Defective insulin signalling, mediated by inflammation, connects obesity to Alzheimer disease; relevant pharmacological therapies and preventive dietary interventions

Current Alzheimer Research

Volumn 14, Issue 8, 2017, Pages 894-911

  Rodriguez Casado, Arantxa ^a   Toledano Díaz, Adolfo ^b   Toledano, Adolfo ^a  

^a INSTITUTO CAJAL   (Spain)

^b INIA   (Spain)

Author keywords

Alzheimer s disease; Diabetes type 2; Diet; Insulin resistance; Nutraceuticals; Nutrition; Obesity; Prevention

Indexed keywords

AMFEBUTAMONE PLUS NALTREXONE; ANTIOBESITY AGENT; ANTIOXIDANT; CARBOHYDRATE; CERAMIDE; CETILISTAT; CHOLESTEROL; INSULIN; LIPID; LIRAGLUTIDE; LORCASERIN; METAL; NATURAL PRODUCT; NOOTROPIC AGENT; PHENTERMINE PLUS TOPIRAMATE; PLANT MEDICINAL PRODUCT; SIBUTRAMINE; TESOFENSINE; TETRAHYDROLIPSTATIN; VITAMIN;

ALZHEIMER DISEASE; COGNITIVE DEFECT; DIET THERAPY; ENCEPHALITIS; FAT INTAKE; FOOD; FRUIT; HEALTHY LIFESTYLE; HUMAN; INSULIN RESISTANCE; INSULIN SIGNALING; METABOLIC DISORDER; MOLECULAR PATHOLOGY; NON INSULIN DEPENDENT DIABETES MELLITUS; NUTRIENT; OBESITY; OXIDATIVE STRESS; PHYSICAL ACTIVITY; PREVENTIVE MEDICINE; PRIORITY JOURNAL; REVIEW; RISK FACTOR; SIGNAL TRANSDUCTION; SUGAR INTAKE; THERAPY EFFECT; VEGETABLE; ANIMAL; COMPLICATION; INFLAMMATION; METABOLISM; PHYSIOLOGY;

ALZHEIMER DISEASE; ANIMALS; HUMANS; INFLAMMATION; INSULIN; INSULIN RESISTANCE; OBESITY; SIGNAL TRANSDUCTION;

EID: 85028957926     PISSN: 15672050     EISSN: 18755828     Source Type: Journal    
DOI: 10.2174/1567205014666170316161848     Document Type: Review

References (206)

1. Zhang PY. Cardiovascular disease in diabetes. Eur Rev Med Pharmacol Sci 18(15): 2205-14 (2014).
2. Ghosh S. Ectopic fat: the potential target for obesity management. J Obes Metab Res 1(1): 30-8 (2014).
3. Smith U. Abdominal obesity: a marker of ectopic fat accumulation. J Clin Invest 125(5): 1790-2 (2015).
4. Profenno LA, Porsteinsson AP, Faraone SV. Meta-analysis of Alzheimer’s disease risk with obesity, diabetes, and related disorders. Biol Psychiatry 67(6): 505-12 (2010).
5. Nguyen JC, Killcross AS, Jenkins TA. Obesity and cognitive decline: role of inflammation and vascular changes. Front Neurosci 8: 375 (2014).
6. Toda N, Ayajiki K, Okamura T. Obesity-induced cerebral hypoperfusion derived from endothelial dysfunction: one of the risk factors for Alzheimer’s disease. Curr Alzheimer Res 11(8): 733-44 (2014).
7. Emmerzaal TL, Kiliaan AJ, Gustafson DR. 2003-2013: a decade of body mass index, Alzheimer’s disease, and dementia. J Alzheimers Dis 43(3): 739-55 (2015).
8. Bedse G, Di Domenico F, Serviddio G, Cassano T. Aberrant insulin signaling in Alzheimer’s disease: current knowledge. Front Neurosci 9: 204 (2015).
9. Hildreth KL, VanPelt RE, Schwartz RS. Obesity, insulin resistance, and Alzheimer’s disease. Obesity (Silver Spring) 20(8):1549-57 (2012).
10. Nuzzo D, Picone P, Baldassano S, Caruana L, Messina E, Marino Gammazza A, et al. Insulin resistance as common molecular denominator linking obesity to Alzheimer’s disease. Curr Alzheimer Res 12(8): 723-35 (2015).
11. Ferreira ST, Clarke JR, Bomfim TR, De Felice FG. Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer’s disease. Alzheimers Dement 10(1 Suppl): S76-83 (2014).
12. DeFelice FG, Lourenco MV, Ferreira ST. How does brain insulin resistance develop in Alzheimer’s disease? Alzheimers Dement 10(Suppl 1): S26-32 (2014).
13. DelaMonte SM. Relationships between diabetes and cognitive impairment. Endocrinol Metab Clin North Am 43(1): 245-67 (2014).
14. DelaMonte SM, Tong M. Brain metabolic dysfunction at the core of Alzheimer’s disease. Biochem Pharmacol 88(4): 548-59 (2014).
15. Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, et al. Demonstrated brain insulin resistance in Alzheimer’s Disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 122(4): 1316-38 (2012).
16. Esser N, Paquot N, Scheen AJ. Inflammatory markers and cardiometabolic diseases. Acta Clin Belg 70(3): 193-9 (2015).
17. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol 14(4): 388-405 (2015).
18. Craft S, Cholerton B, Baker LD. Insulin and Alzheimer’s disease: untangling the web. J Alzheimers Dis 33(Suppl 1): S263-75 (2013).
19. Elwing JE, Lustman PJ, Wang HL, Clouse RE. Depression, anxiety, and nonalcoholic steatohepatitis. Psychosom Med 68(4): 563-9 (2006).
20. DelaMonte SM, Tong M, Lester-Coll N, Plater M Jr, Wands JR. Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: relevance to Alzheimer's disease. J Alzheimers Dis 10(1): 89-109 (2006).
21. Flicker L. Modifiable lifestyle risk factors for Alzheimer's disease. J Alzheimers Dis 20(3): 803-11 (2010).
22. Solfrizzi V, Frisardi V, Seripa D, Logroscino G, Imbimbo BP, D'Onofrio G, et al. Mediterranean diet in predementia and dementia syndromes. Curr Alzheimer Res 8(5): 520-42 (2011).
23. Shah R. The role of nutrition and diet in Alzheimer’s disease: a systematic review. J Am Med Dir Assoc 14(6): 398-402 (2013).
24. Velloso LA, Schwartz MW. Altered hypothalamic function in dietinduced obesity. Int J Obes (Lond) 35(12): 1455-65 (2011).
25. Morris MC, Tangney CC. Dietary fat composition and dementia risk. Neurobiol Aging 35(Suppl 2): S59-64 (2014).
26. Acharya NK, Levin EC, Clifford PM, Han M, Tourtellotte R, Chamberlain D, et al. Diabetes and hypercholesterolemia increase blood-brain barrier permeability and brain amyloid deposition: beneficial effects of the LpPLA2 inhibitor darapladib. J Alzheimers Dis 35(1): 179-98 (2013).
27. Lopez-Ramirez MA, Wu D, Pryce G, Simpson JE, Reijerkerk A, King-Robson J, et al. MicroRNA-155 negatively affects bloodbrain barrier function during neuroinflammation. FASEB J 28(6): 2551-65 (2014).
28. Takeda S, Sato N, Ikimura K, Nishino H, Rakugi H, Morishita R. Increased blood-brain barrier vulnerability to systemic inflammation in an Alzheimer’s disease mouse model. Neurobiol Aging 34(8): 2064-70 (2013).
29. Bosco D, Fava A, Plastino M, Montalcini T, Pujia A. Possible implications of insulin resistance and glucose metabolism in Alzheimer’s Disease pathogenesis. J Cell Mol Med 15(9): 1807-21 (2011).
30. Contreras C, González-García I, Martínez-Sánchez N, Seoane-Collazo P, Jacas J, Morgan DA, et al. Central ceramide-induced hypothalamic lipotoxicity and endoplasmatic reticulum stress regulate energy balance. Cell Rep 9(1): 366-77 (2014).
31. Tong M, Neusner A, Longato L, Lawton M, Wands JR, DelaMonte SM. Nitrosamine exposure causes insulin resistance diseases: relevance to T2DM, non-alcoholic steatohepatitis and Alzheimer’s disease. J Alzheimers Dis 17(4): 827-44 (2009).
32. Capeau J. Insulin resistance and steatosis in humans. Diabetes Metab 34(6 Pt 2): 649-57 (2008).
33. Gontier G, Lin K, Villeda SA. Fat chance for neural stem cells in Alzheimer’s disease. Cell Stem Cell 17(4): 373-4 (2015).
34. Hamilton LK, Dufresne M, Joppé SE, Petryszyn S, Aumont A, Calon F, et al. Aberrant lipid metabolism in the forebrain niche suppresses adult neural stem cell proliferation in an animal model of Alzheimer’s disease. Cell Stem Cell 17(4): 397-411 (2015).
35. Arbor SC, LaFontaine M, Cumbay M. Amyloid-beta Alzheimer targets-protein processing, lipid rafts, and amyloid-beta pores. Yale J Biol Med 89(1): 5-21 (2016).
36. Han X. Lipid alterations in the earliest clinically recognizable stage of Alzheimer’s disease: implication of the role of lipids in the pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 2(1): 65-77 (2005).
37. Contreras C, González-García I, Martínez-Sánchez N, Seoane-Collazo P, Jacas J, Morgan DA, et al. Central ceramide-induced hypothalamic lipotoxicity and endoplasmatic reticulum stress regulate energy balance. Cell Rep 9(1): 366-77 (2014).
38. Panza F, Solfrizzi V, Colacicco AM, D'Introno A, Capurso C, Palasciano R, et al. Cerebrovascular disease in the elderly: lipoprotein metabolism and cognitive decline. Aging Clin Exp Res 18(2): 144-8 (2006).
39. Dong HK, Gim JA, Yeo SH, Kim HS. Integrated late onset Alzheimer’s disease (LOAD) susceptibility genes: cholesterol metabolism and trafficking perspectives. Gene 597: 10-16 (2017).
40. Xue-shan Z, Juan P, Qi W, Zhong R, Li-hong P, Zhi-han T, Zhisheng J, et al. Imbalanced cholesterol metabolism in Alzheimer’s disease. Clin Chim Acta 456: 107-14 (2016).
41. Calay ES, Hotamisligil GS. Turning off the inflammatory, but not the metabolic flames. Nat Med 19(3): 265-7 (2013).
42. Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell 148: 852-71 (2012).
43. Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol 29: 415-45 (2011).
44. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414: 799-806 (2001).
45. Craft S. Insulin resistance syndrome and Alzheimer’s disease: ageand obesity-related effects on memory, amyloid, and inflammation. Neurobiol Aging 26(Suppl 1): 65-9 (2005).
46. Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, DelaMonte SM. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J Alzheimers Dis 8(3): 247-68 (2005).
47. DelaMonte SM. Triangulated mal-signaling in Alzheimer’s disease: roles of neurotoxic ceramides, ER stress, and insulin resistance reviewed. J Alzheimer´s Dis 30: S231-49 (2012).
48. Kuljis RO, Salkovic-Petrisic M. Dementia, diabetes, Alzheimer's disease, and insulin resistance in the brain: progress, dilemmas, new opportunities, and a hypothesis to tackle intersecting epidemics. J Alzheimers Dis 25: 29-41 (2011).
49. Kumar A, Nisha CM, Silakari C, Sharma I, Anusha K, Gupta N, et al. Current and novel therapeutic molecules and targets in Alzheimer’s disease. J Formos Med Assoc 115(1): 3-10 (2016).
50. Mehta M, Adem A, Sabbagh M. New acetylcholinesterase inhibitors for Alzheimer’s Disease. Int J Alzheimers Dis 2012: 728983 (2012).
51. Olivares D, Deshpande VK, Shi Y, Lahiri DK, Greig NH, Rogers JT, et al. N-methyl D-aspartate (NMDA) receptor antagonists and memantine treatment for Alzheimer's disease, vascular dementia and Parkinson's disease. Curr Alzheimer Res 9(6): 746-58 (2012).
52. Corbett A, Williams G, Ballard C. Drug repositioning in Alzheimer’s disease. Front Biosci (Schol Ed) 7: 184-8 (2015).
53. Sirota M, Dudley JT, Kim J, Chiang AP, Morgan AA, Sweet-Cordero A, et al. Discovery and preclinical validation of drug indications using compendia of public gene expression data. Sci Transl Med 3(96): 96ra77 (2011).
54. Zhang XZ, Quan Y, Tang GY. Medical genetics-based drug repurposing for Alzheimer's disease. Brain Res Bull 110: 26-9 (2015).
55. Finsterer J, Frank M. Repurposed drugs in metabolic disorders. Curr Top Med Chem 13(18): 2386-94 (2013).
56. Shim JS, Liu JO. Recent advances in drug repositioning for the discovery of new anticancer drugs. Int J Biol Sci 10(7): 654-63 (2014).
57. Ghezzi L, Scarpini E, GalimbertiD. Disease-modifying drugs in Alzheimer’s disease. Drug Des Devel Ther 7: 1471-8 (2013).
58. Claxton A, Baker LD, Hanson A, Trittschuh EH, Cholerton B, Morgan A, et al. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s Disease dementia. J Alzheimers Dis 44(3): 897-906 (2015).
59. Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 69(1): 29-38 (2012).
60. Freiherr J, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence. CNS Drugs 27(7): 505-14 (2013).
61. Balsamo S, Willardson JM, Frederico Sde S, Prestes J, Balsamo DC, Dahan da CN, et al. Effectiveness of exercise on cognitive impairment and Alzheimer’s disease. Int J Gen Med 6: 387-91 (2013).
62. Gillette-Guyonnet S, Secher M, Vellas B. Nutrition and neurodegeneration: epidemiological evidence and challenges for future research. Br J Clin Pharmacol 75(3): 738-55 (2013).
63. Imfeld P, Bodmer M, Jick SS, Meier CR. Metformin, other antidiabetic drugs, and risk of Alzheimer’s disease: a populationbased case-control study. J Am Geriatr Soc 60(5): 916-21 (2012).
64. Miller BW, Willett KC, Desilets AR. Rosiglitazone and pioglitazone for the treatment of Alzheimer’s disease. Ann Pharmacother 45(11): 1416-24 (2011).
65. Chen Y, Zhou K, Wang R, Liu Y, Kwak YD, Ma T, et al. Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE-1 transcription. Proc Natl Acad Sci USA 106(10): 3907-12 (2009).
66. Hernandez AV, Usmani A, Rajamanickam A, Moheet A. Thiazolidinediones and risk of heart failure in patients with or at high risk of type 2 diabetes mellitus: a meta-analysis and metaregression analysis of placebo-controlled randomized clinical trials. Am J Cardiovasc Drugs 11(2): 115-28 (2011).
67. Geldmacher DS, Fritsch T, McClendon MJ, Landreth G. A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease. Arch Neurol 68(1): 45-50 (2011).
68. Jiang Q, Heneka M, Landreth GE. The role of peroxisome proliferator-activated receptor-gamma (PPARgamma) in Alzheimer’s Disease: therapeutic implications. CNS Drugs 22(1): 1-14 (2008).
69. Pedersen WA, McMillan PJ, Kulstad JJ, Leverenz JB, Craft S, Haynatzki GR. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol 199(2): 265-73 (2006).
70. Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C, et al. Acute treatment with the PPARγ agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain 128(Pt 6): 1442-53 (2005).
71. Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 17(6): 819-37 (2013).
72. Talbot K. Brain insulin resistance in Alzheimer’s disease and its potential treatment with GLP-1 analogs. Neurodegener Dis Manag 4(1): 31-40 (2014).
73. Han WN, Hölscher C, Yuan L, Yang W, Wang XH, Wu MN, et al. Liraglutide protects against amyloid-beta protein-induced impairment of spatial learning and memory in rats. Neurobiol Aging 34(2): 576-88 (2013).
74. Parthsarathy V, Holscher C. Chronic treatment with the GLP1 analogue liraglutide increases cell proliferation and differentiation into neurons in an AD mouse model. PLoSOne 8(3): e58784 (2013).
75. Rodgers RJ, Tschop MH, Wilding JP. Anti-obesity drugs: past, present and future. Dis Model Mech 5(5): 621-6 (2012).
76. Habibuddin M, Humaira T. Pharmacological management of obesity: Past, present and future. Saudi J Obesity 2: 3-12 (2014).
77. Kral JG, NaslundE. Surgical treatment of obesity. Nat Clin Pract Endocrinol Metab 3(8): 574-83 (2007).
78. Sargent BJ, Moore NA. New central targets for the treatment of obesity. Br J Clin Pharmacol 68(6): 852-60 (2009).
79. Kennett GA, Clifton PG. New approaches to the pharmacological treatment of obesity: can they break through the efficacy barrier? Pharmacol Biochem Behav 97(1): 63-83 (2010).
80. Aronne LJ, Halseth AE, Burns CM, Miller S, Shen LZ. Enhanced weight loss following coadministration of pramlintide with sibutramine or phentermine in a multicenter trial. Obesity (Silver Spring) 18(9): 1739-46 (2010).
81. Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean ME, et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond) 36(6): 843-54 (2012).
82. Wilding JP, Hardy K. Glucagon-like peptide-1 analogues for type 2 diabetes. BMJ 342: d410 (2011).
83. Wilcox G. Insulin and insulin resistance. Clin Biochem Rev 26(2): 19-39 (2005).
84. Verspohl EJ. Novel pharmacological approaches to the treatment of T2D. Pharmacol Rev 64(2): 188-237 (2012).
85. Della-Morte D, Palmirotta R, Rehni AK, Pastore D, Capuani B, Pacifici F, et al. Pharmacogenomics and pharmacogenetics of thiazolidinediones: role in diabetes and cardiovascular risk factors. Pharmacogenomics 15(16): 2063-82 (2014).
86. Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 122(6): 253-70 (2012).
87. Tyagi S, Gupta P, Saini AS, Kaushal C, Sharma S. The peroxisome proliferator-activated receptor: a family of nuclear receptors role in various diseases. J Adv Pharm Technol Res 2(4): 236-40 (2011).
88. Soccio RE, Chen ER, Lazar MA. Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metab 20(4): 573-91 (2014).
89. Bae JC. Diabetes Drugs and Cardiovascular Safety. Endocrinol Metab (Seoul) 31(2): 239-44 (2016).
90. Rojas LB, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr 5(1): 6 (2013).
91. Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes study. Lancet Diabetes Endocrinol 3(11): 866-75 (2015).
92. Talbot K, Wang HY. The nature, significance, and glucagon-like peptide-1 analog treatment of brain insulin resistance in Alzheimer’s disease. Alzheimers Dement 10(Suppl 1): S12-25 (2014).
93. Frank M. Minimizing the risk of Alzheimer's Disease. 2012, NY USA Algora Publishing.
94. Davinelli S, Calabrese V, Zella D, Scapagnini G. Epigenetic nutraceutical diets in AD. J Nutr Health Aging 18(9): 800-5 (2014).
95. Nicolia V, Lucarelli M, Fuso A. Environment, epigenetics and neurodegeneration: focus on nutrition in Alzheimer's disease. Exp Gerontol 68: 8-12 (2015).
96. Defina LF, Willis BL, Radford NB, Gao A, Leonard D, Haskell WL, et al. The association between midlife cardiorespiratory fitness levels and later-life dementia: a cohort study. Ann Intern Med 158(3): 162-8 (2013).
97. Duzel E, VanPraag H, Sendtner M. Can physical exercise in old age improve memory and hippocampal function? Brain 139(3): 662-73 (2016).
98. Hotting K, Roder B. Beneficial effects of physical exercise on neuroplasticity and cognition. Neurosci Biobehav Rev 37(9 Pt B): 2243-57 (2013).
99. Reuben DB, Judd-Hamilton L, Harris TB, Seeman TE. The associations between physical activity and inflammatory markers in high-functioning older persons: macArthur Studies of Successful Aging. J Am Geriatr Soc 51(8): 1125-30 (2003).
100. Wang HX, Karp A, Winblad B, Fratiglioni L. Late-life engagement in social and leisure activities is associated with a decreased risk of dementia: a longitudinal study from the Kungsholmen project. Am J Epidemiol 155(12): 1081-7 (2002).
101. Trussardi Fayh AP, Lopes AL, Fernandes PR, Reischak-Oliveira A, Friedman R. Impact of weight loss with or without exercise on abdominal fat and insulin resistance in obese individuals: a randomised clinical trial. Br J Nutr 110(3): 486-92 (2013).
102. Hendrie HC, Osuntokun BO, Hall KS, Ogunniyi AO, Hui SL, Unverzagt FW, et al. Prevalence of Alzheimer's disease and dementia in two communities: Nigerian Africans and African Americans. Am J Psychiatry 152(10): 1485-92 (1995).
103. Graves AB, Larson EB, Edland SD, Bowen JD, McCormick WC, McCurry SM, et al. Prevalence of dementia and its subtypes in the Japanese American population of King County, Washington state. The Kame Project. Am J Epidemiol 144(8): 760-71 (1996).
104. Murray F. Can Alzheimer's disease be prevented? Intractable Rare Dis Res 2(4): 136-8 (2013).
105. Clark TA, Lee HP, Rolston RK, Zhu X, Marlatt MW, Castellani RJ, et al. Oxidative stress and its implications for future treatments and management of Alzheimer’s Disease. Int J Biomed Sci 6(3): 225-227 (2010).
106. Barnard ND, Bunner AE, Agarwal U. Saturated and trans fats and dementia: a systematic review. Neurobiol Aging 35(Suppl 2): S65-73 (2014).
107. Fares H, Lavie CJ, DiNicolantonio JJ, O'Keefe JH, Milani RV. Omega-3 fatty acids: a growing ocean of choices. Curr Atheroscler Rep 16(2): 389 (2014).
108. Cunnane SC, Plourde M, Pifferi F, Bégin M, Féart C, Barberger-Gateau P. Fish, docosahexaenoic acid and Alzheimer's disease. Prog Lipid Res 48(5): 239-56 (2009).
109. Solfrizzi V, Frisardi V, Capurso C, D'Introno A, Colacicco AM, Vendemiale G, et al. Dietary fatty acids in dementia and predementia syndromes: epidemiological evidence and possible underlying mechanisms. Ageing Res Rev 9(2): 184-99 (2010).
110. Vedin I, Cederholm T, Freund-Levi Y, Basun H, Garlind A, Irving GF, et al. Effects of DHA-rich n-3 fatty acid supplementation on gene expression in blood mononuclear leukocytes: the OmegAD study. PLoSOne 7(4): e35425 (2012).
111. Agrawal R, Gomez-Pinilla F. Metabolic syndrome in the brain: deficiency in omega-3 fatty acid exacerbates dysfunctions in insulin receptor signalling and cognition. J Physiol 590(Pt 10): 2485-99 (2012).
112. Fotuhi M, Mohassel P, Yaffe K. Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer’s disease: a complex association. Nat Clin Pract Neurol 5(3): 140-52 (2009).
113. Barberger-Gateau P, Lambert JC, Féart C, Pérès K, Ritchie K, Dartigues JF, et al. From genetics to dietetics: the contribution of epidemiology to understanding Alzheimer's disease. J Alzheimers Dis 33(Suppl 1): S457-63 (2013).
114. Cascio G, Schiera G, DiLiegro I. Dietary fatty acids in metabolic syndrome, diabetes and cardiovascular diseases. Curr Diabetes Rev 8(1): 2-17 (2012).
115. Laitinen MH, Ngandu T, Rovio S, Helkala EL, Uusitalo U, Viitanen M, et al. Fat intake at midlife and risk of dementia and Alzheimer’s disease: a population-based study. Dement Geriatr Cogn Disord 22(1): 99-107 (2006).
116. Solomon TP, Haus JM, Kelly KR, Cook MD, Riccardi M, Rocco M, et al. Randomized trial on the effects of a 7-d low-glycemic diet and exercise intervention on insulin resistance in older obese humans. Am J Clin Nutr 90(5): 1222-9 (2009).
117. Estadella D, DaPenha OllerdoNascimento CM, Oyama LM, Ribeiro EB, Dâmaso AR, DePiano A. Lipotoxicity: effects of dietary saturated and transfatty acids. Mediators Inflamm 2013: 1375-79 (2013).
118. Grimm MO, Rothhaar TL, Grösgen S, Burg VK, Hundsdörfer B, Haupenthal VJ, et al. Trans fatty acids enhance amyloidogenic processing of the Alzheimer amyloid precursor protein (APP). J Nutr Biochem 23(10): 1214-23 (2013).
119. Puglielli L, Tanzi RE, Kovacs D. Alzheimer’s disease: the cholesterol connection. Nat Neurosci 6(4): 345-51 (2003).
120. Kanekiyo T, Xu H, Bu G. ApoE and Abeta in Alzheimer’s disease: accidental encounters or partners? Neuron 81(4): 740-54 (2014).
121. Ooi CP, Loke SC, Yassin Z, Hamid TA. Carbohydrates for improving the cognitive performance of independent-living older adults with normal cognition or MCI. Cochrane Database Syst Rev (4): CD007220 (2011).
122. Moreira PI. High-sugar diets, type 2 diabetes and Alzheimer's disease. Curr Opin Clin Nutr Metab Care 16(4): 440-5 (2013).
123. Wolever TM. Dietary carbohydrates and insulin action in humans. Br J Nutr 83(Suppl 1): S97-102 (2000).
124. Marriott BP, Olsho L, Hadden L, Connor P. Intake of added sugars and selected nutrients in the USA, National Health and Nutrition Examination Survey (NHANES) 2003-2006. Crit Rev Food Sci Nutr 50(3): 228-58 (2010).
125. Bray GA. How bad is fructose? Am J Clin Nutr 86(4): 895-6 (2007).
126. Rizkalla SW. Health implications of fructose consumption: A review of recent data. Nutr Metab (Lond) 7: 82 (2010).
127. Yu Z, Lowndes J, Rippe J. High-fructose corn syrup and sucrose have equivalent effects on energy-regulating hormones at normal human consumption levels. Nutr Res 33(12): 1043-52 (2013).
128. Bocarsly ME, Powell ES, Avena NM, Hoebel BG. High-fructose corn syrup causes characteristics of obesity in rats: increased body weight, body fat and triglyceride levels. Pharmacol Biochem Behav 97(1): 101-6 (2010).
129. Aeberli I, Hochuli M, Gerber PA, Sze L, Murer SB, Tappy L, et al. Moderate amounts of fructose consumption impair insulin sensitivity in healthy young men: a randomized controlled trial. Diabetes Care 36(1): 150-6 (2013).
130. Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 378(9785): 31-40 (2011).
131. Seneff S, Wainwright G, Mascitelli L. Nutrition and Alzheimer's disease: the detrimental role of a high carbohydrate diet. Eur J Intern Med 22(2): 134-40 (2011).
132. Sasaki N, Fukatsu R, Tsuzuki K, Hayashi Y, Yoshida T, Fujii N, et al. Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases. Am J Pathol 153(4): 1149-55 (1998).
133. Ross AP et al. A high fructose diet impairs spatial memory in male rats. Neurobiol Learn Mem 92(3): 410-6 (2009).
134. Stranahan AM, Norman ED, Lee K, Cutler RG, Telljohann RS, Egan JM, et al. Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats. Hippocampus 18(11): 1085-8 (2008).
135. Spruss A, Kanuri G, Wagnerberger S, Haub S, Bischoff SC, Bergheim I. Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology 50(4): 1094-104 (2009).
136. Ye X, Gao X, Scott T, Tucker KL. Habitual sugar intake and cognitive function among middle-aged and older Puerto Ricans without diabetes. Br J Nutr 106(9): 1423-32 (2011).
137. Zamora-Navarro S, Perez-Llamas F. Importance of sucrose in cognitive functions: knowledge and behavior. Nutr Hosp 28(Suppl 4): 106-11 (2013).
138. Orr ME, Salinas A, Buffenstein R, Oddo S. Mammalian target of rapamycin hyperactivity mediates the detrimental effects of a high sucrose diet on Alzheimer’s disease pathology. Neurobiol Aging 35(6): 1233-42 (2014).
139. Goodman L. Alzheimer's Disease; a clinico-pathologic analysis of twenty-three cases with a theory on pathogenesis. J Nerv Ment Dis 118(2): 97-130 (1953).
140. Loef M, Walach H. Copper and iron in Alzheimer's disease: a systematic review and its dietary implications. Br J Nutr 107(1):7-19 (2012).
141. Stankiewicz JM, Brass SD. Role of iron in neurotoxicity: a cause for concern in the elderly? Curr Opin Clin Nutr Metab Care 12(1): 22-9 (2009).
142. Lidsky TI. Is the aluminum hypothesis dead? J Occup Environ Med 56(5 Suppl): S73-9 (2014).
143. Yumoto S, Kakimi S, Ohsaki A, Ishikawa A. Demonstration of aluminum in amyloid fibers in the cores of senile plaques in the brains of patients with Alzheimer's disease. J Inorg Biochem 103(11): 1579-84 (2009).
144. Walton JR. Aluminum involvement in the progression of Alzheimer's Disease. J Alzheimers Dis 35(1): 7-43 (2013).
145. Percy ME, Kruck TP, Pogue AI, Lukiw WJ. Towards the prevention of potential aluminum toxic effects and an effective treatment for Alzheimer's Disease. J Inorg Biochem 105(11): 1505-12 (2011).
146. Morris MC, Evans DA, Tangney CC, Bienias JL, Wilson RS. Associations of vegetable and fruit consumption with age-related cognitive change. Neurology 67(8): 1370-6 (2006).
147. Nooyens AC, Bueno-de-Mesquita HB, van Boxtel MP, van Gelder BM, Verhagen H, Verschuren WM. Fruit and vegetable intake and cognitive decline in middle-aged men and women: the Doetinchem Cohort Study. Br J Nutr 106(5): 752-61 (2011).
148. Guan JZ, Guan WP, Maeda T, Makino N. Effect of vitamin E administration on the elevated oxygen stress and the telomeric and subtelomeric status in Alzheimer's disease. Gerontology 58(1): 62-9 (2012).
149. Mangialasche F, Xu W, Kivipelto M, Costanzi E, Ercolani S, Pigliautile M, et al. Tocopherols and tocotrienols plasma levels are associated with cognitive impairment. Neurobiol Aging 33(10): 2282-90 (2012).
150. Harrison FE. A critical review of vitamin C for the prevention of age-related cognitive decline and Alzheimer's disease. J Alzheimers Dis 29(4): 711-26 (2012).
151. Bowman GL. Ascorbic acid, cognitive function, and Alzheimer's disease: a current review and future direction. Biofactors 38(2): 114-22 (2012).
152. Murakami K, Murata N, Ozawa Y, Kinoshita N, Irie K, Shirasawa T, et al. Vitamin C restores behavioral deficits and amyloid-beta oligomerization without affecting plaque formation in a mouse model of AD. J Alzheimers Dis 26(1): 7-18 (2011).
153. Yatin SM, Varadarajan S, Butterfield DA. Vitamin E prevents Alzheimer's amyloid beta-peptide (1-42)-induced neuronal protein oxidation and ROS production. J Alzheimers Dis 2(2): 123-131 (2000).
154. Morris MC, Evans DA, Tangney CC, Bienias JL, Wilson RS, Aggarwal NT, et al. Relation of the tocopherol forms to incident Alzheimer’s disease and to cognitive change. Am J Clin Nutr 81(2): 508-14 (2005).
155. Devore EE, Stampfer MJ, Breteler MM, Rosner B, Kang JH, Okereke O, et al. Dietary fat intake and cognitive decline in women with type 2 diabetes. Diabetes Care 32(4): 635-40 (2009).
156. Kang JH, Cook N, Manson J, Buring JE, Grodstein F. A randomized trial of vitamin E supplementation and cognitive function in women. Arch Intern Med 166(22): 2462-8 (2006).
157. Farina N, Isaac MG, Clark AR, Rusted J, Tabet N. Vitamin E for Alzheimer's dementia and mild cognitive impairment. Cochrane Database Syst Rev 11: CD002854 (2012).
158. Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M, et al. Effect of vitamin E and memantine on functional decline in Alzheimer`s Disease: the TEAM-AD VA cooperative randomized trial. JAMA 311(1): 33-44 (2014).
159. Yang X, Dai G, Li G, Yang ES. Coenzyme Q10 reduces betaamyloid plaque in an APP/PS1 transgenic mouse model of Alzheimer's Disease. J Mol Neurosci 41(1): 110-3 (2010).
160. Galasko DR, Peskind E, Clark CM, Quinn JF, Ringman JM, Jicha GA, et al. Antioxidants for Alzheimer’s disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. Arch Neurol 69(7): 836-41 (2012).
161. Hofman A, Brusselle GG, Darwish Murad S, van Duijn CM, Franco OH, Goedegebure A, et al. The Rotterdam Study: 2016 objectives and design update. Eur J Epidemiol 30(8): 661-708 (2015).
162. Ono K, Yamada M. Vitamin A and Alzheimer’s Disease. Geriatr Gerontol Int 12(2): 180-8 (2012).
163. Takasaki J, Ono K, Yoshiike Y, Hirohata M, Ikeda T, Morinaga A, et al. Vitamin A has anti-oligomerization effects on amyloid-beta in vitro. J Alzheimers Dis 27(2): 271-80 (2011).
164. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, et al. Oxidative damage is the earliest event in Alzheimer’s disease. J Neuropathol Exp Neurol 60(8): 759-67 (2001).
165. Luchsinger JA, Tang MX, Shea S, Mayeux R. Antioxidant vitamin intake and risk of Alzheimer’s Disease. Arch Neurol 60(2): 203-8 (2003).
166. Banerjee A, Khemka VK, Ganguly A, Roy D, Ganguly U, Chakrabarti S. Vitamin D and Alzheimer's disease: neurocognition to therapeutics. Int J Alzheimers Dis 2015: 192747 (2015).
167. Gu Y, Schupf N, Cosentino SA, Luchsinger JA, Scarmeas N. Nutrient intake and plasma beta-amyloid. Neurology 78(23): 1832-40 (2012).
168. Cardoso BR, Ong TP, Jacob-Filho W, Jaluul O, Freitas MI, Cozzolino SM. Nutritional status of selenium in Alzheimer's Disease patients. Br J Nutr 103(6): 803-6 (2010).
169. Du X, Wang C, Liu Q. Potential roles of selenium and selenoproteins in the prevention of Alzheimer's disease. Curr Top Med Chem 16(8): 835-48 (2016).
170. Xiong S, Markesbery WR, Shao C, Lovell MA. Seleno-Lmethionine protects against beta-amyloid and iron/hydrogen peroxide-mediated neuron death. Antioxid Redox Signal 9(4): 457-67 (2007).
171. Kryscio RJ, Abner EL, Schmitt FA, Goodman PJ, Mendiondo M, Caban-Holt A, et al. A randomized controlled Alzheimer’s disease prevention trial's evolution into an exposure trial: the PREADViSE Trial. J Nutr Health Aging 17(1): 72-5 (2013).
172. Crichton GE, Bryan J, Murphy KJ. Dietary antioxidants, cognitive function and dementia-a systematic review. Plant Foods Hum Nutr 68(3): 279-92 (2013).
173. Morris MS. The role of B vitamins in preventing and treating cognitive impairment and decline. Adv Nutr 3(6): 801-12 (2012).
174. Douaud G, Refsum H, DeJager CA, Jacoby R, Nichols TE, Smith SM, et al. Preventing Alzheimer's Disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci USA 110(23): 9523-8 (2013).
175. Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B(12) and folate in relation to the development of Alzheimer’s Disease. Neurology 56(9): 1188-94 (2001).
176. Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti N, et al. Homocysteine and folate as risk factors for dementia and Alzheimer’s Disease. Am J Clin Nutr 82(3): 636-43 (2005).
177. Corrada MM, Kawas CH, Hallfrisch J, Muller D, Brookmeyer R. Reduced risk of Alzheimer’s disease with high folate intake: the Baltimore Longitudinal Study of Aging. Alzheimers Dement 1(1): 11-8 (2005).
178. Wald DS, Kasturiratne A, Simmonds M. Effect of folic acid, with or without other B vitamins, on cognitive decline: meta-analysis of randomized trials. Am J Med 123(6): 522-527e2 (2010).
179. Luchsinger JA, Tang MX, Miller J, Green R, Mayeux R. Relation of higher folate intake to lower risk of Alzheimer disease in the elderly. Arch Neurol 64(1): 86-92 (2007).
180. Davis KL, Mohs RC, Marin D, Purohit DP, Perl DP, Lantz M, et al. Cholinergic markers in elderly patients with early signs of Alzheimer disease. JAMA 281(15): 1401-6 (1999).
181. Poly C, Massaro JM, Seshadri S, Wolf PA, Cho E, Krall E, et al. The relation of dietary choline to cognitive performance and whitematter hyperintensity in the Framingham Offspring Cohort. Am J Clin Nutr 94(6): 1584-91 (2011).
182. Meck WH, Williams CL. Metabolic imprinting of choline by its availability during gestation: implications for memory and attentional processing across the lifespan. Neurosci Biobehav Rev 27(4): 385-99 (2003).
183. Dickinson-Anson H, Winkler J, Fisher LJ, Song HJ, Poo M, Gage FH. Acetylcholine-secreting cells improve age-induced memory deficits. Mol Ther 8(1): 51-61 (2003).
184. Choi DY, Lee YJ, Hong JT, Lee HJ. Antioxidant properties of natural polyphenols and their therapeutic potentials for Alzheimer's disease. Brain Res Bull 87(2-3): 144-53 (2012).
185. Mori T, Rezai-Zadeh K, Koyama N, Arendash GW, Yamaguchi H, Kakuda N, et al. Tannic acid is a natural beta-secretase inhibitor that prevents cognitive impairment and mitigates Alzheimer-like pathology in transgenic mice. J Biol Chem 287(9): 6912-27 (2012).
186. Mancuso C, Siciliano R, Barone E, Preziosi P. Natural substances and Alzheimer's disease: from preclinical studies to evidence based medicine. Biochim Biophys Acta 1822(5): 616-24 (2012).
187. Ahmed T, Gilani AH. Therapeutic potential of turmeric in Alzheimer's disease: curcumin or curcuminoids? Phytother Res 28(4): 517-25 (2014).
188. Solfrizzi V, Panza F. Plant-based nutraceutical interventions against cognitive impairment and dementia: meta-analytic evidence of efficacy of a standardized gingko biloba extract. J Alzheimers Dis 43(2): 605-11 (2015).
189. Arunkumar E, Bhuvaneswari S, Anuradha CV. An intervention study in obese mice with astaxanthin, a marine carotenoid-effects on insulin signaling and pro-inflammatory cytokines. Food Funct 3(2): 120-6 (2012).
190. Chang CH, Chen CY, Chiou JY, Peng RY, Peng CH. Astaxanthine secured apoptotic death of PC12 cells induced by beta-amyloid peptide 25-35: its molecular action targets. J Med Food 13(3): 548-56 (2010).
191. Liu X, Osawa T. Astaxanthin protects neuronal cells against oxidative damage and is a potent candidate for brain food. Forum Nutr 61: 129-35 (2009).
192. Engelhart MJ, Geerlings MI, Ruitenberg A, VanSwieten JC, Hofman A, Witteman JC, et al. Diet and risk of dementia: does fat matter? The Rotterdam Study. Neurology 59: 1915-21 (2002).
193. Crichton GE, Bryan J, Murphy KJ, Buckley J. Review of dairy consumption and cognitive performance in adults: findings and methodological issues. Dement Geriatr Cogn Disord 30(4): 352-61 (2010).
194. Santos C, Costa J, Santos J, Vaz-Carneiro A, Lunet N. Caffeine intake and dementia: systematic review and meta-analysis. J Alzheimers Dis 20(Suppl 1): S187-204 (2010).
195. Barranco Quintana JL, Allam MF, Serrano Del Castillo A, Fernández-Crehuet Navajas R. Alzheimer's disease and coffee: a quantitative review. Neurol Res 29(1): 91-5 (2007).
196. Song J, Xu H, Liu F, Feng L. Tea and cognitive health in late life: current evidence and future directions. J Nutr Health Aging 16(1): 31-4 (2012).
197. Weyerer S, Schäufele M, Wiese B, Maier W, Tebarth F, van den Bussche H, et al. Current alcohol consumption and its relationship to incident dementia: results from a 3-year follow-up study among primary care attenders aged 75 years and older. Age Ageing 40(4): 456-63 (2011).
198. Huang TC, Lu KT, Wo YY, Wu YJ, Yang YL. Resveratrol protects rats from Abeta-induced neurotoxicity by the reduction of iNOS expression and lipid peroxidation. PLoSOne 6(12): e29102 (2011).
199. Lowing JL, Susick LL, Caruso JP, Provenzano AM, Raghupathi R, Conti AC. Experimental traumatic brain injury alters ethanol consumption and sensitivity. J Neurotrauma 31(20): 1700-10 (2014).
200. Hu N, Yu JT, Tan L, Wang YL, Sun L, Tan L. Nutrition and the risk of Alzheimer's disease. Biomed Res Int 2013: 524820 (2013).
201. Ozawa M, Ninomiya T, Ohara T, Doi Y, Uchida K, Shirota T, et al. Dietary patterns and risk of dementia in an elderly Japanese population: the Hisayama Study. Am J Clin Nutr 97(5): 1076-82 (2013).
202. Singh B, Parsaik AK, Mielke MM, Erwin PJ, Knopman DS, Petersen RC, et al. Association of mediterranean diet with mild cognitive impairment and Alzheimer's disease: a systematic review and meta-analysis. J Alzheimers Dis 39(2): 271-82 (2014).
203. Lourida I, Soni M, Thompson-Coon J, Purandare N, Lang IA, Ukoumunne OC, et al. Mediterranean diet, cognitive function, and dementia: a systematic review. Epidemiology 24(4): 479-89 (2013).
204. Trichopoulou A, Naska A. European food availability databank based on household budget surveys: the Data Food Networking initiative. Eur J Public Health 13(3 Suppl): 24-8 (2003).
205. Willett WC, Sacks F, Trichopoulou A, Drescher G, Ferro-Luzzi A, Helsing E, et al. Mediterranean diet pyramid: a cultural model for healthy eating. Am J Clin Nutr 61(6 Suppl): 1402S-6S (1995).
206. CIHEAM/FAO. 2015. Mediterranean food consumption patterns: diet, environment, society, economy and health. A White Paper Priority 5, Feeding Knowledge Programme, Expo Milan 2015. CIHEAM-IAMB, Bari/FAO, Rome.