title: Disease-modifying therapies in Alzheimer's disease: how far have we come?
abstract: Currently, there are no disease-modifying therapies available for Alzheimer's disease (AD). Acetylcholinesterase inhibitors and memantine are licensed for AD and have moderate symptomatic benefits. Epidemiological studies have suggested that NSAIDs, estrogen, HMG-CoA reductase inhibitors (statins) or tocopherol (vitamin E) can prevent AD. However, prospective, randomised studies have not convincingly been able to demonstrate clinical efficacy. Major progress in molecular medicine suggests further drug targets. The metabolism of the amyloid-precursor protein and the aggregation of its Abeta fragment are the focus of current studies. Abeta peptides are produced by the enzymes beta- and gamma-secretase. Inhibition of gamma-secretase has been shown to reduce Abeta production. However, gamma-secretase activity is also involved in other vital physiological pathways. Involvement of gamma-secretase in cell differentiation may preclude complete blockade of gamma-secretase for prolonged times in vivo. Inhibition of beta-secretase seems to be devoid of serious adverse effects according to studies with knockout animals. However, targeting beta-secretase is hampered by the lack of suitable inhibitors to date. Other approaches focus on enzymes that cut inside the Abeta sequence such as alpha-secretase and neprilysin. Stimulation of the expression or activity of alpha-secretase or neprilysin has been shown to enhance Abeta degradation. Furthermore, inhibitors of Abeta aggregation have been described and clinical trials have been initiated. Peroxisome proliferator activated receptor-gamma agonists and selected NSAIDs may be suitable to modulate both Abeta production and inflammatory activation. On the basis of autopsy reports, active immunisation against Abeta in humans seems to have proven its ability to clear amyloid deposits from the brain. However, a first clinical trial with active vaccination against the full length Abeta peptide has been halted because of adverse effects. Further trials with vaccination or passive transfer of antibodies are planned.
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Freiburg, Hauptstrasse 5, D-79108 Freiburg, Germany. michael.huell@uniklinik-freiburg.de
authors.forename: Michael
authors.initials: M
authors.lastname: Hüll
authors.forename: Mathias
authors.initials: M
authors.lastname: Berger
authors.forename: Michael
authors.initials: M
authors.lastname: Heneka
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000682:Amyloid / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004789:Enzyme Activation; D004967:Estrogens / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007167:Immunotherapy; D008559:Memantine / Q000627:therapeutic use; D008666:Metalloendopeptidases / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000627:therapeutic use; D009414:Nerve Growth Factors / Q000627:therapeutic use; D047495:PPAR gamma / Q000819:agonists; D017891:Pharmacoepidemiology; D016875:tau Proteins / Q000502:physiology
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D004967:Estrogens; D018691:Excitatory Amino Acid Antagonists; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008996:Monoamine Oxidase Inhibitors; D009414:Nerve Growth Factors; D047495:PPAR gamma; D016875:tau Proteins; D007987:Gonadotropin-Releasing Hormone; D053829:Amyloid Precursor Protein Secretases; D008666:Metalloendopeptidases; D008559:Memantine