Sansores-España LD, Morales F, Arriola-Pacheco F, Astorga J, Paula-Lima A, Carrillo-Ávila A, Melgar-Rodríguez S, Martínez-Aguilar V, Díaz-Zúñiga J

Idioma: Ingles.
Referencias bibliográficas: 88
Paginas: 156-176
Archivo PDF: 449.10 Kb.

RESUMEN

La periodontitis es una enfermedad crónica no transmisible que se caracteriza por generar una inflamación sistémica de bajo grado causada por una microbiota disbiótica subgingival. Múltiples estudios han determinado la mayor prevalencia de pérdida de dientes y mala higiene bucal en pacientes con enfermedad de Alzheimer (EA). Sin embargo, el diagnóstico periodontal, bacterias periodontales o mediadores pro-inflamatorio no se ha medido hasta la fecha. Determinar el estado periodontal, los mediadores pro-inflamatorios, la carga de Porphyromonas gingivalis y la apoliporpoteína E (ApoE) en pacientes con EA. Se realizó un examen odontológico completo en 30 pacientes y el estado cognitivo se determinó mediante la Evaluación Cognitiva de Montreal (MoCA). Luego, se tomaron muestras de microbiota subgingival y FCG de todos los pacientes de los sitios más profundos. Se aisló el DNA total de las muestras de microbiota para la cuantificación de la subunidad ribosómica 16S. Los mediadores pro-inflamatorios y la ApoE se cuantificaron a partir del líquido crevicular gingival (GCF). Los pacientes con EA tenían periodontitis en estadio III-IV en 80%, una mayor concentración de mediadores pro-inflamatorios y ApoE, y una mayor carga de P. gingivalis en comparación con los sujetos sanos. Los mediadores pro-inflamatorios y la carga de P. gingivalis tuvieron una correlación negativa con las puntuaciones de la prueba MoCA. Finalmente, se realizó una curva ROC para evaluar la especificidad y sensibilidad de los niveles de ApoE, detectando un área del 84,9%. En los pacientes con EA encontramos una periodontitis más severa, mayores niveles de mediadores pro-inflamatorios y mayor carga bacteriana. Además, un aumento de ApoE que permite determinar claramente a los pacientes con salud, periodontitis y periodontitis y EA.

REFERENCIAS (EN ESTE ARTÍCULO)

1. Cecoro G., Annunziata M., Iuorio M.T., Nastrii L., Guida L. Periodontitis, Low-Grade inflammation and systemic health: a scoping review. Medicina (Kaunas). 2020; 56 (6): 272.

2. Hajishengallis G. Immuno-microbial pathogenesis of periodontitis: Keystones, pathobionts, and the host response. Trends Immunol. 2014; 35 (1): 3-11.

3. Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nature Reviews Immunology. 2015; 15 (1): 30-44.

4. Teixeira F.C.F., Marin-Leon L., Gomes E.P., Pedrao A.M.N., Pereira A.C., Francisco P.M.S.B. Relationship between periodontitis and subclinical risk indicators for chronic non-communicable diseases. Brazilian Oral Research. 2020; 34: 058.

5. Imamura T., Pike R.N., Potempa J., Travis J. Pathogenesis of periodontitis: a major arginine-specific cysteine proteinase from Porphyromonas gingivalis induces vascular permeability enhancement through activation of the kallikrein/kinin pathway. Journal of Clinical Investigation. 1994; 94 (1): 361-7.

6. Laine M.L., Applemelk B.J., van Winkelhoff A.J. Prevalence and distribution of six capsular serotypes of Porphyromonas gingivalis in periodontitis patients. Journal for Dental Research. 1997; 76 (12): 1840-4.

7. van Winkelhoff A.J., Loos B.G., van der Reijden W.A., van der Velden U. Porphyromonas gingivalis, Bacteroides forsythus and other putative periodontal pathogens in subjects with and without periodontal destruction. Journal of Clinical Periodontology. 2002; 29 (11): 1023-8.

8. López N., Smith P., Gutierrez J. Periodontal therapy may reduce the risk of preterm low birth weight in women with periodontal disease: A randomized controlled trial. Journal of Periodontology. 2002; 73 (8): 911-24.

9. López N., Silva I.D., Ipinza J., Gutierrez J. Periodontal therapy reduces the rate of preterm low birth weight women with pregnancy-associates gingivitis. Journal of Periodontology. 2005; 76 (11 Suppl): 2144-53.

10. Marcelino S.L., Gaetti-Jardim E.J., Nakano V., Canonico L.A.D., Nunes F.D., Lotufo R.F.M., et al. Presence of periodontopathic bacteria in coronary arteries from patients with chronic periodontitis. Anaerobe. 2010; 16 (6): 629-32.

11. Szulc M., Kustrzycki W., Janczak D., Michalowska D., Baczynska D., Radwan- Oczko M. Presence of periodontopathic bacteria DNA in atheromatous plaques from coronary and carotid arteries. Biomedical Research International. 2015; 2015: 825397.

12. Udagawa S., Katagiri S., Maekawa S., Takeuchi Y., Komazaki R., Ohtsu A., et al. Effect of Porphyromonas gingivalis infection in the placenta and umbilical cord in pregnant mice with low birth weight. Acta Odontologica Scandinavica. 2018; 76 (6): 433-41.

13. Vanterpool S.F., Been J.V., Houben M.L., Nikkels P.G., De Krijger R.R., Zimmermann L.J., et al. Porphyromonas gingivalis within placental villous mesenchyme and umbilical cord stroma is associated with adverse pregnancy outcome. PLoS One. 2016; 11 (1): e0146157.

14. Dominy S.S., Lynch C., Ermini F., Benedyk M., Marczyk A., Konradi A., et al. Porphyromons gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Science Advances. 2019; 5 (1): eaau3333.

15. Poole S., Singhrao S.K., Kesavalu L., Curtis M.A., Crean S. Determining the presence of periodontopathic virulence factors in shortterm postmortem Alzheimer’s diseas brain tissue. Journal of Alzheimers Disease. 2013; 36 (4): 665-77

16. Selkoe D.J., Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Molecular Medicine. 2016; 8 (6): 595-608.

17. Bayer T.A., Wirths O. Focusing the amyloid cascade hypothesis on N-truncated Abeta peptides as drug targets against Alzheimer's disease. Acta Neuropathologica. 2014; 127 (6): 787-801.

18. Tse K.H., Herrup K. Re-imagining Alzheimer's disease - the diminishing importance of amyloid and a glimpse of what lies ahead. Journal of Neurochemistry. 2017; 143 (4): 432-44.

19. Fulop T., Witkowski J.M., Bourgade K., Khalil A., Zerif E., Larbi A., et al. Can an infection hypothesis explain the Beta amyloid hypothesis of Alzheimer’s disease? Frontiers in Aging Neuroscience. 2018; 10 (224).

20. Pritchard A.B., Crean S, Olsen I., Singhrao S.K. Periodontitis, Microbiomes and their Role in Alzheimer's Disease. Frontiers in Aging Neuroscience. 2017; 24 (9): 336. doi: 10.3389/fnagi.2017.00336

21. Díaz-Zúñiga J., More J., Melgar-Rodríguez S., Jiménez-Unión M., Villalobos-Orchard F., Muñoz-Manríquez C., et al. Alzheimer’s Disease-Like pathology triggered by Porphyromonas gingivalis in wild type rats is serotype dependent. Frontiers in Immunology. 2020; 11 (588036).

22. Ding Y., Ren J., Yu H., Yu W., Zhou Y. Porphyromonas gingivalis, a periodontitis causing bacterium, induces memory impairment and age-dependent neuroinflammation in mice. Immunity Ageing. 2018; 15 (6).

23. Ishida N., Ishihara Y., Ishida K., Tada H., Funaki-Kato Y., Hagiwara M., et al. Periodontitis induced by bacterial infection exacerbates features of Alzheimer’s disease in transgenic mice. NPJ Aging and Mechanisms of Disease. 2017; 3 (15).

24. Leira Y., Iglesias-Rey R., Gómez-Lado N., Aguiar P., Campos F., d’Aiuto F., et al. Porphyromonas gingivalis lipopolysaccharide-induced periodontitis and serum amyloid-neta peptides. Archives in Oral Biology. 2019; 99: 120-5.

25. Poole S., Singhrao S.K., Chukkapalli S., Rivera M., Velsko I., Kesavalu L., et al. Active invasion of Porphyromonas gingivalis and infection-induced complement activation in ApoE-/- mice brains. Journal of Alzheimers Disease. 2015; 43 (1): 67-80.

26. Wu Z., Ni J., Liu Y., Teeling J.L., Takayama F., Collcutt A., et al. Cathepsin B plays a critical role in inducing Alzheimer's disease-like phenotypes following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis in mice. Brain, Behaviour, and Immunity. 2017; 65: 350-61.

27. Zhang J., Yu C., Zhang X., Chen H., Dong J., Lu W., et al. Porphyromonas gingivalis lipopolysaccharide induces cognitive dysfunction, mediated by neuronal inflammation via activation of the TLR4 signaling pathway in C57BL/6 mice. Journal of Neuroinflammation. 2018; 15 (1): 37-52.

28. Lane C.A., Hardy J., Scott J.M. Alzheimer’s disease. European Journal of Neurology. 2017; 25 (1): 59-70.

29. Frost G.R., Li Y.M. The role of astrocytes in amyloid production and Alzheimer’s disease. Open Biology. 2017; 7: 170228.

30. Ritchie C., Smailagic N., Noel-Storr A.H., Ukuomunne O., Ladds E.C., Martin S. CSF tau and the CSF tau/ABeta ratio for the diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Systematic Review. 2017; 3 (3): CD10803.

31. Limon-Sztencel A., Lipska-Zietkiewicz B.S., Chmara M., Wasag B., Bidzan L., Godlewska B.R., et al. The algorithm for Alzheimer risk assessment based on APOE promoter polymorphisms. Alzheimers Research & Therapy. 2016; 8 (1): 19.

32. Liu C.C., Zhao N., Fu Y., Wang N., Linares C., Tsai C.W., et al. ApoE4 accelerates early seeding of amyloid pathology. Neuron Reports. 2017; 96 (5): 1024-32.

33. Singhrao S.K., Harding A., Chukkapalli S., Olsen I., Kesavalu L., Crean S. Apolipoprotein E related co-morbidities and Alzheimer’s Disease. Journal of Alzheimer’s Disease. 2016; 51 (4): 935-48.

34. McKhann G.M., Knopman D.S., Chertkow H., Hyman B.T., Jack Jr. C.R., Kawas C.H., et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia. 2011; 7 (3): 263-9.

35. Papapanou P.N., Sanz M., Buduneli N., Dietrich T., Feres M., Fine D.H., et al. Periodontitis: Consensus report of workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. Journal of Clinical Periodontology. 2018; 45: S162-S70.

36. Tonetti M.S., Greenwell H., Kornman K.S. Staging and grading of periodontitis: framework and proposal of a new classification and case definition. Journal of Periodontology. 2018; 89:159-72.

37. Abusleme L., Dupuy A.K., Dutzan N., Silva N., Burleson J.A., Strausbaugh L.D., et al. The subgingival microbiome in health and periodontitis and its relationship with community biomass and inflammation. International Society for Microbiological Ecology Journal. 2013; 7: 1016-25.

38. Ovalle A., Gamonal J., Martínez M.A., Silva N., Kakarieka E., Fuentes A., et al. Relationship between periodontal diseases and ascending bacterial infection with preterm delivery. Revista Médica de Chile. 2009; 137: 504-14.

39. Vernal R., Dutzan N., Chaparro A., Puente J., Valenzuela M., Gamonal J. Levels of interleukin-17 in gingival crevicular fluid and in supernatants of cellular cultures of gingival tissue from patients with chronic periodontitis. Journal of Clinical Periodontology. 2005; 32 (4): 383-9.

40. Aragón F., Zea-Sevilla M.A., Montero J., Sancho P., Corral R., Tejedor C., et al. Oral health in Alzheimer’s disease: a multicenter case-control study. Clinical Oral Investigations. 2018; 22: 3061-70.

41. Chen X., Shuman S.K., Hodges J.S., Gatewood L.C., Xu J. Patterns of tooth loss in older adults with and without dementia: a retrospective study based on a Minnesota Cohort. Journal of the American Geriatrics Society. 2010; 58 (12): 2300-7.

42. Chen X., Clark J.J.J., Naorungroj S. Oral health in nursing home residents with different cognitive statuses. Gerodontology. 2012; 30 (1): 49-60.

43. Chen C.K., Wu Y.T., Chang Y.C. Association between chronic periodontitis and the risk of Alzheimer’s disease: a retrospective, population-based, matched-cohort study. Alzheimer’s Research Therapy. 2017; 9 (1): 56-62.

44. Gil Montoya J.A., Barrios R., Sanchez- Lara I., Ramos P., Carnero C., Fornieles F., et al. Systemic inflammatory impact of periodontitis on cognitive impairment. Gerodontology. 2019; 37 (1): 11-8.

45. Hatipoglu M.G., Kabay S.C., Güven G. The clinical evaluation of the oral status in Alzheimer-type dementia patients. Gerodontology. 2011; 28 (4): 302-6.

46. Laugisch O., Johnen A., Buergin W., Eick S., Ehmke B., Duning T., et al. Oral and periodontal health in patients with Alzhiemer’s disease and other forms of dementia - A cross-sectional pilot study. Oral Health and Preventie Dentistry. 2021; 19 (1): 255-61.

47. Martande S.S., Pradeep A.R., Singh S.P., Kumari M., Suke D.K., Raju A.P., et al. Periodontal health condition in patients with Alzheimer's disease. American Journal of Alzheimer's Disease and Other Dementias. 2014; 29 (6): 498-502.

48. Noble J.M., Borrell L.N., Papapnou P.N., Elkind M.S.V., Scarmeas N., Wright C.B. Periodontitis is associated with cognitive impairment among older adults: Analysis of NHANES-III. Journal of Neurology, Neurosurgery, and Psychiatry. 2009; 80 (11): 1206-11.

49. Noble J.M., Scarmeas N., Celenti R.S., Elkind M.S., Wright C.B., Schupf N., et al. Serum IgG antibody levels to periodontal microbiota are associated with incident Alzheimer disease. PLoS One. 2014; 9 (12): e114959.

50. Ribeiro G.R., Costa J.L.C., Ambrosano G.M.B., Garcia R.C.M.R. Oral health of the elderly with Alzheimer’s disease. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology. 2012; 114( 3): 338-43.

51. Rong X., Xiang L., Li Y., Yang H., Chen W., Li L., et al. Chronic periodontitis and Alzheimer disease: a putative link of serum proteins identification by 2S-DIGE proteomics. Frontiers in Aging Neuroscience. 2020; 12: 248.

52. Srisilapanan P., Jai-ua C. Oral health status of dementia patients in Chiang Mai Neurological Hospital. Journal of the Medical Association of Thailand. 2013; 96 (3): 351-7.

53. Syrjälä A.M.H., Ylöstalo P., Ruoppi P., Komulainen K., Hartikainen S., Sulkava R., et al. Dementia and oral health among subjects aged 75 years or older. Gerodontology. 2012; 29 (1): 36-42.

54. Tiisanoja A., Syrjälä A.M.H., Tertsonen M., Komulainen K., Pesonen P., Knuuttila M., et al. Oral diseases and inflammatory burden and Alzheimer’s disease among subjectsaged 75 years or older. Special Care in Dentistry. 2019; 39 (2): 158-65.

55. Heneka M.T., Carson M.J., El Khoury J., Landreth G.E., Brosseron F., Feinstein D.L., et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurology. 2015; 14 (4): 388-405.

56. Bowman G.L., Dayon L., Kirkland R., Wojcik J., Peyratout G., Severin I.C., et al. Blood-brain barrier breakdown, neuroinflammation, and cognitive decline in older adults. Alzheimer’s Dementia. 2018.

57. Kebir H., Krymborg K., Ifergan I., Dodelet-Devillers A., Cayrol R., Bernard M., et al. Human Th17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nature Medicine. 2007;1 3 (10): 1173-5.

58. Tao Q., Ang T.F.A., DeCarli C., Auerbach S.H., Devine S., Stein T.D., et al. Association of chronic low-grade inflammation with risk of Alzheimer’s disease in ApoE4 carriers. Journal of American Medical Association Network Open. 2018; 1 (6): 183597.

59. Ueno M., Chiba Y., Murakami R., Matsumoto K., WKawauchi M., Fujihara R. Blood-brain barrier and blood-cerebrospinal fluid barrier in normal and pathological conditions. Brain Tumor Pathology. 2016; 33 (2): 89-96.

60. Walker K.A., Ficek B.N., Westbrook R. Understanding the role of systemic inflammation in Alzheimer’s Disease. ACS Chemical Neuroscience. 2019; 10 (8): 3340-2.

61. Hawkins B.T., Davis T.P. The blood-brain barrier/neurovascular unit in health and disease. Pharmacological Reviews. 2005; 57: 173-85.

62. Rochfort K.D., Collins L.E., Murphy R.P., Cummins P.M. Downregulation of blood-brain barrier phenotype by proinflammatory cytokines involves NADPH oxidase dependent ROS generation: consequences for interendothelial adherens and tight junctions. PLoS One. 2014; 9 (7): e101815.

63. Chen J., Ren C.J., Wu L., Xia L.Y., Shao J., Leng W.D., et al. Tooth loss is associated with increased risk of dementia and with a dose-response relationship. Frontiers in Aging Neuroscience. 2018; 10: 415.

64. Emami E., Freitas de Souza R., Kabawat M., Feine J.S. The impact of edentulism on oral and general health. International Journal of Dentistry. 2013; 2013: 498305.

65. Okamoto N., Morikawa M., Tomioka K., Yanagi M., Amano N., Kurumatani N. Association between tooth loss and the development of mild memory impairment in the elderly: the Fujiwara-kyo Study. Journal of Alzheimer’s Disease. 2015; 44: 777-86.

66. Paganini-Hill A., White S.C., Atchison K.A. Dentition, dental health habits, and dementia: the Leisure World cohort study. Journal of the American Geriatrics Society. 2012; 60 (8): 1556-63.

67. Singhrao S.K., Harding A., Simmons T., Robinson S., Kesavalu L., Crean S. Oral inflammation, tooth loss, risk factors, and association with progression of Alzheimer’s disease. Journal of Alzheimer’s Disease. 2014; 42 (3): 723-37.

68. Stein P.S., Desrosiers M., Donegan S.J., Yepes J.F., Kryscio R.J. Tooth loss, dementia and neuropathy in the Nun study. Journal of the American Dental Association. 2007; 138 (10): 1214-22.

69. Kobayashi R., Ogawa Y., Hashizume-Takizawa T., Kurita-Ochiai T. Oral bacteria affect the gut microbiome and intestinal immunity. Pathology Disease. 2020; 78 (3): 024.

70. Ding Y., Ren J., Yu H., Yu W., Zhou Y. Porphyromonas gingivalis, a periodontitis causing bacterium, induces memory impairment and age-dependent neuroinflammation in mice. Immunity & Ageing. 2018; 15 (6).

71. Gaur S, Agnihotri R. Alzheimer’s disease and chronic periodontitis: Is there an association? Geriatrics Gerontology. 2015;15:391-404.

72. Kamer A.P., Craig R.G., Dasanayake A.P., Brys M., Glodzik-Sobanska L., de Leon M.J. Inflammation and Alzheimer’s disease: Possible role of periodontal diseases. Alzheimer’s Dementia. 2008; 4: 242-50.

73. Kamer A.R., Craig R.G., Pirraglia E., Dasanayake A.P., Norman R.G., Boylan R.J., et al. TNF-alpha and antibodies to periodontal bacteria discriminate between Alzheimer’s disease patients and normal subjects. Journal of Neuroimmunology. 2009; 216 (1-2): 92-7.

74. Sparks Stein P., Steffen M.J., Smith C., Jicha G., Ebersole J.L., Abner E., et al. Serum antibodies to periodontal pathogens are a risk factor for Alzheimer's disease. Alzheimer’s Dementia. 2012; 8 (3): 196-203.

75. Laugisch O., Johnen A., Maldonado A., Ehmke B., Bürgin W., Olsen I., et al. Periodontal Pathogens and Associated Intrathecal Antibodies in Early Stages of Alzheimer's Disease. Journal of Alzheimer’s Disease. 2018; 66 (1): 105-14.

76. Creavin S.T., Wisniewski S., Noel-Storr A.H., Trevelyan C.M., Hampton T., Rayment D., et al. Mini-Mental State Examination (MMSE) for the detection of dementia in clinically unevaluated people aged 65 and over in community and primary care populations. Cochrane Database Systematic Review. 2016; 1: CD011145.

77. Ciesielska N., Sokolowski R., Mazur E., Podhorecka M., Polak-Szabela A., Kedziora- Kornatowska K. Is the Montreal Cognitive Assessment (MoCA) test better suited than the Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI) detection amon people aged over 60? Meta-analysis. Psychiatria Polska. 2016; 50 (5): 1039-52.

78. Nasreddine Z., Phillips N., Bédirian V., Charbonneau S., Whitehead V., Collin I., et al. The Montreal Cognitive Assessment (MoCA): a brief screening tool for mild cognitive impairment. Journal of the American Geriatrics Society. 2005; 53 (4): 695-9.

79. Aggarwal A., Kean E. Comparison of the Folstein Mini Mental State Examination (MMSE) to the Montreal Cognitive Assessment (MoCA) as a cognitive screening tool in an inpatient rehabilitation setting. Neuroscience Medicine. 2010; 1 (39-42).

80. Dong Y.H., Sharma V.K., Chan B.P.L., Venketasubramanian N., Teoh H.L., Seet R.C.S., et al. The Montreal Cognitive Assessment (MoCA) is superior to the Mini-Mental State Examination (MMSE) for the detection of vascular cognitive impairment after acute stroke. Journal of the Neurological Sciences. 2010; 299 (1-2): 15-8.

81. Dong Y.H., Lee W.Y., Basri N.A., Collinson S.L., Merchant R.A., Venkataraman A., et al. The Montreal Cognitive Assessment is superior to the Mini-Mental State Examination in detecting patients at higher rosk of dementia. International Psychogeriatrics. 2012; 24 (1): 1749-55.

82. Godefroy O., Fickl A., Roussel M., Auribault C., Bugnicourt J.M., Lamy C., et al. Is the Montreal Cognitive Assessment superior to the Mini-Mental State Examination to detect poststroke cognitive impairment? A study with neurophychological evaluation. Stroke. 2011; 42 (6): 1712-6.

83. Pendlebury S.T., Cuthbertson F.C., Weich S.J.V., Mehta Z., Rothwell P.M. Underestimation of cognitive impairment by Mini-Mental State Examination versus the Montreal Cognitive Assessment in patients with transient ischemic attack and stroke. Stroke. 2010; 41(6): 1290-3.

84. Morris J.C., Roe C.M., Xiong C., Fagan A.M., Goate A.M., Holtzman D.M., et al. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Annals in Neurology. 2010; 67 (1):122-31.

85. Gao H., Tian Y., Menhg H., Hou J., Xu L., Zhang L., et al. Associations of apolipoprotein E and low-density lipoprotein receptor-related protein 5 polymorphisms with dyslipidemia and generalized aggressive periodontitis in a Chinese population. Journal of Periodontal Research. 2015; 50 (4): 509-18.

86. Linhartova P.B., Bartova J., Poskerova H., Machal J., Vokurka J., Fassmann A., et al. Apolipoprotein E gene polymorphisms in relation to chronic periodontitis, periodontopathic bacteria, and lipid levels. Archives in Oral Biology. 2015; 60 (3): 456-62.

87. Kok E., Haikonen S., Luoto T., Huhtala H., Goebeler S., Haapasalo H., et al. Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age. Annals in Neurology. 2009; 65 (6): 650-7.

88. Reiman E.M., Chen K., Liu X., Bandy D., Yu M., Lee W.Y., et al. Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease. Proceedings of the National Academy of Sciences. 2009; 106 (16): 6820-5.