Obesity and sex interact in the regulation of Alzheimer's disease

Neuroscience and Biobehavioral Reviews

Volumn 67, Issue , 2016, Pages 102-118

  Moser, V Alexandra ^a   Pike, Christian J ^a  

^a UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

Alzheimer's disease; Apolipoprotein E; Estrogen; Inflammation; Obesity; Sex differences; Testosterone; amyloid

Indexed keywords

APOLIPOPROTEIN E; ESTROGEN; TESTOSTERONE;

ALLELE; ALZHEIMER DISEASE; CARDIOVASCULAR RISK; DIET; HUMAN; INFLAMMATION; METABOLIC DISORDER; METABOLIC SYNDROME X; NONHUMAN; OBESITY; PRIORITY JOURNAL; REGULATORY MECHANISM; REVIEW; RISK FACTOR; SEX DIFFERENCE;

ALZHEIMER DISEASE; APOLIPOPROTEINS E; HUMANS; OBESITY; RISK FACTORS;

EID: 84951976499     PISSN: 01497634     EISSN: 18737528     Source Type: Journal    
DOI: 10.1016/j.neubiorev.2015.08.021     Document Type: Review

References (343)

1. Adler-Wailes, D.C., Periwal, V., Ali, A.H., Brady, S.M., McDuffie, J.R., Uwaifo, G.I., Tanofsky-Kraff, M., Salaita, C.G., Hubbard, V.S., Reynolds, J.C., Chow, C.C., Sumner, A.E., Yanovski, J.A., Sex-associated differences in free fatty acid flux of obese adolescents. J. Clin. Endocrinol. Metab. 98 (2013), 1676–1684.
2. Ahonen, T., Vanhala, M., Kautiainen, H., Kumpusalo, E., Saltevo, J., Sex differences in the association of adiponectin and low-grade inflammation with changes in the body mass index from youth to middle age. GENM 9 (2012), 1–8.
3. Alata, W., Ye, Y., St-Amour, I., Vandal, M., Calon, F., Human apolipoprotein E ɛ4 expression impairs cerebral vascularization and blood–brain barrier function in mice. J. Cerebr. Blood Flow Metab. 35 (2015), 86–94.
4. Altmann, A., Tian, L., Henderson, V.W., Greicius, M.D., Alzheimer's Disease Neuroimaging Initiative Investigators. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann. Neurol. 75 (2014), 563–573.
5. Amengual-Cladera, E., Lladó, I., Gianotti, M., Proenza, A.M., Sex differences in the effect of high-fat diet feeding on rat white adipose tissue mitochondrial function and insulin sensitivity. Metabolism 61 (2012), 1108–1117.
6. Amtul, Z., Westaway, D., Cechetto, D.F., Rozmahel, R.F., Oleic acid ameliorates amyloidosis in cellular and mouse models of Alzheimer's disease. Brain Pathol. 21 (2010), 321–329.
7. André, C., Dinel, A.-L., Ferreira, G., Layé, S., Castanon, N., Diet-induced obesity progressively alters cognition, anxiety-like behavior and lipopolysaccharide-induced depressive-like behavior: focus on brain indoleamine 2,3-dioxygenase activation. Brain Behav. Immun. 41 (2014), 10–21.
8. Arbones-Mainar, J.M., Johnson, L.A., Altenburg, M.K., Maeda, N., Differential modulation of diet-induced obesity and adipocyte functionality by human apolipoprotein E3 and E4 in mice. Int. J. Obes. Relat. Metab. Disord. 32 (2008), 1595–1605.
9. Arevalo, M.-A., Santos-Galindo, M., Bellini, M.-J., Azcoitia, I., Garcia-Segura, L.M., Actions of estrogens on glial cells: implications for neuroprotection. Biochem. Biophys. Acta 1800 (2010), 1106–1112.
10. Arkan, M.C., Hevener, A.L., Greten, F.R., Maeda, S., Li, Z.-W., Long, J.M., Wynshaw-Boris, A., Poli, G., Olefsky, J., Karin, M., IKK-beta links inflammation to obesity-induced insulin resistance. Nat. Med. 11 (2005), 191–198.
11. Atabek, M.E., Özkul, Y., Eklioğlu, B.S., Kurtoğlu, S., Baykara, M., Association between apolipoprotein E polymorphism and subclinic atherosclerosis in patients with type 1 diabetes mellitus. J. Clin. Res. Pediatr. Endocrinol. 4 (2012), 8–13.
12. Avila-Muñoz, E., Arias, C., When astrocytes become harmful: functional and inflammatory responses that contribute to Alzheimer's disease. Ageing Res. Rev. 18 (2014), 29–40.
13. Bailey, C.J., Ahmed-Sorour, H., Role of ovarian hormones in the long-term control of glucose homeostasis. Effects of insulin secretion. Diabetologia 19 (1980), 475–481.
14. Barger, S.W., Harmon, A.D., Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature 388 (1997), 878–881.
15. Barnard, N.D., Bunner, A.E., Agarwal, U., Saturated and trans fats and dementia: a systematic review. Neurobiol. Aging 35 (2014), S65–S73.
16. Barron, A.M., Rosario, E.R., Elteriefi, R., Pike, C.J., Sex-specific effects of high fat diet on indices of metabolic syndrome in 3xTg-AD mice: implications for Alzheimer's disease. PLoS One, 8, 2013, e78554.
17. Bartelt, A., Beil, F.T., Schinke, T., Roeser, K., Ruether, W., Heeren, J., Niemeier, A., Apolipoprotein E-dependent inverse regulation of vertebral bone and adipose tissue mass in C57Bl/6 mice: modulation by diet-induced obesity. Bone 47 (2010), 736–745.
18. Belinson, H., Michaelson, D.M., ApoE4-dependent Aβ-mediated neurodegeneration is associated with inflammatory activation in the hippocampus but not the septum. J. Neural Transm. 116 (2009), 1427–1434.
19. Bell, R.D., The imbalance of vascular molecules in Alzheimer's disease. J. Alzheimer's Dis. 32 (2012), 699–709.
20. Bell, R.D., Winkler, E.A., Singh, I., Sagare, A.P., Deane, R., Wu, Z., Holtzman, D.M., Betsholtz, C., Armulik, A., Sallstrom, J., Berk, B.C., Zlokovic, B.V., Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485 (2012), 512–516.
21. Bell, R.D., Zlokovic, B.V., Neurovascular mechanisms and blood–brain barrier disorder in Alzheimer's disease. Acta Neuropathol. 118 (2009), 103–113.
22. Benito-León, J., Mitchell, A.J., Hernández-Gallego, J., Bermejo-Pareja, F., Obesity and impaired cognitive functioning in the elderly: a population-based cross-sectional study (NEDICES). Eur. J. Neurol. 20 (2013), 899–977.
23. Bertram, L., Lange, C., Mullin, K., Parkinson, M., Hsiao, M., Hogan, M.F., Schjeide, B.M.M., Hooli, B., DiVito, J., Ionita, I., Jiang, H., Laird, N., Moscarillo, T., Ohlsen, K.L., Elliott, K., Wang, X., Hu-Lince, D., Ryder, M., Murphy, A., Wagner, S.L., Blacker, D., Becker, K.D., Tanzi, R.E., Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE. Am. J. Hum. Genet. 83 (2008), 623–632.
24. Besser, L.M., Gill, D.P., Monsell, S.E., Brenowitz, W., Meranus, D.H., Kukull, W., Gustafson, D.R., Body mass index, weight change, and clinical progression in mild cognitive impairment and Alzheimer disease. Alzheimer Dis. Assoc. Disord. 28 (2014), 36–43.
25. Beydoun, M.A., Boueiz, A., Abougergi, M.S., Kitner-Triolo, M.H., Beydoun, H.A., Resnick, S.M., O'Brien, R., Zonderman, A.B., Sex differences in the association of the apolipoprotein E epsilon 4 allele with incidence of dementia, cognitive impairment, and decline. Neurobiol. Aging 33 (2012), 720–731.
26. Bhatia, V., Chaudhuri, A., Tomar, R., Dhindsa, S., Ghanim, H., Dandona, P., Low testosterone and high C-reactive protein concentrations predict low hematocrit in type 2 diabetes. Diabetes Care 29 (2006), 2289–2294.
27. Biessels, G.J., Staekenborg, S., Brunner, E., Brayne, C., Scheltens, P., Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 5 (2006), 64–74.
28. Blair, C.K., Folsom, A.R., Knopman, D.S., Bray, M.S., Mosley, T.H., Boerwinkle, E., Boerwinkle, E., APOE genotype and cognitive decline in a middle-aged cohort. Neurology 64 (2005), 268–276.
29. Blasko, I., Beer, R., Bigl, M., Apelt, J., Franz, G., Rudzki, D., Ransmayr, G., Kampfl, A., Schliebs, R., Experimental traumatic brain injury in rats stimulates the expression, production and activity of Alzheimer's disease beta-secretase (BACE-1). J. Neural Transm. 111 (2004), 523–536.
30. Blázquez, G., Cañete, T., Tobeña, A., Giménez-Llort, L., Fernández-Teruel, A., Cognitive and emotional profiles of aged Alzheimer's disease (3xTgAD) mice: effects of environmental enrichment and sexual dimorphism. Behav. Brain Res. 268 (2014), 185–201.
31. Bloor, I.D., Symonds, M.E., Sexual dimorphism in white and brown adipose tissue with obesity and inflammation. Horm. Behav. 66 (2014), 95–103.
32. Blouin, K., Richard, C., Brochu, G., Hould, F.S., Lebel, S., Marceau, S., Biron, S., Luu-The, V., Tchernof, A., Androgen inactivation and steroid-converting enzyme expression in abdominal adipose tissue in men. J. Endocrinol. 191 (2006), 637–649.
33. Bobjer, J., Katrinaki, M., Tsatsanis, C., Lundberg Giwercman, Y., Giwercman, A., Negative association between testosterone concentration and inflammatory markers in young men: a nested cross-sectional study. PLoS One, 8, 2013, e61466.
34. Boissonneault, V., Filali, M., Lessard, M., Relton, J., Wong, G., Rivest, S., Powerful beneficial effects of macrophage colony-stimulating factor on beta-amyloid deposition and cognitive impairment in Alzheimer's disease. Brain 132 (2009), 1078–1092.
35. Botella-Carretero, J.I., Balsa, J.A., Gómez-Martin, J.M., Peromingo, R., Huerta, L., Carrasco, M., Arrieta, F., Zamarron, I., Martin-Hidalgo, A., Vazquez, C., Circulating free testosterone in obese men after bariatric surgery increases in parallel with insulin sensitivity. J. Endocrinol. Investig. 36 (2013), 227–232.
36. Breunig, J.J., Guillot-Sestier, M.-V., Town, T., Brain injury, neuroinflammation and Alzheimer's disease. Front. Aging Neurosci., 5, 2013, 26.
37. Brown, B.M., Peiffer, J.J., Martins, R.N., Multiple effects of physical activity on molecular and cognitive signs of brain aging: can exercise slow neurodegeneration and delay Alzheimer's disease?. Mol. Psychiatry 18 (2013), 864–874.
38. Brown, C.M., Choi, E., Xu, Q., Vitek, M.P., Colton, C.A., The APOE4 genotype alters the response of microglia and macrophages to 17β-estradiol. Neurobiol. Aging 29 (2008), 1783–1794.
39. Brown, C.M., Xu, Q., Okhubo, N., Vitek, M.P., Colton, C.A., Androgen-mediated immune function is altered by the apolipoprotein E gene. Endocrinology 148 (2007), 3383–3390.
40. Brown, L.M., Clegg, D.J., Central effects of estradiol in the regulation of food intake, body weight, and adiposity. J. Steroid Biochem. 122 (2010), 65–73.
41. Brugg, B., Dubreuil, Y.L., Huber, G., Wollman, E.E., Delhaye-Bouchaud, N., Mariani, J., Inflammatory processes induce beta-amyloid precursor protein changes in mouse brain. Proc. Natl. Acad. Sci. USA 92 (1995), 3032–3035.
42. Buckman, L.B., Hasty, A.H., Flaherty, D.K., Buckman, C.T., Thompson, M.M., Matlock, B.K., Weller, K., Ellacott, K.L.J., Obesity induced by a high-fat diet is associated with increased immune cell entry into the central nervous system. Brain Behav. Immun. 35 (2014), 33–42.
43. Burkhardt, M.S., Foster, J.K., Clarnette, R.M., Chubb, S.A.P., Bruce, D.G., Drummond, P.D., Martins, R.N., Yeap, B.B., Interaction between testosterone and apolipoprotein E ɛ4 status on cognition in healthy older men. J. Clin. Endocrinol. Metab. 91 (2006), 1168–1172.
44. Burkhardt, M.S., Foster, J.K., Laws, S.M., Baker, L.D., Craft, S., Gandy, S.E., Stuckey, B.G.A., Clarnette, R., Nolan, D., Hewson-Bower, B., Martins, R.N., Oestrogen replacement therapy may improve memory functioning in the absence of APOE epsilon4. J. Alzheimer's Dis. 6 (2004), 221–228.
45. Butchart, J., Birch, B., Bassily, R., Wolfe, L., Holmes, C., Male sex hormones and systemic inflammation in Alzheimer disease. Alzheimer Dis. Assoc. Disord. 27 (2013), 153–156.
46. Calderón-Garcidueñas, L., Kavanaugh, M., Block, M., D'Angiulli, A., Delgado-Chávez, R., Torres-Jardón, R., González-Maciel, A., Reynoso-Robles, R., Osnaya, N., Villarreal-Calderon, R., Guo, R., Hua, Z., Zhu, H., Perry, G., Diaz, P., Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults. J. Alzheimer's Dis. 28 (2012), 93–107.
47. Canon, M.E., Crimmins, E.M., Sex differences in the association between muscle quality, inflammatory markers, and cognitive decline. J. Nutr. Health Aging 15 (2011), 695–698.
48. Cao, D., Lu, H., Lewis, T.L., Li, L., Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease. J. Biol. Chem. 282 (2007), 36275–36282.
49. Carroll, J.C., Rosario, E.R., Chang, L., Stanczyk, F.Z., Oddo, S., LaFerla, F.M., Pike, C.J., Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice. J. Neurosci. 27 (2007), 13357–13365.
50. Carroll, J.C., Rosario, E.R., Kreimer, S., Villamagna, A., Gentzschein, E., Stanczyk, F.Z., Pike, C.J., Sex differences in β-amyloid accumulation in 3xTg-AD mice: role of neonatal sex steroid hormone exposure. Brain Res. 1366 (2010), 233–245.
51. Carvalho, C., Katz, P.S., Dutta, S., Katakam, P.V., Moreira, P.I., Busija, D.W., Increased susceptibility to amyloid-β toxicity in rat brain microvascular endothelial cells under hyperglycemic conditions. J. Alzheimer's Dis. 38 (2014), 75–83.
52. Cash, J.G., Kuhel, D.G., Basford, J.E., Jaeschke, A., Chatterjee, T.K., Weintraub, N.L., Hui, D.Y., Apolipoprotein E4 impairs macrophage efferocytosis and potentiates apoptosis by accelerating endoplasmic reticulum stress. J. Biol. Chem. 287 (2012), 27876–27884.
53. Castanon, N., Lasselin, J., Capuron, L., Neuropsychiatric comorbidity in obesity: role of inflammatory processes. Front. Endocrinol., 5, 2014 (74).
54. Chandel, A., Dhindsa, S., Topiwala, S., Chaudhuri, A., Dandona, P., Testosterone concentration in young patients with diabetes. Diabetes Care 31 (2008), 2013–2017.
55. Cherry, J.D., Olschowka, J.A.O., Banion, M.K., Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J. Neuroinflamm., 11, 2014, 98.
56. Clément, K., Viguerie, N., Poitou, C., Carette, C., Pelloux, V., Curat, C.A., Sicard, A., Rome, S., Benis, A., Zucker, J.-D., Vidal, H., Laville, M., Barsh, G.S., Basdevant, A., Stich, V., Cancello, R., Langin, D., Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects. FASEB J. 18 (2004), 1657–1669.
57. Colton, C.A., Brown, C.M., Vitek, M.P., Sex steroids, APOE genotype and the innate immune system. Neurobiol. Aging 26 (2005), 363–372.
58. Colton, C.A., Needham, L.K., Brown, C., Cook, D., Rasheed, K., Burke, J.R., Strittmatter, W.J., Schmechel, D.E., Vitek, M.P., APOE genotype-specific differences in human and mouse macrophage nitric oxide production. J. Neuroimmunol. 147 (2004), 62–67.
59. Cook, D.G., Leverenz, J.B., McMillan, P.J., Kulstad, J.J., Ericksen, S., Roth, R.A., Schellenberg, G.D., Jin, L.-W., Kovacina, K.S., Craft, S., Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-ɛ4 allele. Am. J. Pathol. 162 (2003), 313–319.
60. Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G.W., Roses, A.D., Haines, J.L., Pericak-Vance, M.A., Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261 (1993), 921–923.
61. Corella, D., Ordovas, J.M., Aging and cardiovascular diseases: the role of gene–diet interactions. Ageing Res. Rev. 18 (2014), 53–73.
62. Corella, D., Portolés, O., Arriola, L., Chirlaque, M.D., Barrricarte, A., Francés, F., Huerta, J.M., Larrañaga, N., Martínez, C., Martinez-Camblor, P., Molina, E., Navarro, C., Quirós, J.R., Rodríguez, L., Sánchez, M.J., Ros, E., Sala, N., González, C.A., Moreno-Iribas, C., Saturated fat intake and alcohol consumption modulate the association between the APOE polymorphism and risk of future coronary heart disease: a nested case-control study in the Spanish EPIC cohort. J. Nutr. Biochem. 22 (2011), 487–494.
63. Crea, F., Battipaglia, I., Andreotti, F., Sex differences in mechanisms, presentation and management of ischaemic heart disease. Atherosclerosis 241 (2015), 157–168.
64. Currais, A., Prior, M., Lo, D., Jolivalt, C., Schubert, D., Maher, P., Diabetes exacerbates amyloid and neurovascular pathology in aging-accelerated mice. Aging Cell 11 (2012), 1017–1026.
65. Damoiseaux, J.S., Seeley, W.W., Zhou, J., Shirer, W.R., Coppola, G., Karydas, A., Rosen, H.J., Miller, B.L., Kramer, J.H., Greicius, M.D., Alzheimer's Disease Neuroimaging Initiative. Gender modulates the APOE ɛ 4 effect in healthy older adults: convergent evidence from functional brain connectivity and spinal fluid tau levels. J. Neurosci. 32 (2012), 8254–8262.
66. Davidson, T.L., Hargrave, S.L., Swithers, S.E., Sample, C.H., Fu, X., Kinzig, K.P., Zheng, W., Inter-relationships among diet, obesity and hippocampal-dependent cognitive function. Neuroscience 253 (2013), 110–122.
67. Davis, K.E., Neinast, M.D., Sun, K., Skiles, W.M., Bills, J.D., Zehr, J.A., Zeve, D., Hahner, L.D., Cox, D.W., Gent, L.M., Xu, Y., Wang, Z.V., Khan, S.A., Clegg, D.J., The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis. Mol. Metab. 2 (2013), 227–242.
68. De Maddalena, C., Vodo, S., Petroni, A., Aloisi, A.M., Impact of testosterone on body fat composition. J. Cell. Physiol. 227 (2012), 3744–3748.
69. De Souza, C.T., Araujo, E.P., Bordin, S., Ashimine, R., Zollner, R.L., Boschero, A.C., Saad, M.J.A., Velloso, L.A., Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146 (2005), 4192–4199.
70. de-Andrade, F.M., Larrandaburu, M., Callegari-Jacques, S.M., Gastaldo, G., Hutz, M.H., Association of apolipoprotein E polymorphism with plasma lipids and Alzheimer's disease in a Southern Brazilian population. Braz. J. Med. Biol. Res. 33 (2000), 529–537.
71. Debette, S., Beiser, A., Hoffmann, U., DeCarli, C., O'Donnell, C.J., Massaro, J.M., Au, R., Himali, J.J., Wolf, P.A., Fox, C.S., Seshadri, S., Visceral fat is associated with lower brain volume in healthy middle-aged adults. Ann. Neurol. 68 (2010), 136–144.
72. Dhungana, H., Rolova, T., Savchenko, E., Wojciechowski, S., Savolainen, K., Ruotsalainen, A.-K., Sullivan, P.M., Koistinaho, J., Malm, T., Western-type diet modulates inflammatory responses and impairs functional outcome following permanent middle cerebral artery occlusion in aged mice expressing the human apolipoprotein E4 allele. J. Neuroinflamm., 10, 2013, 102.
73. Dik, M.G., Jonker, C., Comijs, H.C., Deeg, D.J.H., Kok, A., Yaffe, K., Penninx, B.W., Contribution of metabolic syndrome components to cognition in older individuals. Diabetes Care 30 (2007), 2655–2660.
74. Doruk, H., Naharci, M.I., Bozoglu, E., Isik, A.T., Kilic, S., The relationship between body mass index and incidental mild cognitive impairment, Alzheimer's disease and vascular dementia in elderly. J. Nutr. Health Aging 14 (2010), 834–838.
75. Du, J., Chang, J., Guo, S., Zhang, Q., Wang, Z., ApoE 4 reduces the expression of Aβ degrading enzyme IDE by activating the NMDA receptor in hippocampal neurons. Neurosci. Lett. 464 (2009), 140–145.
76. Edland, S.D., Insulin-degrading enzyme, apolipoprotein E, and Alzheimer's disease. J. Mol. Neurosci. 23 (2004), 213–217.
77. Eikelenboom, P., Veerhuis, R., van Exel, E., Hoozemans, J.J.M., Rozemuller, A.J.M., van Gool, W.A., The early involvement of the innate immunity in the pathogenesis of late-onset Alzheimer's disease: neuropathological, epidemiological and genetic evidence. Curr. Alzheimer Res. 8 (2011), 142–150.
78. Elias, M.F., Elias, P.K., Sullivan, L.M., Wolf, P.A., D'Agostino, R.B., Lower cognitive function in the presence of obesity and hypertension: the Framingham heart study. Int. J. Obes. Relat. Metab. Disord. 27 (2003), 260–268.
79. Elosua, R., Demissie, S., Cupples, L.A., Meigs, J.B., Wilson, P.W.F., Schaefer, E.J., Corella, D., Ordovas, J.M., Obesity modulates the association among APOE genotype, insulin, and glucose in men. Obes. Res. 11 (2003), 1502–1508.
80. Emmerzaal, T.L., Kiliaan, A.J., Gustafson, D.R., 2003–2013: a decade of body mass index, Alzheimer's disease, and dementia. J. Alzheimer's Dis. 43 (2015), 739–755.
81. Engström, G., Hedblad, B., Stavenow, L., Lind, P., Janzon, L., Lindgärde, F., Inflammation-sensitive plasma proteins are associated with future weight gain. Diabetes 52 (2003), 2097–2101.
82. Erion, J.R., Wosiski-Kuhn, M., Dey, A., Hao, S., Davis, C.L., Pollock, N.K., Stranahan, A.M., Obesity elicits interleukin 1-mediated deficits in hippocampal synaptic plasticity. J. Neurosci. 34 (2014), 2618–2631.
83. Exalto, L.G., Quesenberry, C.P., Barnes, D., Kivipelto, M., Biessels, G.J., Whitmer, R.A., Midlife risk score for the prediction of dementia four decades later. Alzheimer's Dement. 10 (2014), 562–570.
84. Feng, L., Chong, M.S., Lim, W.S., Lee, T.S., Collinson, S.L., Yap, P., Ng, T.P., Metabolic syndrome and amnestic mild cognitive impairment: Singapore longitudinal ageing study-2 findings. J. Alzheimer Dis. 34 (2013), 649–657.
85. Fernandez-Martinez, M., Elcoroaristizabal Martin, X., Blanco Martin, E., Galdos Alcelay, L., Ugarriza Serrano, I., Gomez Busto, F., Alvarez-Alvarez, M., Molano Salazar, A., Bereincua Gandarias, R., Ingles Borda, S., Uterga Valiente, J.M., Indakoetxea Juanbeltz, B., Gomez Beldarrain, M.A., Moraza Lopez, J., Barandiaran Amillano, M., de Pancorbo, M.M., Oestrogen receptor polymorphisms are an associated risk factor for mild cognitive impairment and Alzheimer disease in women APOE 4 carriers: a case-control study. Br Med. J. Open 3 (2013), e003200–e13200.
86. Ferrari, C., Nacmias, B., Bagnoli, S., Piaceri, I., Lombardi, G., Pradella, S., Tedde, A., Sorbi, S., Imaging and cognitive reserve studies predict dementia in presymptomatic Alzheimer's disease subjects. Neurodegener. Dis. 13 (2014), 157–159.
87. Fewlass, D.C., Noboa, K., Pi-Sunyer, F.X., Johnston, J.M., Yan, S.D., Tezapsidis, N., Obesity-related leptin regulates Alzheimer's Abeta. FASEB J. 18 (2004), 1870–1878.
88. Fitzpatrick, A.L., Kuller, L.H., Lopez, O.L., Diehr, P., O'Meara, E.S., Longstreth, W.T., Luchsinger, J.A., Midlife and late-life obesity and the risk of dementia: cardiovascular health study. Arch. Neurol. 66 (2009), 336–342.
89. Francis, H.M., Stevenson, R.J., Higher reported saturated fat and refined sugar intake is associated with reduced hippocampal-dependent memory and sensitivity to interoceptive signals. Behav. Neurosci. 125 (2011), 943–955.
90. Freeman, L.R., Haley-Zitlin, V., Rosenberger, D.S., Granholm, A.-C., Damaging effects of a high-fat diet to the brain and cognition: a review of proposed mechanisms. Nutr. Neurosci. 17 (2014), 241–251.
91. Gale, S.C., Gao, L., Mikacenic, C., Coyle, S.M., Rafaels, N., Murray Dudenkov, T., Madenspacher, J.H., Draper, D.W., Ge, W., Aloor, J.J., Azzam, K.M., Lai, L., Blackshear, P.J., Calvano, S.E., Barnes, K.C., Lowry, S.F., Corbett, S., Wurfel, M.M., Fessler, M.B., APOɛ4 is associated with enhanced in vivo innate immune responses in human subjects. J. Allergy Clin. Immunol. 134 (2014), 127–134.
92. García-Cáceres, C., Yi, C.-X., Tschöp, M.H., Hypothalamic astrocytes in obesity. Endocrinol. Metab. Clin. N. Am. 42 (2013), 57–66.
93. Gautier, A., Bonnet, F., Dubois, S., Massart, C., Grosheny, C., Bachelot, A., Aubé, C., Balkau, B., Ducluzeau, P.-H., Associations between visceral adipose tissue, inflammation and sex steroid concentrations in men. Clin. Endocrinol. 78 (2013), 373–378.
94. Geliebter, A., Pantazatos, S.P., McOuatt, H., Puma, L., Gibson, C.D., Atalayer, D., Sex-based fMRI differences in obese humans in response to high vs. low energy food cues. Behav. Brain Res. 243 (2013), 91–96.
95. Genin, E., Hannequin, D., Wallon, D., Sleegers, K., Hiltunen, M., Combarros, O., Bullido, M.J., Engelborghs, S., De Deyn, P., Berr, C., Pasquier, F., Dubois, B., Tognoni, G., Fiévet, N., Brouwers, N., Bettens, K., Arosio, B., Coto, E., Del Zompo, M., Mateo, I., Epelbaum, J., Frank-Garcia, A., Helisalmi, S., Porcellini, E., Pilotto, A., Forti, P., Ferri, R., Scarpini, E., Siciliano, G., Solfrizzi, V., Sorbi, S., Spalletta, G., Valdivieso, F., Vepsäläinen, S., Alvarez, V., Bosco, P., Mancuso, M., Panza, F., Nacmias, B., Bossù, P., Hanon, O., Piccardi, P., Annoni, G., Seripa, D., Galimberti, D., Licastro, F., Soininen, H., Dartigues, J.-F., Kamboh, M.I., Van Broeckhoven, C., Lambert, J.-C., Amouyel, P., Campion, D., APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol. Psychiatry 16 (2011), 903–907.
96. Ghebranious, N., Mukesh, B., Giampietro, P.F., Glurich, I., Mickel, S.F., Waring, S.C., McCarty, C.A., A pilot study of gene/gene and gene/environment interactions in Alzheimer disease. Clin. Med. Res. 9 (2011), 17–25.
97. Giltay, E.J., Haider, A., Saad, F., Gooren, L.J., C-reactive protein levels and ageing male symptoms in hypogonadal men treated with testosterone supplementation. Andrologia 40 (2008), 398–400.
98. Giménez-Llort, L., Arranz, L., Maté, I., la Fuente, De, M., Gender-specific neuroimmunoendocrine aging in a triple-transgenic 3xTg-AD mouse model for Alzheimer's disease and its relation with longevity. Neuroimmunomodulation 15 (2008), 331–343.
99. Glass, C.K., Saijo, K., Winner, B., Marchetto, M.C., Gage, F.H., Mechanisms underlying inflammation in neurodegeneration. Cell 140 (2010), 918–934.
100. Goncharov, N.P., Katsya, G.V., Chagina, N.A., Gooren, L.J., Three definitions of metabolic syndrome applied to a sample of young obese men and their relation with plasma testosterone. Aging Male 11 (2008), 118–122.
101. Granholm, A.-C., Bimonte-Nelson, H.A., Moore, A.B., Nelson, M.E., Freeman, L.R., Sambamurti, K., Effects of a saturated fat and high cholesterol diet on memory and hippocampal morphology in the middle-aged rat. J. Alzheimer's Dis. 14 (2008), 133–145.
102. Grimm, M.O.W., Rothhaar, T.L., Grösgen, S., Burg, V.K., Hundsdörfer, B., Haupenthal, V.J., Friess, P., Kins, S., Grimm, H.S., Hartmann, T., Trans fatty acids enhance amyloidogenic processing of the Alzheimer amyloid precursor protein (APP). J. Nutr. Biochem. 23 (2012), 1214–1223.
103. Grossmann, M., Tang Fui, M., Dupuis, P., Lowered testosterone in male obesity: mechanisms, morbidity and management. Asian J. Androl., 16, 2014, 223.
104. Guan, J., Zhao, H.-L., Sui, Y., He, L., Lee, H.-M., Lai, F.M.M., Tong, P.C.Y., Chan, J.C.N., Histopathological correlations of islet amyloidosis with apolipoprotein E polymorphisms in type 2 diabetic Chinese patients. Pancreas 42 (2013), 1129–1137.
105. Guo, L., LaDu, M.J., Van Eldik, L.J., A dual role for apolipoprotein e in neuroinflammation: anti- and pro-inflammatory activity. J. Mol. Neurosci. 23 (2004), 205–212.
106. Gupta, S., Knight, A.G., Gupta, S., Keller, J.N., Bruce-Keller, A.J., Saturated long-chain fatty acids activate inflammatory signaling in astrocytes. J. Neurochem. 120 (2012), 1060–1071.
107. Gustafson, D., Lissner, L., Bengtsson, C., Björkelund, C., Skoog, I., A 24-year follow-up of body mass index and cerebral atrophy. Neurology 63 (2004), 1876–1881.
108. Gustafson, D., Rothenberg, E., Blennow, K., Steen, B., Skoog, I., An 18-year follow-up of overweight and risk of Alzheimer disease. Arch. Intern. Med. 163 (2003), 1524–1528.
109. Gustafson, D.R., Bäckman, K., Waern, M., Ostling, S., Guo, X., Zandi, P., Mielke, M.M., Bengtsson, C., Skoog, I., Adiposity indicators and dementia over 32 years in Sweden. Neurology 73 (2009), 1559–1566.
110. Gustafson, D.R., Karlsson, C., Skoog, I., Rosengren, L., Lissner, L., Blennow, K., Mid-life adiposity factors relate to blood–brain barrier integrity in late life. J. Intern. Med. 262 (2007), 643–650.
111. Hadaegh, F., Hasheminia, M., Lotfaliany, M., Mohebi, R., Azizi, F., Tohidi, M., Incidence of metabolic syndrome over 9 years follow-up; the importance of sex differences in the role of insulin resistance and other risk factors. PLoS One, 8, 2013, e76304.
112. Halliday, M.R., Pomara, N., Sagare, A.P., Mack, W.J., Frangione, B., Zlokovic, B.V., Relationship between cyclophilin a levels and matrix metalloproteinase 9 activity in cerebrospinal fluid of cognitively normal apolipoprotein e4 carriers and blood–brain barrier breakdown. J. Am. Med. Assoc. Neurol. 70 (2013), 1198–1200.
113. Hanson, A.J., Bayer-Carter, J.L., Green, P.S., Montine, T.J., Wilkinson, C.W., Baker, L.D., Watson, G.S., Bonner, L.M., Callaghan, M., Leverenz, J.B., Tsai, E., Postupna, N., Zhang, J., Lampe, J., Craft, S., Effect of apolipoprotein E genotype and diet on apolipoprotein E lipidation and amyloid peptides. J. Am. Med. Assoc. Neurol. 70 (2013), 972–980.
114. Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M.L., Pahwa, J.S., Moskvina, V., Dowzell, K., Williams, A., Jones, N., Thomas, C., Stretton, A., Morgan, A.R., Lovestone, S., Powell, J., Proitsi, P., Lupton, M.K., Brayne, C., Rubinsztein, D.C., Gill, M., Lawlor, B., Lynch, A., Morgan, K., Brown, K.S., Passmore, P.A., Craig, D., McGuinness, B., Todd, S., Holmes, C., Mann, D., Smith, A.D., Love, S., Kehoe, P.G., Hardy, J., Mead, S., Fox, N., Rossor, M., Collinge, J., Maier, W., Jessen, F., Schürmann, B., van den Bussche, H., Heuser, I., Kornhuber, J., Wiltfang, J., Dichgans, M., Frölich, L., Hampel, H., Hüll, M., Rujescu, D., Goate, A.M., Kauwe, J.S.K., Cruchaga, C., Nowotny, P., Morris, J.C., Mayo, K., Sleegers, K., Bettens, K., Engelborghs, S., De Deyn, P.P., Van Broeckhoven, C., Livingston, G., Bass, N.J., Gurling, H., McQuillin, A., Gwilliam, R., Deloukas, P., Al-Chalabi, A., Shaw, C.E., Tsolaki, M., Singleton, A.B., Guerreiro, R., Mühleisen, T.W., Nöthen, M.M., Moebus, S., Jöckel, K.-H., Klopp, N., Wichmann, H.-E., Carrasquillo, M.M., Pankratz, V.S., Younkin, S.G., Holmans, P.A., O'Donovan, M., Owen, M.J., Williams, J., Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat. Genet. 41 (2009), 1088–1093.
115. Hawkins, M.A.W., Alosco, M.L., Spitznagel, M.B., Strain, G., Devlin, M., Cohen, R., Crosby, R.D., Mitchell, J.E., Gunstad, J., The association between reduced inflammation and cognitive gains after bariatric surgery. Psychosom. Med. 77 (2015), 688–696.
116. Hayden, K.M., Zandi, P.P., Lyketsos, C.G., Khachaturian, A.S., Bastian, L.A., Charoonruk, G., Tschanz, J.T., Norton, M.C., Pieper, C.F., Munger, R.G., Breitner, J.C.S., Welsh-Bohmer, K.A., Welsh-Bohmer, K.A., Vascular risk factors for incident Alzheimer disease and vascular dementia: the Cache County Study. Alzheimer Dis. Assoc. Disord. 20 (2006), 93–100.
117. Hebert, L.E., Scherr, P.A., Bienias, J.L., Bennett, D.A., Evans, D.A., Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch. Neurol. 60 (2003), 1119–1122.
118. Heine, P.A., Taylor, J.A., Iwamoto, G.A., Lubahn, D.B., Cooke, P.S., Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc. Natl. Acad. Sci. USA 97 (2000), 12729–12734.
119. Heneka, M.T., Kummer, M.P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., Griep, A., Axt, D., Remus, A., Tzeng, T.-C., Gelpi, E., Halle, A., Korte, M., Latz, E., Golenbock, D.T., NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493 (2013), 674–678.
120. Hirata-Fukae, C., Li, H.-F., Hoe, H.-S., Gray, A.J., Minami, S.S., Hamada, K., Niikura, T., Hua, F., Tsukagoshi-Nagai, H., Horikoshi-Sakuraba, Y., Mughal, M., Rebeck, G.W., LaFerla, F.M., Mattson, M.P., Iwata, N., Saido, T.C., Klein, W.L., Duff, K.E., Aisen, P.S., Matsuoka, Y., Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Res. 1216 (2008), 92–103.
121. Hjorth, E., Zhu, M., Toro, V.C., Vedin, I., Palmblad, J., Cederholm, T., Freund-Levi, Y., Faxen-Irving, G., Wahlund, L.-O., Basun, H., Eriksdotter, M., Schultzberg, M., Omega-3 fatty acids enhance phagocytosis of Alzheimer's disease-related amyloid-β42 by human microglia and decrease inflammatory markers. J. Alzheimer's Dis. 35 (2013), 697–713.
122. Ho, A.J., Raji, C.A., Becker, J.T., Lopez, O.L., Kuller, L.H., Hua, X., Lee, S., Hibar, D., Dinov, I.D., Stein, J.L., Jack, C.R. Jr., Weiner, M.W., Toga, A.W., Thompson, P.M., Obesity is linked with lower brain volume in 700 AD and MCI patients. Neurobiol. Aging 31 (2010), 1326–1339.
123. Ho, L., Qin, W., Pompl, P.N., Xiang, Z., Wang, J., Zhao, Z., Peng, Y., Cambareri, G., Rocher, A., Mobbs, C.V., Hof, P.R., Pasinetti, G.M., Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. FASEB J. 18 (2004), 902–904.
124. Hogervorst, E., Lehmann, D.J., Warden, D.R., McBroom, J., Smith, A.D., Apolipoprotein E epsilon4 and testosterone interact in the risk of Alzheimer's disease in men. Int. J. Geriatr. Psychiatry 17 (2002), 938–940.
125. Hogervorst, E., Williams, J., Budge, M., Barnetson, L., Combrinck, M., Smith, A.D., Serum total testosterone is lower in men with Alzheimer's disease. Neuroendocrinol. Lett. 22 (2001), 163–168.
126. Holland, D., Desikan, R.S., Dale, A.M., McEvoy, L.K., Alzheimer's Disease Neuroimaging Initiative. Higher rates of decline for women and apolipoprotein E epsilon4 carriers. Am. J. Neuroradiol. 34 (2013), 2287–2293.
127. Hollingworth, P., et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat. Genet. 43 (2011), 429–435.
128. Hsu, T.M., Konanur, V.R., Taing, L., Usui, R., Kayser, B.D., Goran, M.I., Kanoski, S.E., Effects of sucrose and high fructose corn syrup consumption on spatial memory function and hippocampal neuroinflammation in adolescent rats. Hippocampus 25 (2014), 227–239.
129. Hughe, T.F., Borenstein, A.R., Schofield, E., Wu, Y., Larson, E.B., Association between late-life body mass index and dementia: the Kame project. Neurology 72 (2009), 1741–1746.
130. Hultman, K., Strickland, S., Norris, E.H., The APOE ɛ4/ɛ4 genotype potentiates vascular fibrin(ogen) deposition in amyloid-laden vessels in the brains of Alzheimer's disease patients. J. Cereb. Blood Flow Metab. 33 (2013), 1251–1258.
131. Hwang, L.-L., Wang, C.-H., Li, T.-L., Chang, S.-D., Lin, L.-C., Chen, C.-P., Chen, C.-T., Liang, K.-C., Ho, I.-K., Yang, W.-S., Chiou, L.-C., Sex differences in high-fat diet-induced obesity, metabolic alterations and learning, and synaptic plasticity deficits in mice. Obesity 18 (2010), 463–469.
132. Iqbal, K., Liu, F., Gong, C.-X., Grundke-Iqbal, I., Tau in Alzheimer disease and related tauopathies. Curr. Alzheimer Res. 7 (2010), 656–664.
133. Isaac, V., Sim, S., Zheng, H., Zagorodnov, V., Tai, E.S., Chee, M., Adverse associations between visceral adiposity, brain structure, and cognitive performance in healthy elderly. Front. Aging Neurosci., 3, 2011, 12.
134. Jacobs, E.G., Kroenke, C., Lin, J., Epel, E.S., Kenna, H.A., Blackburn, E.H., Rasgon, N.L., Accelerated cell aging in female APOE-ɛ4 carriers: implications for hormone therapy use. PLoS One, 8, 2013, e54713.
135. Jayaraman, A., Lent-Schochet, D., Pike, C.J., Diet-induced obesity and low testosterone increase neuroinflammation and impair neural function. J. Neuroinflamm., 11, 2014, 162.
136. Jayaraman, A., Pike, C.J., Alzheimer's disease and type 2 diabetes: multiple mechanisms contribute to interactions. Curr. Diab. Rep., 14, 2014, 476.
137. Jefferson, A.L., Massaro, J.M., Wolf, P.A., Seshadri, S., Au, R., Vasan, R.S., Larson, M.G., Meigs, J.B., Keaney, J.F., Lipinska, I., Kathiresan, S., Benjamin, E.J., DeCarli, C., Inflammatory biomarkers are associated with total brain volume: the Framingham Heart Study. Neurology 68 (2007), 1032–1038.
138. Jolivalt, C.G., Lee, C.A., Beiswenger, K.K., Smith, J.L., Orlov, M., Torrance, M.A., Masliah, E., Defective insulin signaling pathway and increased glycogen synthase kinase-3 activity in the brain of diabetic mice: parallels with Alzheimer's disease and correction by insulin. J. Neurosci. Res. 86 (2008), 3265–3274.
139. Jones, M.E., Thorburn, A.W., Britt, K.L., Hewitt, K.N., Wreford, N.G., Proietto, J., Oz, O.K., Leury, B.J., Robertson, K.M., Yao, S., Simpson, E.R., Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc. Natl. Acad. Sci. USA 97 (2000), 12735–12740.
140. Julien, C., Tremblay, C., Phivilay, A., Berthiaume, L., Emond, V., Julien, P., Calon, F., High-fat diet aggravates amyloid-beta and tau pathologies in the 3xTg-AD mouse model. Neurobiol. Aging 31 (2010), 1516–1531.
141. Kalinchenko, S.Y., Tishova, Y.A., Mskhalaya, G.J., Gooren, L.J.G., Giltay, E.J., Saad, F., Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. Clin. Endocrinol. 73 (2010), 602–612.
142. Kanaya, A.M., Lindquist, K., Harris, T.B., Launer, L., Rosano, C., Satterfield, S., Yaffe, K., Health ABC Study. Total and regional adiposity and cognitive change in older adults: the health, aging and body composition (ABC) study. Arch. Neurol. 66 (2009), 329–335.
143. Kanoski, S.E., Davidson, T.L., Western diet consumption and cognitive impairment: links to hippocampal dysfunction and obesity. Physiol. Behav. 103 (2011), 59–68.
144. Kanoski, S.E., Zhang, Y., Zheng, W., Davidson, T.L., The effects of a high-energy diet on hippocampal function and blood–brain barrier integrity in the rat. J. Alzheimer's Dis. 21 (2010), 207–219.
145. Kapoor, D., Aldred, H., Clark, S., Channer, K.S., Jones, T.H., Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes: correlations with bioavailable testosterone and visceral adiposity. Diabetes Care 30 (2007), 911–917.
146. Kapoor, D., Malkin, C.J., Channer, K.S., Jones, T.H., Androgens, insulin resistance and vascular disease in men. Clin. Endocrinol. 63 (2005), 239–250.
147. Keene, C.D., Cudaback, E., Li, X., Montine, K.S., Montine, T.J., Apolipoprotein E isoforms and regulation of the innate immune response in brain of patients with Alzheimer's disease. Curr. Opin. Neurobiol. 21 (2011), 920–928.
148. Khan, N.A., Raine, L.B., Donovan, S.M., Hillman, C.H., IV. The cognitive implications of obesity and nutrition in childhood. Monogr. Soc. Res. Child Dev. 79 (2014), 51–71.
149. Khera, A., Vega, G.L., Das, S.R., Ayers, C., McGuire, D.K., Grundy, S.M., de Lemos, J.A., Sex differences in the relationship between C-reactive protein and body fat. J. Clin. Endocrinol. Metab. 94 (2009), 3251–3258.
150. Kim, B., Backus, C., Oh, S., Hayes, J.M., Feldman, E.L., Increased tau phosphorylation and cleavage in mouse models of type 1 and type 2 diabetes. Endocrinology 150 (2009), 5294–5301.
151. Kim, B., Backus, C., Oh, S., Feldman, E.L., Hyperglycemia-induced tau cleavage in vitro and in vivo: a possible link between diabetes and Alzheimer's disease. J. Alzheimer's Dis. 34 (2013), 727–739.
152. Kleinberger, G., et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci. Transl. Med., 6, 2014 (243ra86-243ra86).
153. Knight, E.M., Martins, I.V.A., Gümüsgöz, S., Allan, S.M., Lawrence, C.B., High-fat diet-induced memory impairment in triple-transgenic Alzheimer's disease (3xTgAD) mice is independent of changes in amyloid and tau pathology. Neurobiol. Aging 35 (2014), 1821–1832.
154. Kohjima, M., Sun, Y., Chan, L., Increased food intake leads to obesity and insulin resistance in the Tg2576 Alzheimer's disease mouse model. Endocrinology 151 (2010), 1532–1540.
155. Kunzler, J., Youmans, K.L., Yu, C., LaDu, M.J., Tai, L.M., APOE modulates the effect of estrogen therapy on Aβ accumulation EFAD-Tg mice. Neurosci. Lett. 560 (2014), 131–136.
156. Kupelian, V., Chiu, G.R., Araujo, A.B., Williams, R.E., Clark, R.V., McKinlay, J.B., Association of sex hormones and C-reactive protein levels in men. Clin. Endocrinol. 72 (2010), 527–533.
157. Kypreos, K.E., Karagiannides, I., Fotiadou, E.H., Karavia, E.A., Brinkmeier, M.S., Giakoumi, S.M., Tsompanidi, E.M., Mechanisms of obesity and related pathologies: role of apolipoprotein E in the development of obesity. FEBS J. 276 (2009), 5720–5728.
158. Laaksonen, D.E., Niskanen, L., Punnonen, K., Nyyssönen, K., Tuomainen, T.-P., Salonen, R., Rauramaa, R., Salonen, J.T., Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur. J. Endocrinol. 149 (2003), 601–608.
159. LaDu, M.J., Shah, J.A., Reardon, C.A., Getz, G.S., Bu, G., Hu, J., Guo, L., Van Eldik, L.J., Apolipoprotein E and apolipoprotein E receptors modulate A beta-induced glial neuroinflammatory responses. Neurochem. Int. 39 (2001), 427–434.
160. LaFerla, F.M., Pathways linking Aβ and tau pathologies. Biochem. Soc. Trans., 38, 2010, 993.
161. Lakhan, S.E., Kirchgessner, A., The emerging role of dietary fructose in obesity and cognitive decline. Nutr. J., 12, 2013 (1–1).
162. Lambert, J.-C., et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat. Genet. 41 (2009), 1094–1099.
163. Lathe, R., Sapronova, A., Kotelevtsev, Y., Atherosclerosis and Alzheimer—diseases with a common cause? Inflammation, oxysterols, vasculature. BMC Geriatr. 14 (2014), 1–30.
164. Laughlin, G.A., Barrett-Connor, E., Bergstrom, J., Low serum testosterone and mortality in older men. J. Clin. Endocrinol. Metab. 93 (2008), 68–75.
165. Lebbadi, M., Julien, C., Phivilay, A., Tremblay, C., Emond, V., Kang, J.X., Calon, F., Endogenous conversion of omega-6 into omega-3 fatty acids improves neuropathology in an animal model of Alzheimer's disease. J. Alzheimer's Dis. 27 (2011), 853–869.
166. Leboucher, A., Laurent, C., Fernandez-Gomez, F.-J., Burnouf, S., Troquier, L., Eddarkaoui, S., Demeyer, D., Caillierez, R., Zommer, N., Vallez, E., Bantubungi, K., Breton, C., Pigny, P., Buée-Scherrer, V., Staels, B., Hamdane, M., Tailleux, A., Buée, L., Blum, D., Detrimental effects of diet-induced obesity on τ pathology are independent of insulin resistance in τ transgenic mice. Diabetes 62 (2013), 1681–1688.
167. Li, J., Deng, J., Sheng, W., Zuo, Z., Metformin attenuates Alzheimer's disease-like neuropathology in obese, leptin-resistant mice. Pharmacol. Biochem. Behav. 101 (2012), 564–574.
168. Li, R., Singh, M., Sex differences in cognitive impairment and Alzheimer's disease. Front. Neuroendocrinol. 35 (2014), 385–403.
169. Li, Z.-G., Zhang, W., Sima, A.A.F., Alzheimer-like changes in rat models of spontaneous diabetes. Diabetes 56 (2007), 1817–1824.
170. Liu, C.-C., Kanekiyo, T., Xu, H., Bu, G., Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9 (2013), 106–118.
171. Liu, H.-Q., Qiu, Y., Mu, Y., Zhang, X.-J., Liu, L., Hou, X.-H., Zhang, L., Xu, X.-N., Ji, A.-L., Cao, R., Yang, R.-H., Wang, F., A high ratio of dietary n-3/n-6 polyunsaturated fatty acids improves obesity-linked inflammation and insulin resistance through suppressing activation of TLR4 in SD rats. Nutr. Res. 33 (2013), 849–858.
172. Liu, Y., Paajanen, T., Westman, E., Wahlund, L.-O., Simmons, A., Tunnard, C., Sobow, T., Proitsi, P., Powell, J., Mecocci, P., Tsolaki, M., Vellas, B., Muehlboeck, S., Evans, A., Spenger, C., Lovestone, S., Soininen, H., Soininen, H., Effect of APOE ɛ4 allele on cortical thicknesses and volumes: the addneuromed study. J. Alzheimer's Dis. 21 (2010), 947–966.
173. Luchsinger, J.A., Cheng, D., Tang, M.X., Schupf, N., Mayeux, R., Central obesity in the elderly is related to late-onset Alzheimer disease. Alzheimer Dis. Assoc. Disord. 26 (2012), 101–105.
174. Luchsinger, J.A., Tang, M.-X., Shea, S., Mayeux, R., Caloric intake and the risk of Alzheimer disease. Arch. Neurol. 59 (2002), 1258–1263.
175. Lynch, J.R., Morgan, D., Mance, J., Matthew, W.D., Laskowitz, D.T., Apolipoprotein E modulates glial activation and the endogenous central nervous system inflammatory response. J. Neuroimmunol. 114 (2001), 107–113.
176. Lynch, J.R., Tang, W., Wang, H., Vitek, M.P., Bennett, E.R., Sullivan, P.M., Warner, D.S., Laskowitz, D.T., APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response. J. Biol. Chem. 278 (2003), 48529–48533.
177. Macotela, Y., Boucher, J., Tran, T.T., Kahn, C.R., Sex and depot differences in adipocyte insulin sensitivity and glucose metabolism. Diabetes 58 (2009), 803–812.
178. Maezawa, I., Nivison, M., Montine, K.S., Maeda, N., Montine, T.J., Neurotoxicity from innate immune response is greatest with targeted replacement of E4 allele of apolipoprotein E gene and is mediated by microglial p38MAPK. FASEB J. 20 (2006), 797–799.
179. Maezawa, I., Zaja-Milatovic, S., Milatovic, D., Stephen, C., Sokal, I., Maeda, N., Montine, T.J., Montine, K.S., Apolipoprotein E isoform-dependent dendritic recovery of hippocampal neurons following activation of innate immunity. J. Neuroinflamm., 3, 2006, 21.
180. Maggio, M., Basaria, S., Ble, A., Lauretani, F., Bandinelli, S., Ceda, G.P., Valenti, G., Ling, S.M., Ferrucci, L., Correlation between testosterone and the inflammatory marker soluble interleukin-6 receptor in older men. J. Clin. Endocrinol. Metab. 91 (2006), 345–347.
181. Malkin, C.J., Pugh, P.J., Jones, R.D., Kapoor, D., Channer, K.S., Jones, T.H., The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J. Clin. Endocrinol. Metab. 89 (2004), 3313–3318.
182. Manly, J.J., Merchant, C.A., Jacobs, D.M., Small, S.A., Bell, K., Ferin, M., Mayeux, R., Endogenous estrogen levels and Alzheimer's disease among postmenopausal women. Neurology 54 (2000), 833–837.
183. Marques-Vidal, P., Bongard, V., Ruidavets, J.-B., Fauvel, J., Hanaire-Broutin, H., Perret, B., Ferrières, J., Obesity and alcohol modulate the effect of apolipoprotein E polymorphism on lipids and insulin. Obes. Res. 11 (2003), 1200–1206.
184. Martens, E.A.P., Lemmens, S.G.T., Adam, T.C.M., Westerterp-Plantenga, M.S., Sex differences in HPA axis activity in response to a meal. Physiol. Behav. 106 (2012), 272–277.
185. Mascarenhas-Melo, F., Marado, D., Palavra, F., Sereno, J., Coelho, Á., Pinto, R., Teixeira-Lemos, E., Teixeira, F., Reis, F., Diabetes abrogates sex differences and aggravates cardiometabolic risk in postmenopausal women. Cardiovasc. Diabetol., 12, 2013, 61.
186. Mazzoccoli, G., Dagostino, M.P., Vinciguerra, M., Ciccone, F., Paroni, G., Seripa, D., Addante, F., Montella, R.C., De Cosmo, S., Sera, F., Greco, A., An association study between epicardial fat thickness and cognitive impairment in the elderly. Am J. Physiol. Heart Circ. 307 (2014), H1269–H1276.
187. McAllister, C., Long, J., Bowers, A., Walker, A., Cao, P., Honda, S.-I., Harada, N., Staufenbiel, M., Shen, Y., Li, R., Genetic targeting aromatase in male amyloid precursor protein transgenic mice down-regulates beta-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment. J. Neurosci. 30 (2010), 7326–7334.
188. McNelis, J.C., Olefsky, J.M., Macrophages, immunity, and metabolic disease. Immunity 41 (2014), 36–48.
189. Medrikova, D., Jilkova, Z.M., Bardova, K., Janovska, P., Rossmeisl, M., Kopecky, J., Sex differences during the course of diet-induced obesity in mice: adipose tissue expandability and glycemic control. Int. J. Obes. Relat. Metab. Disord. 36 (2012), 262–272.
190. Mehla, J., Chauhan, B.C., Chauhan, N.B., Experimental induction of type 2 diabetes in aging-accelerated mice triggered Alzheimer-like pathology and memory deficits. J. Alzheimer's Dis. 39 (2014), 145–162.
191. Meigs, J.B., Ordovas, J.M., Cupples, L.A., Singer, D.E., Nathan, D.M., Schaefer, E.J., Wilson, P.W., Apolipoprotein E isoform polymorphisms are not associated with insulin resistance: the Framingham offspring study. Diabetes Care 23 (2000), 669–674.
192. Meng, X.-F., Yu, J.-T., Wang, H.-F., Tan, M.-S., Wang, C., Tan, C.-C., Tan, L., Midlife vascular risk factors and the risk of Alzheimer's disease: a systematic review and meta-analysis. J. Alzheimer's Dis. 42 (2014), 1295–1310.
193. Meyer, M.R., Clegg, D.J., Prossnitz, E.R., Barton, M., Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors. Acta Physiol. 203 (2011), 259–269.
194. Milanski, M., Arruda, A.P., Coope, A., Ignacio-Souza, L.M., Nunez, C.E., Roman, E.A., Romanatto, T., Pascoal, L.B., Caricilli, A.M., Torsoni, M.A., Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver. Diabetes 61 (2012), 1455–1462.
195. Milanski, M., Degasperi, G., Coope, A., Morari, J., Denis, R., Cintra, D.E., Tsukumo, D.M.L., Anhe, G., Amaral, M.E., Takahashi, H.K., Curi, R., Oliveira, H.C., Carvalheira, J.B.C., Bordin, S., Saad, M.J., Velloso, L.A., Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J. Neurosci. 29 (2009), 359–370.
196. Miller, A.A., Spencer, S.J., Obesity and neuroinflammation: a pathway to cognitive impairment. Brain Behav. Immun. 42 (2014), 10–21.
197. Moffat, S.D., Zonderman, A.B., Metter, E.J., Kawas, C., Blackman, M.R., Harman, S.M., Resnick, S.M., Free testosterone and risk for Alzheimer disease in older men. Neurology 62 (2004), 188–193.
198. Mogri, M., Dhindsa, S., Quattrin, T., Ghanim, H., Dandona, P., Testosterone concentrations in young pubertal and post-pubertal obese males. Clin. Endocrinol. 78 (2013), 593–599.
199. Moralejo, D.H., Hansen, C.T., Treuting, P., Hessner, M.J., Fuller, J.M., Van Yserloo, B., Jensen, R., Osborne, W., Kwitek, A.E., Lernmark, A., Differential effects of leptin receptor mutation on male and female BBDR.Gimap5-/Gimap5- spontaneously diabetic rats. Physiol. Genom. 41 (2010), 9–20.
200. Moreira, P.I., High-sugar diets, type 2 diabetes and Alzheimerʼs disease. Curr. Opin. Clin. Nutr. Metab. Care 16 (2013), 440–445.
201. Morris, G.P., Clark, I.A., Vissel, B., Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer's disease. Acta Neuropathol. Commun., 2, 2014, 135.
202. Morris, M.C., Tangney, C.C., Dietary fat composition and dementia risk. Neurobiol. Aging 35 (2014), S59–S64.
203. Mucke, L., Selkoe, D.J., Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. Cold Spring Harb. Perspect. Med., 2, 2012, a006338.
204. Mueller, K., Anwander, A., Möller, H.E., Horstmann, A., Lepsien, J., Busse, F., Mohammadi, S., Schroeter, M.L., Stumvoll, M., Villringer, A., Pleger, B., Sex-dependent influences of obesity on cerebral white matter investigated by diffusion-tensor imaging. PLoS One, 6, 2011, e18544.
205. Murray, A.J., Knight, N.S., Cochlin, L.E., McAleese, S., Deacon, R.M.J., Rawlins, J.N.P., Clarke, K., Deterioration of physical performance and cognitive function in rats with short-term high-fat feeding. FASEB J. 23 (2009), 4353–4360.
206. Musatov, S., Chen, W., Pfaff, D.W., Mobbs, C.V., Yang, X.-J., Clegg, D.J., Kaplitt, M.G., Ogawa, S., Silencing of estrogen receptor α in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proc. Natl. Acad. Sci. USA 104 (2007), 2501–2506.
207. Nadal-Casellas, A., Bauzá-Thorbrügge, M., Proenza, A.M., Gianotti, M., Lladó, I., Sex-dependent differences in rat brown adipose tissue mitochondrial biogenesis and insulin signaling parameters in response to an obesogenic diet. Mol. Cell. Biochem. 373 (2012), 125–135.
208. Naj, A.C., et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat. Genet. 43 (2011), 436–441.
209. Nägga, K., Wattmo, C., Zhang, Y., Wahlund, L.-O., Palmqvist, S., Cerebral inflammation is an underlying mechanism of early death in Alzheimer's disease: a 13-year cause-specific multivariate mortality study. Alzheimer's Res. Ther. 6 (2014), 1–8.
210. Niedowicz, D.M., Reeves, V.L., Platt, T.L., Kohler, K., Beckett, T.L., Powell, D.K., Lee, T.L., Sexton, T.R., Song, E.S., Brewer, L.D., Latimer, C.S., Kraner, S.D., Larson, K.L., Ozcan, S., Norris, C.M., Hersh, L.B., Porter, N.M., Wilcock, D.M., Murphy, M.P., Obesity and diabetes cause cognitive dysfunction in the absence of accelerated β-amyloid deposition in a novel murine model of mixed or vascular dementia. Acta Neuropathol. Commun., 2, 2014, 64.
211. Nishitsuji, K., Hosono, T., Nakamura, T., Bu, G., Michikawa, M., Apolipoprotein E regulates the integrity of tight junctions in an isoform-dependent manner in an in vitro blood–brain barrier model. J. Biol. Chem. 286 (2011), 17536–17542.
212. Niu, W., Qi, Y., Qian, Y., Gao, P., Zhu, D., The relationship between apolipoprotein E e2/e3/e4 polymorphisms and hypertension: a meta-analysis of six studies comprising 1812 cases and 1762 controls. Hypertens. Res. 32 (2009), 1060–1066.
213. Norata, G.D., Tibolla, G., Seccomandi, P.M., Poletti, A., Catapano, A.L., Dihydrotestosterone decreases tumor necrosis factor-α and lipopolysaccharide-induced inflammatory response in human endothelial cells. J. Clin. Endocrinol. Metab. 91 (2006), 546–554.
214. Ogden, C.L., Carroll, M.D., Kit, B.K., Flegal, K.M., Prevalence of childhood and adult obesity in the United States, 2011–2012. J. Am. Med. Assoc., 311, 2014, 806.
215. Oh, J.Y., Barrett-Connor, E., Barrett-Connor, E., Apolipoprotein E polymorphism and lipid levels differ by gender and family history of diabetes: the Rancho Bernardo Study. Clin. Genet. 60 (2001), 132–137.
216. Oksman, M., Iivonen, H., Hogyes, E., Amtul, Z., Penke, B., Leenders, I., Broersen, L., Lütjohann, D., Hartmann, T., Tanila, H., Impact of different saturated fatty acid, polyunsaturated fatty acid and cholesterol containing diets on beta-amyloid accumulation in APP/PS1 transgenic mice. Neurobiol. Dis. 23 (2006), 563–572.
217. Olgiati, P., Politis, A., Malitas, P., Albani, D., Dusi, S., Polito, L., De Mauro, S., Zisaki, A., Piperi, C., Stamouli, E., Mailis, A., Batelli, S., Forloni, G., De Ronchi, D., Kalofoutis, A., Liappas, I., Serretti, A., APOE epsilon-4 allele and cytokine production in Alzheimer's disease. Int. J. Geriatr. Psychiatry 25 (2010), 338–344.
218. Ophir, G., Amariglio, N., Jacob-Hirsch, J., Elkon, R., Rechavi, G., Michaelson, D.M., Apolipoprotein E4 enhances brain inflammation by modulation of the NF-κB signaling cascade. Neurobiol. Dis. 20 (2005), 709–718.
219. Ophir, G., Meilin, S., Efrati, M., Chapman, J., Karussis, D., Roses, A., Michaelson, D.M., Human apoE3 but not apoE4 rescues impaired astrocyte activation in apoE null mice. Neurobiol. Dis. 12 (2003), 56–64.
220. Orr, M.E., 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 (2014), 1233–1242.
221. Panizzon, M.S., Hauger, R., Dale, A.M., Eaves, L.J., Eyler, L.T., Fischl, B., Fennema-Notestine, C., Franz, C.E., Grant, M.D., Jak, A.J., Jacobson, K.C., Lyons, M.J., Mendoza, S.P., Neale, M.C., Prom-Wormley, E.C., Seidman, L.J., Tsuang, M.T., Xian, H., Kremen, W.S., Testosterone modifies the effect of APOE genotype on hippocampal volume in middle-aged men. Neurology 75 (2010), 874–880.
222. Panizzon, M.S., Hauger, R., Xian, H., Vuoksimaa, E., Spoon, K.M., Mendoza, S.P., Jacobson, K.C., Vasilopoulos, T., Rana, B.K., McKenzie, R., McCaffery, J.M., Lyons, M.J., Kremen, W.S., Franz, C.E., Interaction of APOE genotype and testosterone on episodic memory in middle-aged men. Neurobiol. Aging 35 (2014), 1778.e1–1778.e8.
223. Paoletti, A.M., Congia, S., Lello, S., Tedde, D., Orrù, M., Pistis, M., Pilloni, M., Zedda, P., Loddo, A., Melis, G.B., Low androgenization index in elderly women and elderly men with Alzheimer's disease. Neurology 62 (2004), 301–303.
224. Payami, H., Montee, K.R., Kaye, J.A., Bird, T.D., Yu, C.-E., Wijsman, E.M., Schellenberg, G.D., Alzheimer's disease, apolipoprotein E4, and gender. J. Am. Med. Assoc. 271 (1994), 1316–1317.
225. Pedroni, S.M.A., Turban, S., Kipari, T., Dunbar, D.R., McInnes, K., Saunders, P.T.K., Morton, N.M., Norman, J.E., Pregnancy in obese mice protects selectively against visceral adiposity and is associated with increased adipocyte estrogen signalling. PLoS One, 9, 2014, e94680.
226. Peila, R., Rodriguez, B.L., Launer, L.J., Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu–Asia Aging Study. Diabetes 51 (2002), 1256–1262.
227. Pereira, T.M., Teixeira, F., Aguilar, E., Matoso, R.O., Soares, F.L.P., Ferreira, A.F.B., Alvarez-Leite, J.I., Differences in adipose tissue inflammation and oxidative status in C57BL/6 and ApoE-/- mice fed high fat diet. Anim. Sci. J. 83 (2012), 549–555.
228. Pettersson, U.S., Waldén, T.B., Carlsson, P.-O., Jansson, L., Phillipson, M., Female mice are protected against high-fat diet induced metabolic syndrome and increase the regulatory T cell population in adipose tissue. PLoS One, 7, 2012, e46057.
229. Petty, K.H., Li, K., Dong, Y., Fortenberry, J., Stallmann-Jorgensen, I., Guo, D., Zhu, H., Sex dimorphisms in inflammatory markers and adiposity in African-American youth. Int. J. Pediatr. Obes. 5 (2010), 327–333.
230. Pfankuch, T., Rizk, A., Olsen, R., Poage, C., Raber, J., Role of circulating androgen levels in effects of apoE4 on cognitive function. Brain Res. 1053 (2005), 88–96.
231. Pike, C.J., Carroll, J.C., Rosario, E.R., Barron, A.M., Protective actions of sex steroid hormones in Alzheimer's disease. Front. Neuroendocrinol. 30 (2009), 239–258.
232. Planel, E., Tatebayashi, Y., Miyasaka, T., Liu, L., Wang, L., Herman, M., Yu, W.H., Luchsinger, J.A., Wadzinski, B., Duff, K.E., Takashima, A., Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J. Neurosci. 27 (2007), 13635–13648.
233. Pradhan, A.D., Sex differences in the metabolic syndrome: implications for cardiovascular health in women. Clin. Chem. 60 (2013), 44–52.
234. Premkumar, D.R., Cohen, D.L., Hedera, P., Friedland, R.P., Kalaria, R.N., Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer's disease. Am. J. Pathol. 148 (1996), 2083–2095.
235. Profenno, L.A., Porsteinsson, A.P., Faraone, S.V., Meta-analysis of Alzheimer's disease risk with obesity, diabetes, and related disorders. Biol. Psychiatry 67 (2010), 505–512.
236. Puig, J., Blasco, G., Daunis-i-Estadella, J., Molina, X., Xifra, G., Ricart, W., Pedraza, S., Fernández-Aranda, F., Fernández-Real, J.M., Hypothalamic damage is associated with inflammatory markers and worse cognitive performance in obese subjects. J. Clin. Endocrinol. Metab. 100 (2015), E276–E281.
237. Qizilbash, N., Gregson, J., Johnson, M.E., Pearce, N., Douglas, I., Wing, K., Evans, S.J.W., Pocock, S.J., BMI and risk of dementia in two million people over two decades: a retrospective cohort study. Lancet Diabetes Endocrinol. 3 (2015), 431–436.
238. Raber, J., Androgens, apoE, and Alzheimer's disease. Sci. Aging Knowl. Environ., 11, 2004, re2.
239. Raber, J., Bongers, G., LeFevour, A., Buttini, M., Mucke, L., Androgens protect against apolipoprotein E4-induced cognitive deficits. J. Neurosci. 22 (2002), 5204–5209.
240. Rafnsson, S.B., Deary, I.J., Smith, F.B., Whiteman, M.C., Rumley, A., Lowe, G.D.O., Fowkes, F.G.R., Cognitive decline and markers of inflammation and hemostasis: the Edinburgh Artery Study. J. Am. Geriatr. Soc. 55 (2007), 700–707.
241. Ragogna, F., Lattuada, G., Ruotolo, G., Luzi, L., Perseghin, G., Lack of association of apoE ɛ4 allele with insulin resistance. Acta Diabetol. 49 (2011), 25–32.
242. Ramos-Rodriguez, J.J., Ortiz, O., Jimenez-Palomares, M., Kay, K.R., Berrocoso, E., Murillo-Carretero, M.I., Perdomo, G., Spires-Jones, T., Cozar-Castellano, I., Lechuga-Sancho, A.M., Garcia-Alloza, M., Differential central pathology and cognitive impairment in pre-diabetic and diabetic mice. Psychoneuroendocrinology 38 (2013), 2462–2475.
243. Reinert, K.R.S., Po'e, E.K., Barkin, S.L., The relationship between executive function and obesity in children and adolescents: a systematic literature review. J. Obes. 2013 (2013), 1–10.
244. Ringman, J.M., Elashoff, D., Geschwind, D.H., Welsh, B.T., Gylys, K.H., Lee, C., Cummings, J.L., Cole, G.M., Plasma signaling proteins in persons at genetic risk for Alzheimer disease: influence of APOE genotype. Arch. Neurol. 69 (2012), 757–764.
245. Rippon, G.A., Tang, M.X., Lee, J.H., Lantigua, R., Medrano, M., Mayeux, R., Familial Alzheimer disease in Latinos: interaction between APOE, stroke, and estrogen replacement. Neurology 66 (2006), 35–40.
246. Ritzel, R.M., Capozzi, L.A., McCullough, L.D., Sex, stroke, and inflammation: the potential for estrogen-mediated immunoprotection in stroke. Horm. Behav. 63 (2013), 238–253.
247. Rodriguez, G.A., Tai, L.M., LaDu, M.J., Rebeck, G.W., Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition. J. Neuroinflamm., 11, 2014, 111.
248. Rontu, R., Ojala, P., Hervonen, A., Goebeler, S., Karhunen, P.J., Nikkila, M., Kunnas, T., Jylha, M., Eklund, C., Hurme, M., Lehtimaki, T., Apolipoprotein E genotype is related to plasma levels of C-reactive protein and lipids and to longevity in nonagenarians. Clin. Endocrinol. 64 (2006), 265–270.
249. Rosario, E.R., Carroll, J.C., Oddo, S., LaFerla, F.M., Pike, C.J., Androgens regulate the development of neuropathology in a triple transgenic mouse model of Alzheimer's disease. J. Neurosci. 26 (2006), 13384–13389.
250. Rosario, E.R., Chang, L., Head, E.H., Stanczyk, F.Z., Pike, C.J., Brain levels of sex steroid hormones in men and women during normal aging and in Alzheimer's disease. Neurobiol. Aging 32 (2011), 604–613.
251. Rosario, E.R., Chang, L., Stanczyk, F.Z., Pike, C.J., Age-related testosterone depletion and the development of Alzheimer disease. J. Am. Med. Assoc. 292 (2004), 1431–1432.
252. Ross, A.P., Bartness, T.J., Mielke, J.G., Parent, M.B., A high fructose diet impairs spatial memory in male rats. Neurobiol. Learn. Mem. 92 (2009), 410–416.
253. Rudnicka, A.R., Rumley, A., Whincup, P.H., Lowe, G.D., Strachan, D.P., Sex differences in the relationship between inflammatory and hemostatic biomarkers and metabolic syndrome: British 1958 Birth Cohort. J. Thromb. Haemost. 9 (2011), 2337–2344.
254. Ryan, J., Carrière, I., Scali, J., Dartigues, J.-F., Tzourio, C., Poncet, M., Ritchie, K., Ancelin, M.L., Characteristics of hormone therapy, cognitive function, and dementia: the prospective 3C study. Neurology 73 (2009), 1729–1737.
255. Samaras, K., Sachdev, P.S., Diabetes and the elderly brain: sweet memories?. Ther. Adv. Endocrinol. Metab. 3 (2012), 189–196.
256. Sastre, M., Walter, J., Gentleman, S.M., Interactions between APP secretases and inflammatory mediators. J. Neuroinflamm., 5, 2008, 25.
257. Saunders, A.M., Strittmatter, W.J., Schmechel, D., George-Hyslop, P.H., Pericak-Vance, M.A., Joo, S.H., Rosi, B.L., Gusella, J.F., Crapper-MacLachlan, D.R., Alberts, M.J., Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43 (1993), 1467–1472.
258. Schäfer, S., Wirths, O., Multhaup, G., Bayer, T.A., Gender dependent APP processing in a transgenic mouse model of Alzheimer's disease. J. Neural Transm. 114 (2006), 387–394.
259. Schram, M.T., Euser, S.M., De Craen, A.J.M., Witteman, J.C., Frölich, M., Hofman, A., Jolles, J., Breteler, M.M.B., Westendorp, R.G.J., Systemic markers of inflammation and cognitive decline in old age. J. Am. Geriatr. Soc. 55 (2007), 708–716.
260. Schulte, D., Hahn, M., Oberhäuser, F., Malchau, G., Schubert, M., Heppner, C., Müller, N., Güdelhöfer, H., Faust, M., Krone, W., Laudes, M., Caloric restriction increases serum testosterone concentrations in obese male subjects by two distinct mechanisms. Horm. Metab. Res. 46 (2014), 283–286.
261. Schwartz, D.H., Leonard, G., Perron, M., Richer, L., Syme, C., Veillette, S., Pausova, Z., Paus, T., Visceral fat is associated with lower executive functioning in adolescents. Int. J. Obes. Relat. Metab. Disord. 37 (2013), 1336–1343.
262. Schwinge, D., Carambia, A., Quaas, A., Krech, T., Wegscheid, C., Tiegs, G., Prinz, I., Lohse, A.W., Herkel, J., Schramm, C., Testosterone suppresses hepatic inflammation by the downregulation of IL-17, CXCL-9, and CXCL-10 in a mouse model of experimental acute cholangitis. J. Immunol. 194 (2015), 2522–2530.
263. Selkoe, D.J., Alzheimer's disease. Cold Spring Harb. Perspect. Biol., 3, 2011 (a004457–a004457).
264. Sharp, E.S., Gatz, M., Relationship between education and dementia. Alzheimer Dis. Assoc. Disord. 25 (2011), 289–304.
265. Shen, L., Tso, P., Woods, S.C., Clegg, D.J., Barber, K.L., Carey, K., Liu, M., Brain apolipoprotein E: an important regulator of food intake in rats. Diabetes 57 (2008), 2092–2098.
266. Sheng, J.G., Bora, S.H., Xu, G., Borchelt, D.R., Price, D.L., Koliatsos, V.E., Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid β peptide in APPswe transgenic mice. Neurobiol. Dis. 14 (2003), 133–145.
267. Shi, H., Clegg, D.J., Sex differences in the regulation of body weight. Physiol. Behav. 97 (2009), 199–204.
268. Sima, A., Iordan, A., Stancu, C., Apolipoprotein E polymorphism—a risk factor for metabolic syndrome. Clin. Chem. Lab. Med. 45 (2007), 1149–1153.
269. Simpson, E., Jones, M., Misso, M., Hewitt, K., Hill, R., maffei, L., Carani, C., Boon, W.C., Estrogen, a fundamental player in energy homeostasis. J. Steroid Biochem. Mol. Biol. 95 (2005), 3–8.
270. Singh, T., Newman, A.B., Inflammatory markers in population studies of aging. Ageing Res. Rev. 10 (2011), 319–329.
271. Soczynska, J.K., Kennedy, S.H., Woldeyohannes, H.O., Liauw, S.S., Alsuwaidan, M., Yim, C.Y., McIntyre, R.S., Mood disorders and obesity: understanding inflammation as a pathophysiological nexus. Neuromol. Med. 13 (2010), 93–116.
272. Spence, R.D., Voskuhl, R.R., Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration. Front. Neuroendocrinol. 33 (2012), 105–115.
273. Stellato, R.K., Feldman, H.A., Hamdy, O., Horton, E.S., McKinlay, J.B., Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care 23 (2000), 490–494.
274. Stone, D.J., Rozovsky, I., Morgan, T.E., Anderson, C.P., Hajian, H., Finch, C.E., Astrocytes and microglia respond to estrogen with increased apoE mRNA in vivo and in vitro. Exp. Neurol. 143 (1997), 313–318.
275. Strachan, M.W.J., Reynolds, R.M., Marioni, R.E., Price, J.F., Cognitive function, dementia and type 2 diabetes mellitus in the elderly. Nat. Rev. Endocrinol. 7 (2011), 108–114.
276. Stranahan, A.M., Norman, E.D., Lee, K., Cutler, R.G., Telljohann, R.S., Egan, J.M., Mattson, M.P., Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats. Hippocampus 18 (2008), 1085–1088.
277. Strittmatter, W.J., Saunders, A.M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G.S., Roses, A.D., 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 90 (1993), 1977–1981.
278. Struble, R.G., Nathan, B.P., Cady, C., Cheng, X., McAsey, M., Estradiol regulation of astroglia and apolipoprotein E: an important role in neuronal regeneration. Exp. Gerontol. 42 (2007), 54–63.
279. Stubbins, R.E., Najjar, K., Holcomb, V.B., Hong, J., Núñez, N.P., Oestrogen alters adipocyte biology and protects female mice from adipocyte inflammation and insulin resistance. Diabetes, Obes. Metab. 14 (2011), 58–66.
280. Sugiyama, M.G., Agellon, L.B., Sex differences in lipid metabolism and metabolic disease risk. Biochem. Cell Biol. 90 (2012), 124–141.
281. Syme, C., Abrahamowicz, M., Leonard, G.T., Perron, M., Pitiot, A., Qiu, X., Richer, L., Totman, J., Veillette, S., Xiao, Y., Gaudet, D., Paus, T., Pausova, Z., Intra-abdominal adiposity and individual components of the metabolic syndrome in adolescence: sex differences and underlying mechanisms. Arch. Pediatr. Adolesc. Med. 162 (2008), 453–461.
282. Takalo, M., Haapasalo, A., Martiskainen, H., Kurkinen, K.M.A., Koivisto, H., Miettinen, P., Khandelwal, V.K.M., Kemppainen, S., Kaminska, D., Mäkinen, P., Leinonen, V., Pihlajamäki, J., Soininen, H., Laakso, M., Tanila, H., Hiltunen, M., High-fat diet increases tau expression in the brain of T2DM and AD mice independently of peripheral metabolic status. J. Nutr. Biochem. 25 (2014), 634–641.
283. Takechi, R., Pallebage-Gamarallage, M.M., Lam, V., Giles, C., Mamo, J.C., Aging-related changes in blood–brain barrier integrity and the effect of dietary fat. Neurodegener. Dis. 12 (2013), 125–135.
284. Takeda, K., Toda, K., Saibara, T., Nakagawa, M., Saika, K., Onishi, T., Sugiura, T., Shizuta, Y., Progressive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency. J. Endocrinol. 176 (2003), 237–246.
285. Takeda, S., Sato, N., Uchio-Yamada, K., Sawada, K., Kunieda, T., Takeuchi, D., Kurinami, H., Shinohara, M., Rakugi, H., Morishita, R., Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes. Proc. Natl. Acad. Sci. USA 107 (2010), 7036–7041.
286. Taki, Y., Kinomura, S., Sato, K., Inoue, K., Goto, R., Okada, K., Uchida, S., Kawashima, R., Fukuda, H., Relationship between body mass index and gray matter volume in 1,428 healthy individuals. Obesity 16 (2008), 119–124.
287. Tan, Z.S., Beiser, A.S., Vasan, R.S., Roubenoff, R., Dinarello, C.A., Harris, T.B., Benjamin, E.J., Au, R., Kiel, D.P., Wolf, P.A., Seshadri, S., Inflammatory markers and the risk of Alzheimer disease: the Framingham Study. Neurology 68 (2007), 1902–1908.
288. Tanzi, R.E., The genetics of Alzheimer disease. Cold Spring Harb. Perspect. Med., 2, 2012, a006296.
289. Thaler, J.P., Schwartz, M.W., Minireview: inflammation and obesity pathogenesis: the hypothalamus heats up. Endocrinology 151 (2010), 4109–4115.
290. Thaler, J.P., Yi, C.-X., Schur, E.A., Guyenet, S.J., Hwang, B.H., Dietrich, M.O., Zhao, X., Sarruf, D.A., Izgur, V., Maravilla, K.R., Nguyen, H.T., Fischer, J.D., Matsen, M.E., Wisse, B.E., Morton, G.J., Horvath, T.L., Baskin, D.G., Tschöp, M.H., Schwartz, M.W., Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122 (2012), 153–162.
291. Thorand, B., Baumert, J., Kolb, H., Meisinger, C., Chambless, L., Koenig, W., Herder, C., Sex Differences in the prediction of type 2 diabetes by inflammatory markers: results from the MONICA/KORA Augsburg case-cohort study, 1984–2002. Diabetes Care 30 (2007), 854–860.
292. Tolppanen, A.-M., Solomon, A., Kulmala, J., Kåreholt, I., Ngandu, T., Rusanen, M., Laatikainen, T., Soininen, H., Kivipelto, M., Leisure-time physical activity from mid- to late life, body mass index, and risk of dementia. Alzheimer's Dement. 11 (2015), 434–443 (e6).
293. Trollor, J.N., Smith, E., Agars, E., Kuan, S.A., Baune, B.T., Campbell, L., Samaras, K., Crawford, J., Lux, O., Kochan, N.A., Brodaty, H., Sachdev, P., The association between systemic inflammation and cognitive performance in the elderly: the Sydney Memory and Ageing Study. Age 34 (2011), 1295–1308.
294. Trollor, J.N., Smith, E., Baune, B.T., Kochan, N.A., Campbell, L., Samaras, K., Crawford, J., Brodaty, H., Sachdev, P., Systemic inflammation is associated with MCI and its subtypes: the Sydney Memory and Aging Study. Dement. Geriatr. Cogn. Disord. 30 (2010), 569–578.
295. Tsilidis, K.K., Rohrmann, S., McGlynn, K.A., Nyante, S.J., Lopez, D.S., Bradwin, G., Feinleib, M., Joshu, C.E., Kanarek, N., Nelson, W.G., Selvin, E., Platz, E.A., Association between endogenous sex steroid hormones and inflammatory biomarkers in US men. Andrology 1 (2013), 919–928.
296. Ueda, H., Ikegami, H., Yamato, E., Fu, J., Fukuda, M., Shen, G., Kawaguchi, Y., Takekawa, K., Fujioka, Y., Fujisawa, T., The NSY mouse: a new animal model of spontaneous NIDDM with moderate obesity. Diabetologia 38 (1995), 503–508.
297. van Exel, E., Eikelenboom, P., Comijs, H., Frölich, M., Smit, J.H., Stek, M.L., Scheltens, P., Eefsting, J.E., Westendorp, R.G.J., Vascular factors and markers of inflammation in offspring with a parental history of late-onset Alzheimer disease. Arch. Gen. Psychiatry 66 (2009), 1263–1270.
298. Vegeto, E., Belcredito, S., Etteri, S., Ghisletti, S., Brusadelli, A., Meda, C., Krust, A., Dupont, S., Ciana, P., Chambon, P., Maggi, A., Estrogen receptor-alpha mediates the brain antiinflammatory activity of estradiol. Proc. Natl. Acad. Sci. USA 100 (2003), 9614–9619.
299. Vegeto, E., Benedusi, V., Maggi, A., Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases. Front. Neuroendocrinol. 29 (2008), 507–519.
300. Vest, R.S., Pike, C.J., Gender, sex steroid hormones, and Alzheimer's disease. Horm. Behav. 63 (2013), 301–307.
301. Vignozzi, L., Morelli, A., Sarchielli, E., Comeglio, P., Filippi, S., Cellai, I., Maneschi, E., Serni, S., Gacci, M., Carini, M., Piccinni, M.P., Saad, F., Adorini, L., Vannelli, G.B., Maggi, M., Testosterone protects from metabolic syndrome-associated prostate inflammation: an experimental study in rabbit. J. Endocrinol. 212 (2011), 71–84.
302. Viscogliosi, G., Andreozzi, P., Chiriac, I.M., Cipriani, E., Servello, A., Marigliano, B., Ettorre, E., Marigliano, V., Depressive symptoms in older people with metabolic syndrome: is there a relationship with inflammation?. Int. J. Geriatr. Psychiatry 28 (2012), 242–247.
303. Vitek, M.P., Brown, C.M., Colton, C.A., APOE genotype-specific differences in the innate immune response. Neurobiol. Aging 30 (2009), 1350–1360.
304. Walker, L.C., Pahnke, J., Madauss, M., Vogelgesang, S., Pahnke, A., Herbst, E.W., Stausske, D., Walther, R., Kessler, C., Warzok, R.W., Apolipoprotein E4 promotes the early deposition of Aβ42 and then Aβ40 in the elderly. Acta Neuropathol. 100 (2000), 36–42.
305. Wang, G.-J., Volkow, N.D., Telang, F., Jayne, M., Ma, Y., Pradhan, K., Zhu, W., Wong, C.T., Thanos, P.K., Geliebter, A., Biegon, A., Fowler, J.S., Evidence of gender differences in the ability to inhibit brain activation elicited by food stimulation. Proc. Natl. Acad. Sci. USA 106 (2009), 1249–1254.
306. Wang, J., Perrard, X.D., Perrard, J.L., Mukherjee, A., Rosales, C., Chen, Y., Smith, C.W., Pownall, H.J., Ballantyne, C.M., Wu, H., ApoE and the role of very low density lipoproteins in adipose tissue inflammation. Atherosclerosis 223 (2012), 342–349.
307. Wang, J.M., Irwin, R.W., Brinton, R.D., Activation of estrogen receptor alpha increases and estrogen receptor beta decreases apolipoprotein E expression in hippocampus in vitro and in vivo. Proc. Natl. Acad. Sci. USA 103 (2006), 16983–16988.
308. Wang, P., Menheere, P.P.C.A., Astrup, A., Andersen, M.R., van Baak, M.A., Larsen, T.M., Jebb, S., Kafatos, A., Pfeiffer, A.F.H., Martinez, J.A., Handjieva-Darlenska, T., Hlavaty, P., Viguerie, N., Langin, D., Saris, W.H.M., Mariman, E.C.M., Diogenes consortium, Metabolic syndrome, circulating RBP4, testosterone, and SHBG predict weight regain at 6 months after weight loss in men. Obesity 21 (2013), 1997–2006.
309. Wang, X., Zheng, W., Xie, J.-W., Wang, T., Wang, S.-L., Teng, W.-P., Wang, Z.-Y., Insulin deficiency exacerbates cerebral amyloidosis and behavioral deficits in an Alzheimer transgenic mouse model. Mol. Neurodegen., 5, 2010 (46–46).
310. Ward, A., Crean, S., Mercaldi, C.J., Collins, J.M., Boyd, D., Cook, M.N., Arrighi, H.M., Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer's disease: a systematic review and meta-analysis. Neuroepidemiology 38 (2012), 1–17.
311. Weisberg, S.P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R.L., Ferrante, A.W. Jr., Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112 (2003), 1796–1808.
312. White, U.A., Tchoukalova, Y.D., Sex dimorphism and depot differences in adipose tissue function. Biochem. Biophys. Acta 1842 (2014), 377–392.
313. Whitmer, R.A., Gunderson, E.P., Quesenberry, C.P., Zhou, J., Yaffe, K., Body mass index in midlife and risk of Alzheimer disease and vascular dementia. Curr. Alzheimer Res. 4 (2007), 103–109.
314. Whitmer, R.A., Gustafson, D.R., Barrett-Connor, E., Haan, M.N., Gunderson, E.P., Yaffe, K., Central obesity and increased risk of dementia more than three decades later. Neurology 71 (2008), 1057–1064.
315. Wolf, A.B., Braden, B.B., Bimonte-Nelson, H., Kusne, Y., Young, N., Engler-Chiurazzi, E., Garcia, A.N., Walker, D.G., Moses, G.S.D., Tran, H., LaFerla, F., Lue, L., Lombardo, N.E., Valla, J., Broad-based nutritional supplementation in 3xTg mice corrects mitochondrial function and indicates sex-specificity in response to Alzheimer's disease intervention. J. Alzheimer's Dis. 32 (2012), 217–232.
316. Wyss-Coray, T., Rogers, J., Inflammation in Alzheimer disease—a brief review of the basic science and clinical literature. Cold Spring Harb. Perspect. Med., 2, 2012 (a006346–a006346).
317. Xing, Y., Qin, W., Li, F., Jia, X.-F., Jia, J., Apolipoprotein E ɛ4 status modifies the effects of sex hormones on neuropsychiatric symptoms of Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 33 (2012), 35–42.
318. Xu, W.L., Atti, A.R., Gatz, M., Pedersen, N.L., Johansson, B., Fratiglioni, L., Midlife overweight and obesity increase late-life dementia risk a population-based twin study. Neurology 76 (2011), 1568–1574.
319. Yaffe, K., Haan, M.N., Byers, A., Tangen, C., Kuller, L., Estrogen use APOE, and cognitive decline: evidence of gene-environment interaction. Neurology 54 (2000), 1949–1954.
320. Yaffe, K., Lindquist, K., Penninx, B.W., Simonsick, E.M., Pahor, M., Kritchevsky, S., Launer, L., Kuller, L., Rubin, S., Harris, T., Inflammatory markers and cognition in well-functioning African-American and white elders. Neurology 61 (2003), 76–80.
321. Yan, Q., Zhang, J., Liu, H., Babu-Khan, S., Vassar, R., Biere, A.L., Citron, M., Landreth, G., Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J. Neurosci. 23 (2003), 7504–7509.
322. Yang, H.-T., Sheen, Y.-J., Kao, C.-D., Chang, C.-A., Hu, Y.-C., Lin, J.-L., Association between the characteristics of metabolic syndrome and Alzheimer's disease. Metab. Brain Dis. 28 (2013), 597–604.
323. Yang, Y., Ruiz-Narvaez, E., Kraft, P., Campos, H., Effect of apolipoprotein E genotype and saturated fat intake on plasma lipids and myocardial infarction in the central valley of Costa Rica. Hum. Biol. 79 (2007), 637–647.
324. Yassin, D.-J., Doros, G., Hammerer, P.G., Yassin, A.A., Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life. J. Sex Med. 11 (2014), 1567–1576.
325. Yau, P.L., Castro, M.G., Tagani, A., Tsui, W.H., Convit, A., Obesity and metabolic syndrome and functional and structural brain impairments in adolescence. Pediatrics 130 (2012), e856–e864.
326. Yip, A.G., McKee, A.C., Green, R.C., Wells, J., Young, H., Cupples, L.A., Farrer, L.A., APOE, vascular pathology, and the AD brain. Neurology 65 (2005), 259–265.
327. Yoon, D.H., Choi, S.H., Yu, J.H., Ha, J.H., Ryu, S.H., Park, D.H., The relationship between visceral adiposity and cognitive performance in older adults. Age Ageing 41 (2012), 456–461.
328. Yoshitake, T., Kiyohara, Y., Kato, I., Ohmura, T., Iwamoto, H., Nakayama, K., Ohmori, S., Nomiyama, K., Kawano, H., Ueda, K., Incidence and risk factors of vascular dementia and Alzheimer's disease in a defined elderly Japanese population: the Hisayama Study. Neurology 45 (1995), 1161–1168.
329. Youmans, K.L., Tai, L.M., Nwabuisi-Heath, E., Jungbauer, L., Kanekiyo, T., Gan, M., Kim, J., Eimer, W.A., Estus, S., Rebeck, G.W., Weeber, E.J., Bu, G., Yu, C., LaDu, M.J., APOE4-specific changes in amyloid-beta accumulation in a new transgenic mouse model of Alzheimer disease. J. Biol. Chem. 287 (2012), 41774–41786.
330. Yue, X., Lu, M., Lancaster, T., Cao, P., Honda, S.-I., Staufenbiel, M., Harada, N., Zhong, Z., Shen, Y., Li, R., Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer's disease animal model. Proc. Natl. Acad. Sci. USA 102 (2005), 19198–19203.
331. Zade, D., Beiser, A., McGlinchey, R., Au, R., Seshadri, S., Palumbo, C., Wolf, P.A., DeCarli, C., Milberg, W., Apolipoprotein epsilon 4 allele modifies waist-to-hip ratio effects on cognition and brain structure. J. Stroke Cerebrovasc. Dis. 22 (2013), 119–125.
332. Zandi, P.P., Anthony, J.C., Hayden, K.M., Mehta, K., Mayer, L., Breitner, J.C.S., Breitner, J.C.S., Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study. Neurology 59 (2002), 880–886.
333. Zarkesh, M., Daneshpour, M.S., Faam, B., Hedayati, M., Azizi, F., Is there any association of apolipoprotein E gene polymorphism with obesity status and lipid profiles? Tehran lipid and glucose study (TLGS). Gene 509 (2012), 282–285.
334. Zempel, H., Mandelkow, E., Lost after translation: missorting of tau protein and consequences for Alzheimer disease. Trends Neurosci. 37 (2014), 721–732.
335. Zerbi, V., Jansen, D., Wiesmann, M., Fang, X., Broersen, L.M., Veltien, A., Heerschap, A., Kiliaan, A.J., Multinutrient diets improve cerebral perfusion and neuroprotection in a murine model of Alzheimer's disease. Neurobiol. Aging 35 (2014), 600–613.
336. Zeyda, M., Stulnig, T.M., Obesity, inflammation, and insulin resistance—a mini-review. Gerontology 55 (2009), 379–386.
337. Zhang, Y., Gao, Y., Tan, A., Yang, X., Zhang, H., Zhang, S., Wu, C., Lu, Z., Wang, M., Liao, M., Qin, X., Li, L., Hu, Y., Mo, Z., Endogenous sex hormones and C-reactive protein in healthy chinese men. Clin. Endocrinol. 78 (2012), 60–66.
338. Zhao, J., Zhai, L., Liu, Z., Wu, S., Xu, L., Leptin level and oxidative stress contribute to obesity-induced low testosterone in Murine testicular tissue. Oxid. Med. Cell. Longev. 2014 (2014), 1–14.
339. Zhao, L., Lin, S., Bales, K.R., Gelfanova, V., Koger, D., Delong, C., Hale, J., Liu, F., Hunter, J.M., Paul, S.M., Macrophage-mediated degradation of beta-amyloid via an apolipoprotein E isoform-dependent mechanism. J. Neurosci. 29 (2009), 3603–3612.
340. Ziko, I., De Luca, S., Dinan, T., Barwood, J.M., Sominsky, L., Cai, G., Kenny, R., Stokes, L., Jenkins, T.A., Spencer, S.J., Neonatal overfeeding alters hypothalamic microglial profiles and central responses to immune challenge long-term. Brain Behav. Immun. 41 (2014), 32–43.
341. Zitzmann, M., Testosterone deficiency, insulin resistance and the metabolic syndrome. Nat. Rev. Endocrinol. 5 (2009), 673–681.
342. Zlokovic, B.V., Cerebrovascular effects of apolipoprotein E. J. Am. Med. Assoc. Neurol., 70, 2013, 440.
343. Zoth, N., Weigt, C., Laudenbach-Leschowski, U., Diel, P., Physical activity and estrogen treatment reduce visceral body fat and serum levels of leptin in an additive manner in a diet induced animal model of obesity. J. Steroid Biochem. 122 (2010), 100–105.