Journal of Neurology

, Volume 259, Issue 2, pp 201–211 | Cite as

Progress in Alzheimer’s disease



After more than one century from Alois Alzheimer and Gaetano Perusini’s first report, progress has been made in understanding the pathogenic steps of Alzheimer’s disease (AD), as well as in its early diagnosis. This review discusses recent findings leading to the formulation of novel criteria for diagnosis of the disease even in a preclinical phase, by using biological markers. In addition, treatment options will be discussed, with emphasis on new disease-modifying compounds and future trial design suitable to test these drugs in an early phase of the disease.


Alzheimer’s disease Amyloid Tau Inflammation Genetics Biomarkers Diagnosis Disease-modifying drugs 


  1. 1.
    Griffin WS (2006) Inflammation and neurodegenerative diseases. Am J Clin Nutr 3(suppl):470S–474SGoogle Scholar
  2. 2.
    Galimberti D, Fenoglio C, Scarpini E (2008) Inflammation in neurodegenerative disorders: friend or foe? Curr Aging Sci 1(1):30–41PubMedCrossRefGoogle Scholar
  3. 3.
    Reddy VP, Zhu X, Perry G, Smith MA (2009) Oxidative stress in diabetes and Alzheimer’s disease. J Alzheimers Dis 16(4):763–774PubMedGoogle Scholar
  4. 4.
    Adlard PA, Bush AI (2006) Metals and Alzheimer’s disease. J Alzheimers Dis 10(2–3):145–163PubMedGoogle Scholar
  5. 5.
    Santos RX, Correia SC, Wang X, Perry G, Smith MA, Moreira PI, Zhu X (2010) Alzheimer’s disease: diverse aspects of mitochondrial malfunctioning. Int J Clin Exp Pathol 3(6):570–581PubMedGoogle Scholar
  6. 6.
    Pimplikar SW, Nixon RA, Robakis NK, Shen J, Tsai LH (2010) Amyloid-independent mechanisms in Alzheimer’s disease pathogenesis. J Neurosci 30(45):14946–14954PubMedCrossRefGoogle Scholar
  7. 7.
    Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek DC (1987) Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease. Science 235(4791):877–880PubMedCrossRefGoogle Scholar
  8. 8.
    Robakis NK, Ramakrishna N, Wolfe G, Wisniewski HM (1987) Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides. Proc Natl Acad Sci USA 84(12):4190–4194PubMedCrossRefGoogle Scholar
  9. 9.
    Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St George-Hyslop P, Van Keuren ML et al (1987) Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 235(4791):880–884PubMedCrossRefGoogle Scholar
  10. 10.
    Vassar R (2004) BACE1: the beta-secretase enzyme in Alzheimer’s disease. J Mol Neurosci 23(1–2):105–114PubMedCrossRefGoogle Scholar
  11. 11.
    Allinson TM, Parkin ET, Turner AJ, Hooper NM (2003) ADAMs family members as amyloid precursor protein alpha-secretases. J Neurosci Res 74(3):342–352PubMedCrossRefGoogle Scholar
  12. 12.
    Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C (2003) Reconstitution of gamma-secretase activity. Nat Cell Biol 5(5):486–488PubMedCrossRefGoogle Scholar
  13. 13.
    Crews L, Masliah E (2010) Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum Mol Genet 19(1):R12–R20PubMedCrossRefGoogle Scholar
  14. 14.
    Castellani RJ, Nunomura A, Lee H, Perry G, Smith MA (2008) Phosphorylated tau: toxic, protective, or none of the above. J Alzheimers Dis 14:377–383PubMedGoogle Scholar
  15. 15.
    Jack CRJ Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW et al (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 9:119–128PubMedCrossRefGoogle Scholar
  16. 16.
    McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944PubMedGoogle Scholar
  17. 17.
    Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J et al (2007) Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 6(8):734–746PubMedCrossRefGoogle Scholar
  18. 18.
    Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E (1999) Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 56(3):303–308PubMedCrossRefGoogle Scholar
  19. 19.
    Bouwman FH, Verwey NA, Klein M, Kok A, Blankenstein MA, Sluimer JD et al (2010) New research criteria for the diagnosis of Alzheimer’s disease applied in a memory clinic population. Dement Geriatr Cogn Disord 30(1):1–7PubMedCrossRefGoogle Scholar
  20. 20.
    de Jager CA, Honey TE, Birks J, Wilcock GK (2010) Retrospective evaluation of revised criteria for the diagnosis of Alzheimer’s disease using a cohort with post-mortem diagnosis. Int J Geriatr Psychiatry 25(10):988–997PubMedCrossRefGoogle Scholar
  21. 21.
    Frisoni GB, Galluzzi S, Signorini M, Garibotto V, Paghera B, Binetti G et al (2010) Preliminary evidence of validity of the revised criteria for Alzheimer disease diagnosis: report of 2 cases. Alzheimer Dis Assoc Disord 24(1):108–114PubMedCrossRefGoogle Scholar
  22. 22.
    Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P et al (2010) Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 9(11):1118–1127PubMedCrossRefGoogle Scholar
  23. 23.
    Jack RJ Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC et al (2011) Introduction to the recommendations from the National Institute on Aging and the Alzheimer’s Association workgroup on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3):257–262PubMedCrossRefGoogle Scholar
  24. 24.
    McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH et al (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging and the Alzheimer’s Association workgroup. Alzheimers Dement 7(3):263–269PubMedCrossRefGoogle Scholar
  25. 25.
    Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC et al (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging and Alzheimer’s Association workgroup. Alzheimers Dement 7(3):270–279PubMedCrossRefGoogle Scholar
  26. 26.
    Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM et al (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging and the Alzheimer’s Association workgroup. Alzheimers Dement 7(3):280–292PubMedCrossRefGoogle Scholar
  27. 27.
    Lawrence AD, Sahakian BJ (1998) The cognitive psychopharmacology of Alzheimer’s disease: focus on cholinergic systems. Neurochem Res 23(5):787–794PubMedCrossRefGoogle Scholar
  28. 28.
    Farlow M (2002) A clinical overview of cholinesterase inhibitors in Alzheimer’s disease. Int Psychogeriatr/IPA 14(Suppl 1):93–126CrossRefGoogle Scholar
  29. 29.
    Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E et al (2004) Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial. Lancet 363(9427):2105–2115PubMedCrossRefGoogle Scholar
  30. 30.
    Birks J (2006) Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 1:CD005593PubMedGoogle Scholar
  31. 31.
    Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M et al (2008) Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med 148(5):379–397PubMedGoogle Scholar
  32. 32.
    Alva G, Cummings JL (2008) Relative tolerability of Alzheimer’s disease treatments. Psychiatry (Edgmont) 5(11):27–36Google Scholar
  33. 33.
    Scarpini E, Scheltens P, Feldman H (2003) Treatment of Alzheimer’s disease: current status and new perspectives. Lancet Neurol 2(9):539–547Google Scholar
  34. 34.
    Gervais F, Chalifour R, Garceau D, Kong X, Laurin J, Mclaughlin R et al (2001) Glycosaminoglycan mimetics: a therapeutic approach to cerebral amyloid angiopathy. Amyloid 8(Suppl 1):28–35PubMedGoogle Scholar
  35. 35.
    Aisen PS, Saumier D, Briand R, Laurin J, Gervais F, Tremblay P et al (2006) A phase II study targeting amyloid-beta with 3APS in mild-to-moderate Alzheimer disease. Neurology 67(10):1757–1763PubMedCrossRefGoogle Scholar
  36. 36.
    Galimberti D, Scarpini E (2011) Alzheimer’s disease: from pathogenesis to disease-modifying approaches. CNS Neurol Disord Drug Targets 10(2):163–174PubMedGoogle Scholar
  37. 37.
    Santa-Maria I, Hernández F, Del Rio J, Moreno FJ, Avila J (2007) Tramiprosate, a drug of potential interest for the treatment of Alzheimer’s disease, promotes an abnormal aggregation of tau. Mol Neurodegener 2(1):17PubMedCrossRefGoogle Scholar
  38. 38.
    Leszek J, Inglot AD, Janusz M, Lisowski J, Krukowska K, Georgiades JA (1999) Colostrinin: a proline-rich polypeptide (PRP) complex isolated from ovine colostrum for treatment of Alzheimer’s disease. A double-blind, placebo-controlled study. Arch Immunol Ther Exp (Warsz) 47(6):377–385Google Scholar
  39. 39.
    Bilikiewicz A, Gaus W (2004) Colostrinin (a naturally occurring, proline-rich, polypeptide mixture) in the treatment of Alzheimer’s disease. J Alzheimer’s Dis 6:17–26Google Scholar
  40. 40.
    Townsend KP, Praticò D (2005) Novel therapeutic opportunities for Alzheimer’s disease: focus on nonsteroidal anti-inflammatory drugs. FASEB J 19(12):1592–1601PubMedCrossRefGoogle Scholar
  41. 41.
    Schenk D, Barbour R, Dunn W (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in PDAPP mouse. Nature 400:173–177PubMedCrossRefGoogle Scholar
  42. 42.
    Gilman S, Koller M, Black RS (2005) Clinical effects of Aβ immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64:1553–1562PubMedCrossRefGoogle Scholar
  43. 43.
    Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A et al (2008) Long-term effect of Aβ42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372:216–223PubMedCrossRefGoogle Scholar
  44. 44.
    Grundman M, Black R (2008) Clinical trials of bapineuzumab, a beta-amyloid targeted immunotherapy in patients with mild to moderate Alzheimer’s disease. Alzheimers Dement 4(Suppl.2):T166Google Scholar
  45. 45.
    Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE et al (2010) 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol 9(4):363–372PubMedCrossRefGoogle Scholar
  46. 46.
    Dodel R, Neff F, Noelker C, Pul R, Du Y, Bacher M et al (2010) Intravenous immunoglobulins as a treatment for Alzheimer’s disease: rationale and current evidence. Drugs 70(5):513–528PubMedCrossRefGoogle Scholar
  47. 47.
    Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU et al (2001) A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 414(6860):212–216PubMedCrossRefGoogle Scholar
  48. 48.
    Beher D, Clarke EE, Wrigley JD, Martin AC, Nadin A, Churcher I et al (2004) Selected nonsteroidal anti-inflammatory drugs and their derivatives target γ-secretase at a novel site: evidence for an allosteric mechanism. J Biol Chem 279:43419–43426PubMedCrossRefGoogle Scholar
  49. 49.
    Kukar T, Prescott S, Eriksen JL, Holloway V, Murphy MP, Koo EH et al (2007) Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neurosci 8:54PubMedCrossRefGoogle Scholar
  50. 50.
    Galasko DR, Graff-Radford N, May S, Hendrix S, Cottrell BA, Sagi SA et al (2007) Safety, tolerability, pharmacokinetics, and Aβ levels after short-term administration of R-flurbiprofen in healthy elderly individuals. Alzheimer Dis Assoc Disord 21(4):292–299PubMedCrossRefGoogle Scholar
  51. 51.
    Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA et al (2008) Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: a randomised phase II trial. Lancet Neurol 7(6):483–493PubMedCrossRefGoogle Scholar
  52. 52.
    Pollack SJ, Lewis H (2005) Secretase inhibitors for Alzheimer’s disease: challenges of promiscuous protease. Curr Opin Investig Drugs 6:35–47PubMedGoogle Scholar
  53. 53.
    Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T et al (2004) Chronic treatment with the γ-secretase inhibitor LY-411, 575 inhibit β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 279:12876–12882PubMedCrossRefGoogle Scholar
  54. 54.
    Siemers E, Skinner M, Dean RA, Gonzales C, Satterwhite J, Farlow M et al (2005) Safety, tolerability, and changes in in amyloid β concentrations after administration of a γ-secretase inhibitor in volunteers. Clin Neuropharmacol 28:126–132PubMedCrossRefGoogle Scholar
  55. 55.
    Siemers ER, Quinn JF, Kaye J, Farlow MR, Porsteinsson A, Tariot P et al (2006) Effects of a γ-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 66:602–604PubMedCrossRefGoogle Scholar
  56. 56.
    Marcade M, Bourdin J, Loiseau N, Peillon H, Rayer A, Drouin D et al (2008) Etazolate, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor protein processing. J Neurochem 106(1):392–404PubMedCrossRefGoogle Scholar
  57. 57.
    Wischik CM, Edwards PC, Lai RY, Roth M, Harrington CR (1996) Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc Natl Acad Sci USA 93(20):11213–11218PubMedCrossRefGoogle Scholar
  58. 58.
    Balaraman Y, Limaye AR, Levey AI, Srinivasan S (2006) Glycogen synthase kinase 3β and Alzheimer’s disease: pathophysiological and therapeutic significance. Cell Mol Life Sci 63:1226–1235PubMedCrossRefGoogle Scholar
  59. 59.
    Martinez A, Perez DI (2008) GSK-3 inhibitors: a ray of hope for the treatment of Alzheimer’s disease? J Alzheimers Dis 15:181–191PubMedGoogle Scholar
  60. 60.
    Schneider A, Mandelkow E (2008) Tau-based treatment strategies in neurodegenerative diseases. Neurotherapeutics 5:443–457PubMedCrossRefGoogle Scholar
  61. 61.
    McGeer PL, Schulzer M, Mc Geer EG (1996) Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology 47:425–432PubMedGoogle Scholar
  62. 62.
    Reines SA, Block GA, Morris JC, Liu G, Nessly ML, Lines CR et al (2004) Rofecoxib Protocol 091 Study Group. Rofecoxib: no effect on Alzheimer’s disease in a 1-year, randomized, blinded, controlled study. Neurology 62:66–71PubMedGoogle Scholar
  63. 63.
    Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL et al (2003) Effects of rofecoxib or naproxen vs placebo on Alzheimer’s disease progression: a randomized controlled trial. JAMA 289:2819–2826PubMedCrossRefGoogle Scholar
  64. 64.
    Scharf S, Mander A, Ugoni A, Vajda F, Christophidis N (1999) A double-blind, placebo controlled trial of diclofenac/misoprostol in Alzheimer’s disease. Neurology 53:197–201PubMedGoogle Scholar
  65. 65.
    Soininen H, West C, Robbins J, Niculescu L (2007) Long-term efficacy and safety of celecoxib in Alzheimer’s disease. Dement Geriatr Cogn Disord 23(1):8–21PubMedCrossRefGoogle Scholar
  66. 66.
    Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC et al (2003) NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lowe Abeta 42 in vivo. J Clin Invest 112(3):440–449PubMedGoogle Scholar
  67. 67.
    Aisen PS, Marin DB, Brickman AM, Santoro J, Fusco M (2001) Pilot tolerability studies of hydroxychloroquine and colchicine in Alzheimer disease. Alz Dis Assoc Disord 15(2):96–101CrossRefGoogle Scholar
  68. 68.
    Aisen PS, Schmeidler J, Pasinetti GM (2002) Randomized pilot study of nimesulide treatment in Alzheimer’s disease. Neurology 58(7):1050–1054PubMedGoogle Scholar
  69. 69.
    Rogers J, Kirby LC, Hempelman SR, Berry DL, McGeer PL, Kaszniak AW et al (1993) Clinical trial of indomethacin in Alzheimer’s disease. Neurology 43:1609–1611PubMedGoogle Scholar
  70. 70.
    Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF et al (2008) High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA 300(15):1774–1783PubMedCrossRefGoogle Scholar
  71. 71.
    Barten DM, Albright CF (2008) Therapeutic strategies for Alzheimer’s disease. Mol Neurobiol 37:171–186PubMedCrossRefGoogle Scholar
  72. 72.
    Bush AI, Pettingell WH, Multhaup G, Paradis M, Vonsattel JP, Gusella JF et al (1994) Rapid induction of Alzheimer Aβ amyloid formation by zinc. Science 265:1464–1467PubMedCrossRefGoogle Scholar
  73. 73.
    Bush AI (2008) Drug development based on the metals hypothesis of Alzheimer’s disease. J Alzheimers Dis 15:223–240PubMedGoogle Scholar
  74. 74.
    Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA et al (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 30:665–676PubMedCrossRefGoogle Scholar
  75. 75.
    Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J et al (2008) Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomized, placebo-controlled trial. Lancet Neurol 7(9):779–786PubMedCrossRefGoogle Scholar
  76. 76.
    Ritchie CW, Bush AI, Mackinnon, Macfarlane S, Mastwyk M, MacGregor L et al (2003) Metal-protein attenuation with iodochlorhydroxyquin (Clioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer disease. Arch Neurol 60:1685–1691PubMedCrossRefGoogle Scholar
  77. 77.
    Jenagaratnam L, McShane R (2006) Clioquinol for the treatment of Alzheimer’s disease. Cochrane Database Syst Rev 25(1):CD005380Google Scholar
  78. 78.
    Aisen PS, Andrieu S, Sampaio C, Carrillo M, Khachaturian ZS, Dubois B et al (2011) Report of the task force on designing clinical trials in early (predementia) AD. Neurology 76(3):280–286PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of Neurological Sciences, “Dino Ferrari” Center, Fondazione Cà Granda, IRCCS Ospedale Maggiore PoliclinicoUniversity of MilanMilanItaly

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