Abeta42 lowering agents

Abstract

The invention provides a method of preventing, delaying, or reversing the progression of Alzheimer's disease by administering an Aβ 42 lowering agent to a mammal under conditions in which levels of Aβ 42 are selectively reduced, levels of Aβ 38 are increased, and levels of Aβ 40 are unchanged. The invention provides methods and materials for developing and identifying Aβ 42 lowering agents. In addition, the invention provides methods for identifying agents that increase the risk of developing, or hasten progression of, Alzheimer's disease. The invention also provides compositions of Aβ 42 lowering agents and antioxidants, Aβ 42 lowering agents and non-selective secretase inhibitors, as well as Aβ 42 lowering agents and acetylcholinesterase inhibitors. The invention also provides kits containing Aβ 42 lowering agents, antioxidants, non-selective secretase inhibitors, and/or acetylcholinesterase inhibitors as well as instructions related to dose regimens for Aβ 42 lowering agents, antioxidants, non-selective secretase inhibitors, and acetylcholinesterase inhibitors.

1 . A method of identifying a selective Aβ 42  lowering agent capable of reducing the ratio of Aβ 42  to Aβ 40  comprising the steps of: (a) identifying a candidate Aβ 42  lowering agent; (b) contacting said candidate Aβ 42  lowering agent with a biological composition capable of producing Aβ 42  and Aβ 40 ; (c) comparing the ratio of Aβ 42  to Aβ 40  in said biological composition contacted with said candidate Aβ 42  lowering agent to the ratio of Aβ 42  to Aβ 40  in a biological composition not contacted with said candidate Aβ 42  lowering agent; (d) identifying said candidate Aβ 42  lowering agent as a selective Aβ 42  lowering agent if a reduction in the ratio of Aβ 42  to Aβ 40  in said biological composition contacted with said candidate Aβ 42  lowering agent is observed when compared with the ratio of Aβ 42  to Aβ 40  in said biological composition not contacted with said candidate Aβ 42  lowering agent.  
     
     
         2 . The method of  claim 1  wherein said biological composition capable of producing Aβ 42  and Aβ 40  comprises a cell-free composition, an in vitro cell-based composition, or an in vivo animal-based composition.  
     
     
         3 . The method of  claim 2  wherein said biological composition is cell-free.  
     
     
         4 . The method of  claim 3  wherein said cell free biological composition comprises a purified enzyme preparation, a partially purified enzyme preparation, or a cell lysate.  
     
     
         5 . The method of  claim 2  wherein said biological composition is an in vitro cell based composition.  
     
     
         6 . The method of  claim 5  wherein said in vitro cell-based biological composition is a cell culture.  
     
     
         7 . The method of  claim 5  wherein said in vitro cell-based biological composition comprises cells that express one or more familial Alzheimer's disease gene.  
     
     
         8 . The method of  claim 5  wherein said in vitro cell-based biological composition comprises cells that express a mutant amyloid precursor protein (APP).  
     
     
         9 . The method of  claim 5  wherein said in vitro cell-based biological composition comprises cells that express a mutant amyloid precursor protein having the Swedish mutation (APP695NL).  
     
     
         10 . The method of  claim 5  wherein said in vitro cell-based biological composition comprises cells that express a mutant presenilin-1.  
     
     
         11 . The method of  claim 5  wherein said in vitro cell-based biological composition comprises cells that express a mutant presenilin-2.  
     
     
         12 . The method of  claim 6  wherein the cells of said cell culture are capable of secreting one or more Aβ peptides selected from the group consisting of Aβ 34 , Aβ 36 , Aβ 37 , Aβ 38 , Aβ 39 , Aβ 40  and Aβ 42 .  
     
     
         13 . The method of  claim 6  wherein the cells of said cell culture are capable of secreting Aβ 42 .  
     
     
         14 . The method of  claim 1  wherein the step of comparing the ratio of Aβ 42  to Aβ 40  produced by said biological composition comprises determining the level of Aβ 42  and Aβ 40  with one or more techniques selected from the group consisting of an immunoprecipitation, western hybridization, sandwich enzyme-linked immunosorbent assays (ELISA), and mass-spectrometry.  
     
     
         15 . The method of  claim 14  wherein said Aβ 42  or Aβ 40  levels are determined using an ELISA assay.  
     
     
         16 . The method of  claim 1  wherein said Aβ 42  to Aβ 40  ratio is determined by measuring Aβ 42  and Aβ 40  levels with an antibody based assay.  
     
     
         17 . The method of  claim 14  wherein said Aβ 42  or Aβ 40  levels are determined by mass spectrometry.  
     
     
         18 . The method of  claim 2  wherein said biological composition is an in vivo animal-based composition.  
     
     
         19 . The method of  claim 1  wherein said biological composition is a transgenic animal.  
     
     
         20 . The method of  claim 19  wherein said transgenic animal expresses one or more familial Alzheimer's disease genes.  
     
     
         21 . The method of  claim 20  wherein the one or more familial Alzheimer's disease genes are selected from a mutant APP, a mutant presenilin-1, and a mutant presenilin-2.  
     
     
         22 . The method of  claim 21  wherein the familial Alzheimer's disease gene is APP having the Swedish mutation (APP695NL).  
     
     
         23 . The method of  claim 1  wherein said biological composition comprises mammalian cells expressing APP and capable of being cultured under conditions that allow for APP expression, APP processing, and Aβ 42  secretion from said mammalian cells.  
     
     
         24 . The method of  claim 1  wherein said biological composition comprises a cell line that expresses APP751.  
     
     
         25 . The method of  claim 1  wherein said biological composition comprises a cell line expresses APP695.  
     
     
         26 . The method of  claim 13  wherein said cells are selected from the group consisting of CHO cells, human neuroglioma cells, fibroblast cells, HEK293 cells, and HS683 cells.  
     
     
         27 . The method of  claim 1 , wherein said biological composition comprises an enzyme.  
     
     
         28 . The method of  claim 1 , wherein said selective Aβ 42  lowering agent does not substantially change the level of Aβ 40 .  
     
     
         29 . The method of  claim 1 , wherein said selective Aβ 42  lowering agent increases the level of one or more of Aβ 34 , Aβ 36 , Aβ 37 , Aβ 38 , and Aβ 39 .  
     
     
         30 . The method of  claim 1 , wherein said selective Aβ 42  lowering agent lowers Aβ 42  levels by about 5% or more.  
     
     
         31 . The method of  claim 1 , wherein said selective Aβ 42  lowering agent lowers Aβ 42  levels by about 15% or more.  
     
     
         32 . A method for identifying a selective Aβ 42  lowering agent comprising the steps of: 
 assaying a test compound for Aβ 42  lowering activity; and    assaying said test compound for inhibiting COX-1 activity; COX-2 activity; or COX-1 and COX-2 activity;    wherein said test compound is a selective Aβ 42  lowering agent if said test compound has increased selectivity for Aβ 42  lowering than for COX-1 activity; COX-2 activity; or COX-1 and COX-2 activity.    
     
     
         33 . The method of  claim 32  wherein said assaying a test compound for Aβ 42  lowering activity is selected from the group consisting of cell-free assaying, in vitro cell-based assaying, and in vivo animal-based assaying.  
     
     
         34 . The method of  claim 33  wherein said assaying step comprises cell-free assaying.  
     
     
         35 . The method of  claim 33  wherein said assaying step comprises in vitro cell-based assaying.  
     
     
         36 . The method of  claim 33  wherein said assaying step comprises in vivo animal-based assaying.  
     
     
         37 . The method of  claim 36  wherein said in vivo animal based assaying is a transgenic animal based assaying.  
     
     
         38 . The method of  claim 33  wherein said in vitro cell-based assaying step comprises assaying said test compound in a cell line capable of expressing APP and secreting Aβ 42 .  
     
     
         39 . The method of  claim 33  wherein said in vitro cell-based assaying step comprises comparing the Aβ 42  levels of a cell culture treated with a candidate Aβ 42  lowering agent with a control cell culture not treated with said candidate Aβ 42  lowering agent.  
     
     
         40 . The method of  claim 32  wherein assaying a test compound for Aβ 42  lowering activity is performed by detecting Aβ 42  levels with a technique selected from the group consisting of, immunoprecipitation, western hybridization, sandwich enzyme-linked immunosorbent assays (ELISA), and mass-spectrometry.  
     
     
         41 . The method of  claim 40  wherein said Aβ 42  levels are detected using an ELISA assay.  
     
     
         42 . The method of  claim 40  wherein said Aβ 42  levels are detected with an antibody based assay.  
     
     
         43 . The method of  claim 40  wherein said Aβ 42  levels are detected by mass spectrometry.  
     
     
         44 . The method of  claim 32  wherein said assaying a test compound for Aβ 42  lowering activity comprises assaying a mammalian cell line expressing APP and cultured under conditions that allow for APP expression, APP processing, and Aβ 42  secretion into the supernatant for Aβ 42 .  
     
     
         45 . The method of  claim 44  wherein said mammalian cell line expresses one or more familial Alzheimer's disease genes.  
     
     
         46 . The method of  claim 46  wherein said one or more familial Alzheimer's disease genes encode a protein selected from the group consisting of a mutant APP, a mutant presenilin-1, and a mutant presenilin-2.  
     
     
         47 . The method of  claim 45  wherein said one or more familial Alzheimer's disease genes encodes a mutant APP.  
     
     
         48 . The method of  claim 45  wherein said one or more familial Alzheimer's disease genes encodes APP having the Swedish mutation (APP695NL).  
     
     
         49 . The method of  claim 45  wherein said one or more familial Alzheimer's disease genes encodes a mutant presenilin-1.  
     
     
         50 . The method of  claim 45  wherein said one or more familial Alzheimer's disease genes encode a mutant presenilin-2.  
     
     
         51 . The method of  claim 44  wherein said cell line capable of expressing APP and secreting Aβ 42  expresses APP751.  
     
     
         52 . The method of  claim 44  wherein said cell line capable of expressing APP and secreting Aβ 42  expresses APP695.  
     
     
         53 . The method of  claim 44  wherein said cell line is selected from the group consisting of CHO cells, human neuroglioma cells, fibroblast cell, HEK293 cells, and HS683 cells.  
     
     
         54 . The method of  claim 34 , wherein said cell free assaying comprises assaying an enzyme.  
     
     
         55 . The method of  claim 34  wherein said cell free assaying comprises assaying a purified enzyme preparation, a partially purified enzyme preparation, or a cell lysate capable of processing APP into Aβ 42 .  
     
     
         56 . The method of  claim 32 , wherein said selective Aβ 42  lowering agent does not substantially change the levels of Aβ 40 .  
     
     
         57 . The method of  claim 32 , wherein said selective Aβ 42  lowering agent increases the levels of one or more of Aβ 34 , Aβ 36 , Aβ 37 , Aβ 38 , and Aβ 39 .  
     
     
         58 . The method of  claim 32  wherein said selective Aβ 42  lowering agent lowers Aβ 42  levels by about 5% or more.  
     
     
         59 . The method of  claim 32  wherein said selective Aβ 42  lowering agent lowers Aβ 42  levels by about 15% or more.  
     
     
         60 . The method of  claim 37  wherein said transgenic animal expresses one or more familial Alzheimer's disease genes encoding a protein selected from the group consisting of a mutant APP, a mutant presenilin-1, and a mutant presenilin-2.  
     
     
         61 . The method of  claim 60  wherein said one or more familial Alzheimer's disease gene encodes a mutant APP.  
     
     
         62 . The method of  claim 60  wherein said one or more familial Alzheimer's disease gene encodes APP having the Swedish mutation (APP695NL).  
     
     
         63 . The method of  claim 60  wherein said familial Alzheimer's disease gene encodes a mutant presenilin-1.  
     
     
         64 . The method of  claim 60  wherein said familial Alzheimer's disease gene encodes a mutant presenilin-2.  
     
     
         65 . The method of  claim 32  wherein assaying said test compound for inhibiting COX-1 activity, COX-2 activity, or COX-1 and COX-2 activity, comprises assaying inhibiting COX-1 activity, COX-2 activity, or COX-1 and COX-2 in vitro.  
     
     
         66 . The method of  claim 32  wherein assaying said test compound for inhibiting COX-1 activity, COX-2 activity, or COX-1 and COX-2 activity, comprises assaying inhibiting COX-1 activity, COX-2 activity, or COX-1 and COX-2 in vivo.  
     
     
         67 . The method of  claim 32  wherein assaying said test compound for inhibiting COX-1 activity, COX-2 activity, or COX-1 and COX-2 activity, comprises a carregeneenan-induced footpad edema assay.  
     
     
         68 . The method of  claim 32  wherein assaying said test compound for inhibiting COX-1 activity, COX-2 activity, or COX-1 and COX-2 activity, comprises assaying said compound in in vivo animal-based studies for COX related side-effects.  
     
     
         69 . The method of  claim 32  wherein said selective Aβ 42  lowering agent has increased selectivity for Aβ 42  lowering than for inhibiting COX-1 activity, COX-2 activity, or COX-1 and COX-2 activity, when the IC 50  for Aβ 42  lowering is lower than the IC 50  for inhibiting COX-1 activity, COX-2 activity, or COX-1 and COX-2.  
     
     
         70 . The method of  claim 32  wherein said selective Aβ 42  lowering agent has increased selectivity for Aβ 42  lowering than for inhibiting COX-1 activity, COX-2 activity, or COX-1 and COX-2 activity, when the IC 50  for Aβ 42  lowering is ten-fold or more potent than the IC 50  for inhibiting COX-1 activity, COX-2 activity, or COX-1 and COX-2  
     
     
         71 . The method of  claim 32  wherein said selective Aβ 42  lowering agent has increased selectivity for Aβ 42  lowering than for inhibiting COX-1 activity, COX-2 activity, or COX-1 and COX-2 activity, when, at a given concentration, the compounds lowers Aβ 42  and does not or minimally inhibits COX-1 activity, COX-2 activity, or COX-1 and COX-2 activity.  
     
     
         72 . A method for identifying an Aβ 42  lowering agent comprising: (a) providing a candidate Aβ 42  lowering agent which is a NSAID, NSAID derivative, or NSAID analogue; and (b) determining the effects of said candidate Aβ 42  lowering agent on levels of Aβ 42  in a biological composition following contact of said candidate Aβ 42  lowering agent with said biological composition, wherein a decrease in the level of Aβ 42  indicates that said candidate Aβ 42  lowering agent is an Aβ 42  lowering agent.  
     
     
         73 . The method of  claim 72  wherein said NSAID is selected from the group consisting of amino aryl carboxylic acid derivatives, aryl acetic acid derivatives, and aryl propionic acid derivatives.  
     
     
         74 . The method of  claim 72  wherein said NSAID derivative is selected from the group consisting of a derivative of an amino aryl carboxylic acid derivative, a derivative of an aryl acetic acid derivative, and a derivative of an aryl propionic acid derivative.  
     
     
         75 . The method of  claim 72  wherein said NSAID analogue is selected from the group consisting of an analogue of an amino aryl carboxylic acid derivative, an analogue of an aryl acetic acid derivative, and an analogue of an aryl propionic acid derivative.  
     
     
         76 . The method of  claim 72  wherein said NSAID is selected from the group consisting of NPPB, mefenamic acid, APHS, reservatrol, SC560, NS398, guaiazulene, ketorolac, benzylamine, ketoprofen, fenbufen, isoixicam, tenoxicam, tolfenamic acid, acemetacin, niflumic acid, dapsone, sulindac sulfone, nimesulide, suxibuzone, acetylsalicyclic acid, salicylic acid, carprofen, celecoxib, rofecoxib, fenoprofen, flurbiprofen, ibuprofen, naproxen, sulindac, sulindac sulfide, diclofenac, piroxicam, ketoprofen, diflunisal, nabumetone, etodolac, oxaprozin, meloxicam, flufenamic acid, meclofenamic acid, and indomethacin.  
     
     
         77 . The method of  claim 72  wherein said NSAID derivative is a derivative of a NSAID selected from the group consisting of NPPB, mefenamic acid, APHS, reservatrol, SC560, NS398, guaiazulene, ketorolac, benzylamine, ketoprofen, fenbufen, isoixicam, tenoxicam, tolfenamic acid, acemetacin, niflumic acid, dapsone, sulindac sulfone, nimesulide, suxibuzone, acetylsalicyclic acid, salicylic acid, carprofen, celecoxib, rofecoxib, fenoprofen, flurbiprofen, ibuprofen, naproxen, sulindac, sulindac sulfide, diclofenac, piroxicam, ketoprofen, diflunisal, nabumetone, etodolac, oxaprozin, meloxicam, flufenamic acid, meclofenamic acid, and indomethacin.  
     
     
         78 . The method of  claim 72  wherein said NSAID analogue is an analogue of a NSAID selected from the group consisting of NPPB, mefenamic acid, APHS, reservatrol, SC560, NS398, guaiazulene, ketorolac, benzylamine, ketoprofen, fenbufen, isoixicam, tenoxicam, tolfenamic acid, acemetacin, niflumic acid, dapsone, sulindac sulfone, nimesulide, suxibuzone, acetylsalicyclic acid, salicylic acid, carprofen, celecoxib, rofecoxib, fenoprofen, flurbiprofen, ibuprofen, naproxen, sulindac, sulindac sulfide, diclofenac, piroxicam, ketoprofen, diflunisal, nabumetone, etodolac, oxaprozin, meloxicam, flufenamic acid, meclofenamic acid, and indomethacin.  
     
     
         79 . The method of  claim 72  wherein said candidate Aβ 42  lowering agent is a derivative or analogue of a NSAID selected from meclofenamic acid and flufenamic acid, wherein said NSAID derivative or analogue is modified from said NSAID by altering the position of the carboxylic acid group on the phenyl ring of said NSAID, altering the position or type of substituents on the phenyl ring opposite the carboxylic acid group of said NSAID, altering the bond connecting the two phenyl rings of said NSAID, altering the carboxylic acid group of said NSAID to propionic acid or another substituent, or performing any combination of these alterations, to generate a candidate Aβ 42  lowering agent.  
     
     
         80 . The method of  claim 72  wherein said candidate Aβ 42  lowering agent is a derivative or analogue of a NSAID selected from fenoprofen, flurbiprofen, and carprofen, wherein said NSAID derivative or analogue is modified from said NSAID by altering the position of the propionic acid group on the phenyl ring of said NSAID, altering the position or type of substituents on the phenyl ring opposite the propionic acid group of said NSAID, altering the bond connecting the two phenyl rings of said NSAID, altering the acetic acid group of said NSAID to carboxylic acid or another substituent, or performing any combination of these alterations, to generate a candidate Aβ 42  lowering agent.  
     
     
         81 . The method of  claim 72  wherein said candidate Aβ 42  lowering agent is a derivative or analogue of indomethacin, wherein said indomethacin derivative or analogue is modified from said indomethacin by altering the carboxylic acid group of indomethacin to another substituent, altering the indole nitrogen to another substituent, or performing any combination of these alterations to generate a candidate Aβ 42  lowering agent.  
     
     
         82 . The method of  claim 72  wherein said candidate Aβ 42  lowering agent is a derivative or analogue of sulindac sulfide, wherein said sulindac sulfide derivative or analogue is modified from said sulindac sulfide by altering the methylthiol group of sulindac sulfide to another substituent, altering the propionic acid group of sulindac sulfide to another substituent, altering the fluoride moiety of sulindac sulfide to another substituent, or performing any combination of these alterations, to generate a candidate Aβ 42  lowering agent.  
     
     
         83 . The method of  claim 72  wherein said biological composition comprises a cell-free composition, an in vitro cell-based composition, or an in vivo animal-based composition.  
     
     
         84 . The method of  claim 83  wherein said biological composition is a cell-free composition.  
     
     
         85 . The method of  claim 84  wherein said cell free biological composition comprises a purified enzyme preparation, a partially purified enzyme preparation, or a cell-lysate.  
     
     
         86 . The method of  claim 83  wherein said biological composition is in vitro cell-based composition.  
     
     
         87 . The method of  claim 86  wherein said in vitro cell-based composition is a cell-culture.  
     
     
         88 . The method of  claim 86  wherein said in vitro cell-based composition comprises cells that express a mutant familial Alzheimer's disease gene.  
     
     
         89 . The method of  claim 83  wherein said in vitro cell-based composition comprises cells that express a mutant APP.  
     
     
         90 . The method of  claim 83  wherein said in vitro cell-based composition comprises cells that express a mutant presenilin-1.  
     
     
         91 . The method of  claim 83  wherein said in vitro cell-based composition comprises cells that express a mutant presenilin-2.  
     
     
         92 . The method of  claim 87  wherein the cells of said cell culture are capable of secreting one or more Aβ peptides selected from the group consisting of Aβ 34 , Aβ 36 , Aβ 37 , Aβ 38 , Aβ 39 , Aβ 40 , and Aβ 42 .  
     
     
         93 . The method of  claim 87  wherein the cells of said cell culture are capable of secreting Aβ 42 .  
     
     
         94 . The method of  claim 72  wherein said determining the effects of said candidate Aβ 42  lowering agent on levels of Aβ 42  in a biological composition following contact of said candidate Aβ 42  lowering agent with said biological composition comprises determining the level of Aβ 42  by one or more techniques selected from the group consisting of immunoprecipitation, western hybridization, sandwich enzyme-linked immunoadsorbent assay (ELISA), and mass spectrometry.  
     
     
         95 . The method of  claim 94  wherein said Aβ 42  levels are determined using an ELISA assay.  
     
     
         96 . The method of  claim 94  wherein said Aβ 42  levels are determined with an antibody based assay.  
     
     
         97 . The method of  claim 91  wherein said Aβ 42  levels are determined by mass spectrometry.  
     
     
         98 . The method of  claim 83  wherein said biological composition is in vivo animal-based composition.  
     
     
         99 . The method of  claim 83  wherein said biological composition is a transgenic animal.  
     
     
         100 . The method of  claim 99  wherein said transgenic animal expresses one or more familial Alzheimer's disease genes.  
     
     
         101 . The method of  claim 100  wherein said one or more familial Alzheimer's disease genes encode a protein selected from the group consisting of a mutant APP, a mutant presenilin-1, and a mutant presenilin-2.  
     
     
         102 . The method of  claim 99  wherein said transgenic animal expresses APP having the Swedish mutation.  
     
     
         103 . The method of  claim 72  wherein said biological composition comprises mammalian cells expressing APP that are capable of being cultured under conditions that allow for APP expression, APP processing, and Aβ 42  secretion into the supernatant.  
     
     
         104 . The method of  claim 72  wherein said biological composition comprises a cell line that expresses APP751.  
     
     
         105 . The method of  claim 72  wherein said biological composition comprises a cell line that expresses APP695.  
     
     
         106 . The method of  claim 103  wherein said cells are selected from the group consisting of CHO cells, human neuroglioma cells, fibroblast cells, HEK293 cells, and HS683 cells.  
     
     
         107 . The method of  claim 72 , wherein said biological composition comprises an enzyme.  
     
     
         108 . The method of  claim 72 , wherein said selective Aβ 42  lowering agent does not substantially change the levels of Aβ 40 .  
     
     
         109 . The method of  claim 72 , wherein said selective Aβ 42  lowering agent increases the levels of one or more of Aβ 34 , Aβ 36 , Aβ 37 , Aβ 38 , and Aβ 39 .  
     
     
         110 . The method of  claim 72 , wherein said selective Aβ 42  lowering agent lowers Aβ 42  levels by about 5% or more.  
     
     
         111 . The method of  claim 72 , wherein said selective Aβ 42  lowering agent lowers Aβ 42  levels by about 15% or more.  
     
     
         112 . The method of  claim 72  wherein said NSAID derivative or NSAID analogue inhibits COX-1, COX-2, or COX-1 and COX-2 less than the respective parent NSAID.  
     
     
         113 . A method for identifying an Aβ 42  lowering agent comprising the steps of: (a) providing a candidate Aβ 42  lowering agent selected from the group consisting of fenoprofen, flurbiprofen, and carprofen having the position of the propionic acid group on the phenyl ring altered, having the position or type of substituents on the phenyl ring opposite the propionic acid group altered, having the bond connecting the two phenyl rings altered, having the acetic acid group altered to another carboxylic acid or altered to another substituent, or any combination of these alterations; and (b) determining the effects of said candidate Aβ 42  lowering agent on levels of Aβ 42  in a biological composition following contact of said candidate Aβ 42  lowering agent with said biological composition, wherein a decrease in the level of Aβ 42  indicate that said candidate Aβ 42  lowering agent is a an Aβ 42  lowering agent.  
     
     
         114 . The method of  claim 113 , wherein said Aβ 42  lowering agent lowers Aβ 42  levels by about 5% or more.  
     
     
         115 . The method of  claim 113 , wherein said Aβ 42  lowering agent lowers Aβ 42  levels by about 15% or more.  
     
     
         116 . The method of  claim 113  wherein said NSAID is flurbiprofen.  
     
     
         117 . The method of  claim 113  wherein said biological composition comprises a cell-free composition, an in vitro cell-based composition, or an in vivo animal-based composition.  
     
     
         118 . The method of  claim 117  wherein said biological composition is a cell-free composition.  
     
     
         119 . The method of  claim 118  wherein said cell free biological composition comprises a purified enzyme preparation, a partially purified enzyme preparation, or a cell-lysate.  
     
     
         120 . The method of  claim 117  wherein said biological composition is in vitro cell-based composition.  
     
     
         121 . The method of  claim 117  wherein said in vitro cell-based composition is a cell-culture.  
     
     
         122 . The method of  claim 117  wherein said in vitro cell-based composition comprises cells that express a mutant familial Alzheimer's disease gene.  
     
     
         123 . The method of  claim 117  wherein said in vitro cell-based composition comprises cells that express a mutant APP.  
     
     
         124 . The method of  claim 117  wherein said in vitro cell-based composition comprises cells that express a mutant presenilin-1.  
     
     
         125 . The method of  claim 117  wherein said in vitro cell-based composition comprises cells that express a mutant presenilin-2.  
     
     
         126 . The method of  claim 117  wherein said in vitro cell-based composition comprises cells that express APP having the Swedish mutation (APP695NL).  
     
     
         127 . The method of  claim 113  further comprising the step of determining if said candidate Aβ 42  lowering agent inhibits COX-1, COX-2, or COX-1 and COX-2.  
     
     
         128 . A method for identifying an Aβ 42  lowering agent comprising the steps of: (a) providing a candidate Aβ 42  lowering agent having the carboxylic acid group of indomethacin altered to another substituent, having the indole nitrogen of indomethacin altered to another substituent, or having any combination of these alterations; and (b) determining the effects of said candidate Aβ 42  lowering agent on levels of Aβ 42  in a biological composition following contact of said candidate Aβ 42  lowering agent with said biological composition, wherein a decrease in the level of Aβ 42  indicate that said candidate Aβ 42  lowering agent is a an Aβ 42  lowering agent.  
     
     
         129 . The method of  claim 128 , wherein said Aβ 42  lowering agent lowers Aβ 42  levels by about 5% or more.  
     
     
         130 . The method of  claim 128 , wherein said Aβ 42  lowering agent lowers Aβ 42  levels by about 15% or more.  
     
     
         131 . The method of  claim 128  wherein said biological composition comprises a cell-free composition, an in vitro cell-based composition, or an in vivo animal-based composition.  
     
     
         132 . The method of  claim 131  wherein said in vitro cell-based composition comprises cells that express APP having the Swedish mutation (APP695NL).  
     
     
         133 . A method for identifying an Aβ 42  lowering agent comprising the steps of: (a) providing a candidate Aβ 42  lowering agent having the methylthiol group of sulindac sulfide altered to another substituent, having the propionic acid group of sulindac sulfide altered to another substituent, having the fluoride moiety of sulindac sulfide altered to another substituent, or any combination of these alterations and (b) determining the effects of said candidate Aβ 42  lowering agent on levels of Aβ 42  in a biological composition following contact of said candidate Aβ 42  lowering agent with said biological composition, wherein a decrease in the level of Aβ 42  indicate that said candidate Aβ 42  lowering agent is a an Aβ 42  lowering agent.  
     
     
         134 . The method of  claim 133 , wherein said Aβ 42  lowering agent lowers Aβ 42  levels by about 5% or more.  
     
     
         135 . The method of  claim 133 , wherein said Aβ 42  lowering agent lowers Aβ 42  levels by about 15% or more.  
     
     
         136 . The method of  claim 133  wherein said biological composition comprises a cell-free composition, an in vitro cell-based composition, or an in vivo animal-based composition.  
     
     
         137 . The method of  claim 136  wherein said in vitro cell-based composition comprises cells that express APP having the Swedish mutation (APP695NL).  
     
     
         138 . A method for identifying an Aβ 42  lowering agent comprising the steps of: (a) providing a candidate Aβ 42  lowering agent selected from the group consisting of meclofenamic acid or flufenamic acid having the position of the carboxylic acid group on the phenyl ring altered, having the position or type of substituents on the phenyl ring opposite the carboxylic acid group altered, having the bond connecting the two phenyl rings altered, having the carboxylic acid group altered to propionic acid or altered another substituent, or any combination of these alterations; and (b) determining the effects of said candidate Aβ 42  lowering agent on levels of Aβ 42  in a biological composition following contact of said candidate Aβ 42  lowering agent with said biological composition, wherein a decrease in the level of Aβ 42  indicate that said candidate Aβ 42  lowering agent is a an Aβ 42  lowering agent.  
     
     
         139 . The method of  claim 138 , wherein said Aβ 42  lowering agent lowers Aβ 42  levels by about 5% or more.  
     
     
         140 . The method of  claim 138 , wherein said Aβ 42  lowering agent lowers Aβ 42  levels by about 15% or more.  
     
     
         141 . The method of  claim 138  wherein said biological composition comprises a cell-free composition, an in vitro cell-based composition, or an in vivo animal-based composition.  
     
     
         142 . The method of  claim 141  wherein said in vitro cell-based composition comprises cells that express APP having the Swedish mutation (APP695NL).