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Translational Neuroscience

, Volume 4, Issue 1, pp 34–45 | Cite as

The olfactory system in Alzheimer’s disease: Pathology, pathophysiology and pathway for therapy

  • Tibor KovácsEmail author
Review Article

Abstract

Olfaction is frequently mentioned as a “neglected sense”, although the olfactory system has several interesting and unique anatomical and physiological features. Olfactory involvement is present in several degenerative disorders, especially in Alzheimer’s disease (AD). The peripheral and central parts of the olfactory system are damaged even in the early stages of AD, manifesting in profound olfactory deficits. Besides the early pathology, the olfactory system may be involved in the pathogenesis of AD by providing a route of entry for pathological agents still unknown. In contrast to this olfactory vector hypothesis, the olfactory system can be used to deliver therapeutic agents in AD, such as nerve growth factor and insulin, by decreasing the side-effects of the therapy or providing a non-invasive method of delivery.

Keywords

Olfaction Neurofibrillary tangles Limbic system Olfactory vector hypothesis Alzheimer’s disease 

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References

  1. [1]
    Querfurth H.W., LaFerla F.M., Alzheimer’s disease, N. Engl. J. Med., 2010, 362, 329–344PubMedCrossRefGoogle Scholar
  2. [2]
    Kovács T., Mechanism of olfactory dysfunction in aging and neurodegenerative disorders, Ageing Res. Rev., 2004, 3, 215–232PubMedCrossRefGoogle Scholar
  3. [3]
    Blanchart A., López-Mascaraque L., From the periphery to the brain: wiring the olfactory system, Transl. Neurosci., 2011, 2, 293–309CrossRefGoogle Scholar
  4. [4]
    Gloor P., The temporal lobe and limbic system, Oxford University Press, New York, 1997Google Scholar
  5. [5]
    Halász N., The vertebrate olfactory system: chemical neuroanatomy, function and development, Akadémiai Kiadó, Budapest, 1990Google Scholar
  6. [6]
    Talamo B.R., Rudel R., Kosik K.S., Lee V.M-Y., Neff S., Adelman L., et al., Pathological changes in olfactory neurons in patients with Alzheimer’s disease, Nature, 1989, 337, 736–739PubMedCrossRefGoogle Scholar
  7. [7]
    Lee J.H., Goedert M., Hill W.D., Lee V.M., Trojanowski J.Q., Tau proteins are abnormally expressed in olfactory epithelium of Alzheimer patients and developmentally regulated in human fetal spinal cord, Exp. Neurol., 1993, 121, 93–105PubMedCrossRefGoogle Scholar
  8. [8]
    Yamagishi M., Ishizuka Y., Seki K., Pathology of olfactory mucosa in patients with Alzheimer’s disease, Ann. Otol. Rhinol. Laryngol., 1994, 103, 421–427PubMedGoogle Scholar
  9. [9]
    Tabaton M., Cammarata S., Mancardi G.L., Cordone G., Perry G., Loeb C., Abnormal tau-reactive filaments in olfactory mucosa in biopsy specimens of patients with probable Alzheimer’s disease, Neurology, 1991, 41, 391–394PubMedCrossRefGoogle Scholar
  10. [10]
    Trojanowski J.Q., Newman P.D., Hill W.D., Lee V.M.Y., Human olfactory epithelium in normal aging, Alzheimer’s disease, and other neurodegenerative disorders, J. Comp. Neurol., 1991, 310, 365–376PubMedCrossRefGoogle Scholar
  11. [11]
    Kaakkola S., Palo J., Malmberg H., Sulkava R., Virtanen I., Neurofilament profile in olfactory mucosa of patients with a clinical diagnosis of Alzheimer’s disease, Virchows Arch., 1994, 424, 315–319PubMedCrossRefGoogle Scholar
  12. [12]
    Kishikawa M., Iseki M., Sakae M., Kawaguchi S., Fujii H., Early diagnosis of Alzheimer’s?, Nature, 1994, 369, 365–366PubMedCrossRefGoogle Scholar
  13. [13]
    Hock C., Golombowski S., Mullerspahn F., Peschel O., Riederer A., Probst A., et al., Histological markers in nasal mucosa of patients with Alzheimer’s disease, Eur. Neurol., 1998, 40, 31–36PubMedCrossRefGoogle Scholar
  14. [14]
    Arnold S.E., Lee E.B., Moberg P.J., Stutzbach L, Kazi H., Han L-Y., et al., Olfactory epithelium amyloid-beta and paired helical filaments-tau pathology in Alzheimer’s disease, Ann. Neurol., 2010, 67, 462–469PubMedCrossRefGoogle Scholar
  15. [15]
    Duda J.E., Arnold S.E., Lee V.M.Y., Trojanowski J.Q., The expression of α-, β-, and γ-synucleins in olfactory mucosa from patients with and without neurodegenerative diseases, Exp. Neurol., 1999, 160, 515–522PubMedCrossRefGoogle Scholar
  16. [16]
    Crino P.B., Martin J.A., Hill W.D., Greenberg B., Lee V.M., Trojanowski J.Q., Beta-amyloid peptide and amyloid precursor proteins in olfactory mucosa of patients with Alzheimer’s disease, Parkinson’s disease, and Down syndrome, Ann. Otol. Rhinol. Laryngol., 1995, 104, 655–661PubMedGoogle Scholar
  17. [17]
    Yamagishi M., Getchell M.L., Takami S., Getchell T.V., Increased density of olfactory receptor neurons immunoreactive for apolipoprotein E in patients with Alzheimer’s disease, Ann. Otol. Rhinol. Laryngol., 1998, 107, 421–426PubMedGoogle Scholar
  18. [18]
    Getchell M.L., Shah D.S., Buch S.K., Davis D.G., Getchell T.V., 3-Nitrotyrosine immunoreactivity in olfactory receptor neurons of patients with Alzheimer’s disease: implications for impaired odor sensitivity, Neurobiol. Aging, 2003, 24, 663–673PubMedCrossRefGoogle Scholar
  19. [19]
    Kulkarni-Narla A., Getchell T.V., Schmitt F.A., Getchell M.L., Manganese and copper-zinc superoxide dismutases in the human olfactory mucosa: increased immunoreactivity in Alzheimer’s disease, Exp. Neurol., 1996, 140, 115–125PubMedCrossRefGoogle Scholar
  20. [20]
    Chuah M.I., Getchell M.L., Metallothionein in olfactory mucosa of Alzheimer’s disease patients and apoE-deficient mice, Neuroreport, 1999, 10, 1919–1924PubMedCrossRefGoogle Scholar
  21. [21]
    Perry G., Castellani R.J., Smith M.A., Harris P.L.R., Kubat Z., Ghanbari K., et al., Oxidative damage in the olfactory system in Alzheimer’s disease, Acta Neuropathol., 2003, 106, 552–556PubMedCrossRefGoogle Scholar
  22. [22]
    Yamagishi M., Takami S., Getchell T.V., Ontogenetic expression of spot 35 protein (calbindin-D28k) in human olfactory receptor neurons and its decrease in Alzheimer’s disease patients, Ann. Otol. Rhinol. Laryngol., 1996, 105, 132–139PubMedGoogle Scholar
  23. [23]
    Bhatnagar K.P., Kennedy R.C., Baron G., Greenberg R.A., Number of mitral cells and the bulb volume in the aging human olfactory bulb: a quantitative morphological study, Anat. Rec., 1987, 218, 73–87PubMedCrossRefGoogle Scholar
  24. [24]
    Smith R.L., Baker H., Greer C.A., Immunohistochemical analysis of the human olfactory bulb, J. Comp. Neurol., 1993, 333, 519–530PubMedCrossRefGoogle Scholar
  25. [25]
    Struble R.G., Clark H.B., Olfactory bulb lesions in Alzheimer’s disease, Neurobiol. Aging, 1991, 13, 469–473CrossRefGoogle Scholar
  26. [26]
    Kovács T., Cairns N.J., Lantos P.L., β-Amyloid deposition and neurofibrillary tangle formation in the olfactory bulb in ageing and Alzheimer’s disease, Neuropathol. Appl. Neurobiol., 1999, 25, 481–491PubMedCrossRefGoogle Scholar
  27. [27]
    Hoogland P.V., van den Berg R., Huisman E., Misrouted olfactory fibres and ectopic olfactory glomeruli in normal humans and in Parkinson and Alzheimer patients, Neuropathol. Appl. Neurobiol., 2003, 29, 303–311PubMedCrossRefGoogle Scholar
  28. [28]
    Loopuijt L.D., Sebens J.B., Loss of dopamine receptors in the olfactory bulb of patients with Alzheimer’s disease, Brain Res., 1990, 529, 239–244PubMedCrossRefGoogle Scholar
  29. [29]
    Averback P., Two new lesions in Alzheimer’s disease, Lancet, 1983, 19, 1203CrossRefGoogle Scholar
  30. [30]
    Esiri M.M., Wilcock G.K., The olfactory bulbs in Alzheimer’s disease, J. Neurol. Neurosurg. Psychiatry, 1984, 47, 56–60PubMedCrossRefGoogle Scholar
  31. [31]
    Mann D.M.A., Tucker C.M., Yates P.O., Alzheimer’s disease: an olfactory connection?, Mech. Ageing Dev., 1988, 42, 1–15PubMedCrossRefGoogle Scholar
  32. [32]
    Ohm T.G., Braak H., Olfactory bulb changes in Alzheimer’s disease, Acta Neuropathol., 1987, 73, 365–369PubMedCrossRefGoogle Scholar
  33. [33]
    Hyman B.T., Arriagada P.V., van Hoesen G.W., Pathologic changes in the olfactory bulb in ageing and Alzheimer’s disease, Ann. N.Y. Acad. Sci., 1991, 640, 14–19PubMedGoogle Scholar
  34. [34]
    Reyes P.F., Deems D.A., Suarez M.G., Olfactory-related changes in Alzheimer’s disease: a quantitative neuropathologic study, Brain Res. Bull., 1993, 32, 1–5PubMedCrossRefGoogle Scholar
  35. [35]
    ter Laak H.J., Renkawek K., van Workum F.P.A., The olfactory bulb in Alzheimer disease: a morphologic study of neuron loss, tangles, and senile plaques in relation to olfaction, Alz. Dis. Assoc. Dis., 1994, 8, 38–48CrossRefGoogle Scholar
  36. [36]
    Arnold S.E., Smutzer G.S., Trojanowski J.Q., Moberg P.J., Cellular and molecular neuropathology of the olfactory epithelium and central olfactory pathways in Alzheimer’s disease and schizophrenia, Ann. NY Acad. Sci., 1998, 855, 762–775PubMedCrossRefGoogle Scholar
  37. [37]
    Kovacs I., Török I., Zombori J., Kása P., Cholinergic structures and neuropathologic alterations in the olfactory bulb of Alzheimer’s disease brain samples, Brain Res., 1998, 789, 167–170PubMedCrossRefGoogle Scholar
  38. [38]
    Christen-Zaech S., Kraftsik R., Pillevuit O., Kiraly M., Martins R., Khalili K., et al., Early olfactory involvement in Alzheimer’s disease, Can. J. Neurol. Sci., 2003, 30, 20–25PubMedGoogle Scholar
  39. [39]
    Tsuboi Y., Wszolek Z.K., Graff-Radford N.R., Cookson N., Dickson D.W., Tau pathology in the olfactory bulb correlates with Braak stage, Lewy body pathology and apolipoprotein ɛ4, Neuropathol. Appl. Neurobiol., 2003, 29, 503–510PubMedCrossRefGoogle Scholar
  40. [40]
    Attems J., Lintner F., Jellinger K.A., Olfactory involvement in aging and Alzheimer’s disease: an autopsy study, J. Alzheimers Dis., 2005, 7, 149–157PubMedGoogle Scholar
  41. [41]
    Attems J., Jellinger K.A., Olfactory tau pathology in Alzheimer disease and mild cognitive impairment, Clin. Neuropathol., 2006, 25, 265–271PubMedGoogle Scholar
  42. [42]
    Fujishiro H., Tsuboi Y., Lin W.-L., Uchikado H., Dickson D.W., Colocalization of tau and α-synuclein in the olfactory bulb in Alzheimer’s disease with amygdala Lewy bodies, Acta Neuropathol., 2008, 116, 17–24PubMedCrossRefGoogle Scholar
  43. [43]
    Saiz-Sanchez D., Ubeda-Bañon I., de la Rosa-Prieto C., Argandoña-Palacios L., Garcia-Muñozguren S., Insausti R., et al., Somatostatin, tau, and β-amyloid within the anterior olfactory nucleus in Alzheimer disease, Exp. Neurol., 2010, 223, 347–350PubMedCrossRefGoogle Scholar
  44. [44]
    Kovács T., Cairns N.J., Lantos P.L., Olfactory centres in Alzheimer’s disease: olfactory bulb is involved in early Braak’s stages, Neuroreport, 2001, 12, 285–288PubMedCrossRefGoogle Scholar
  45. [45]
    Braak H., Braak E., Neuropathological stageing of Alzheimer-related changes, Acta Neuropathol., 1991, 82, 239–259PubMedCrossRefGoogle Scholar
  46. [46]
    Wisniewski H.M., Weigel J., Kotula L., Some neuropathological aspects of Alzheimer’s disease and its relevance to other disciplines, Neuropathol. Appl. Neurobiol., 1996, 22, 3–11PubMedCrossRefGoogle Scholar
  47. [47]
    Sengoku R., Saito Y., Ikemura M., Hatsuta H., Sakiyama Y., Kanemaru K., et al., Incidence and extent of Lewy body-related α-synucleinopathy in aging human olfactory bulb, J. Neuropathol. Exp. Neurol., 2008, 67, 1072–1083PubMedCrossRefGoogle Scholar
  48. [48]
    Beach T.G., White C.L. 3rd, Hladik C.L., Sabbagh M.N., Connor D.J., Shill H.A., et al., Olfactory bulb α-synucleinopathy has high specificity and sensitivity for Lewy body disorders, Acta Neuropathol., 2009, 117, 169–174PubMedCrossRefGoogle Scholar
  49. [49]
    Attems J., Alpar A., Spence L., McParland S., Heikenwalder M., Ehlén M., et al., Clusters of secretagogin-expressing neurons in the aged human olfactory tract lack terminal differentiation, Proc. Natl. Acad. Sci. USA, 2012, 109, 6259–6264PubMedCrossRefGoogle Scholar
  50. [50]
    Mundinano I-C., Caballero M-C., Ordónez C, Hernandez M., DiCaudo C., Marcilla I., et al., Increased dopaminergic cells and protein aggregates in the olfactory bulb of patients with neurodegenerative disorders, Acta Neuropathol., 2011, 122, 61–74PubMedCrossRefGoogle Scholar
  51. [51]
    Davies D.C., Brooks J.W., Lewis D.A., Axonal loss from the olfactory tracts in Alzheimer’s disease, Neurobiol. Aging, 1993, 14, 353–357PubMedCrossRefGoogle Scholar
  52. [52]
    Armstrong R.A., Syed A.B., Smith C.U.M., Density and cross-sectional areas of axons in the olfactory tract in control subjects and Alzheimer’s disease: an image analysis study, Neurol. Sci., 2008, 29, 23–27PubMedCrossRefGoogle Scholar
  53. [53]
    Thomann P.A., Dos Santos V., Seidl U., Toro P., Essig M., Schröder J., MRI-derived atrophy of the olfactory bulb and tract in mild cognitive impairment and Alzheimer’s disease, J. Alzheimers Dis., 2009, 17, 213–221PubMedGoogle Scholar
  54. [54]
    Thomann P.A., Dos Santos V., Toro P., Schönknecht P., Essig M., Schröder J., Reduced olfactory bulb and tract volume in early Alzheimer’s disease — a MRI study, Neurobiol. Aging, 2009, 30, 838–841PubMedCrossRefGoogle Scholar
  55. [55]
    Zatorre R.J., Jones-Gotman M., Evans A.C., Meyer E., Functional localization and lateralization of human olfactory cortex, Nature, 1992, 360, 339–340PubMedCrossRefGoogle Scholar
  56. [56]
    Insausti R., Marcos P., Arroyo-Jiménez M.M., Blaizot X., Martínez-Marcos A., Comparative aspects of the olfactory portion of the entorhinal cortex and its projection to the hippocampus in rodents, nonhuman primates, and the human brain, Brain Res. Bull., 2002, 57, 557–560PubMedCrossRefGoogle Scholar
  57. [57]
    Prestia A., Drago V., Rasser P.E., Bonetti M., Thompson P.M., Frisoni G.B., Cortical changes in incipient Alzheimer’s disease, J. Alzheimers Dis., 2010, 22, 1339–1349PubMedGoogle Scholar
  58. [58]
    Murphy C, Jernigan T.L., Fennema-Notestine C., Left hippocampal volume loss in Alzheimer’s disease is reflected in performance on odor identification: a structural MRI study, J. Int. Neuropsychol. Soc., 2003, 9, 459–471PubMedCrossRefGoogle Scholar
  59. [59]
    Li Y., Wang Y., Wu G., Shi F., Zhou L., Lin W., et al., Discriminant analysis of longitudinal cortical thickness changes in Alzheimer’s disease using dynamic and network features, Neurobiol. Aging, 2012, 33, 427.e15–30CrossRefGoogle Scholar
  60. [60]
    Frisoni G.B., Prestia A., Rasser P.E., Bonetti M., Thompson P.M., In vivo mapping of incremental cortical atrophy from incipient to overt Alzheimer’s disease, J. Neurol., 2009, 256, 916–924PubMedCrossRefGoogle Scholar
  61. [61]
    Cavedo E., Boccardi M., Ganzola R., Canu E., Beltramello A., Caltagirone C, et al., Local amygdala structural differences with 3T MRI in patients with Alzheimer disease, Neurology, 2011, 76, 727–733PubMedCrossRefGoogle Scholar
  62. [62]
    Hedner M., Larsson M., Arnold N., Zucco G.M., Hummel T., Cognitive factors in odor detection, odor discrimination, and odor identification tasks, J. Clin. Exp. Neuropsychol., 2010, 32, 1062–1067PubMedCrossRefGoogle Scholar
  63. [63]
    Laing D.G., Natural sniffing gives optimum odor perception for humans, Perception, 1983, 12, 99–107PubMedCrossRefGoogle Scholar
  64. [64]
    Sobel N., Thomason M.E., Stappen I., Tanner C.M., Tetrud J.W., Bower J.M., et al., An impairment in sniffing contributes to the olfactory impairment in Parkinson’s disease, Proc. Natl. Acad. Sci. USA, 2001, 98, 4154–4159PubMedCrossRefGoogle Scholar
  65. [65]
    Rahayel S., Frasnelli J., Joubert S., The effect of Alzheimer’s disease and Parkinson’s disease on olfaction: a meta-analysis, Behav. Brain Res., 2012, 231, 60–74PubMedCrossRefGoogle Scholar
  66. [66]
    Mesholam R.I., Moberg P.J., Mahr R.N., Doty R.L., Olfaction in neurodegenerative disease: a meta-analysis of olfactory functioning in Alzheimer’s and Parkinson’s diseases, Arch. Neurol., 1998, 55, 84–90PubMedCrossRefGoogle Scholar
  67. [67]
    McShane R.H., Nagy Z., Esiri M.M., King E., Joachim C., Sullivan N. et al., Anosmia in dementia is associated with Lewy bodies rather than Alzheimer’s pathology, J. Neurol. Neurosurg. Psychiatry, 2001, 70, 739–743PubMedCrossRefGoogle Scholar
  68. [68]
    Olichney J.M., Murphy C., Hofstetter C.R., Foster K., Hansen L.A., Thal J.L., et al., Anosmia is very common in the Lewy body variant of Alzheimer’s disease, J. Neurol. Neurosurg. Psychiatry, 2005, 76, 1342–1347PubMedCrossRefGoogle Scholar
  69. [69]
    Williams S.S., Williams J., Combrick M., Christie S., Smith A.D., McShane R., Olfactory impairment is more marked in patients with mild dementia with Lewy bodies than those with mild Alzheimer disease, J. Neurol. Neurosurg. Psychiatry, 2009, 80, 667–670PubMedCrossRefGoogle Scholar
  70. [70]
    Sato T, Hanyu H, Kume K., Takada Y, Onuma T., Iwamoto T., Difference in olfactory dysfunction with dementia with Lewy bodies and Alzheimer’s disease, J. Am. Geriat. Soc., 2011, 59, 947–948PubMedCrossRefGoogle Scholar
  71. [71]
    Duyckaerts C., Delatour B., Patier M.C., Classification and basic pathology of Alzheimer disease, Acta Neuropathol., 2009, 118, 5–36PubMedCrossRefGoogle Scholar
  72. [72]
    Doty R.L., Shaman P., Applebaum S.L., Giberson R., Siksorski L., Rosenberg L., Smell identification ability: changes with age, Science, 1984, 226, 1441–1443PubMedCrossRefGoogle Scholar
  73. [73]
    Wilson R.S., Yu L., Schneider J.A., Arnold S.E., Buchman A.S., Bennett D.A., Lewy bodies and olfactory dysfunction in old age, Chem. Senses, 2011, 36, 367–373PubMedCrossRefGoogle Scholar
  74. [74]
    Wilson R.S., Arnold S.E., Schneider J.A., Tang Y., Bennett D.A., The relationship between cerebral Alzheimer’s disease pathology and odour identification in old age, J. Neurol. Neurosurg. Psychiatry, 2007, 78, 30–35PubMedCrossRefGoogle Scholar
  75. [75]
    Wilson R.S., Arnold S.E., Schneider J.A., Boyle P.A., Buchman A.S., Bennett D.A., Olfactory impairment in presymptomatic Alzheimer’s disease, Ann. N.Y. Acad. Sci., 2009, 1170, 730–735PubMedCrossRefGoogle Scholar
  76. [76]
    Chen Y., Getchell T.V., Larry Sparks D., Getchell M.L., Patterns of adrenergic and peptidergic innervation in human olfactory mucosa: age-related trends, J. Comp. Neurol. 1993, 334, 104–116PubMedCrossRefGoogle Scholar
  77. [77]
    Paik S.I., Lehman M.N., Seiden A.M., Duncan H.J., Smith D.V., Human olfactory biopsy. The influence of age and receptor distribution, Arch. Otolaryngol. Head Neck Surg., 1992, 118, 731–738PubMedCrossRefGoogle Scholar
  78. [78]
    Schubert C.R., Carmichael L.L., Murphy C., Klein B.E.K., Klein R, Cruickshanks K.J., Olfaction and the 5-year incidence of cognitive impairment in an epidemiological study of older adults, J. Am. Geriatr. Soc., 2008, 56, 1517–1521PubMedCrossRefGoogle Scholar
  79. [79]
    Sohrabi H.R., Bates K.A., Weinborn M.G., Johnston A.N.B., Bahramian A., Taddei K., et al., Olfactory discrimination predicts cognitive decline among community-dwelling older adults, Transl. Psychiatry, 2012, 2, e118PubMedCrossRefGoogle Scholar
  80. [80]
    Wilson R.S., Schneider J.A., Arnold S.E., Tang Y., Boyle P.A., Bennett D.A., Olfactory identification and incidence of mild cognitive impairment in older age, Arch. Gen. Psychiatry, 2007, 67, 802–808CrossRefGoogle Scholar
  81. [81]
    Sohrabi H.R., Bates K.A., Rodrigues M., Taddei K., Laws S.M., Lautenschlager N.T., et al., Olfactory dysfunction is associated with subjective memory complaints in community-dwelling elderly individuals, J. Alzheimer Dis., 2009, 17, 135–142Google Scholar
  82. [82]
    Royall D.R., Chiodo L.K., Polk M.J., Jaramillo C.J., Severe dysosmia is specifically associated with Alzheimer-like memory deficits in nondemented elderly retirees, Neuroepidemiology, 2002, 21, 68–73PubMedCrossRefGoogle Scholar
  83. [83]
    Djordjevic J., Jones-Gotman M., De Sousa K., Chertkow H., Olfaction in patients with mild cognitive impairment and Alzheimer’s disease, Neurobiol. Aging, 2008, 29, 693–706PubMedCrossRefGoogle Scholar
  84. [84]
    Westervelt H.J., Bruce J.M., Coon W.G., Tremont G., Odor identification in mild cognitive impairment subtypes, J. Clin. Exp. Neuropsychol., 2008, 30, 151–156PubMedCrossRefGoogle Scholar
  85. [85]
    Devanand D.P., Liu X., Tabert M.H., Pradhaban G, Cuasay K., Bell K., et al., Combining early markers strongly predicts conversion from mild cognitive impairment to Alzheimer’s disease, Biol. Psychiatry, 2008, 64, 871–879PubMedCrossRefGoogle Scholar
  86. [86]
    Lojkowska W., Eawicka B., Gugala M., Sienkiewicz-Jarosz H., Bochynska A., Scinska A., et al., Follow-up study of olfactory deficits, cognitive functions, and volume loss of medial temporal lobe structures in patients with mild cognitive impairment, Curr. Alzheimer Res., 2011, 8, 689–698PubMedCrossRefGoogle Scholar
  87. [87]
    Devanand D.P., Michaels-Marston K.S., Liu X., Pelton G.H., Padilla M., Marder K., et al., Olfactory deficits in patients with mild cognitive impairment predict Alzheimer’s disease at follow-up, Am. J. Psychiatry, 2000, 157, 1399–1405PubMedCrossRefGoogle Scholar
  88. [88]
    Bahar-Fuchs A., Moss S., Rowe C., Savage G., Awareness of olfactory deficits in healthy aging, amnestic mild cognitive impairment and Alzheimer’s disease, Int. Psychogeriatr., 2011, 23, 1097–1106PubMedCrossRefGoogle Scholar
  89. [89]
    Bahar-Fuchs A., Chételat G, Villemagne V.L., Moss S., Pike K., Masters C.L., et al., Olfactory deficits and amyloid-β burden in Alzheimer’s disease, mild cognitive impairment, and healthy aging: a PiB PET study, J. Alzheimer Dis., 2010, 22, 1081–1087Google Scholar
  90. [90]
    Schofield P.W., Ebrahimi H., Jones A.L., Bateman G.A., Murray S.R., An olfactory ‘stress test’ may detect preclinical Alzheimer’s disease, BMC Neurol., 2012, 12, 24PubMedCrossRefGoogle Scholar
  91. [91]
    Wang J, Eslinger P.J., Doty R.L., Zimmerman E.K., Grunfeld R., Sun X., et al., Olfactory deficit detected by fMRI in early Alzheimer’s disease, Brain Res., 2010, 1357, 184–194PubMedCrossRefGoogle Scholar
  92. [92]
    Li W., Howard J.D., Gottfried J.A., Disruption of odour quality coding in piriform cortex mediates olfactory deficits in Alzheimer’s disease, Brain, 2010, 133, 2714–2726PubMedCrossRefGoogle Scholar
  93. [93]
    Kareken D.A., Doty R.L., Moberg P.J., Mosnik D, Chen SH, Farlow M.R., et al., Olfactory-evoked regional cerebral blood flow in Alzheimer’s disease, Neuropsychology, 2001, 15, 18–29PubMedCrossRefGoogle Scholar
  94. [94]
    Wang Q-S., Tian L., Huang Y-L., Qin S, He L-Q., Zhou J-N., Olfactory identification and apolipoprotein ɛ4 allele in mild cognitive impairment, Brain Res., 2002, 951, 77–81PubMedCrossRefGoogle Scholar
  95. [95]
    Olofsson J.K., Nordin S., Wiens S, Hedner M., Nilsson L-G., Larsson M., Odor identification in carriers of ApoE-ɛ4 is independent of clinical dementia, Neurobiol. Aging, 2010, 31, 567–577PubMedCrossRefGoogle Scholar
  96. [96]
    Calhoun-Haney R., Murphy C., Apolipoprotein ɛ4 is associated with more rapid decline in odor identification than in odor threshold or Dementia Rating Scale scores, Brain Cogn., 2005, 58, 178–182PubMedCrossRefGoogle Scholar
  97. [97]
    Sperling R.A., Aisen P.S., Beckett L.A., Bennett D.A., Craft S., Fagan A.M., et al., Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease, Alzheimers Dement., 2011, 7, 280–292PubMedCrossRefGoogle Scholar
  98. [98]
    Handley O.J., Morrison C.M., Miles C., Bayer A.J., ApoE gene and familial risk of Alzheimer’s disease as predictors of odour identification in older adults, Neurobiol. Aging, 2006, 27, 1425–1430PubMedCrossRefGoogle Scholar
  99. [99]
    Schiffmann S.S., Graham B.G., Sattely-Miller E.A., Zervakis J., Welsh-Bohmer K., Taste, smell and neuropsychological performance of individuals at familial risk for Alzheimer’s disease, Neurobiol. Aging, 2002, 23, 397–404Google Scholar
  100. [100]
    Nee L.E., Lippa C.F., Inherited Alzheimer’s disease PS-1 olfactory function: a 10-year follow-up study, Am. J. Alzheimers Dis. Other Demen., 2001, 16, 83–84PubMedCrossRefGoogle Scholar
  101. [101]
    Larsson M., Semb H., Winblad B., Amberla K., Wahlund L.O., Bäckman L., Odor identification in normal aging and early Alzheimer’s disease: effects of retrieval support, Neuropsychology, 1999, 13, 47–53PubMedCrossRefGoogle Scholar
  102. [102]
    Suzuki Y., Yamamoto S., Umegaki H., Onishi J., Mogi N., Fujishiro H. et al., Smell identification test as an indicator for cognitive impairment in Alzheimer’s disease, Int. J. Geriatr. Psychiatry, 2004, 19, 727–733PubMedCrossRefGoogle Scholar
  103. [103]
    Tkalčić M., Spasić N., Ivanković M., Pokrajac-Bulian A., Bosanac D., Odor identification and cognitive abilities in Alzheimer’s disease, Transl. Neurosci., 2011, 2, 233–240CrossRefGoogle Scholar
  104. [104]
    McCaffrey R.J., Duff K., Solomon G.S., Olfactory dysfunction discriminates probable Alzheimer’s dementia from major depression: a cross-validation and extension, J. Neuropsychiatry Clin. Neurosci., 2000, 12, 29–33PubMedGoogle Scholar
  105. [105]
    Luzzi S., Snowden J.S., Neary D., Coccia M., Provinciali L., Lambon Ralph M.A., Distinct patterns of olfactory impairment in Alzheimer’s disease, semantic dementia, frontotemporal dementia, and corticobasal degeneration, Neuropsychologia, 2007, 45, 1823–1831PubMedCrossRefGoogle Scholar
  106. [106]
    Hawkes C.H., Del Tredici K., Braak H., Parkinson’s disease: the dual hit theory revisited, Ann. NY Acad. Sci., 2009, 1170, 615–622PubMedCrossRefGoogle Scholar
  107. [107]
    Ferrera-Moyano H., Barragan E., The olfactory system and Alzheimer’s disease, Int. J. Neurosci., 1989, 49, 157–197CrossRefGoogle Scholar
  108. [108]
    Doty R.L., The olfactory vector hypothesis of neurodegenerative disease: is it viable?, Ann. Neurol., 2008, 63, 7–15PubMedCrossRefGoogle Scholar
  109. [109]
    Tonelli L.H., Postolache T.T., Airborne inflammatory factors: “from the nose to the brain”, Front. Biosci. (Schol. Ed.), 2010, 2, 135–152CrossRefGoogle Scholar
  110. [110]
    Honjo K., van Reekum R., Verhoeff N.P., Alzheimer’s disease and infection: do infectious agents contribute to progression of Alzheimer’s disease?, Alzheimers Dement., 2009, 5, 348–360PubMedCrossRefGoogle Scholar
  111. [111]
    Špeljko T, Jutric D, Šimić G., HSV1 in Alzheimer’s disease: myth or reality?, Transl. Neurosci., 2011, 2, 61–68CrossRefGoogle Scholar
  112. [112]
    Esiri M.M., Herpes simplex encephalitis. An immunohistological study of the distribution of viral antigen within the brain, J. Neurol. Sci., 1982, 54, 209–226PubMedCrossRefGoogle Scholar
  113. [113]
    Landis B.N., Vodicka J., Hummel T., Olfactory dysfunction following herpetic meningoencephalitis, J. Neurol., 2010, 257, 439–443PubMedCrossRefGoogle Scholar
  114. [114]
    Mann D.M., Tinkler A.M., Yates P.O., Neurological disease and herpes simplex virus. An immunohistochemical study, Acta Neuropathol., 1983, 60, 24–28PubMedCrossRefGoogle Scholar
  115. [115]
    Twomey J.A., Barker C.M., Robinson G., Howell D.A., Olfactory mucosa in herpes simplex encephalitis, J. Neurol. Neurosurg. Psychiatry, 1979, 42, 983–987PubMedCrossRefGoogle Scholar
  116. [116]
    Dinn J.J., Transolfactory spread of virus in herpes simplex encephalitis, Br. Med. J., 1980, 281, 1392PubMedCrossRefGoogle Scholar
  117. [117]
    Balin B.J., Scott Little C., Hammond C.J., Appelt D.M., Whittum-Hudson J.A., Gérard H.C., et al., Chlamydophila pneumoniae and the etiology of late-onset Alzheimer’s disease, J. Alzheimers Dis., 2008, 13, 371–380PubMedGoogle Scholar
  118. [118]
    Balin B.J., Gerard H.C., Arking E.J., Appelt D.M., Branigan P.J., Abrams J.T., et al., Identification and localization of Chlamydia pneumoniae in the Alzheimer’s brain, Med. Microbiol. Immunol., 1998, 187, 23–42PubMedCrossRefGoogle Scholar
  119. [119]
    Roberts E., Alzheimer’s disease may begin in the nose and may be caused by aluminosilicates, Neurobiol. Aging, 1986, 7, 561–567PubMedCrossRefGoogle Scholar
  120. [120]
    Samudralwar D.L., Diprete C.C., Ni B-F., Ehmann W.D., Markesbery W.R., Elemental imbalances in the olfactory pathway in Alzheimer’s disease, J. Neurol. Sci., 1995, 130, 139–145PubMedCrossRefGoogle Scholar
  121. [121]
    Arriagada P.V., Louis D.N., Hedley-Whyte E.T., Hyman B.T., Neurofibrillary tangles and olfactory dysgenesis, Lancet, 1991, 337, 559PubMedCrossRefGoogle Scholar
  122. [122]
    Pearson R.C., Esiri M.M., Hiorns R.W., Wilcock G.K., Powell T.P.S., Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer’s disease, Proc. Natl. Acad. Sci. USA, 1985, 82, 4531–4534PubMedCrossRefGoogle Scholar
  123. [123]
    Pearson R.C., Cortical connections and the pathology of Alzheimer’s disease, Neurodegeneration, 1996, 5, 429–434PubMedCrossRefGoogle Scholar
  124. [124]
    Murray M.E., Graff-Radford N.R., Ross O.A., Petersen R.C., Duara R., Dickson D.W., Neuropathologically defined subtypes of Alzheimer’s disease with distinct clinical characteristics: a retrospective study, Lancet Neurol., 2011, 10, 785–796PubMedCrossRefGoogle Scholar
  125. [125]
    Castellani R.J., Perry G., Pathogenesis and disease-modifying therapy in Alzheimer’s disease: the flat line of progress, Arch. Med. Res., 2012, 43, 694–698PubMedCrossRefGoogle Scholar
  126. [126]
    Lemere C.A., Maron R., Selkoe D.J., Weiner H.L., Nasal vaccination with beta-amyloid peptide for the treatment of Alzheimer’s disease, DNA Cell Biol., 2001, 20, 705–711PubMedCrossRefGoogle Scholar
  127. [127]
    Sipos E., Kurunczi A., Fehér A., Penke Z., Fülöp L, Kasza A., et al., Intranasal delivery of human beta-amyloid peptide in rats: effective brain targeting, Cell. Mol. Neurobiol., 2010, 30, 405–413PubMedCrossRefGoogle Scholar
  128. [128]
    Pepeu G., Giovannini M.G., Cholinesterase inhibitors and beyond, Curr. Alzheimer Res., 2009, 6, 86–96PubMedCrossRefGoogle Scholar
  129. [129]
    Capsoni S., Giannotta S., Cattaneo A., Nerve growth factor and galantamine ameliorate early signs of neurodegeneration in antinerve growth factor mice, Proc. Natl. Acad. Sci. USA, 2002, 99, 12432–12437PubMedCrossRefGoogle Scholar
  130. [130]
    Cuello A.C., Bruno M.A., Allard S., Leon W., Iulta M.F., Cholinergic involvement in Alzheimer’s disease. A link with NGF maturation and degradation, J. Mol. Neurosci., 2010, 40, 230–235PubMedCrossRefGoogle Scholar
  131. [131]
    Tuszinsky M.H., Thal L., Pay M., Salmon D.P., U H.S., Bakay R., A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease, Nat. Med., 2005, 11, 551–555CrossRefGoogle Scholar
  132. [132]
    Mandel R.J., CERE-110, an adeno-associated virus-based gene delivery vector expressing human nerve growth factor for the treatment of Alzheimer’s disease, Curr. Opin. Mol. Ther., 2010, 12, 240–247PubMedGoogle Scholar
  133. [133]
    Eriksdotter-Jönhagen M., Linderoth B., Lind G., Aladellie L, Almkvist O, Andreasen N., et al., Encapsulated cell biodelivery of nerve growth factor to the basal forebrain in patients with Alzheimer’s disease, Dement. Geriatr. Cogn. Disord., 2012, 33, 18–28PubMedCrossRefGoogle Scholar
  134. [134]
    Chen X.Q., Fawcett J.R., Rahman Y.E., Ala T.A., Frey W.H., Delivery of nerve growth factor to the brain via the olfactory pathway, J. Alzheimers Dis., 1998, 1, 35–44PubMedGoogle Scholar
  135. [135]
    Capsoni S., Covaveuszach S., Ugolini G., Spirito F., Vignone D., Stefanini B., et al., Delivery of NGF to the brain: intranasal versus ocular administration in anti-NGF transgenic mice, J. Alzheimers Dis. 2009, 16, 371–388PubMedGoogle Scholar
  136. [136]
    Chiu S.L., Chen C.M., Cline H.T., Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo, Neuron, 2008, 58, 708–719Google Scholar
  137. [137]
    McNay E.C., Ong C.T., McCrimmon R.J., Cresswell J., Bogan J.S., Sherwin R.S., Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance, Neurobiol. Learn. Mem., 2010, 93, 546–553PubMedCrossRefGoogle Scholar
  138. [138]
    Bosco D., Fava A., Plastino M., Montalcini T., Pujia A., Possible implications of insulin-resistance and glucose metabolism in Alzheimer’s disease pathogenesis, J. Cell. Mol. Med., 2011, 15, 1807–1821PubMedCrossRefGoogle Scholar
  139. [139]
    Steen E., Terry B.M., Rivera E.J., Cannon J.L., Neely T.R., Tavares R., et al., Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease — is this type 3 diabetes?, J. Alzheimers Dis., 2005, 7, 63–80PubMedGoogle Scholar
  140. [140]
    Shemesh E., Rudich A., Harman-Boehm I, Cukiernab-Yaffe T., Effect of intranasal insulin on cognitive function: a systematic review, J. Clin. Endocrinol. Metab., 2012, 97, 366–376PubMedCrossRefGoogle Scholar
  141. [141]
    Ott V., Benedict C., Schultes B., Born J., Hallschmid M., Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism, Diabetes Obes. Metab., 2012, 14, 214–221PubMedCrossRefGoogle Scholar
  142. [142]
    Reger M.A., Watson G.S., Green P.S., Baker L.D., Cholerton B., Fishel M.A., et al., Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults, J. Alzheimers Dis., 2008, 13, 323–331PubMedGoogle Scholar
  143. [143]
    Reger M.A., Watson G.S., Green P.S., Wilkinson C.W., Baker L.D., Cholerton B., et al., Intranasal insulin improves cognition and modulates beta-amyloid in early Alzheimer’s disease, Neurology, 2008, 70, 440–448PubMedCrossRefGoogle Scholar
  144. [144]
    Craft S., Baker L.D., Montine T.J., Minoshima S., Watson G.S., Claxton A., et al., Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial, Arch. Neurol., 2012, 69, 29–38PubMedCrossRefGoogle Scholar
  145. [145]
    Maestro B., Davila N., Carranza M.C., Calle C., Identification of a vitamin D response element in the human insulin receptor gene promoter, J. Steroid Biochem. Mol. Biol., 2003, 84, 223–230PubMedCrossRefGoogle Scholar
  146. [146]
    von Hurst P.R., Stonehouse W., Coad J., Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient — a randomised, placebo-controlled trial, Br. J. Nutr., 2010, 103, 549–555CrossRefGoogle Scholar
  147. [147]
    Stein M.S., Scherer S.C., Ladd K.S., Harrison L.C., A randomized controlled trial of high-dose vitamin D2 followed by intranasal insulin in Alzheimer’s disease, J. Alzheimers Dis., 2011, 26, 477–484PubMedCrossRefGoogle Scholar
  148. [148]
    Jogani V.V., Shah P.J., Mishra P., Mishra A.K., Misra A.R., Nose-to-brain delivery of tacrine, J. Pharm. Pharmacol., 2007, 59, 1199–1205PubMedCrossRefGoogle Scholar
  149. [149]
    Jogani V.V., Shah P.J., Mishra A.K., Misra A.R., Intranasal mucoadhesive microemulsion of tacrine to improve brain targeting, Alzheimer Dis. Assoc. Disord., 2008, 22, 116–124PubMedCrossRefGoogle Scholar
  150. [150]
    Durand M., Coronas V., Jourdan F., Quirion R., Developmental and aging aspects of the cholinergic innervation of the olfactory bulb, Int. J. Dev. Neurosci., 1998, 16, 777–785PubMedCrossRefGoogle Scholar
  151. [151]
    Kása P., Rakonczay Z., Gulya K., The cholinergic system in Alzheimer’s disease, Prog. Neurobiol., 1997, 52, 511–535PubMedCrossRefGoogle Scholar
  152. [152]
    Velayudhan L., Lovestone S., Smell identification test as a treatment response marker in patients with Alzheimer disease receiving donepezil, J. Clin. Psychopharmacol., 2009, 29, 387–390PubMedCrossRefGoogle Scholar
  153. [153]
    Burns A., Perry E., Holmes C., Francis P., Morris J., Howes M.J., et al., A double-blind placebo-controlled randomized trial of Melissa officinalis oil and donepezil for the treatment of agitation in Alzheimer’s disease, Dement. Geriatr. Cogn. Disord., 2011, 31, 158–164PubMedCrossRefGoogle Scholar
  154. [154]
    Papp M.I., Komoly S., Szirmai I.G., Kovács T., Similarities between CSF-brain extracellular transfer and neurofibrillary tangle invasion in Alzheimer’s disease, Neurobiol. Aging, 2006, 27, 402–412PubMedCrossRefGoogle Scholar

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© Versita Warsaw and Springer-Verlag Wien 2013

Authors and Affiliations

  1. 1.Department of NeurologySemmelweis UniversityBudapestHungary

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