular concentrations (54), leading to conflicting data across the field. Epidemiological evidence has established hyperhomocysteinemia as a strong prognostic marker for poor cognitive performance and future decline. Excessive Hcy concentrations and B vitamin deficiencies are considered to be modifiable risk factors with regard to dementia (42, 44). The preventative nature of vitamin B in relation to neurodegenerative diseases could be demonstrated by larger observational or random control trials.

Vitamin D is also considered essential for the prevention of cognitive decline, as it has the positive effects of stimulating phagocytosis and clearance of b-amyloid plaques, whilst additionally protecting against glucocorticoid-induced apoptosis in hippocampal cells that would otherwise result in atrophy, a characteristic component of Alzheimer’s development (55). Vitamin D can be obtained by sun exposure, oily fish intake, and is fortified in all margarine and some milks in Australia (56). However, the question of reverse causation is still unanswered, as many elderly people have restricted physical access to direct sunlight, possibly due to other ailments (55). Many of the studies surrounding vitamin D and dementia have been cross-sectional or case-control, with little observation into the disease progression related to physical mobility and sun exposure.

Dementia is physically characterised by the over production and accumulation of b-amyloid proteins in vulnerable cerebral tissue. Hippocampal and lobular atrophy are often also observed. The two most common modifiable risk factors for b-amyloid dysfunction are elevated cholesterol levels and plasma homocysteine concentrations. The Mediterranean diet has been highly recommended as a preventative diet. Evidence suggests that the high polyunsaturated fat intake can counteract the saturated fat risk factor associated with high cholesterol profiles. Elevated circulating cholesterol levels are considered to be directly linked to cognitive decline and cardiovascular diseases. In addition, the high concentration of fibre, antioxidants, and B vitamins found in the Mediterranean diet may aid in regulating and monitoring the plasma homocysteine levels. This may in turn prevent the over accumulation of the b-amyloid proteins in the cerebral tissue. Due to the strong association between dementia and other physical diseases such as obesity, Type 2 diabetes, hypertension, and cardiovascular risk, the healthy and balanced nature of the Mediterranean diet will also greatly decrease cognitive decline simply by decreasing the risk of developing metabolic disorders.


1. Qiu WQ, Folstein MF. Insulin, insulin-degrading enzyme and amyloid-β peptide in Alzheimer’s disease: review and hypothesis. Neurobiol Aging 2006 2;27(2)190-198.

2. Cole GM, Qiu-Lan Ma, Frautschy SA. Dietary fatty acids and the aging brain. Nutr Rev 2010 12/02;68:S102-S111.

3. Cummings JL. Alzheimer’s Disease. N Engl J Med 2004 07;351(1):56-67.

4. Bishop GM, Robinson SR. Physiological roles of amyloid-beta and implications for its removal in Alzheimer’s disease. Drugs Aging 2004;21(10):621-630.

5. Ambrose CT. Alzheimer’s Disease: The Great Morbidity of the 21st Century. Am Sci 2013 May;101(3):194.

6. Puglielli, LuigiTanzi, Rudolph E.Kovacs,Dora M. Alzheimer’s disease: the cholesterol connection. Nat Neurosci 2003 04;6(4):345.

7. Kandiah N, Feldman HH. Therapeutic potential of statins in Alzheimer’s disease. J Neurol Sci 2009 08/15;283(1):230-234.

8. Posse dC. Reciprocal regulation of cholesterol and beta amyloid at the subcellular level in Alzheimer’s disease. Canadian Journal of Physiology & Pharmacology 2012 06;90(6):753-764.

9. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993 08/13;261(5123):921-923.

10. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 1993 03/01;90(5):1977-1981.

11. Poirier J, Davignon J. Apolipoprotein E polymorphism and Alzheimer’s disease. Lancet 1993 09/18;342(8873):697.

12. Chartier-Harlin M, Parfitt M, Legrain S, Pérez-Tur J, Brousseau T, Evans A, et al. Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer’s disease: analysis of the 19q13.2 chromosomal region. Hum Mol Genet 1994 04;3(4):569-574.

13. Solfrizzi V, D’Introno A, Colacicco AM, Capurso C, Todarello O, Pellicani V, et al. Circulating biomarkers of cognitive decline and dementia. Clin Chim Acta 2006 02;364(1-2):91-112.

14. Abramov AY, Ionov M, Pavlov E, Duchen MR. Membrane cholesterol content plays a key role in the neurotoxicity of ß-amyloid: implications for Alzheimer’s disease. Aging Cell 2011 08;10(4):595-603.

15. Guardia-Laguarta C, Coma M, Pera M, Clarimón J, Sereno L, Agulló JM, et al. Mild cholesterol depletion reduces amyloid-β production by impairing APP trafficking to the cell surface. J Neurochem 2009 07;110(1):220-230

16. Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, et al. Simvastatin strongly reduces levels of Alzheimer’s disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci USA 2001 05/08;98(10):5856-5861.

17. Ledesma MD, Dotti CG. Amyloid excess in Alzheimer’s disease: what is cholesterol to be blamed for? FEBS Lett 2006 10/09;580(23):5525-5532.

18. Solfrizzi V, Capurso C, D’Introno A, Colacicco AM, Frisardi V, Santamato A, et al. Dietary fatty acids, age-related cognitive decline, and mild cognitive impairment. J Nutr Health Aging 2008 01/01;12(6):382-386.

19. Combinations of Food May Affect Alzheimer’s Risk. Tufts University Health & Nutrition Letter 2010 07;28(5):1-3.

20. de la Torre JC. Vascular basis of Alzheimer’s pathogenesis. Ann N Y Acad Sci 2002 11;977:196-215.

21. de la Torre JC. Cerebral hypoperfusion, capillary degeneration, and development of Alzheimer disease. Alzheimer Dis Assoc Disord 2000;14 Suppl 1:S72-S81.18).

Laitinen MH, Ngandu T, Rovio S, Helkala E-, Uusitalo U, Viitanen M, et al. Fat Intake at Midlife and Risk of Dementia and Alzheimer’s Disease: A Population-Based Study. Dementia & Geriatric Cognitive Disorders 2006 07;22(1):99-107

22. Whitmer RA, Gunderson EP, Quesenberry Jr. CP, Zhou J, Yaffe K. Body Mass Index in Midlife and Risk of Alzheimer Disease and Vascular Dementia. Current Alzheimer Research 2007 04;4(2):103-109.

23. Goble AJ, Tabet N, Raza G, Vreugdenhil A, Whitmer R, Quesenberry C, J, et al. Obesity in middle age and future risk of dementia. Whitmer RA, Gunderson EP, Barrett-Connor E et al. Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ 2005;330:1360-2. (11 June). BMJ 2005 08/20;331(7514):454-455.

24. Cheng G, Huang C, Deng H, Wang H. Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J 2012 05;42(5):484-491.

25. Barnard ND. FEED Your BRAIN, (cover story). Vegetarian Times 2013 03(401):72-75.

26. Tripathi M, Vibha D, Gupta P, Bhatia R, Srivastava MV, Vivekanandhan S, et al. Risk factors of dementia in North India: a case-control study. Aging Ment Health 2012 03;16(2):228-235.

27. Ferraz Alves, Tânia Corrêa,de Toledo, Ferreira LK, Wajngarten M, Busatto GF. Cardiac Disorders as Risk Factors for Alzheimer’s Disease. J Alzheimer’s Dis 2010 07;20(3):749-763.

28. Solfrizzi V, Capurso C, D’Introno A, Colacicco AM, Santamato A, Ranieri M, et al. Lifestyle-related factors in predementia and dementia syndromes. Expert Rev Neurother 2008 01;8(1):133-158.

29. Lim WS, Gammack JK, Van Niekerk J, Dangour AD. Omega 3 fatty acid for the prevention of dementia. Cochrane Database Syst Rev 2006 01/25(1):CD005379.

30. Snipes GJ, Suter U. Cholesterol and myelin. Subcell Biochem 1997;28:173-204.

31. Solfrizzi V, Panza F, Capurso A. The role of diet in cognitive decline. J Neural Transm 2003 01;110(1):95-110.

32. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging 2000 05/20;21(3):383-421.

33. Cole GM, Ma Q, Frautschy SA. Omega-3 fatty acids and dementia. Prostaglandins Leukot Essent Fatty Acids 2009 08/20;81(2-3):213-221.

34. Weichselbaum E, Coe S, Buttriss J, Stanner S. Fish in the diet: a review. Nutr Bull 2013 01/01;38(2):128-177.

35. Huang TL, Zandi PP, Tucker KL, Fitzpatrick AL, Kuller LH, Fried LP, et al. Benefits of fatty fish on dementia risk are stronger for those without APOE epsilon4. Neurology 2005 11/08;65(9):1409-1414.

36. Joshi YB, Praticò D. Vitamin E in aging, dementia, and Alzheimer’s disease. Biofactors 2012 Mar;38(2):90-97.

37. Guérin O, Andrieu S, Schneider SM, Milano M, Boulahssass R, Brocker P, et al. Different modes of weight loss in Alzheimer disease: a prospective study of 395 patients. Am J Clin Nutr 2005 08;82(2):435-441.
38. Morris MC, Evans DA, Tangney CC, Bienias JL, Wilson RS. Associations of vegetable and fruit consumption with age-related cognitive change. Neurology 2006 10/24;67(8):1370-1376.

39. Scarmeas N, Stern Y, Tang MX, Mayeux R, Luchsinger JA. Mediterranean diet and risk for Alzheimer’s disease. Ann Neurol 2006 06;59(6):912-921.

40. Scarmeas N, Stern Y, Mayeux R, Luchsinger JA. Mediterranean diet, Alzheimer disease, and vascular mediation. Arch Neurol 2006 12;63(12):1709-1717.

41. Ambring A, Friberg P, Axelsen M, Laffrenzen M, Taskinen M, Basu S, et al. Effects of a Mediterranean-inspired diet on blood lipids, vascular function and oxidative stress in healthy subjects. Clin Sci (Lond) 2004 05;106(5):519-525.
42. Smith AD. The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull 2008 06;29(2):S143-S172.

43. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998 11;55(11):1449-1455.

44. Van Dam F, Van Gool W. Hyperhomocysteinemia and Alzheimer’s disease: a systematic review. Arch Gerontol Geriatr 2009 2009;48(3):425-430.

45. Sachdev PS. Homocysteine and brain atrophy. Prog Neuropsychopharmacol Biol Psychiatry 2005 09;29(7):1152-1161.

46. Ho PI, Collins SC, Dhitavat S, Ortiz D, Ashline D, Rogers E, et al. Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress. J Neurochem 2001 07;78(2):249-253

47. White AR, Huang X, Jobling MF, Barrow CJ, Beyreuther K, Masters CL, et al. Homocysteine potentiates copper and amyloid beta peptide-mediated toxicity in primary neuronal cultures: possible risk factors in the Alzheimer’s-type neurodegenerative pathways. J Neurochem 2001 03;76(5):1509-1520.

48. Williams JH, Pereira E, Budge MM, Bradley KM. Minimal hippocampal width relates to plasma homocysteine in community-dwelling older people. Age Ageing 2002 11;31(6):440-444.

49. Seshadri S, Wolf PA, Beiser AS, Selhub J, Au R, Jacques PF, et al. Association of plasma total homocysteine levels with subclinical brain injury: cerebral volumes, white matter hyperintensity, and silent brain infarcts at volumetric magnetic resonance imaging in the Framingham Offspring Study. Arch Neurol 2008 05;65(5):642-649.

50. Sachdev PS, Valenzuela M, Wang XL, Looi JCL, Brodaty H. Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individuals. Neurology 2002 05/28;58(10):1539-1541.

51. Nurk E, Refsum H, Tell GS, Engedal K, Vollset SE, Ueland PM, et al. Plasma total homocysteine and memory in the elderly: the Hordaland Homocysteine Study. Ann Neurol 2005 12;58(6):847-857.

52. Tucker KL, Qiao N, Scott T, Rosenberg I, Spiro A, 3rd. High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study. Am J Clin Nutr 2005 09;82(3):627-635.

53. Dangour AD, Whitehouse PJ, Rafferty K, Mitchell SA, Smith L, Hawkesworth S, et al. B-Vitamins and Fatty Acids in the Prevention and Treatment of Alzheimer’s Disease and Dementia: A Systematic Review. J Alzheimer’s Dis 2010 12/08;22(1):205-224.

54. Clarke R. B-vitamins and prevention of dementia. Proc Nutr Soc 2008 02;7(1):75-81.

55. Dickens AP, Lang IA, Langa KM, Kos K, Llewellyn DJ. Vitamin D, Cognitive Dysfunction and Dementia in Older Adults. CNS Drugs 2011 08;25(8):629-639.

56. Slinin Y, Paudel M, Taylor BC, Ishani A, Rossom R, Yaffe K, et al. Association between serum 25(OH) vitamin D and the risk of cognitive decline in older women. J Gerontol A Biol Sci Med Sci 2012 10;67(10):1092-1098.

Want to read the other articles in this issue? SUBSCRIBE TODAY for as little as $99 to improve your practice and stay up to date on the latest in dementia research and training.