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Advances and Challenges in the Prevention and Treatment of Alzheimer's Disease

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Abstract

Alzheimer's disease (AD) is the most common cause of dementia and accounts for one-half to three-fourths of all cases of dementia. In the United States, AD is the leading cause of a loss of independent living and subsequent institutionalization. Approximately 4 million Americans are currently diagnosed with Alzheimer's disease—which results in greater than $100 billion dollars in health care costs. This review provides a description of the cognitive and neuropathological features of AD and the challenge that aging populations around the globe pose to health care systems and to societies. A review of new and promising therapeutic strategies for the prevention of AD is discussed which includes estrogen replacement therapy and anti-inflammatory therapeutics. Pharmaceutical approaches that delay the progression of the disease, such as antioxidants, are discussed as well as therapeutic strategies for improvement of cognitive function in AD patients, including the new generation of compounds aimed at enhancing cholinergic function. This section is followed by a review of the current status on nerve growth factor trials. The final section addresses the issue of the genetic linkages of AD, the impact of transgenic and gene knockout mouse models of AD on research in the field and the potential use of gene therapy to treat AD.

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REFERENCES

  1. V. W. Henderson. Estrogen replacement therapy for the prevention and treatment of Alzheimer's disease. CNS Drugs In press. (1997).

  2. S. Solodkin and G. W. Van Hoesen. Neuropathology and functional anatomy of Alzheimer's disease. In: Pharmacological Treatment of Alzheimer's Disease. J. D. Brioni & M. W. Decker, editors. Wiley-Liss, N. Y., N. Y. 151–177 (1997).

    Google Scholar 

  3. D. A. Snowdon, L. H. Greiner, J. A. Mortimer, K. P. Riley, P. A. Greiner, and W. R. Markesbery. Brain infarction and the clinical expression of Alzheimer disease: The nun study. JAMA 277:813–817 (1997).

    Article  PubMed  Google Scholar 

  4. S. J. Birge. The role of estrogen in the treatment of Alzheimer's disease. Neurology 48:S36–S41 (1997).

    PubMed  Google Scholar 

  5. W. Roush. Live long and prosper? Science 273:42–46 (1996).

    PubMed  Google Scholar 

  6. P. J. Whitehouse. Alzheimer's disease: An international public health problem—clinical goals. strategies, and outcomes. In: Pharmacological Treatment of Alzheimer's Disease. J. D. Brioni and M. W. Decker, editors. Wiley-Liss, N. Y., N. Y. 331–343 (1997).

    Google Scholar 

  7. C. Holden. New populations of old add to poor nations' burdens. Science 273:46–48 (1996).

    PubMed  Google Scholar 

  8. R. D. Brinton, P. Proffitt, J. Tran, and R. Luu. Equilin, a principal component of the estrogen replacement therapy, Premarin, increases the growth of cortical neurons via an NMDA receptor dependent mechanism. Experimental Neurology 147:211–220 (1997).

    PubMed  Google Scholar 

  9. S. Shumaker and S. Rapp. Hormone replacement therapy in dementia prevention: The women's health initiative memory study. Neurobiol. of Aging 17:S34 (1996).

    Google Scholar 

  10. R. D. Brinton, J. Tran, P. Profitt, and M. Kahil. 17 β-Estradiol increases the growth and survival of cultured cortical neurons. Neurochemical Research 22:1339–1351 (1997).

    PubMed  Google Scholar 

  11. C. Behl, T. Skutella, F. Lezoualc'h, A. Post, M. Widmann, C.J. Newton, and F. Holsboer. Neuroprotection against oxidative stress by estrogens: Structure-activity relationship. Molecular Pharmacology 51:535–541 (1997).

    PubMed  Google Scholar 

  12. Y. Goodman, A. J. Bruce, B. Cheng, and M. P. Mattson. Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid beta-peptide toxicity in hippocampal neurons. J. of Neurochemistry 66:1836–1844 (1996).

    Google Scholar 

  13. VN Luine. Estradiol increases acetyltransferase activity in specific basal forebrain nuclei and projection areas of the female rat brain. Exp. Neurology 89:484–490 (1985).

    Google Scholar 

  14. O. Rabbani, K-S. Panickar, G. Rajakumar, M-A. King, N. Bodor, E-M Meyer, and J-W. Simpkins. 17 beta-estradiol attenuates fimbrial lesion-induced decline of ChAT-immunoreactive neurons in the rat medial septum. Exp. Neurology 146:179–86 (1997).

    Google Scholar 

  15. M. Singh, E. M. Meyer, W. J., Millard, and J. W. Simpkin. The effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor messenger ribonucleic acid expression in cortical and hippocampal brain regions of the female Sprague-Dawlcy rats. Endocrinology 136:2320–2324 (1995).

    PubMed  Google Scholar 

  16. C. D., Toran-Allerand, R. C., Miranda, W. D., Benthamn, F., Sohrabjio, T. J., Brown, R. B. Hocber, and N. J. MacLusky. Estrogen receptors colocalize with low affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain. Proc. Natl. Acad. Sci., USA 89:4668–4672 (1992).

    Google Scholar 

  17. R. B. Gibbs, and D. W. Pfaff. Effects of estrogen and fimbria/fornix transection on p75NFGR and ChAT expression in the medial septum and diagonal band of Broca. Exp. Neurol. 116:23–39 (1992).

    PubMed  Google Scholar 

  18. F., Sohrabjio, R. C. Miranda, and C. D. Toran-Allerand. Estrogen differentially regulates estrogen and nerve growth factor receptor mRNAs in adult sensory neurons. J. Neurosci. 14:459–471 (1994).

    PubMed  Google Scholar 

  19. R. C., Miranda, F. Sohrabjio, and D. Toran-Allerand. Interactions of estrogen with the neurotrophins and their receptors during neural development. Hormones and Behavior 28:367–375 (1994).

    PubMed  Google Scholar 

  20. M. J., Knapp, D. S., Knopman, P. R., Solomon et al. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. JAMA 271:985–991 (1994).

    PubMed  Google Scholar 

  21. R. D., Brinton, M. Montoya, and D. Hsieh. Premarin increases the growth of neurons from the cerebral cortex. Soc. for Neurosci. Absts. 22:299.3 (1996).

    Google Scholar 

  22. R. D., Brinton, M., Muhammad, D. Hsieh, and E. Chen. The estrogen replacement therapy, Premarin, increases neuronal survival and protects neurons against oxidative damage: Implications for Alzheimer's disease. Soc. for Neurosci. Absts. 23:20.5 (1997).

    Google Scholar 

  23. J., Xua, X. Xiea, R. D. Brinton, and T. W. Berger. Direct enhancement of NMDA receptor-mediated EPSPs by 17 β-estradiol in hippocampal CA1. Soc. For Neurosci. Absts. 23(2)818.5 (1997).

    Google Scholar 

  24. P.S., Green, K. E., Gridley, and J. W. Simpkins. Estrogen receptor-independent neuroprotection by estratrienes: A novel interaction with glutathione. In press (1997).

  25. P. S., Green, K., Gordon, and J. W. Simpkins. Phenolic A ring requirement for the neuroprotective effects of steroids. J. Steroid Biochem. Mol. Biology. In press (1997).

  26. R. D. Brinton. Estrogen Induction of rapid changes in the growth of cultured hippocampal nerve cells. Molecular and Cellular Neurosciences 4:36–46 (1993).

    Google Scholar 

  27. K. Paech, P. Webb, G. G. J. M. Kuiper, S. Nilsson, J-A. Gustafsson, P. J. Kushner, and T. S. Scanian. Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 Sites. Science. 277:1508–1510 (1997).

    PubMed  Google Scholar 

  28. M., Byers, G. J. M., Kuiper, J. A., Gustafsson, and O. K. Park-Sarge. Estrogen receptor-beta mRNA expression in rat ovary: Down regulation by gonadotropins Molecular Endocrinology 11:172–182 (1997).

    PubMed  Google Scholar 

  29. G. G. J. M., Kuiper, E., Enmark, M., Pelto-Huikko, S., Nilsson, and J. A. Gustafsson. Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93:5925–5930 (1996).

    Article  PubMed  Google Scholar 

  30. K. S. Korach. Insights from the study of animals lacking functional estrogen receptor. Science 266:1524–1527 (1994).

    Google Scholar 

  31. G. G. J. M. Kuiper, B. Carlsson, K. Grabdien, E. Enmark, J. Haggblad, S. Nilsson, and J. A. Gustafsson. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology 138: 863–870 (1997).

    Article  PubMed  Google Scholar 

  32. X., Li, P., Schwartz, and E. Rissman. Distribution of estrogen receptor-beta-like immunoreactivity in rat forebrain. Neuroendocrinology 66:63–67 (1997).

    PubMed  Google Scholar 

  33. D. J. Grainger and J. C. Metcalfe. Tamoxifen: teaching an old drug new tricks? Nature Med 2:381–385 (1996).

    PubMed  Google Scholar 

  34. J. A., Katzenellenbogen, B. W., O'Malley, and B. S. Katzenellenbogen. Tripartite steroid hormone receptor pharmacology: interaction with multiple effector sites as a basis for the cell-and promoter-specific action of these hormones. Molec Endocrinology 10: 119–131 (1996).

    Google Scholar 

  35. K. F. H. Grandien, A. Berkenstam, S. Nilsson, and I. A. Gustafsson. Localization of Dnase I hypersensitive sites in the human oestrogen receptor gene correlates with the transcriptional activity of two differentially used promoters. J. Mol Endocrinology 10:269–277 (1993).

    Google Scholar 

  36. S., Makela, V. I. Davis, W., Tally, J., Korkman, L., Salo, R., Vihko, R., Santti, and K. Korach, Dietary estrogens act through estrogen receptor-mediated processes and show no antiestrogenicity in cultured breast cancer cells. Environ Health Perspect 102:572–581 (1994).

    PubMed  Google Scholar 

  37. H., Adlercreutz, H., Markkanen, and S. Watanabe, Plasma concentration of phyto-estrogens in Japanese men. Lancet 342:1209–1210 (1993).

    PubMed  Google Scholar 

  38. C. Ezzell. Evolutions: Alzheimer's disease. J. NIH Research. 7:108 (1995).

    Google Scholar 

  39. D. B., Lubahn, J. S., Moyer, T. S. Golding, J. F. Couse, K. S. Korach, and O. Smithies. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci USA 90:11162–11166 (1993).

    PubMed  Google Scholar 

  40. P. L. McGeer and J. Rogers. Anti-inflammatory agents as a therapeutic approach to Alzheimer's disease. Neurology. 42:447–449 (1992).

    PubMed  Google Scholar 

  41. P. L. McGeer, J. Rogers, and E. G. McGeer. Neuroimmune mechanisms in Alzheimer disease pathogenessis. Alzheimer Disease and Associated Disorders. 8:149–158 (1994).

    PubMed  Google Scholar 

  42. P. L., McGeer, E., McGeer, J., Rogers, and J. Sibley. Anti-inflammatory drugs and Alzheimer disease. Lancet 335:1037 (1990).

    Google Scholar 

  43. J. C. S. Breitner. The role of anti-inflammatory drugs in the prevention and treatment of Alzheimer's disease. Annual Review of Medicine. 47:401–411 (1996).

    PubMed  Google Scholar 

  44. J. C. S. Breitner, K. A. Welsh, B. L. Plassman, W. M. McDonald, M. J. Helms, and J. C. Anthony. Inverse association of anti-inflammatory treatments and Alzheimer's disease: Initial results of a co-twin control study. Neurology. 44:227–231 (1994).

    PubMed  Google Scholar 

  45. J. B. Rich, D. X. Rasmusson, M. F. Folstein, K. A. Carson, C. Kawas, and J. Brandt. Nonsteroidal anti-inflammatory drugs in Alzheimer's disease. Neurology. 45:51–55 (1995).

    PubMed  Google Scholar 

  46. J. Rogers, L. C. Kirby, S. R. Hempelman, et al. Clinical trial of indomethacin in Alzheimer's disease. Neurology. 43:1609–1611 (1993).

    PubMed  Google Scholar 

  47. P.S., Aisen and K. L., Davis. Inflammatory mechanisms in Alzheimer's disease: Implications for therapy. Am J. Psychiatry 151:1105–1113 (1994).

    PubMed  Google Scholar 

  48. J. C. S. Breitner. Inflammatory Processes and antiinflammatory drugs in Alzheimer's disease: A current appraisal. Neurobiology of Aging. 17:789–794 (1996).

    PubMed  Google Scholar 

  49. S. D., Yan, X., Chen, J., Fu, M., Chen, H., Zhu, A., Roher, T., Slattery, L., Zhao, M., Nagashima, J., Morser, A., Migheli, P., Nawroth, D., Stern, and A. M., Schmidt. RAGE and amyloidbeta peptide neurotoxicity in Alzheimer's disease. Nature 382:685–91 (1996).

    PubMed  Google Scholar 

  50. J., El Khoury, S. E., Hickman, C. A., Thomas, L., Cao, S. C., Silverstein, and J. D., Loike. Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 382:716–9 (1996).

    PubMed  Google Scholar 

  51. S. W. Barger and A. D. Harmon. Microglial activation by Alzheimer amyloid precursor protein and modulation by apoliprotein E. Nature. 388:878–881 (1997).

    PubMed  Google Scholar 

  52. S. D., Yan, H., Zhu, J., Fu, S. F., Yan, A., Roher, W. W., Tourellott, T., Rajavashisth, X., Chen, G. C., Godman, D., Stern, and A. M. Schmidt. Amyloid-β peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: A proinflammatory pathway in Alzheimer disease. Proc. Natl. Acad. Sci. USA 94:5296–5301 (1997).

    PubMed  Google Scholar 

  53. P. S., Aisen. Inflammation and Alzheimer's disease. Molecular and Chemical Neuropathology 28:83–88 (1996).

    PubMed  Google Scholar 

  54. J. Rogers, S. Webster, L-F. Lue, L. Brachova, W. H. Civin, M. Emmerling, B. Shivers, D. Walker, and P. McGeer. Inflammation and Alzheimer's disease pathogenesis. Neurobiology of Aging 17:681–686 (1996).

    PubMed  Google Scholar 

  55. C. Behl, F. Lezoualc'h, T. Trapp, M. Widmann, T. Skutella, and T. Holsboer. Glucocorticoids enhance oxidative stress-induced cell death in hippocampal neurons in vitro. Endocrinology 138:101–106 (1997).

    PubMed  Google Scholar 

  56. P. Insel. Analgesic-antipyretics and antiinflammatory agents: Drugs employed in the treatment of rheumatoid arthritis and gout. In: The Pharmacological Basis of Therapeutics 8th edition. A. G. Goodman, T. W. Rall, A. S. Nies, P. Tayor, editors. Pergamon Press, 638–681 (1990).

  57. S., Vasan, X., Zhang, A., Kapurniotu, J., Bernhagen, S., Teichberg, J., Basgen, D., Wagle, D., Shih, I., Terlecky, R., Bucala, A., Cerami, J., Egan, and P., Ulrich. An agent cleaving glucose-derived protein crosslinks in vitro and in vivo. Nature 382:275–8 (1996).

    PubMed  Google Scholar 

  58. M. A., Smith, G., Perry, P. L., Richey, L. M., Syre, V. E., Anderson, M. F., Beal, and N., Kowall. Oxidative damage in Alzheimer's. Nature 382:120–1 (1996).

    Article  Google Scholar 

  59. K. V., Subbarao, J. S., Richardson, and L. C., Ang. Autopsy samples of Alzheimer's cortex show increased peroxidation in vitro. J. of Neurochemistry 55:342–345 (1990).

    Google Scholar 

  60. B. N., Ames, M. K., Shigenaga, and T. M., Hagen. Oxidants, antioxidants, and the degenerative diseases of aging. Proc. Natl. Acad. Sci. USA 90:7915–7922 (1993).

    PubMed  Google Scholar 

  61. P. S. Aisen and K. L. Davis. The search for disease-modifying treatment for Alzheimer's disease. Neurology 48:S35–S41 (1997).

    PubMed  Google Scholar 

  62. M. Sano, C. Ernesto, R. G. Thomas, M. R. Klauber, K. Schafer, M. Grundman, P. Woodbury, J. Growdon, C. W. Cotman, E. Pfeiffer, L. S. Schneider, and L. J. Thal. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The New England Journal of Medicine 336:1216–1222 (1997).

    PubMed  Google Scholar 

  63. D. M. Bowen. Alzheimer's disease. In: The Molecular Basis of Neuropathology. A. N. Davison and R. H. S. Thompson, eds. Edward Arnold. London, England 649–665 (1981).

    Google Scholar 

  64. L. Schneider. New therapeutic approaches to Alzheimer's disease. J. Clin Psychiatry 57:30–35 (1996).

    PubMed  Google Scholar 

  65. E. Giacobini. Cholinometric therapy of Alzheimer's disease: does it slow down deterioration? In: Recent Advances in the Treatment of Neurodegenerative Disorders and Cognitive Dysfunction. G. Racagni, N. Brunello, and S. Z. Langer, eds. Karger. Basel, Switzerland 7:51–57 (1994).

    Google Scholar 

  66. F. Hefti. Development of effective therapy for Alzheimer's disease based on neurotrophic factors. Neurobiology of Aging 15:S193–S194 (1994).

    PubMed  Google Scholar 

  67. A. J. Dekker, J. Winkler, J. Ray, L. J. Thal, and F. H. Gage. Grafting of nerve growth factor-producing fibroblasts reduces behavioral deficits in rats with Llesions of the nucleus basalis magnocellularis. Neuroscience 60:299–309 (1994).

    PubMed  Google Scholar 

  68. A. Martinez-Serrano, W. Fischer, and A. Bjorklund. Reversal of age-dependent cognitive impairments and cholinergic neuron atrophy by NGF-secreting neural progenitors grafted to the basal forebrain. Neuron 15:473–484 (1995).

    PubMed  Google Scholar 

  69. T., Nabeshima, A., Nitta, K., Fuji, T., Kameyama, and T. Hasegawa. Oral administration of NGF synthesis stimulators recovers reduced brain NGF content in aged rats and cognitive dysfunction in basal-forebrain-lesioned rats. Gerontology 40:46–56 (1994).

    PubMed  Google Scholar 

  70. R., Clark and A., Goate. Recent developments in the genetics of Alzheimer's disease. In: Pharmacological Treatment of Alzheimer's Disease. J. D. Brioni and M. W. Decker, editors. Wiley-Liss, N.Y., N.Y 193–215 (1997).

    Google Scholar 

  71. D. J., Selkoe. Alzheimer's disease: a central role for amyloid. J. of Neuropathology and Experimental Neurology 53:438–47 (1994).

    Google Scholar 

  72. J. K., Teller, C., Russo, L. M., DeBusk, G., Angelini, D., Zaccheo, F., Dagna-Bricarrelli, P., Scartezzini, S., Bertolini, D. M., Mann, M., Tabaton, and P., Gambetti. Presence of soluble amyloid beta peptide precedes amyloid plaque formation in Down's Syndrome Nature Medicine 2:93–5 (1996).

    PubMed  Google Scholar 

  73. J. Li, M. Xu, H. Zhou, J. Ma, and H. Potter. Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation. Cell. 90:917–927 (1997).

    PubMed  Google Scholar 

  74. E. Corder, A., Saunders, W., Strittmatter, et al., Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261:921–923 (1997).

    Google Scholar 

  75. D. A., Evans, L. A., Beckett, T. S., Field, L., Feng, M. S., Albert, D. A., Bennett, B., Tycko, and R., Mayeux. Apolipoprotein E ε4 and incidence of Alzheimer disease in a community population of older persons. JAMA 277:822–824 (1997).

    PubMed  Google Scholar 

  76. D., Blacker, J. L., Haines, L., Rodes, H., Terwedow, R. C. P., Go, L. E., Harrell, R. T. Perry, S. S., Bassett, G., Chase, D., Meyers, M. S., Albert, and R. Tanzi. ApoE-4 and age at onset of Alzheimer's disease. Neurology 48:139–147 (1997).

    PubMed  Google Scholar 

  77. H., Payami, G. D., Schellenberg, MS., Zareparsi, M. D., Kaye, G. J., Sexton, M. A., Head, S. S., Matsuyama, M. D., Jarvik, B., Miller, D. Q., McManus, T. D., Bird, M. D., Katzman, L., Heston, D., Norman, and G. W. Small. Evidence for association of HLA-A2 allele with onset age of Alzheimer's disease. Neurology 49:512–518 (1997).

    PubMed  Google Scholar 

  78. C. L., Lendon, F., Ashall, and A. M. Goate. Exploring the etiology of Alzheimer disease using molecular genetics. JAMA 227:825–31 (1997).

    Google Scholar 

  79. K., Chandrasekaran, T., Giordano, D. R., Brady, J., Stoll, L. J., Martin, and S. I. Rapoport. Impairment in mitochodrial cytochrome oxidase gene expression in Alzheimer disease. Brain Research. Molecular Brain Research 24:336–40 (1994).

    PubMed  Google Scholar 

  80. K., Chandrasekaran, K. Hatanpaea, S. I., Rapoport, and D. R. Brady. Decreased expression of nuclear and mitochondrial DNA-encoded genes of oxidative phosphorylation in association neocortex in Alzheimer disease. Brain Research. Molecular Brain Research 44:99–104 (1997).

    PubMed  Google Scholar 

  81. W. D. Parker, Jr., N. J., Mahr, C. M., Filley, J. K., Parks, D., Hughes, D. A., Young, and C.M., Cullum. Reduced platelet cytochrome c oxidase activity in Alzheimer's disease. Neurology 44:1086–90 (1994).

    PubMed  Google Scholar 

  82. R. E., Davis, S., Miller, C., Herrnstadt, S. S., Ghosh, E., Fahy, L. A., Shinobu, D., Galasko, L. J., Thal, M. F., Beal, N., Howell, and W. D., Parker, Jr. Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease. Proc. Natl. Acad. Sci. USA 94:4526–31 (1997).

    Google Scholar 

  83. M. P. Mattson. Mother's legacy: mitochondrial DNA mutations and Alzheimer's disease. Trends in Neurosciences 20:373–375 (1997).

    PubMed  Google Scholar 

  84. S. G., Post, P. J., Whitehouse, R. H., Binstock, T. D., Bird, S. K., Eckert, L. A., Farrer, L. M., Fleck, A. D., Gaines, E. T., Juengst, H., Karlinsky, S., Miles, T. H., Murray, K. A., Quaid, N. R., Relkin, A. D., Roses, P.H., St. George-Hyslop, G. A., Sachs, B., Steinbock, E. F., Truschke, and A. B. Zinn. The clinical introduction of genetic testing for Alzheimer disease: An ethical perspective JAMA 277:832–836 (1997).

    PubMed  Google Scholar 

  85. A. D., Roses. The Alzheimer's diseases. Current Biology 6:644–650 (1996).

    Google Scholar 

  86. K., Duff. Alzheimer transgenic mouse models come of age. Trends in Neurosciences 20:279–80 (1997).

    PubMed  Google Scholar 

  87. M. L. Oster-Granite, D. L. McPhie, J. Greenan, and R. L. Neve. Age-dependent neuronal and synaptic degeneration in micetransgenic for the C terminus of the amyloid precursor protein. J. Neurosci. 16:6732–41 (1996).

    PubMed  Google Scholar 

  88. J., Nalbantoglu, G., Tirado-Santiago, A. Lahsaini, J. Poirier, O., Gonsalvo, G. Verge, F., Momoli, S. A., Welner, G., Julien, J. P., Messicote, and M. L. Shapiro. Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor. Nature 387:500–505 (1997).

    PubMed  Google Scholar 

  89. C.J., Heyser, E., Masliah, A., Samimi, I. L., Campbell, and L. H. Gold. Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain. Proc. Natl. Acad. Sci. 94:1500–1505 (1997).

    PubMed  Google Scholar 

  90. P. K., Molsa, R. J., Marttila, and U. K., Rinne. Epidemiology of dementia in a Finnish population Acta Neurol. Scand. 65:541–552 (1982).

    PubMed  Google Scholar 

  91. L. S., Schneider, M. R., Farlow, V. W., Henderson, and J. M., Pogoda. Effects of estrogen replacement therapy on response to tacrine in patients with Alzheimer's disease. Neurology 46:1580–84 (1996).

    PubMed  Google Scholar 

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  1. Department of Molecular Pharmacology and Toxicology, University of Southern California, Pharmaceutical Sciences Center, 1985 Zonal Avenue, Los Angeles, California, 90033

    Roberta Diaz Brinton & Rose S. Yamazaki

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Brinton, R.D., Yamazaki, R.S. Advances and Challenges in the Prevention and Treatment of Alzheimer's Disease. Pharm Res 15, 386–398 (1998). https://doi.org/10.1023/A:1011963929012

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