Etiology and Pathogenesis of Late-Onset Alzheimer’s Disease

Part of the following topical collections:
  1. Topical Collection on Basic and Applied Science


Alzheimer’s disease (AD) is a neurodegenerative condition that occurs in two forms, an early-onset form that is genetically determined and a far more common late-onset form that is not. In both cases, the disease results in severe cognitive dysfunction, among other problems, and the late-onset form of the disease is now considered to be the most common cause of dementia among the elderly. While a good deal of research has been focused on elucidating the etiology of the late-onset form for more than two decades, results to date have been modest and have not yet engendered useful therapeutic strategies for cure of the disease. In this review, we discuss the prevalent ideas that have governed this research for several years, and we challenge these ideas with alternative findings suggesting a multifactorial etiology. We review promising newer ideas that may prove effective as therapeutic interventions for late-onset AD, as well as providing reliable means of earlier and more specific diagnosis of the disease process. In the discussions included here, we reference relevant clinical and basic science literature underlying research into disease etiology and pathogenesis, and we highlight current reviews on the various topics addressed.


Alzheimer’s disease Late onset Amyloid cascade hypothesis Inflammation Infection Neuropathogenesis Etiology Pathogenesis Diagnosis 


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Allg Zeitschr Psychiatr. 1907;64:146–8.Google Scholar
  2. 2.•
    Defina PA, Moser RS, Glenn M, Lichtenstein JD, Fellus J. Alzheimer's Disease clinical and research update for health care practitioners. J Aging Res. 2013 in press. A thorough and readable summary of clinical aspects, as well as some promising research aspects, of disease characteristics.Google Scholar
  3. 3.
    Muller U, Winter P, Graeber MB. A presenilin 1 mutation in the first case of Alzheimer’s disease. Lancet Neurol. 2013;12:129–30.PubMedGoogle Scholar
  4. 4.•
    Anand R, Gill KD, Mahdi AA. Therapeutics of Alzheimer’s disease: past, present and future. Neuropharmacology. 2013;in press. As above, a timely summary of the present state of therapeutics as available and in use for this disease. Google Scholar
  5. 5.
    Alzheimer’s Disease International, World Alzheimer’s Report 2010.Google Scholar
  6. 6.••
    Dorsey ER, George BP, Leff B, Willis AW. The coming crisis: obtaining care for the growing burden of neurodegenerative conditions. Neurology. 2013;80:1989–96. In our view, an important summary of the impending problem with regard to the care, costs, and therapy of Alzheimer’s Disease.PubMedGoogle Scholar
  7. 7.
    Schellenberg GD. Genetic dissection of Alzheimer Disease, a heterogeneous disorder. Proc Natl Acad Sci U S A. 1995;92:8552–9.PubMedCentralPubMedGoogle Scholar
  8. 8.
    Tanzi RE, Bertram L. New frontiers in Alzheimer’s disease genetics. Neuron. 2001;32:181–4.PubMedGoogle Scholar
  9. 9.
    Madeo J, Frieri M. Alzheimer’s disease and immunotherapy. Aging Dis. 2013;4:210–20.PubMedCentralPubMedGoogle Scholar
  10. 10.
    Keefover RW. The clinical epidemiology of Alzheimer’s disease. Neurol Clin. 1996;14:337–51.PubMedGoogle Scholar
  11. 11.
    Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, et al. Secreted amyloid β peptide similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 mutations linked to familial Alzheimer’s disease. Nature Med. 1996;2:864–70.PubMedGoogle Scholar
  12. 12.
    Alonso AC, Grundke Iqbal I, Iqbal R. Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nature Med. 1996;2:783–7.PubMedGoogle Scholar
  13. 13.
    Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991;349:704–6.PubMedGoogle Scholar
  14. 14.
    Levy-Lahad E, Wijsman EM, Nemens E, Anderson L, Goddard KA, Weber JL, et al. A familial Alzheimer's disease locus on chromosome 1. Science. 1995;269:970–3.PubMedGoogle Scholar
  15. 15.
    Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995;376:775–8.PubMedGoogle Scholar
  16. 16.
    Wolfe MS. When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 2007;8:136–40.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Selkoe DJ, Podlisny MB, Joachim CL, Vickers EA, Lee G, Fritz LC, et al. Beta-amyloid precursor protein of Alzheimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neural and nonneural tissues. Proc Natl Acad Sci U S A. 1988;85:7341–5.PubMedCentralPubMedGoogle Scholar
  18. 18.
    Gandy S. The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease. J Clin Invest. 2005;115:1121–9.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: Evidence that an initially deposited species is A beta 42(43). Neuron. 1994;13:45–53.PubMedGoogle Scholar
  20. 20.
    Lee VM, Balin BJ, Otvos Jr L, Trojanowski JQ. A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science. 1991;251:675–8.PubMedGoogle Scholar
  21. 21.
    Claeyson S, Cochet M, Donegar R, Dumuis A, Bockaert J, Giannoni P. Alzheimer culprits: cellular crossroads and interplay. Cell Signal. 2012;24:1831–40.Google Scholar
  22. 22.
    Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256:184–5.PubMedGoogle Scholar
  23. 23.
    Jack Jr CR, Wiste HJ, Vemuri P, Weigand SD, Senjem ML, Zeng G, et al. Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer's disease. Brain. 2010;133:3336–48.PubMedGoogle Scholar
  24. 24.
    Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, et al. Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc Natl Acad Sci U S A. 1999;96:3228–33.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Mucke L, Yu GQ, McConlogue L, Rockenstein EM, Abraham CR, Masliah E. Astroglial expression of human alpha(1)-antichymotrypsin enhances alzheimer-like pathology in amyloid protein precursor transgenic mice. Am J Pathol. 2000;157:2003–10.PubMedGoogle Scholar
  26. 26.
    Nalivaeva NN, Turner AJ. The amyloid precursor protein: a biochemical enigma in brain development, function, and disease. FEBS Lett. 2013;587:2046–54.PubMedGoogle Scholar
  27. 27.
    McGeer PL, McGeer EG. The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol. 2013;in press.Google Scholar
  28. 28.
    Carreiras MC, Mendes E, Perry MJ, Francisco AP, Marco-Contellas J. The multifactorial nature of Alzheimer’s disease for developing potential therapeutics. Curr Top Med Chem. 2013;13:1745–70.PubMedGoogle Scholar
  29. 29.
    Okura Y, Matsumoto Y. Recent advances in immunotherapy for Alzheimer’s disease: with special reference to DNA vaccination. Hum Vaccin. 2009;5:373–80.PubMedGoogle Scholar
  30. 30.••
    Bishop GM, Robinson SR. The amyloid hypothesis: let sleeping dogmas lie? Neurobiol Aging. 2002;23:1101–5.PubMedGoogle Scholar
  31. 31.••
    Krstic D, Knuesel I. The airbag problem – a potential culprit for bench-to-bedside translational efforts: relevance for Alzheimer’s disease. Acta Neuropathol Comm. 2013;1:62–9. An interesting and timely re-examination of the underlying premises of the Amyloid Cascade Hypothesis.Google Scholar
  32. 32.
    de la Torre JC. How do heart disease and stroke become risk factors for Alzheimer's Disease? Neurol Res. 2006;28:637–44.PubMedGoogle Scholar
  33. 33.
    Revill P, Moral MA, Prous JR. Impaired insulin signaling and the pathogenesis of Alzheimer's disease. Drugs Today. 2006;42:785–90.PubMedGoogle Scholar
  34. 34.
    Szczygielski J, Mautes A, Steudel WI, Falkai P, Bayer TA, Wirths O. Traumatic brain injury: cause or risk of Alzheimer's disease? A review of experimental studies. J Neural Transm. 2005;112:1547–64.PubMedGoogle Scholar
  35. 35.
    Balin BJ, Gerard HC, Arking EJ, Appelt DM, Branigan PJ, Abrams JT, et al. Identification and localization of Chlamydia pneumoniae in the Alzheimer's brain. Med Microbiol Immunol. 1998;187:23–42.PubMedGoogle Scholar
  36. 36.
    Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA. Herpes simplex virus type 1 in brain and risk of Alzheimer's disease. Lancet. 1997;349:241–4.PubMedGoogle Scholar
  37. 37.
    Miklossy J. Alzheimer's Disease–a spirochetosis? Neuroreport. 1993;4:841–88.PubMedGoogle Scholar
  38. 38.
    Lue LF, Brachova L, Civin WH, Rogers J. Inflammation, A beta deposition, and neurofibrillary tangle formation as correlates of Alzheimer's Disease neurodegeneration. J Neuropathol Exp Neurol. 1996;55:1083–108.PubMedGoogle Scholar
  39. 39.
    Ordovas JM, Litwack-Klein L, Wilson PW, Schaefer MM, Schaefer EJ. Apolipoprotein E isoform phenotyping methodology and population frequency with identification of apoE1 and apoE5 isoforms. J Lipid Res. 1987;28:371–80.PubMedGoogle Scholar
  40. 40.
    Mahley RW. Apolipoprotein E: cholesterol transport protein with an expanding role in cell biology. Science. 1988;240:622–30.PubMedGoogle Scholar
  41. 41.
    Strittmatter WJ. Apolipoprotein E, and Alzheimer's disease: signal transduction mechanisms. Biochem Soc Symp. 2001;67:101–9.PubMedGoogle Scholar
  42. 42.
    Roses AD. Apolipoprotein E, alleles as risk factors in Alzheimer’s disease. Annu Rev Med. 1996;47:387–400.PubMedGoogle Scholar
  43. 43.
    Deary IJ, Whiteman MC, Pattie A, Starr JM, Hayward C, Wright AF, et al. Cognitive change and the APOE epsilon 4 allele. Nature. 2002;418:932.PubMedGoogle Scholar
  44. 44.
    Bennett DA, Wilson RS, Schneider JA, Evans DA, Aggarwal NT, Arnold SE, et al. Apolipoprotein E epsilon4 allele, AD pathology, and the clinical expression of Alzheimer's disease. Neurology. 2003;60:246–52.PubMedGoogle Scholar
  45. 45.
    Swanborg RH, Whittum-Hudson JA, Hudson AP. Infectious agents and multiple sclerosis: are human herpes virus 6 and Chlamydia pneumoniae involved? J Neuroimmunol. 2003;136:1–8.PubMedGoogle Scholar
  46. 46.
    Fazekas F, Strasser-Fuchs S, Kollegger H, Berger T, Kristoferitsch W, Schmidt H, et al. Apolipoprotein E epsilon 4 is associated with rapid progression of multiple sclerosis. Neurology. 2001;57:853–7.PubMedGoogle Scholar
  47. 47.
    Lovestone S, Anderton B, Betts J, Dayanandan R, Gibb G, Ljungberg C, et al. Apolipoprotein E gene and Alzheimer's disease: is tau the link? Biochem Soc Symp. 2001;67:111–20.PubMedGoogle Scholar
  48. 48.
    Huang Y, Liu XQ, Wyss-Coray T, Brecht WJ, Sanan DA, Mahley RW. Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc Natl Acad Sci U S A. 2001;98:8848–53.Google Scholar
  49. 49.
    Hartman RE, Laurer H, Longhi L, Bales KR, Paul SM, McIntosh TK, et al. Apolipoprotein E4 influences amyloid deposition but not cell loss after traumatic brain injury in a mouse model of Alzheimer's disease. J Neurosci. 2002;22:10083–7.PubMedGoogle Scholar
  50. 50.
    Hashimoto T, Serrano-Pozo A, Hori Y, Adams KW, Takeda S, Banerji AO, et al. Apolipoprotein E, especially apolipoprotein E4, enhances the oligomerization of amyloid β peptide. J Neurosci. 2012;32:15181–92.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Carter DB. The interaction of amyloid-beta with apoE. Subcell Biochem. 2005;38:255–72.PubMedGoogle Scholar
  52. 52.
    Puglielli L, Tanzi RE, Kovacs DM. Alzheimer’s disease: the cholesterol connection. Nat Neurosci. 2003;6:345–51.PubMedGoogle Scholar
  53. 53.
    Gerard HC, Wildt KL, Whittum-Hudson JA, Lai Z, Ager JL, Hudson AP. The load of Chlamydia pneumoniae in the Alzheimer’s brain varies with APOE genotype. Microbiol Pathog. 2005;39:19–26.Google Scholar
  54. 54.
    Sastra M, Richardson JC, Gentleman SM, Brooks DJ. Inflammatory risk factors and pathologies associated with Alzheimer’s disease. Curr Alzheimers Res. 2011;8:132–41.Google Scholar
  55. 55.••
    Meraz-Ríos MA, Toral-Rios D, Franco-Bocanegra D, Villeda-Hernández J, Campos-Peña V. The inflammatory process in Alzheimer disease. Front Integr Neurosci. 2013;7:59. doi:10.3389/fnint.2013.00059. An important examination of the role of inflammation in the pathogenesis of Alzheimer’s disease.PubMedGoogle Scholar
  56. 56.
    Breitner JC. The role of anti-inflammatory drugs in the prevention and treatment of Alzheimer’s disease. Annu Rev Med. 1996;47:401–11.PubMedGoogle Scholar
  57. 57.
    Pasinetti GM. From epidemiology to therapeutic trials with anti-inflammatory drugs in Alzheimer's disease: the role of NSAIDs and cyclo-oxygenase in beta-amyloidosis and clinical dementia. J Alzheimers Dis. 2002;4:435–45.PubMedGoogle Scholar
  58. 58.
    Wood PL. Role of CNS macrophages in neurodegeneration. In: Wood PL, editor. Neuroinflammation mechanisms and management. Totowa: Humana Press; 1998. p. 1–59.Google Scholar
  59. 59.••
    Tanzi RE. The genetics of Alzheimer’s disease. Cold Spring Harb Perspect Med. 2012;2:doi:10.1101/cshperspect.a006296. A current and thorough review of genome studies relating to the underlying genetics of Alzheimer’s disease.
  60. 60.
    Ebbert MT, Ridge PG, Wilson AR, Sharp AR, Bailey M, Norton MC, Tschanz JT, Munger RG, Corcoran CD, Kauwe JS. Population-based analysis of Alzheimer's Disease risk alleles implicates genetic interactions. Biol Psychiatry. 2013;in press.Google Scholar
  61. 61.
    Kamboh MI, Demirci FY, Wang X, Minster RL, Carrasquillo MM, Pankratz VS, et al. Genome-wide association study of Alzheimer’s disease. Transl Psychiatry. 2012;2:e117.PubMedCentralPubMedGoogle Scholar
  62. 62.
    Kauwe JS, Cruchaga C, Karch CM, Sadler B, Lee M, Mayo K, et al. Fine mapping of genetic variants in BIN1, CLU, CR1 and PICALM for association with cerebrospinal fluid biomarkers for Alzheimer's disease. PLoS One. 2011;6:e15918.PubMedCentralPubMedGoogle Scholar
  63. 63.
    Hu X, Pickering E, Liu YC, Hall S, Fournier H, Katz E, et al. Meta-analysis for genome-wide association study identifies multiple variants at the BIN1 locus associated with late-onset Alzheimer's disease. PLoS One. 2011;6:e16616.PubMedCentralPubMedGoogle Scholar
  64. 64.
    Walton JR. Aluminum involvement in the progression of Alzheimer’s disease. J Alzheimers Dis. 2013;35:7–43.PubMedGoogle Scholar
  65. 65.
    Perl DP, Pendlebury WW. Aluminum neurotoxicity – potential role in the pathogenesis of neurofibrillary tangle formation. Can J Neurol Sci. 1986;13:441–5.PubMedGoogle Scholar
  66. 66.
    Perl DP, Moalem S. Aluminum and Alzheimer’s disease: a personal perspective after twenty-five years. J Alzheimers Dis. 2006;9:291–300.PubMedGoogle Scholar
  67. 67.
    Walton JR. Aluminum disruption of calcium homeostasis and signal transduction resembles change in aging and Alzheimer’s disease. J Alzheimers Dis. 2012;29:255–73.PubMedGoogle Scholar
  68. 68.
    Moulton PV, Yang W. Air pollution, oxidative stress, and Alzheimer’s disease. J Environ Pub Health. 2012:472751. doi:10.1155/2012/472751.
  69. 69.
    Cherry JD, Liu B, Frost JL, Lemere CA, Williams JP, Olschowka JA, et al. Galactic cosmic radiation leads to cognitive impairment and increased aβ plaque accumulation in a mouse model of Alzheimer's disease. PLoS One. 2012;7:e53275.PubMedCentralPubMedGoogle Scholar
  70. 70.
    Gérard HC, Dreses-Werringloer U, Wildt KS, Oszust C, Balin BJ, Frey WH, et al. Chlamydia (Chlamydophila) pneumoniae in the Alzheimer’s brain. FEMS Immunol Med Microbiol. 2006;48:355–66.PubMedGoogle Scholar
  71. 71.
    Hammond CJ, Hallock LR, Howanski RJ, Appelt DM, Little CS, Balin BJ. Immunohistological detection of Chlamydia pneumoniae in the Alzheimer's disease brain. BMC Neurosci. 2010;11:121.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Hu J, Van Eldik L. Glial-derived proteins activate cultures astrocytes and enhance beta amyloid-induced glial activation. Brain Res. 1999;842:46–54.PubMedGoogle Scholar
  73. 73.
    Simpson JE, Newcombe J, Cuzner ML, Woodroofe MN. Expression of monocyte chemoattractant protein-1 and other beta-chemokines by resident glia and inflammatory cells in multiple sclerosis lesions. J Neuroimmunol. 1998;84:238–49.PubMedGoogle Scholar
  74. 74.
    Boelen E, Steinbusch HW, van der Ven AJ, Grauls G, Bruggeman CA, Stassen FR. Chlamydia pneumoniae infection of brain cells: an in vitro study. Neurobiol Aging. 2007;28:524–32.PubMedGoogle Scholar
  75. 75.
    Roulis E, Polkinghome A, Timms P. Chlamydia pneumoniae: modern insights into an ancient pathogen. Trends Microbiol. 2013;21:120–8.PubMedGoogle Scholar
  76. 76.
    Gérard HC, Fomicheva E, Whittum-Hudson JA, Hudson AP. Apolipoprotein E4 enhances attachment of Chlamydophila (Chlamydia) pneumoniae elementary bodies to host cells. Microb Pathog. 2008;44:279–85.PubMedGoogle Scholar
  77. 77.
    Little CS, Hammond CJ, MacIntyre A, Balin BJ, Appelt DM. Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice. Neurobiol Aging. 2004;25:419–25.PubMedGoogle Scholar
  78. 78.
    Kountouras J, Boziki M, Zavos C, Gavalas E, Giartza-Taxidou E, Venizelos I, et al. A potential impact of chronic Helicobacter pylori infection on Alzheimer's disease pathobiology and course. Neurobiol Aging. 2012;33:e3–4.PubMedGoogle Scholar
  79. 79.
    Jung BK, Pyo KH, Shin KY, Hwang YS, Lim H, Lee SJ, et al. Toxoplasma gondii infection in the brain inhibits neuronal degeneration and learning and memory impairments in a murine model of Alzheimer's disease. PLoS One. 2012;7:e33312.PubMedCentralPubMedGoogle Scholar
  80. 80.
    Itzhaki RF, Wozniak MA. Herpes simplex virus type 1 in Alzheimer's disease: the enemy within. J Alzheimers Dis. 2008;13:393–405.PubMedGoogle Scholar
  81. 81.
    Lurain NS, Hanson BA, Martinson J, Leurgans SE, Landay AL, Bennett DA, et al. Virological and immunological characteristics of human cytomegalovirus infection associated with Alzheimer disease. J Infect Dis. 2013;208:564–72.PubMedGoogle Scholar
  82. 82.•
    Miklossy J. Emerging roles of pathogens in Alzheimer’s disease. Exp Rev Mol Med. 2011;13:e30. An interesting review of the possible role of infectious agents in the genesis of Alzheimer’s disease.Google Scholar
  83. 83.
    Krstic D, Madhusudan A, Doehner J, Vogel P, Notter T, Imhof C, et al. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J Neuroinflammation. 2012;9:151–9.PubMedCentralPubMedGoogle Scholar
  84. 84.
    Reis HJ, Mukhamedyarov MA, Rizvanov AA, Palotás A. A new story about an old guy: is Alzheimer’s disease infectious? Neurodegener Dis. 2011;7:272–8.Google Scholar
  85. 85.
    Nochlin D, Shaw CM, Campbell LA, Kuo CC. Failure to detect Chlamydia pneumoniae in brain tissues of Alzheimer's disease. Neurology. 1999;53:1888.PubMedGoogle Scholar
  86. 86.
    Ring RH, Lyons JM. Failure to detect Chlamydia pneumoniae in the late-onset Alzheimer’s brain. J Clin Microbiol. 2000;38:2591–4.PubMedCentralPubMedGoogle Scholar
  87. 87.
    Gieffers J, Reusche E, Solbach W, Maass M. Failure to detect Chlamydia pneumoniae in brain sections of Alzheimer’s disease patients. J Clin Microbiol. 2000;38:881–2.PubMedCentralPubMedGoogle Scholar
  88. 88.
    Prvulovic D, Hampel H. Amyloid β (Aβ) and phosphor-tau (p-tau) as biomarkers in Alzheimer’s disease. Clin Chem Lab Med. 2011;49:367–74.PubMedGoogle Scholar
  89. 89.
    Hampel H, Mitchell A, Blennow K, Frank RA, Brettschneider S, Weller L, et al. Core biological marker candidates of Alzheimer's disease - perspectives for diagnosis, prediction of outcome and reflection of biological activity. J Neural Transm. 2004;111:247–72.PubMedGoogle Scholar
  90. 90.
    Risacher SL, Saykin AJ, West JD, Shen L, Firpi HA, McDonald BC, et al. Baseline MRI predictors of conversion from MCI to probable AD in the ADNI cohort. Curr Alzheimers Res. 2009;6:347–61.Google Scholar
  91. 91.
    Teipel SJ, Grothe M, Lista S, Toschi N, Garaci FG, Hampel H. Relevance of magnetic resonance imaging for early detection and diagnosis of Alzheimer’s disease. Med Clin North Am. 2013;97:399–424.PubMedGoogle Scholar
  92. 92.
    95 Stamps JJ, Bartoshuk LM, Heilman KM. A brief olfactory test for Alzheimer’s disease. J Neurol Sci. 2013;in press.Google Scholar
  93. 93.
    Djordjevic J, Jones-Gotman M, De Sousa K, Chertkow H. Olfaction in mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging. 2008;29:693–706.PubMedGoogle Scholar
  94. 94.
    Lau P, de Strooper B. Dysregulated microRNAs in neurodegenerative disorders. Semin Cell Dev Biol. 2010;21:768–73.PubMedGoogle Scholar
  95. 95.
    Sonntag KC. MicroRNAs and deregulated gene expression networks in neurodegeneration. Brain Res. 2010;1338:48–57.PubMedGoogle Scholar
  96. 96.
    Holohan KN, Lahiri DK, Schneider BP, Foroud T, Saykin AJ. Functional microRNAs in Alzheimer’s disease and cancer: differential regulation of common mechanisms and pathways. Front Gen. 2013;3:323.Google Scholar
  97. 97.
    Lukiw WJ. NF-ΚB-regulated micro RNAs (miRNAs) in primary human brain cells. Exp Neurol. 2012;235:484–90.PubMedCentralPubMedGoogle Scholar
  98. 98.
    Sethi P, Lukiw WJ. Micro-RNA abundance and stability in human brain: specific alterations in Alzheimer’s disease temporal lobe neocortex. Neurosci Lett. 2009;459:100–4.PubMedGoogle Scholar
  99. 99.
    Cogswell JP, Ward J, Taylor IA, Waters M, Shi Y, Cannon B, et al. Identification of miRNA changes in Alzheimer’s disease brain and CSF yields putative biomarkers and insights into disease pathways. J Alzheimers Dis. 2008;14:27–41.PubMedGoogle Scholar
  100. 100.
    Lukiw WJ, Zhao Y, Cui JG. An NF-KB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem. 2008;283:31315–22.PubMedGoogle Scholar
  101. 101.
    Lukiw WJ, Alexandrov PN. Regulation of complement factor H (CFH) by multiple miRNAs in Alzheimer’s disease (AD) brain. Mol Neurobiol. 2012;46:11–9.PubMedCentralPubMedGoogle Scholar
  102. 102.
    Wang WX, Huang Q, Hu Y, Stromberg AJ, Nelson PT. Patterns of microRNA expression in normal and early Alzheimer’s disease human temporal cortex: white matter versus gray matter. Acta Neuropathol. 2011;121:193–205.PubMedCentralPubMedGoogle Scholar
  103. 103.
    Hebert SS, Horre K, Nicolai L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, et al. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci U S A. 2008;105:6415–20.PubMedCentralPubMedGoogle Scholar
  104. 104.•
    Rafii MS. Update on Alzheimer’s disease therapeutics. Rev Recent Clin Trials. 2013;in press. As the title indicates, a review on the current and potential therapeutics for the disease. Google Scholar
  105. 105.
    Zurita MP, Muñoz G, Sepúlveda FJ, Gómez P, Castillo C, Burgos CF, et al. Ibuprofen inhibits the synaptic failure induced by the amyloid-β peptide in hippocampal neurons. J Alzheimers Dis. 2013;35:463–73.PubMedGoogle Scholar
  106. 106.
    Gasparini L, Rusconi L, Xu H, del Soldato P, Ongini E. Modulation of beta-amyloid metabolism by non-steroidal anti-inflammatory drugs in neuronal cell cultures. J Neurochem. 2004;337–48.Google Scholar
  107. 107.
    Ho L, Qin W, Stetka BS, Pasinetti GM. Is there a future for cyclo-oxygenase inhibitors in Alzheimer's disease? CNS Drugs. 2006;20:85–98.PubMedGoogle Scholar
  108. 108.
    Walker D, Lue LF. Anti-inflammatory and immune therapy for Alzheimer's disease: current status and future directions. Curr Neuropharmacol. 2007;5:232–43.PubMedGoogle Scholar
  109. 109.
    Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003;61:46e54.Google Scholar
  110. 110.
    Hanson LR, Frey WH. Intranasal delivery bypasses the blood–brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci. 2008;9:S5.PubMedCentralPubMedGoogle Scholar
  111. 111.
    Dhuria SV, Hanson LR, Frey WH. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci. 2010;99:1654–53.PubMedGoogle Scholar
  112. 112.•
    De Rosa G, Salzano G, Caraglia M, Abbruzzese A. Nanotechnologies: a strategy to overcome blood–brain barrier. Curr Drug Metab. 2012;13:61–9. A good review of current thinking regarding nanotechnological approaches to the delivery of therapeutic molecules to the central nervous system.PubMedGoogle Scholar
  113. 113.
    Michelia M-R, Bovab R, Maginib A, Polidorob M, Emiliani C. Lipid-based nanocarriers for CNS-targeted drug delivery. Recent Patients CNS Drug Discov. 2012;7:71–86.Google Scholar
  114. 114.
    Silva GA. Nanotechnology approaches to crossing the blood brain barrier and drug delivery to the CNS. BMC Neurosci. 2008;9:S4.PubMedCentralPubMedGoogle Scholar
  115. 115.
    Silva GA. Nanotechnology applications and approaches for neuroregeneration and drug delivery to the central nervous system. Ann N Y Acad Sci. 2010;99:221–30.Google Scholar
  116. 116.
    Syed S, Zubair A, Frieri M. Immune response to nanomaterials: implications for medicine and literature review. Curr Asthma Allergy Rep. 2012;13:50–7.Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Pathology, Microbiology, Immunology, and Forensic MedicinePhiladelphia College of Osteopathic MedicinePhiladelphiaUSA
  2. 2.Department of Immunology and MicrobiologyWayne State University School of MedicineDetroitUSA

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