Animal models of Alzheimer disease: Historical pitfalls and a path forward

Altex

Volumn 31, Issue 3, 2014, Pages 279-302

  Cavanaugh, Sarah E ^a   Pippin, John J ^a   Barnard, Neal D ^a,b  

^a PHYSICIANS COMMITTEE FOR RESPONSIBLE MEDICINE   (United States)

^b GEORGE WASHINGTON UNIVERSITY SCHOOL OF MEDICINE AND HEALTH SCIENCES   (United States)

Author keywords

Alzheimer disease; Animal experimentation; Clinical research; Research models; Therapy

Indexed keywords

BETA SECRETASE INHIBITOR; CHOLINESTERASE INHIBITOR; IMMUNOMODULATING AGENT; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT;

ALZHEIMER DISEASE; CLINICAL RESEARCH; CLINICAL TRIAL (TOPIC); GENE EXPRESSION; GENE MUTATION; HUMAN; INCIDENCE; LIFESTYLE; NONHUMAN; PROMOTER REGION; REVIEW; TRANSGENE; ANIMAL; COMPUTER SIMULATION; DISEASE MODEL; HISTORY; MEDICAL RESEARCH; MOUSE; RAT; RISK FACTOR;

ALZHEIMER DISEASE; ANIMALS; BIOMEDICAL RESEARCH; CHOLINESTERASE INHIBITORS; COMPUTER SIMULATION; DISEASE MODELS, ANIMAL; HISTORY, 20TH CENTURY; HISTORY, 21ST CENTURY; HUMANS; MICE; RATS; RISK FACTORS;

EID: 84904869948     PISSN: 1868596X     EISSN: 18688551     Source Type: Journal    
DOI: 10.14573/altex.1310071     Document Type: Review

References (355)

1. Adlard, P. A., Cherny, R. A., Finkelstein, D. I. et al. (2008). Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron 59, 43-55. http://dx.doi.org/10.1016/ j.neuron.2008.06.018
2. Adolfsson, O., Pihlgren, M., Toni, N. et al. (2012). An effector-reduced anti-beta-amyloid (Abeta) antibody with unique abeta binding properties promotes neuroprotection and glial engulfment of Abeta. J Neurosci 32, 9677-9689. http://dx.doi.org/10.1523/JNEUROSCI.4742-11.2012
3. Aisen, P. S. (2005). The development of anti-amyloid therapy for Alzheimer's disease: From secretase modulators to polymerisation inhibitors. CNS Drugs 19, 989-996.
4. Aisen, P. S., Gauthier, S., Ferris, S. H. et al. (2011). Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Arch Med Sci 7, 102-111. http://dx.doi.org/10.5114/aoms.2011.20612
5. Akiyama, H., Barger, S., Barnum, S. et al. (2000). Inflammation and Alzheimer's disease. Neurobiol Aging 21, 383-421. (Pubitemid 30349107)
6. Allen, B., Ingram, E., Takao, M. et al. (2002). Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 22, 9340-9351. (Pubitemid 35356177)
7. Almeida, S., Gascon, E., Tran, H. et al. (2013). Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol 126, 385-399. http://dx.doi.org/10.1007/s00401-013-1149-y
8. AlzForum (2014). Drugs and Therapies. http://www.alzforum.org/ therapeutics
9. Alzheimer's Association (2013). 2013 Alzheimer's Disease Facts and Figures. http://www.alz.org/alzheimers-disease-facts-and-figures.asp
10. Alzheimer's Disease International (2009). World Alzheimer Report 2009. http://www.alz.co.uk/research/files/WorldAlzheimerReport.pdf
11. Andorfer, C., Kress, Y., Espinoza, M. et al. (2003). Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 86, 582-590. (Pubitemid 36897439)
12. Bachurin, S., Bukatina, E., Lermontova, N. et al. (2001). Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. Ann N Y Acad Sci 939, 425-435. (Pubitemid 32620096)
13. Barberger-Gateau, P., Raffaitin, C., Letenneur, L. et al. (2007). Dietary patterns and risk of dementia: The Three-City cohort study. Neurology 69, 1921-1930. http://dx.doi.org/10.1212/01.wnl.0000278116.37320.52 (Pubitemid 350100350)
14. Bard, F., Cannon, C., Barbour, R. et al. (2000). Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6, 916-919. http://dx.doi.org/10.1038/78682 (Pubitemid 30644751)
15. Bard, F., Fox, M., Friedrich, S. et al. (2012). Sustained levels of antibodies against Abeta in amyloid-rich regions of the CNS following intravenous dosing in human APP transgenic mice. Exp Neurol 238, 38-43. http://dx.doi.org/10.1016/j.expneurol.2012.07.022
16. Barnes, C. A., Danysz, W. and Parsons, C. G. (1996). Effects of the uncompetitive NMDA receptor antagonist memantine on hippocampal long-term potentiation, short-term exploratory modulation and spatial memory in awake, freely moving rats. Eur J Neurosci 8, 565-571. (Pubitemid 26090761)
17. Baxter International, Inc. (2013). Baxter announces topline results of phase III study of immunoglobulin for Alzheimer's disease. http://www.baxter. com/press-room/press-releases/ 2013/05-07-13-gap-study.html
18. Becker, R. E. and Greig, N. H. (2012). Was phenserine a failure or were investigators mislead by methods? Curr Alzheimer Res 9, 1174-1181.
19. Benzing, W. C., Wujek, J. R., Ward, E. K. et al. (1999). Evidence for glial-mediated inflammation in aged APP(SW) transgenic mice. Neurobiol Aging 20, 581-589. (Pubitemid 30064403)
20. Bienias, J. L., Beckett, L. A., Bennett, D. A. et al. (2003). Design of the Chicago Health and Aging Project (CHAP). J Alzheimers Dis 5, 349-355. (Pubitemid 37474764)
21. Bierer, L. M., Hof, P. R., Purohit, D. P. et al. (1995). Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer's disease. Arch Neurol 52, 81-88.
22. Blanchard, V., Czech, C., Bonici, B. et al. (1997). Immunohisto-chemical analysis of presenilin 2 expression in the mouse brain: Distribution pattern and co-localization with presenilin 1 protein. Brain Res 758, 209-217. (Pubitemid 27310659)
23. Blanchard, V., Moussaoui, S., Czech, C. et al. (2003). Time sequence of maturation of dystrophic neurites associated with Abeta deposits in APP/PS1 transgenic mice. Exp Neurol 184, 247-263. (Pubitemid 37444035)
24. Bodendorf, U., Danner, S., Fischer, F. et al. (2002). Expression of human beta-secretase in the mouse brain increases the steady-state level of beta-amyloid. J Neurochem 80, 799-806. (Pubitemid 34809232)
25. Boissart, C., Poulet, A., Georges, P. et al. (2013). Differentiation from human pluripotent stem cells of cortical neurons of the superficial layers amenable to psychiatric disease modeling and high-throughput drug screening. Transl Psychiatry 3, e294. http://dx.doi.org/10.1038/tp.2013.71
26. Bons, N., Rieger, F., Prudhomme, D. et al. (2006). Microcebus murinus: A useful primate model for human cerebral aging and Alzheimer's disease? Genes Brain Behav 5, 120-130. http://dx.doi.org/10.1111/j.1601-183X.2005.00149.x (Pubitemid 43344964)
27. Borchelt, D. R., Ratovitski, T., van Lare, J. et al. (1997). Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19, 939-945. (Pubitemid 27471397)
28. Bores, G. M., Huger, F. P., Petko, W. et al. (1996). Pharmacological evaluation of novel Alzheimer's disease therapeutics: Acetylcholinesterase inhibitors related to galanthamine. J Pharmacol Exp Ther 277, 728-738. (Pubitemid 27168982)
29. Brion, J. P., Tremp, G. and Octave, J. N. (1999). Transgenic expression of the shortest human tau affects its compartmentalization and its phosphorylation as in the pretangle stage of Alzheimer's disease. Am J Pathol 154, 255-270. http://dx.doi.org/10.1016/S0002-9440(10)65272-8
30. Bristol-Myers Squibb (2012). Statement on Avagacestat development status. http://www.bms.com/news/features/2012/Pages/AvagacestatDevelopmentStatus.aspx
31. Burkhardt, M. F., Martinez, F. J., Wright, S. et al. (2013). A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells. Mol Cell Neurosci 56C, 355-364. http://dx.doi.org/10.1016/j.mcn.2013.07.007
32. Buttini, M., Masliah, E., Barbour, R. et al. (2005). Beta-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer's disease. J Neurosci 25, 9096-9101. http://dx.doi.org/10.1523/JNEUROSCI.1697-05. 2005 (Pubitemid 41500817)
33. Cai, H., Wang, Y., McCarthy, D. et al. (2001). BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci 4, 233-234. http://dx.doi.org/10.1038/85064 (Pubitemid 32194867)
34. Calhoun, M. E., Wiederhold, K. H., Abramowski, D. et al. (1998). Neuron loss in APP transgenic mice. Nature 395, 755-756. http://dx.doi.org/10.1038/ 27351 (Pubitemid 28485431)
35. Casas, C., Sergeant, N., Itier, J. M. et al. (2004). Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am J Pathol 165, 1289-1300. (Pubitemid 39297734)
36. Cavallucci, V., D'Amelio, M. and Cecconi, F. (2012). Abeta toxicity in Alzheimer's disease. Mol Neurobiol 45, 366-378. http://dx.doi.org/10.1007/ s12035-012-8251-3
37. Chai, C. K. (2007). The genetics of Alzheimer's disease. Am J Alzheimers Dis Other Demen 22, 37-41.
38. Chan, A. W. and Yang, S. H. (2009). Generation of transgenic monkeys with human inherited genetic disease. Methods 49, 78-84. http://dx.doi.org/10.1016/ j.ymeth.2009.05.007
39. Chapman, P. F., White, G. L., Jones, M. W. et al. (1999). Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci 2, 271-276. http://dx.doi.org/10.1038/6374 (Pubitemid 30491299)
40. Charlton Research Company (2009). America speaks: Poll data summary, volume 10. http://www.researchamerica.org/uploads/AmericaSpeaksV10.pdf
41. Chartier-Harlin, M. C., Crawford, F., Houlden, H. et al. (1991). Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 353, 844-846. http://dx.doi.org/10. 1038/353844a0 (Pubitemid 21912637)
42. Chen, Y., Niu, Y. and Ji, W. (2012). Transgenic nonhuman primate models for human diseases: Approaches and contributing factors. J Genet Genomics 39, 247-251. http://dx.doi.org/10.1016/ j.jgg.2012.04.007
43. Cheng, I. H., Palop, J. J., Esposito, L. A. et al. (2004). Aggressive amyloidosis in mice expressing human amyloid peptides with the Arctic mutation. Nat Med 10, 1190-1192. http://dx.doi.org/10.1038/nm1123 (Pubitemid 39540434)
44. Cheng, I. H., Scearce-Levie, K., Legleiter, J. et al. (2007). Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J Biol Chem 282, 23818-23828. http://dx.doi.org/10.1074/jbc.M701078200 (Pubitemid 47328006)
45. Cherny, R. A., Atwood, C. S., Xilinas, M. E. et al. (2001). Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 30, 665-676. (Pubitemid 32607332)
46. Chin, J., Palop, J. J., Puolivali, J. et al. (2005). Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer's disease. J Neurosci 25, 9694-9703. http://dx.doi.org/10.1523/JNEUROSCI.2980-05. 2005 (Pubitemid 41510910)
47. Chishti, M. A., Yang, D. S., Janus, C. et al. (2001). Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem 276, 21562-21570. http://dx.doi.org/10.1074/jbc.M100710200 (Pubitemid 37413154)
48. Chopin, P. and Briley, M. (1992). Effects of four non-cholinergic cognitive enhancers in comparison with tacrine and galanthamine on scopolamine-induced amnesia in rats. Psychopharmacology (Berl) 106, 26-30.
49. Cohen, R. M., Rezai-Zadeh, K., Weitz, T. M. et al. (2013). A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric abeta, and Frank neuronal loss. J Neurosci 33, 6245-6256. http://dx.doi.org/10. 1523/JNEURO SCI.3672-12.2013
50. Colle, M. A., Hauw, J. J., Crespeau, F. et al. (2000). Vascular and parenchymal Abeta deposition in the aging dog: Correlation with behavior. Neurobiol Aging 21, 695-704.
51. Comery, T. A., Martone, R. L., Aschmies, S. et al. (2005). Acute gamma-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer's disease. J Neurosci 25, 8898-8902. http://dx.doi.org/10.1523/JNEURO SCI.2693-05.2005
52. Corder, E. H., Saunders, A. M., Strittmatter, W. J. et al. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921-923. (Pubitemid 23275809)
53. Cotman, C. W. and Head, E. (2008). The canine (dog) model of human aging and disease: Dietary, environmental and immunotherapy approaches. J Alzheimers Dis 15, 685-707.
54. Cramer, C., Haan, M. N., Galea, S. et al. (2008). Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study. Neurology 71, 344-350. http://dx.doi.org/10.1212/01.wnl.0000319647.15752. 7b
55. Cuijpers, P. (2005). Depressive disorders in caregivers of dementia patients: A systematic review. Aging Ment Health 9, 325-330. http://dx.doi.org/10.1080/13607860500090078
56. Cummings, B. J., Head, E., Afagh, A. J. et al. (1996a). Beta-amyloid accumulation correlates with cognitive dysfunction in the aged canine. Neurobiol Learn Mem 66, 11-23. http://dx.doi.org/10.1006/nlme.1996.0039 (Pubitemid 26195731)
57. Cummings, B. J., Head, E., Ruehl, W. et al. (1996b). The canine as an animal model of human aging and dementia. Neurobiol Aging 17, 259-268. (Pubitemid 26167637)
58. Cunnane, S. C., Schneider, J. A., Tangney, C. et al. (2012). Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer's disease. J Alzheimers Dis 29, 691-697. http://dx.doi.org/10.3233/JAD-2012-110629
59. Danysz, W. and Parsons, C. G. (2003). The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer's disease: Preclinical evidence. Int J Geriatr Psychiatry 18, S23-32. http://dx.doi.org/10.1002/gps.938 (Pubitemid 37150475)
60. Davis, J., Maillet, M., Miano, J. M. et al. (2012). Lost in transgenesis: A user's guide for genetically manipulating the mouse in cardiac research. Circ Res 111, 761-777. http://dx.doi.org/10.1161/CIRCRESAHA.111.262717
61. Dawson, G. R. and Iversen, S. D. (1993). The effects of novel cholinesterase inhibitors and selective muscarinic receptor agonists in tests of reference and working memory. Behav Brain Res 57, 143-153. (Pubitemid 24027144)
62. de Bruijn, R. F., Schrijvers, E. M., de Groot, K. A. et al. (2013). The association between physical activity and dementia in an elderly population: The Rotterdam Study. Eur J Epidemiol 28, 277-283. http://dx.doi.org/10.1007/s10654- 013-9773-3
63. de la Monte, S. M. and Wands, J. R. (2005). Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: Relevance to Alzheimer's disease. J Alzheimers Dis 7, 45-61.
64. de Vugt, M. E., Stevens, F., Aalten, P. et al. (2005). A prospective study of the effects of behavioral symptoms on the institutionalization of patients with dementia. Int Psychogeriatr 17, 577-589. http://dx.doi.org/10. 1017/S1041610205002292 (Pubitemid 41758763)
65. Decker, M. W., Bannon, A. W., Curzon, P. et al. (1997). ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride]: II. A novel cholinergic channel modulator with effects on cognitive performance in rats and monkeys. J Pharmacol Exp Ther 283, 247-258. (Pubitemid 27438968)
66. Del Valle, J., Duran-Vilaregut, J., Manich, G. et al. (2010). Early amyloid accumulation in the hippocampus of SAMP8 mice. J Alzheimers Dis 19, 1303-1315. http://dx.doi.org/10.3233/JAD-2010-1321
67. DeMattos, R. B., Bales, K. R., Cummins, D. J. et al. (2001). Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 98, 8850-8855. http://dx.doi.org/10.1073/pnas.151261398 (Pubitemid 32678116)
68. Dickson, D. W., Crystal, H. A., Bevona, C. et al. (1995). Correlations of synaptic and pathological markers with cognition of the elderly. Neurobiol Aging 16, 285-298; discussion 298-304.
69. Dodart, J. C., Mathis, C., Saura, J. et al. (2000). Neuroanatomical abnormalities in behaviorally characterized APP(V717F) transgenic mice. Neurobiol Dis 7, 71-85. http://dx.doi.org/10.1006/nbdi.1999.0278 (Pubitemid 30241204)
70. Dodart, J. C., Bales, K. R., Gannon, K. S. et al. (2002). Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat Neurosci 5, 452-457. http://dx.doi.org/10.1038/nn842 (Pubitemid 34454251)
71. Dodel, R., Rominger, A., Bartenstein, P. et al. (2013). Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: A phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol 12, 233-243. http://dx.doi.org/10.1016/S1474-4422(13)70014-0
72. Doody, R. S., Thomas, R. G., Farlow, M. et al. (2014). Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med 370, 311-321. http://dx.doi.org/10.1056/NEJMoa1312889
73. Dovey, H. F., John, V., Anderson, J. P. et al. (2001). Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem 76, 173-181. (Pubitemid 32044380)
74. Duff, K., Eckman, C., Zehr, C. et al. (1996). Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383, 710-713. http://dx.doi.org/10.1038/383710a0 (Pubitemid 26360645)
75. Duff, K., Knight, H., Refolo, L. M. et al. (2000). Characterization of pathology in transgenic mice over-expressing human genomic and cDNA tau transgenes. Neurobiol Dis 7, 87-98. http://dx.doi.org/10.1006/nbdi.1999.0279 (Pubitemid 30241205)
76. Duke Medical News(2013). Enocuraging news in Alzheimer's prevention and treatment. Research continues to underscore the value of cardiovascular health in relation to brain function. Duke Med Health News 19, 4-5.
77. Duyckaerts, C., Potier, M. C. and Delatour, B. (2008). Alzheimer disease models and human neuropathology: Similarities and differences. Acta Neuropathol 115, 5-38. http://dx.doi.org/10.1007/s00401-007-0312-8 (Pubitemid 50005258)
78. Eapen, Z. J., Vavalle, J. P., Granger, C. B. et al. (2013). Rescuing clinical trials in the United States and beyond: A call for action. Am Heart J 165, 837-847. http://dx.doi.org/10.1016/ j.ahj.2013.02.003
79. Eikelenboom, P. and Stam, F. C. (1982). Immunoglobulins and complement factors in senile plaques. An immunoperoxidase study. Acta Neuropathol 57, 239-242. (Pubitemid 12085182)
80. Eikelenboom, P., Hack, C. E., Rozemuller, J. M. et al. (1989). Complement activation in amyloid plaques in Alzheimer's dementia. Virchows Arch B Cell Pathol Incl Mol Pathol 56, 259-262. (Pubitemid 19049180)
81. Eikelenboom, P. and Veerhuis, R. (1996). The role of complement and activated microglia in the pathogenesis of Alzheimer's disease. Neurobiol Aging 17, 673-680. (Pubitemid 26348867)
82. Eli Lilly and Company (2013a). Lilly Halts development of Semagacestat for Alzheimer's disease based on preliminary results of phase III clinical trials. http://newsroom.lilly.com/ releasedetail.cfm?releaseid=499794
83. Eli Lilly and Company (2013b). Lilly voluntarily terminates phase II study for LY2886721, a beta secretase inhibitor, being investigated as a treatment for Alzheimer's disease. https://investor.lilly.com/releasedetail.cfm? ReleaseID=771353
84. Engelhart, M. J., Geerlings, M. I., Ruitenberg, A. et al. (2002). Dietary intake of antioxidants and risk of Alzheimer disease. JAMA 287, 3223-3229. (Pubitemid 34686103)
85. Erickson, K. I., Weinstein, A. M. and Lopez, O. L. (2012). Physical activity, brain plasticity, and Alzheimer's disease. Arch Med Res 43, 615-621. http://dx.doi.org/10.1016/j.arcmed.2012.09.008
86. Extance, A. (2010). Alzheimer's failure raises questions about disease-modifying strategies. Nat Rev Drug Discov 9, 749-751. http://dx.doi.org/10.1038/nrd3288
87. Farlow, M., Anand, R., Messina, J., Jr. et al. (2000). A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer's disease. Eur Neurol 44, 236-241. http://dx.doi.org/8243
88. Feldman, H. H., Doody, R. S., Kivipelto, M. et al. (2010). Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology 74, 956-964. http://dx.doi.org/10.1212/WNL.0b013e3181d6476a
89. Fenili, D., Brown, M., Rappaport, R. et al. (2007). Properties of scyllo-inositol as a therapeutic treatment of AD-like pathology. J Mol Med (Berl) 85, 603-611. http://dx.doi.org/10.1007/s00109-007-0156-7 (Pubitemid 46870891)
90. Ferri, C. P., Ames, D., Prince, M. et al. (2004). Behavioral and psychological symptoms of dementia in developing countries. Int Psychogeriatr 16, 441-459. (Pubitemid 40189310)
91. Fisher, A., Brandeis, R., Bar-Ner, R. H. et al. (2002a). AF150(S) and AF267B: M1 muscarinic agonists as innovative therapies for Alzheimer's disease. J Mol Neurosci 19, 145-153. http://dx.doi.org/10.1007/s12031-002-0025-3 (Pubitemid 35013348)
92. Fisher, A., Brandeis, R., Haring, R. et al. (2002b). Impact of muscarinic agonists for successful therapy of Alzheimer's disease. J Neural Transm 62, Suppl, 189-202. (Pubitemid 37046664)
93. Fisher, A., Pittel, Z., Haring, R. et al. (2003). M1 muscarinic agonists can modulate some of the hallmarks in Alzheimer's disease: Implications in future therapy. J Mol Neurosci 20, 349-356. http://dx.doi.org/10.1385/JMN:20:3: 349 (Pubitemid 38146993)
94. Fitzpatrick, A. L., Kuller, L. H., Lopez, O. L. et al. (2005). Survival following dementia onset: Alzheimer's disease and vascular dementia. J Neurol Sci 229-230, 43-49. http://dx.doi.org/10.1016/j.jns.2004.11.022 (Pubitemid 40341563)
95. Freund-Levi, Y., Hjorth, E., Lindberg, C. et al. (2009). Effects of omega-3 fatty acids on inflammatory markers in cerebrospinal fluid and plasma in Alzheimer's disease: The OmegAD study. Dement Geriatr Cogn Disord 27, 481-490. http://dx.doi.org/10.1159/000218081
96. Frolich, L., Ashwood, T., Nilsson, J. et al. (2011). Effects of AZD3480 on cognition in patients with mild-to-moderate Alzheimer's disease: A phase IIb dose-finding study. J Alz-heimers Dis 24, 363-374. http://dx.doi.org/10.3233/ JAD-2011-101554
97. Fu, H., Li, W., Lao, Y. et al. (2006). Bis(7)-tacrine attenuates beta amyloid-induced neuronal apoptosis by regulating L-type calcium channels. J Neurochem 98, 1400-1410. http://dx.doi.org/10.1111/j.1471-4159.2006.03960.x (Pubitemid 44200432)
98. Fu, H., Li, W., Luo, J. et al. (2008). Promising anti-Alzheimer's dimer bis(7)-tacrine reduces beta-amyloid generation by directly inhibiting BACE-1 activity. Biochem Biophys Res Commun 366, 631-636. http://dx.doi.org/10.1016/j. bbrc.2007.11.068
99. Games, D., Adams, D., Alessandrini, R. et al. (1995). Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373, 523-527. http://dx.doi.org/10.1038/373523a0
100. Ganguli, M., Dodge, H. H., Shen, C. et al. (2005). Alzheimer disease and mortality: A 15-year epidemiological study. Arch Neurol 62, 779-784. http://dx.doi.org/10.1001/archneur.62.5.779 (Pubitemid 40656094)
101. Garnier, J. P. (2008). Rebuilding the R&D engine in big pharma. Harv Bus Rev 86, 68-70, 72-66, 128.
102. Gatto, G. J., Bohme, G. A., Caldwell, W. S. et al. (2004). TC-1734: An orally active neuronal nicotinic acetylcholine receptor modulator with antidepressant, neuroprotective and long-lasting cognitive effects. CNS Drug Rev 10, 147-166. (Pubitemid 38879108)
103. Gatz, M., Reynolds, C. A., Fratiglioni, L. et al. (2006). Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 63, 168-174. http://dx.doi.org/10.1001/archpsyc.63.2.168 (Pubitemid 43213878)
104. Gearing, M., Rebeck, G. W., Hyman, B. T. et al. (1994). Neuropathology and apolipoprotein E profile of aged chimpanzees: Implications for Alzheimer disease. Proc Natl Acad Sci U S A 91, 9382-9386. (Pubitemid 24297918)
105. Gearing, M., Tigges, J., Mori, H. et al. (1996). A beta40 is a major form of beta-amyloid in nonhuman primates. Neurobiol Aging 17, 903-908. (Pubitemid 27022744)
106. Gearing, M., Tigges, J., Mori, H. et al. (1997). beta-Amyloid (A beta) deposition in the brains of aged orangutans. Neurobiol Aging 18, 139-146. (Pubitemid 27355931)
107. Geghman, K. and Li, C. (2011). Practical considerations of genetic rodent models for neurodegenerative diseases. Methods Mol Biol 793, 185-193. http://dx.doi.org/10.1007/978-1-61779-328-8-12
108. Geling, A., Steiner, H., Willem, M. et al. (2002). A gamma-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish. EMBO Rep 3, 688-694. http://dx.doi.org/10.1093/embo- reports/kvf124
109. Gervais, F., Chalifour, R., Garceau, D. et al. (2001). Glycosaminoglycan mimetics: A therapeutic approach to cerebral amyloid angiopathy. Amyloid 8, Suppl 1, 28-35. (Pubitemid 32889453)
110. Gervais, F., Paquette, J., Morissette, C. et al. (2007). Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain amyloidosis. Neurobiol Aging 28, 537-547. http://dx.doi.org/10.1016/j.neurobiolaging.2006.02. 015 (Pubitemid 46282205)
111. Ghribi, O., Golovko, M. Y., Larsen, B. et al. (2006). Deposition of iron and beta-amyloid plaques is associated with cortical cellular damage in rabbits fed with long-term cholesterol-enriched diets. J Neurochem 99, 438-449. http://dx.doi.org/10.1111/j.1471-4159.2006.04079.x (Pubitemid 44477201)
112. Glenner, G. G. and Wong, C. W. (1984). Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120, 885-890. (Pubitemid 14104991)
113. Goate, A., Chartier-Harlin, M. C., Mullan, M. et al. (1991). Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704-706. http://dx.doi.org/10.1038/349704a0 (Pubitemid 21912142)
114. Gold, M., Alderton, C., Zvartau-Hind, M. et al. (2010). Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: Results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord 30, 131-146. http://dx.doi.org/10.1159/000318845
115. Gonzalez-Lima, F., Berndt, J. D., Valla, J. E. et al. (2001). Reduced corpus callosum, fornix and hippocampus in PDAPP transgenic mouse model of Alzheimer's disease. Neuroreport 12, 2375-2379. (Pubitemid 32684580)
116. Gotz, J., Probst, A., Spillantini, M. G. et al. (1995). Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J 14, 1304-1313.
117. Gotz, J., Chen, F., van Dorpe, J. et al. (2001). Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293, 1491-1495. http://dx.doi.org/10.1126/science.1062097 (Pubitemid 32807681)
118. Green, R. C., Schneider, L. S., Amato, D. A. et al. (2009). Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: A randomized controlled trial. JAMA 302, 2557-2564. http://dx.doi.org/10.1001/jama.2009.1866
119. Grunblatt, E., Hoyer, S. and Riederer, P. (2004). Gene expression profile in streptozotocin rat model for sporadic Alzheimer's disease. J Neural Transm 111, 367-386. http://dx.doi.org/10.1007/s00702-003-0030-x (Pubitemid 38316611)
120. Gutteridge, J. M. (1994). Hydroxyl radicals, iron, oxidative stress, and neurodegeneration. Ann N Y Acad Sci 738, 201-213.
121. Haag, M. D., Hofman, A., Koudstaal, P. J. et al. (2009). Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study. J Neurol Neurosurg Psychiatry 80, 13-17. http://dx.doi.org/10.1136/jnnp.2008.150433
122. Hardy, J. A. and Higgins, G. A. (1992). Alzheimer's disease: The amyloid cascade hypothesis. Science 256, 184-185.
123. Hare, B. and Tomasello, M. (2005). Human-like social skills in dogs? Trends Cogn Sci 9, 439-444. http://dx.doi.org/10.1016/j.tics.2005.07.003 (Pubitemid 41208253)
124. Haroutunian, V., Greig, N., Pei, X. F. et al. (1997). Pharmacological modulation of Alzheimer's beta-amyloid precursor protein levels in the CSF of rats with forebrain cholinergic system lesions. Brain Res Mol Brain Res 46, 161-168. (Pubitemid 27214367)
125. Harrison, S. M., Harper, A. J., Hawkins, J. et al. (2003). BACE1 (beta-secretase) transgenic and knockout mice: Identification of neurochemical deficits and behavioral changes. Mol Cell Neurosci 24, 646-655. (Pubitemid 37506009)
126. Head, E., Mehta, R., Hartley, J. et al. (1995). Spatial learning and memory as a function of age in the dog. Behav Neurosci 109, 851-858.
127. Head, E., Callahan, H., Muggenburg, B. A. et al. (1998). Visual-discrimination learning ability and beta-amyloid accumulation in the dog. Neurobiol Aging 19, 415-425. (Pubitemid 29065491)
128. Head, E., McCleary, R., Hahn, F. F. et al. (2000). Region-specific age at onset of beta-amyloid in dogs. Neurobiol Aging 21, 89-96. (Pubitemid 30224790)
129. Hebert, L. E., Weuve, J., Scherr, P. A. et al. (2013). Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology 80, 1778-1783. http://dx.doi.org/10.1212/WNL.0b013e31828726f5
130. Heinrich, J. N., Butera, J. A., Carrick, T. et al. (2009). Pharmacological comparison of muscarinic ligands: Historical versus more recent muscarinic M1-preferring receptor agonists. Eur J Pharmacol 605, 53-56. http://dx.doi.org/10.1016/j.ejphar.2008.12.044
131. Heneka, M. T., Sastre, M., Dumitrescu-Ozimek, L. et al. (2005). Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain 128, 1442-1453. http://dx.doi.org/10.1093/brain/awh452 (Pubitemid 40826196)
132. Henley, D. B., May, P. C., Dean, R. A. et al. (2009). Development of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of Alzheimer's disease. Expert Opin Pharmacother 10, 1657-1664. http://dx.doi.org/ 10.1517/14656560903044982
133. Herzig, M. C., Winkler, D. T., Burgermeister, P. et al. (2004). Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci 7, 954-960. http://dx.doi.org/10.1038/nn1302 (Pubitemid 39129504)
134. Hilt, D.C., Gawryl, M., Koenig, G. et al. (2012). EVP-6124, A selective Alpha-7 partial agonist, has positive effects on cognition and clinical function in mild to moderate Alzheimer's disease patients: Results of a six-month, double-blind, placebo controlled, dose ranging study. http://www.envivopharma. com/pdf/EVP-6124AAICPressConf.pdf
135. Hock, C., Maddalena, A., Raschig, A. et al. (2003). Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of A beta 42 in patients with Alzheimer's disease. Amyloid 10, 1-6. (Pubitemid 36520922)
136. Holcomb, L., Gordon, M. N., McGowan, E. et al. (1998). Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4, 97-100. (Pubitemid 28133087)
137. Honjo, K., Black, S. E. and Verhoeff, N. P. (2012). Alzheimer's disease, cerebrovascular disease, and the beta-amyloid cascade. Can J Neurol Sci 39, 712-728.
138. Hou, Y., White, R. G., Bobik, M. et al. (1997). Distribution of beta-amyloid in the canine brain. Neuroreport 8, 1009-1012.
139. Hsia, A. Y., Masliah, E., McConlogue, L. et al. (1999). Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc Natl Acad Sci U S A 96, 3228-3233. (Pubitemid 29148873)
140. Hsiao, K., Chapman, P., Nilsen, S. et al. (1996). Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274, 99-102. (Pubitemid 26332733)
141. Humpel, C. (2011). Identifying and validating biomarkers for Alzheimer's disease. Trends Biotechnol 29, 26-32. http://dx.doi.org/10.1016/j.tibtech.2010. 09.007
142. Ieda, M. (2013). Direct reprogramming into desired cell types by defined factors. Keio J Med 62, 74-82.
143. Imbimbo, B. P. and Giardina, G. A. (2011). gamma-secretase inhibitors and modulators for the treatment of Alzheimer's disease: Disappointments and hopes. Curr Top Med Chem 11, 1555-1570.
144. Imbimbo, B. P., Ottonello, S., Frisardi, V. et al. (2012). Solanezumab for the treatment of mild-to-moderate Alzheimer's disease. Expert Rev Clin Immunol 8, 135-149. http://dx.doi.org/10.1586/eci.11.93
145. Inestrosa, N. C., Alvarez, A., Perez, C. A. et al. (1996). Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer's fibrils: Possible role of the peripheral site of the enzyme. Neuron 16, 881-891. (Pubitemid 26124065)
146. Irizarry, M. C., Soriano, F., McNamara, M. et al. (1997). Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J Neurosci 17, 7053-7059. (Pubitemid 27427884)
147. Irvine, G. B., El-Agnaf, O. M., Shankar, G. M. et al. (2008). Protein aggregation in the brain: The molecular basis for Alzheimer's and Parkinson's diseases. Mol Med 14, 451-464. http://dx.doi.org/10.2119/2007-00100.Irvine
148. Isaac, M. G., Quinn, R. and Tabet, N. (2008). Vitamin E for Alzheimer's disease and mild cognitive impairment. Cochrane Database Syst Rev, CD002854. http://dx.doi.org/10.1002/14651858.CD002854.pub2
149. Ishihara, T., Hong, M., Zhang, B. et al. (1999). Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 24, 751-762.
150. Iwatsubo, T., Odaka, A., Suzuki, N. et al. (1994). 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 13, 45-53.
151. Johnstone, E. M., Chaney, M. O., Norris, F. H. et al. (1991). Conservation of the sequence of the Alzheimer's disease amyloid peptide in dog, polar bear and five other mammals by cross-species polymerase chain reaction analysis. Brain Res Mol Brain Res 10, 299-305.
152. Kalback, W., Watson, M. D., Kokjohn, T. A. et al. (2002). APP transgenic mice Tg2576 accumulate A beta peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer's disease senile plaques. Biochemistry 41, 922-928. (Pubitemid 34061994)
153. Kanemaru, K., Iwatsubo, T. and Ihara, Y. (1996). Comparable amyloid beta-protein (A beta) 42(43) and A beta 40 deposition in the aged monkey brain. Neurosci Lett 214, 196-198. (Pubitemid 26284465)
154. Kavanagh, S., Van Baelen, B. and Schauble, B. (2011). Long-term effects of galantamine on cognitive function in Alzheimer's disease: A large-scale international retrospective study. J Alzheimers Dis 27, 521-530. http://dx.doi.org/10.3233/JAD-2011-110417
155. Kiatipattanasakul, W., Nakayama, H., Yongsiri, S. et al. (2000). Abnormal neuronal and glial argyrophilic fibrillary structures in the brain of an aged albino cynomolgus monkey (Macaca fascicularis). Acta Neuropathol 100, 580-586.
156. Kim, E. S., Carrigan, T. P. and Menon, V. (2011). International participation in cardiovascular randomized controlled trials sponsored by the National Heart, Lung, and Blood Institute. J Am Coll Cardiol 58, 671-676. http://dx.doi.org/10.1016/j.jacc.2011.01.066 \
157. Kingwell, K. (2012). Alzheimer disease: Amyloid-beta immunotherapy CAD106 passes first safety test in patients with Alzheimer disease. Nat Rev Neurol 8, 414. http://dx.doi.org/10.1038/nrneurol.2012.128
158. Kirkby, D. L., Jones, D. N., Barnes, J. C. et al. (1996). Effects of anticholinesterase drugs tacrine and E2020, the 5-HT(3) antagonist ondansetron, and the H(3) antagonist thioperamide, in models of cognition and cholinergic function. Behav Pharmacol 7, 513-525. (Pubitemid 27046781)
159. Klein, J. (2007). Phenserine. Expert Opin Investig Drugs 16, 1087-1097. http://dx.doi.org/10.1517/13543784.16.7.1087
160. Kosik, K. S., Joachim, C. L. and Selkoe, D. J. (1986). Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci U S A 83, 4044-4048. (Pubitemid 16062419)
161. Kukar, T., Prescott, S., Eriksen, J. L. et al. (2007). Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neurosci 8, 54. http://dx.doi.org/10.1186/ 1471-2202-8-54
162. Kuo, Y. M., Kokjohn, T. A., Beach, T. G. et al. (2001). Comparative analysis of amyloid-beta chemical structure and amyloid plaque morphology of transgenic mouse and Alzheimer's disease brains. J Biol Chem 276, 12991-12998. http://dx.doi.org/10.1074/jbc.M007859200
163. Landsberg, G. (2005). Therapeutic agents for the treatment of cognitive dysfunction syndrome in senior dogs. Prog Neuro-psychopharmacol Biol Psychiatry 29, 471-479. http://dx.doi.org/10.1016/j.pnpbp.2004.12.012
164. Langui, D., Girardot, N., El Hachimi, K. H. et al. (2004). Subcellular topography of neuronal Abeta peptide in APPxPS1 transgenic mice. Am J Pathol 165, 1465-1477. (Pubitemid 39435147)
165. Lanz, T. A., Himes, C. S., Pallante, G. et al. (2003). The gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S- phenylglycine t-butyl ester reduces A beta levels in vivo in plasma and cerebrospinal fluid in young (plaque-free) and aged (plaque-bearing) Tg2576 mice. J Pharmacol Exp Ther 305, 864-871. http://dx.doi.org/10.1124/jpet.102. 048280 (Pubitemid 36617962)
166. La Porte, S. L., Bollini, S. S., Lanz, T. A. et al. (2012). Structural basis of C-terminal beta-amyloid peptide binding by the antibody ponezumab for the treatment of Alzheimer's disease. J Mol Biol 421, 525-536. http://dx.doi.org/10.1016/j.jmb.2011.11.047
167. Larson, E. B., Wang, L., Bowen, J. D. et al. (2006). Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med 144, 73-81. (Pubitemid 46768225)
168. Lazarov, O., Morfini, G. A., Pigino, G. et al. (2007). Impairments in fast axonal transport and motor neuron deficits in transgenic mice expressing familial Alzheimer's disease-linked mutant presenilin 1. J Neurosci 27, 7011-7020. http://dx.doi.org/10.1523/JNEUROSCI.4272-06.2007 (Pubitemid 47015908)
169. Lemere, C. A., Oh, J., Stanish, H. A. et al. (2008). Cerebral amyloid-beta protein accumulation with aging in cotton-top tamarins: A model of early Alzheimer's disease? Rejuvenation Res 11, 321-332. http://dx.doi.org/10. 1089/rej.2008.0677 (Pubitemid 351601183)
170. Lermontova, N. N., Lukoyanov, N. V., Serkova, T. P. et al. (2000). Dimebon improves learning in animals with experimental Alzheimer's disease. Bull Exp Biol Med 129, 544-546.
171. Lesne, S., Koh, M. T., Kotilinek, L. et al. (2006). A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440, 352-357. http://dx.doi.org/10.1038/nature04533
172. Leusch, A., Troger, W., Greischel, A. et al. (2000). Pharmacokinetics of the M1-agonist talsaclidine in mouse, rat, rabbit and monkey, and extrapolation to man. Xenobiotica 30, 797-813. http://dx.doi.org/10.1080/00498250050119853
173. Levy-Lahad, E., Wasco, W., Poorkaj, P. et al. (1995). Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269, 973-977.
174. Lewczuk, P., Kornhuber, J., Vanderstichele, H. et al. (2008). Multiplexed quantification of dementia biomarkers in the CSF of patients with early dementias and MCI: A multicenter study. Neurobiol Aging 29, 812-818. http://dx.doi.org/10.1016/j.neurobiolaging.2006.12.010
175. Lewis, J., McGowan, E., Rockwood, J. et al. (2000). Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25, 402-405. http://dx.doi.org/10.1038/78078 (Pubitemid 32983430)
176. Lilja, A. M., Luo, Y., Yu, Q. S. et al. (2013a). Neurotrophic and neuroprotective actions of (-)- and (+)-phenserine, candidate drugs for Alzheimer's disease. PLoS One 8, e54887. http://dx.doi.org/10.1371/journal.pone. 0054887
177. Lilja, A. M., Rojdner, J., Mustafiz, T. et al. (2013b). Age-dependent neuroplasticity mechanisms in Alzheimer Tg2576 mice following modulation of brain amyloid-beta levels. PLoS One 8, e58752. http://dx.doi.org/10.1371/ journal.pone.0058752
178. Lippiello, P., Letchworth, S. R., Gatto, G. J. et al. (2006). Ispronicline: A novel alpha4beta2 nicotinic acetylcholine receptor-selective agonist with cognition-enhancing and neuroprotective properties. J Mol Neurosci 30, 19-20. http://dx.doi.org/10.1385/JMN:30:1:19 (Pubitemid 46035302)
179. Liu, J., Ho, W., Lee, N. T. et al. (2000). Bis(7)-tacrine, a novel acetylcholinesterase inhibitor, reverses AF64A-induced deficits in navigational memory in rats. Neurosci Lett 282, 165-168. (Pubitemid 30136453)
180. Lopez-Arrieta, J. M. and Schneider, L. (2006). Metrifonate for Alzheimer's disease. Cochrane Database Syst Rev, CD003155. http://dx.doi.org/10. 1002/14651858.CD003155.pub3
181. Luchsinger, J. A., Tang, M. X., Shea, S. et al. (2002). Caloric intake and the risk of Alzheimer disease. Arch Neurol 59, 1258-1263. (Pubitemid 34856378)
182. Luchsinger, J. A., Tang, M. X., Shea, S. et al. (2003). Antioxidant vitamin intake and risk of Alzheimer disease. Arch Neurol 60, 203-208. (Pubitemid 36193963)
183. Mangialasche, F., Solomon, A., Winblad, B. et al. (2010). Alzheimer's disease: Clinical trials and drug development. Lancet Neurol 9, 702-716. http://dx.doi.org/10.1016/S1474-4422(10)70119-8
184. Marder, K. (2004). Memantine approved to treat moderate to severe Alzheimer's disease. Curr Neurol Neurosci Rep 4, 349-350.
185. Martin, L. J., Pardo, C. A., Cork, L. C. et al. (1994). Synaptic pathology and glial responses to neuronal injury precede the formation of senile plaques and amyloid deposits in the aging cerebral cortex. Am J Pathol 145, 1358-1381. (Pubitemid 24378491)
186. Martinez-Coria, H., Green, K. N., Billings, L. M. et al. (2010). Memantine improves cognition and reduces Alzheimer's-like neuropathology in transgenic mice. Am J Pathol 176, 870-880. http://dx.doi.org/10.2353/ajpath. 2010.090452
187. Martone, R. L., Zhou, H., Atchison, K. et al. (2009). Begacestat (GSI-953): A novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease. J Pharmacol Exp Ther 331, 598-608. http://dx.doi.org/10.1124/jpet.109.152975
188. Masliah, E., Sisk, A., Mallory, M. et al. (2001). Neurofibrillary pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. J Neuropathol Exp Neurol 60, 357-368. (Pubitemid 32274051)
189. Masters, C. L., Simms, G., Weinman, N. A. et al. (1985). Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 82, 4245-4249. (Pubitemid 15053619)
190. Matsuoka, Y., Picciano, M., Malester, B. et al. (2001). Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease. Am J Pathol 158, 1345-1354. http://dx.doi.org/10.1016/S0002-9440(10)64085-0 (Pubitemid 32281298)
191. Mattson, M. P., Gary, D. S., Chan, S. L. et al. (2001). Perturbed endoplasmic reticulum function, synaptic apoptosis and the pathogenesis of Alzheimer's disease. Biochem Soc Symp 67, 151-162. (Pubitemid 33602683)
192. May, P., Boggs, L., Brier, R. et al. (2012). Preclinical characterization of LY2886721: A BACE1 inhibitor in clinical development for early Alzheimer's disease. Alzheimer's and Dementia 8, P95. http://www.alzheimersanddementia.com/ article/S1552-5260%2812%2900367-6/fulltext
193. Mayer, M. L. and Westbrook, G. L. (1987). The physiology of excitatory amino acids in the vertebrate central nervous system. Prog Neurobiol 28, 197-276. (Pubitemid 17023404)
194. Mayer, S. C., Kreft, A. F., Harrison, B. et al. (2008). Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease. J Med Chem 51, 7348-7351. http://dx.doi.org/10.1021/ jm801252w
195. Mayo Clinic Staff (2013). Risk factors. http://www.mayoclinic.com/health/ alzheimers-disease/DS00161/DSECTION=risk-factors
196. McGowan, E., Sanders, S., Iwatsubo, T. et al. (1999). Amyloid phenotype characterization of transgenic mice overexpressing both mutant amyloid precursor protein and mutant presenilin 1 transgenes. Neurobiol Dis 6, 231-244. http://dx.doi.org/10.1006/nbdi.1999.0243 (Pubitemid 29470035)
197. McLaurin, J., Kierstead, M. E., Brown, M. E. et al. (2006). Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med 12, 801-808. http://dx.doi.org/10.1038/ nm1423 (Pubitemid 44050070)
198. Mehlhorn, G., Hollborn, M. and Schliebs, R. (2000). Induction of cytokines in glial cells surrounding cortical beta-amyloid plaques in transgenic Tg2576 mice with Alzheimer pathology. Int J Dev Neurosci 18, 423-431. (Pubitemid 30243072)
199. Micchelli, C. A., Esler, W. P., Kimberly, W. T. et al. (2003). Gamma-secretase/presenilin inhibitors for Alzheimer's disease phenocopy Notch mutations in Drosophila. FASEB J 17, 79-81. http://dx.doi.org/10.1096/fj.02- 0394fje
200. Middleton, L. E., Mitnitski, A., Fallah, N. et al. (2008). Changes in cognition and mortality in relation to exercise in late life: A population based study. PLoS One 3, e3124. http://dx.doi.org/10.1371/journal.pone.0003124
201. Miguel-Hidalgo, J. J., Alvarez, X. A., Cacabelos, R. et al. (2002). Neuroprotection by memantine against neurodegeneration induced by beta-amyloid(1-40). Brain Res 958, 210-221. (Pubitemid 35441230)
202. Miller, B. W., Willett, K. C. and Desilets, A. R. (2011). Rosiglita-zone and pioglitazone for the treatment of Alzheimer's disease. Ann Pharmacother 45, 1416-1424. http://dx.doi.org/10.1345/aph.1Q238
203. Minkeviciene, R., Banerjee, P. and Tanila, H. (2004). Memantine improves spatial learning in a transgenic mouse model of Alzheimer's disease. J Pharmacol Exp Ther 311, 677-682. http://dx.doi.org/10.1124/jpet.104.071027 (Pubitemid 39391555)
204. Mitani, Y., Yarimizu, J., Saita, K. et al. (2012). Differential effects between gamma-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice. J Neurosci 32, 2037-2050. http://dx.doi.org/10.1523/JNEUROSCI.4264-11.2012
205. Moechars, D., Dewachter, I., Lorent, K. et al. (1999). Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem 274, 6483-6492. (Pubitemid 29111064)
206. Morgan, D., Diamond, D. M., Gottschall, P. E. et al. (2000). A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 408, 982-985. http://dx.doi.org/10.1038/35050116 (Pubitemid 32101645)
207. Mori, F., Cuadra, G. and Giacobini, E. (1995). Metrifonate effects on acetylcholine and biogenic amines in rat cortex. Neurochem Res 20, 1081-1088.
208. Morris, M. C., Evans, D. A., Bienias, J. L. et al. (2002). Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA 287, 3230-3237. (Pubitemid 34686104)
209. Morris, M. C., Evans, D. A., Bienias, J. L. et al. (2003). Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol 60, 940-946. http://dx.doi.org/10.1001/archneur.60.7.940 (Pubitemid 36858352)
210. Morrissette, D. A., Parachikova, A., Green, K. N. et al. (2009). Relevance of transgenic mouse models to human Alzheimer disease. J Biol Chem 284, 6033-6037. http://dx.doi.org/10.1074/jbc.R800030200
211. Mucke, L., Masliah, E., Yu, G. Q. et al. (2000). High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: Synaptotoxicity without plaque formation. J Neurosci 20, 4050-4058. (Pubitemid 30365675)
212. Mullan, M., Crawford, F., Axelman, K. et al. (1992). A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1, 345-347. http://dx.doi.org/10.1038/ng0892-345
213. Nakamura, S., Tamaoka, A., Sawamura, N. et al. (1995). Carboxyl end-specific monoclonal antibodies to amyloid beta protein (A beta) subtypes (A beta 40 and A beta 42(43)) differentiate A beta in senile plaques and amyloid angiopathy in brains of aged cynomolgus monkeys. Neurosci Lett 201, 151-154.
214. Neale, T. (2010). Novel Alzheimer's Drug Flops. http://www.medpagetoday. com/Neurology/AlzheimersDisease/18794
215. NIA (1997). Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease. Neurobiol Aging 18, S1-2.
216. NIH (2010). Tolerability and safety of subcutaneous administration of AFFITOPE AD02 in mild to moderate Alzheimer's disease. http://clinicaltrials. gov/ct2/show/NCT00633841
217. NIH (2011). Safety and efficacy study of ABT-089 in adults with mild to moderate Alzheimer's disease. http://www.clinicaltrials.gov/ct2/show/ NCT00555204?term=NCT00555204&rank=1
218. NIH (2012). Safety and efficacy study of ABT-089 in adults with mild to moderate Alzheimer's disease. http://www.clinicaltrials.gov/ct2/show/ NCT00555204?term=NCT00555204&rank=1
219. NIH (2013a). Efficacy and safety study of ELND005 as a treatment for agitation and aggression in Alzheimer's disease. http://www.clinicaltrials.gov/ ct2/show/NCT01735630?term=NCT01735630&rank=1
220. NIH (2013b). Sunphenon EGCg (Epigallocatechin-Gallate) in the early stage of Alzheimer's disease (SUN-AK). http://clinicaltrials. gov/ct2/show/ NCT00951834
221. NIH (2013c). A study to evaluate the efficacy and safety of MABT5102A in patients with mild to moderate Alzheimer's Dsease (ABBY). http://clinicaltrials. gov/ct2/show/NCT01343966?term=NCT01343966&rank=1
222. Niva, C., Parkinson, J., Olsson, F. et al. (2013). Has inhibition of Abeta production adequately been tested as therapeutic approach in mild AD? A model-based meta-analysis of gamma-secretase inhibitor data. Eur J Clin Pharmacol 69, 1247-1260. http://dx.doi.org/10.1007/s00228-012-1459-3
223. Notkola, I. L., Sulkava, R., Pekkanen, J. et al. (1998). Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease. Neuroepidemiology 17, 14-20. (Pubitemid 28153361)
224. Oakley, H., Cole, S. L., Logan, S. et al. (2006). Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: Potential factors in amyloid plaque formation. J Neurosci 26, 10129-10140. http://dx.doi.org/10.1523/JNEURO SCI.1202-06.2006
225. Obermeyer, T. S., Yonick, D., Lauing, K. et al. (2012). Mesenchymal stem cells facilitate fracture repair in an alcohol-induced impaired healing model. J Orthop Trauma 26, 712-718. http://dx.doi.org/10.1097/BOT.0b013e3182724298
226. Oddo, S., Caccamo, A., Shepherd, J. D. et al. (2003). Triple-transgenic model of Alzheimer's disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction. Neuron 39, 409-421. (Pubitemid 36937044)
227. Opii, W. O., Joshi, G., Head, E. et al. (2008). Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: Relevance to Alzheimer's disease. Neurobiol Aging 29, 51-70. http://dx.doi.org/10.1016/j. neuro biolaging.2006.09.012
228. Orgogozo, J. M., Gilman, S., Dartigues, J. F. et al. (2003). Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61, 46-54. (Pubitemid 36818745)
229. Oyama, F., Sawamura, N., Kobayashi, K. et al. (1998). Mutant presenilin 2 transgenic mouse: Effect on an age-dependent increase of amyloid beta-protein 42 in the brain. J Neurochem 71, 313-322. (Pubitemid 28292564)
230. Panza, F., Solfrizzi, V., Imbimbo, B. P. et al. (2014). Amyloid-based immunotherapy for Alzheimer's disease in the time of prevention trials: The way forward. Expert Rev Clin Immunol 10, 405-419. http://dx.doi.org/10.1586/ 1744666X.2014. 883921
231. Papaioannou, N., Tooten, P. C., van Ederen, A. M. et al. (2001). Immunohistochemical investigation of the brain of aged dogs. I. Detection of neurofibrillary tangles and of 4-hydroxynonenal protein, an oxidative damage product, in senile plaques. Amyloid 8, 11-21. (Pubitemid 32210176)
232. Patel, N., Spangler, E. L., Greig, N. H. et al. (1998). Phenserine, a novel acetylcholinesterase inhibitor, attenuates impaired learning of rats in a 14-unit T-maze induced by blockade of the N-methyl-D-aspartate receptor. Neuroreport 9, 171-176. (Pubitemid 28046677)
233. Pedersen, W. A., McMillan, P. J., Kulstad, J. J. et al. (2006). Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol 199, 265-273. http://dx.doi.org/10.1016/j.expneurol.2006.01.018 (Pubitemid 43928978)
234. Perez, S. E., Nadeem, M., Sadleir, K. R. et al. (2012). Dimebon alters hippocampal amyloid pathology in 3xTg-AD mice. Int J Physiol Pathophysiol Pharmacol 4, 115-127.
235. Perez-Tur, J., Froelich, S., Prihar, G. et al. (1995). A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene. Neuroreport 7, 297-301. (Pubitemid 26077246)
236. Pfizer (2011). Pfizer Pipeline. http://www.pfizer.com/files/ research/pipeline/2011-0228/pipeline-2011-0228.pdf
237. Pitkala, K. H., Poysti, M. M., Laakkonen, M. L. et al. (2013). Effects of the Finnish Alzheimer Disease Exercise Trial (FINALEX): A randomized controlled trial. JAMA Intern Med 173, 894-901. http://dx.doi.org/10.1001/jamainternmed. 2013.359
238. Pizzie, R., Hindman, H., Roe, C. M. et al. (2013). Physical activity and cognitive trajectories in cognitively normal adults: The adult children study. Alzheimer Dis Assoc Disord 28, 50-57. http://dx.doi.org/10.1097/WAD. 0b013e31829628d4
239. Podewils, L. J., Guallar, E., Kuller, L. H. et al. (2005). Physical activity, APOE genotype, and dementia risk: Findings from the cardiovascular health cognition study. Am J Epidemiol 161, 639-651. http://dx.doi.org/10.1093/ aje/kwi092 (Pubitemid 40411092)
240. Portelius, E., Zhang, B., Gustavsson, M. K. et al. (2009). Effects of gamma-secretase inhibition on the amyloid beta isoform pattern in a mouse model of Alzheimer's disease. Neurodegener Dis 6, 258-262. http://dx.doi.org/10.1159/ 000264639
241. Prickaerts, J., Fahrig, T. and Blokland, A. (1999). Cognitive performance and biochemical markers in septum, hippocampus and striatum of rats after an i.c.v. injection of streptozotocin: A correlation analysis. Behav Brain Res 102, 73-88. (Pubitemid 29314570)
242. Prickaerts, J., van Goethem, N. P., Chesworth, R. et al. (2012). EVP-6124, a novel and selective alpha7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of alpha7 nicotinic acetylcholine receptors. Neuropharmacology 62, 1099-1110. http://dx.doi.org/10.1016/j.neuropharm.2011.10.024
243. Prince, M. and Dementia Research, G. (2004). Care arrangements for people with dementia in developing countries. Int J Geriatr Psychiatry 19, 170-177. http://dx.doi.org/10.1002/gps.1046
244. Probst, A., Gotz, J., Wiederhold, K. H. et al. (2000). Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein. Acta Neuropathol 99, 469-481. (Pubitemid 30201307)
245. Puglielli, L., Tanzi, R. E. and Kovacs, D. M. (2003). Alzheimer's disease: The cholesterol connection. Nat Neurosci 6, 345-351. http://dx.doi.org/10.1038/nn0403-345 (Pubitemid 36373979)
246. Pugliese, M., Mascort, J., Mahy, N. et al. (2006). Diffuse beta-amyloid plaques and hyperphosphorylated tau are unrelated processes in aged dogs with behavioral deficits. Acta Neuropathol 112, 175-183. http://dx.doi.org/10.1007/ s00401-006-0087-3
247. Radak, Z., Hart, N., Sarga, L. et al. (2010). Exercise plays a preventive role against Alzheimer's disease. J Alzheimers Dis 20, 777-783. http://dx.doi.org/10.3233/JAD-2010-091531
248. Rapp, P. R. and Amaral, D. G. (1992). Individual differences in the cognitive and neurobiological consequences of normal aging. Trends Neurosci 15, 340-345.
249. Raskind, M. A., Peskind, E. R., Wessel, T. et al. (2000). Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology 54, 2261-2268. (Pubitemid 30416276)
250. Redwine, J. M., Kosofsky, B., Jacobs, R. E. et al. (2003). Dentate gyrus volume is reduced before onset of plaque formation in PDAPP mice: A magnetic resonance microscopy and stereologic analysis. Proc Natl Acad Sci U S A 100, 1381-1386. http://dx.doi.org/10.1073/pnas.242746599 (Pubitemid 36184010)
251. Reisberg, B., Doody, R., Stoffler, A. et al. (2003). Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 348, 1333-1341. http://dx.doi.org/10.1056/NEJMoa013128 (Pubitemid 36384100)
252. Roberts, R. O., Geda, Y. E., Knopman, D. S. et al. (2013). Cardiac disease associated with increased risk of nonamnestic cognitive impairment: Stronger effect on women. JAMA Neurol 70, 374-382. http://dx.doi.org/10.1001/ jamaneurol.2013.607
253. Rockenstein, E., Mante, M., Alford, M. et al. (2005). High beta-secretase activity elicits neurodegeneration in transgenic mice despite reductions in amyloid-beta levels: Implications for the treatment of Alzheimer disease. J Biol Chem 280, 32957-32967. http://dx.doi.org/10.1074/jbc.M507016200 (Pubitemid 41368345)
254. Rodrigue, K. M., Rieck, J. R., Kennedy, K. M. et al. (2013). Risk factors for beta-amyloid deposition in healthy aging: Vascular and genetic effects. JAMA Neurol 70, 600-606. http://dx.doi.org/10.1001/jamaneurol.2013.1342
255. Rogaev, E. I., Sherrington, R., Rogaeva, E. A. et al. (1995). 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 376, 775-778. http://dx.doi.org/10.1038/376775a0
256. Rogers, S. L. and Friedhoff, L. T. (1996). The efficacy and safety of donepezil in patients with Alzheimer's disease: Results of a US multicentre, randomized, double-blind, placebo-controlled trial. The Donepezil Study Group. Dementia 7, 293-303. (Pubitemid 26341258)
257. Roher, A. E., Palmer, K. C., Yurewicz, E. C. et al. (1993). Morphological and biochemical analyses of amyloid plaque core proteins purified from Alzheimer disease brain tissue. J Neurochem 61, 1916-1926. (Pubitemid 23317220)
258. Rose, C., Peoc'h, K., Chasseigneaux, S. et al. (2012). New highly sensitive rodent and human tests for soluble amyloid precursor protein alpha quantification: Preclinical and clinical applications in Alzheimer's disease. BMC Neurosci 13, 84. http://dx.doi.org/10.1186/1471-2202-13-84
259. Rosen, R. F., Farberg, A. S., Gearing, M. et al. (2008). Tauopathy with paired helical filaments in an aged chimpanzee. J Comp Neurol 509, 259-270. http://dx.doi.org/10.1002/cne.21744
260. Rosenberg, P. B. (2005). Clinical aspects of inflammation in Alzheimer's disease. Int Rev Psychiatry 17, 503-514. http://dx.doi.org/10.1080/ 02646830500382037
261. Rosler, M., Anand, R., Cicin-Sain, A. et al. (1999). Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. BMJ 318, 633-638.
262. Ross, C. A. and Poirier, M. A. (2004). Protein aggregation and neurodegenerative disease. Nat Med 10, Suppl, S10-17. http://dx.doi.org/10.1038/ nm1066 (Pubitemid 38901862)
263. Rossor, M. N., Fox, N. C., Freeborough, P. A. et al. (1996). Clinical features of sporadic and familial Alzheimer's disease. Neurodegeneration 5, 393-397. (Pubitemid 27077899)
264. Rovio, S., Kareholt, I., Helkala, E. L. et al. (2005). Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease. Lancet Neurol 4, 705-711. http://dx.doi.org/10.1016/S1474-4422(05)70198-8 (Pubitemid 41457285)
265. Rubio-Perez, J. M. and Morillas-Ruiz, J. M. (2012). A review: Inflammatory process in Alzheimer's disease, role of cytokines. ScientificWorldJournal 2012, 756357. http://dx.doi.org/10.1100/2012/756357
266. Rueter, L. E., Anderson, D. J., Briggs, C. A. et al. (2004). ABT-089: Pharmacological properties of a neuronal nicotinic acetylcholine receptor agonist for the potential treatment of cognitive disorders. CNS Drug Rev 10, 167-182. (Pubitemid 38879109)
267. Sadigh-Eteghad, S., Talebi, M. and Farhoudi, M. (2012). Association of apolipoprotein E epsilon 4 allele with sporadic late onset Alzheimer's disease. A meta-analysis. Neurosciences (Riyadh) 17, 321-326.
268. Salem, N., Jr., Wegher, B., Mena, P. et al. (1996). Arachidonic and docosahexaenoic acids are biosynthesized from their 18-carbon precursors in human infants. Proc Natl Acad Sci U S A 93, 49-54.
269. Salkovic-Petrisic, M., Tribl, F., Schmidt, M. et al. (2006). Alzheimer-like changes in protein kinase B and glycogen synthase kinase-3 in rat frontal cortex and hippocampus after damage to the insulin signalling pathway. J Neurochem 96, 1005-1015. http://dx.doi.org/10.1111/j.1471-4159.2005.03637.x
270. Salkovic-Petrisic, M., Knezovic, A., Hoyer, S. et al. (2013). What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer's disease, about the therapeutic strategies in Alzheimer's research. J Neural Transm 120, 233-252. http://dx.doi.org/10.1007/s00702-012-0877-9
271. Salloway, S., Sperling, R., Gilman, S. et al. (2009). A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73, 2061-2070. http://dx.doi.org/10.1212/WNL.0b013e3181c67808
272. Salloway, S., Sperling, R., Keren, R. et al. (2011). A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology 77, 1253-1262. http://dx.doi.org/10.1212/WNL.0b013e3182309fa5
273. Sampson, E. L., Jenagaratnam, L. and McShane, R. (2012). Metal protein attenuating compounds for the treatment of Alzheimer's dementia. Cochrane Database Syst Rev 5, CD005380. http://dx.doi.org/10.1002/14651858.CD005380.pub4
274. Samson, K. (2010). NerveCenter: Phase III Alzheimer trial halted: Search for therapeutic biomarkers continues. Ann Neurol 68, A9-A12. http://dx.doi.org/10.1002/ana.22249
275. Sarasa, M. and Pesini, P. (2009). Natural non-trasgenic animal models for research in Alzheimer's disease. Curr Alzheimer Res 6, 171-178.
276. Satou, T., Cummings, B. J., Head, E. et al. (1997). The progression of beta-amyloid deposition in the frontal cortex of the aged canine. Brain Res 774, 35-43. (Pubitemid 28007880)
277. Sawamura, N., Morishima-Kawashima, M., Waki, H. et al. (2000). Mutant presenilin 2 transgenic mice. A large increase in the levels of Abeta 42 is presumably associated with the low density membrane domain that contains decreased levels of glycero-phospholipids and sphingomyelin. J Biol Chem 275, 27901-27908. http://dx.doi.org/10.1074/jbc.M004308200
278. Scarmeas, N., Luchsinger, J. A., Schupf, N. et al. (2009). Physical activity, diet, and risk of Alzheimer disease. JAMA 302, 627-637. http://dx.doi.org/10.1001/jama.2009.1144
279. Schaefer, E. J., Bongard, V., Beiser, A. S. et al. (2006). Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: The Framingham Heart Study. Arch Neurol 63, 1545-1550. http://dx.doi.org/10.1001/archneur.63.11.1545 (Pubitemid 44748796)
280. Schaeffer, E. L., Figueiro, M. and Gattaz, W. F. (2011). Insights into Alzheimer disease pathogenesis from studies in transgenic animal models. Clinics (Sao Paulo) 66, Suppl 1, 45-54.
281. Schellenberg, G. D., Bird, T. D., Wijsman, E. M. et al. (1992). Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14.
282. Schenk, D., Barbour, R., Dunn, W. et al. (1999). Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173-177. http://dx.doi.org/10.1038/22124 (Pubitemid 29327547)
283. Schindowski, K., Bretteville, A., Leroy, K. et al. (2006). Alzheimer's disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am J Pathol 169, 599-616. http://dx.doi.org/10.2353/ajpath.2006.060002 (Pubitemid 44156317)
284. Schmitz, C., Rutten, B. P., Pielen, A. et al. (2004). Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease. Am J Pathol 164, 1495-1502. http://dx.doi.org/10.1016/S0002-9440(10) 63235-X (Pubitemid 38387814)
285. Schneeberger, A., Mandler, M., Otawa, O. et al. (2009). Development of AFFITOPE vaccines for Alzheimer's disease (AD)-from concept to clinical testing. J Nutr Health Aging 13, 264-267.
286. Schneider, J., Murray, J., Banerjee, S. et al. (1999). EUROCARE: A cross-national study of co-resident spouse carers for people with Alzheimer's disease: I-Factors associated with carer burden. Int J Geriatr Psychiatry 14, 651-661. (Pubitemid 29403284)
287. Schroeter, E. H., Ilagan, M. X., Brunkan, A. L. et al. (2003). A presenilin dimer at the core of the gamma-secretase enzyme: Insights from parallel analysis of Notch 1 and APP proteolysis. Proc Natl Acad Sci U S A 100, 13075-13080. http://dx.doi.org/10.1073/pnas.1735338100 (Pubitemid 37340028)
288. Schultz, C., Hubbard, G. B., Rub, U. et al. (2000). Age-related progression of tau pathology in brains of baboons. Neurobiol Aging 21, 905-912.
289. Schulz, R. and Beach, S. R. (1999). Caregiving as a risk factor for mortality: The Caregiver health effects study. JAMA 282, 2215-2219. (Pubitemid 30002964)
290. Schulz, R. and Martire, L. M. (2004). Family caregiving of persons with dementia: Prevalence, health effects, and support strategies. Am J Geriatr Psychiatry 12, 240-249. (Pubitemid 38569151)
291. Schwab, C., Hosokawa, M. and McGeer, P. L. (2004). Transgenic mice overexpressing amyloid beta protein are an incomplete model of Alzheimer disease. Exp Neurol 188, 52-64. http://dx.doi.org/10.1016/j.expneurol.2004.03. 016 (Pubitemid 38748804)
292. Sergeant, N., Bombois, S., Ghestem, A. et al. (2003). Truncated beta-amyloid peptide species in pre-clinical Alzheimer's disease as new targets for the vaccination approach. J Neurochem 85, 1581-1591. (Pubitemid 36702570)
293. Sherrington, R., Rogaev, E. I., Liang, Y. et al. (1995). Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, 754-760. http://dx.doi.org/10.1038/375754a0
294. Shoji, M., Golde, T. E., Ghiso, J. et al. (1992). Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science 258, 126-129.
295. Shukkur, E. A., Shimohata, A., Akagi, T. et al. (2006). Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome. Hum Mol Genet 15, 2752-2762. http://dx.doi.org/10.1093/hmg/ddl211 (Pubitemid 44400402)
296. Siddiqi, Z. A. and Peters, A. (1999). The effect of aging on pars compacta of the substantia nigra in rhesus monkey. J Neuropathol Exp Neurol 58, 903-920. (Pubitemid 29441920)
297. Simonian, N. A. and Coyle, J. T. (1996). Oxidative stress in neurodegenerative diseases. Annu Rev Pharmacol Toxicol 36, 83-106. http://dx.doi.org/10.1146/annurev.pa.36.040196.000503 (Pubitemid 26168695)
298. Smid, S. D., Maag, J. L. and Musgrave, I. F. (2012). Dietary polyphenol-derived protection against neurotoxic beta-amyloid protein: From molecular to clinical. Food Funct 3, 1242-1250. http://dx.doi.org/10.1039/ c2fo30075c
299. Smith, J. C., Nielson, K. A., Antuono, P. et al. (2013). Semantic memory functional MRI and cognitive function after exercise intervention in mild cognitive impairment. J Alzheimers Dis 37, 197-215. http://dx.doi.org/10.3233/ JAD-130467
300. Smith, M. A. and Perry, G. (1995). Free radical damage, iron, and Alzheimer's disease. J Neurol Sci 134, Suppl, 92-94.
301. Sopher, B. L., Fukuchi, K., Kavanagh, T. J. et al. (1996). Neurodegenerative mechanisms in Alzheimer disease. A role for oxidative damage in amyloid beta protein precursor-mediated cell death. Mol Chem Neuropathol 29, 153-168. (Pubitemid 27016926)
302. Sparks, D. L. and Schreurs, B. G. (2003). Trace amounts of copper in water induce beta-amyloid plaques and learning deficits in a rabbit model of Alzheimer's disease. Proc Natl Acad Sci U S A 100, 11065-11069. http://dx.doi.org/10.1073/pnas.1832769100 (Pubitemid 37140153)
303. Spencer, N. G., Bridges, L. R., Elderfield, K. et al. (2013). Quantitative evaluation of MRI and histological characteristics of the 5xFAD Alzheimer mouse brain. Neuroimage 76, 108-115. http://dx.doi.org/10.1016/j. neuroimage.2013.02.071
304. Spillantini, M. G., Murrell, J. R., Goedert, M. et al. (1998). Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A 95, 7737-7741. (Pubitemid 28293323)
305. Spittaels, K., Van den Haute, C., Van Dorpe, J. et al. (1999). Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am J Pathol 155, 2153-2165. http://dx.doi.org/10. 1016/S0002-9440(10)65533-2
306. Steele, J. W. and Gandy, S. (2013). Latrepirdine (Dimebon(R)), a potential Alzheimer therapeutic, regulates autophagy and neuropathology in an Alzheimer mouse model. Autophagy 9, 617-618. http://dx.doi.org/10.4161/auto. 23487
307. Strittmatter, W. J., Saunders, A. M., Schmechel, D. et al. (1993). Apolipoprotein E: High-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 90, 1977-1981. (Pubitemid 23069980)
308. Sturchler-Pierrat, C., Abramowski, D., Duke, M. et al. (1997). Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A 94, 13287-13292. (Pubitemid 27518514)
309. Su, Y., Ryder, J., Li, B. et al. (2004). Lithium, a common drug for bipolar disorder treatment, regulates amyloid-beta precursor protein processing. Biochemistry 43, 6899-6908. http://dx.doi.org/10.1021/bi035627j (Pubitemid 38720508)
310. Sudduth, T. L., Greenstein, A. and Wilcock, D. M. (2013). Intracranial injection of Gammagard, a human IVIg, modulates the inflammatory response of the brain and lowers Abeta in APP/PS1 mice along a different time course than anti-Abeta antibodies. J Neurosci 33, 9684-9692. http://dx.doi.org/10.1523/ JNEUROSCI.1220-13.2013
311. Sullivan, J. P., Donnelly-Roberts, D., Briggs, C. A. et al. (1997). ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine]: I. A potent and selective cholinergic channel modulator with neuroprotective properties. J Pharmacol Exp Ther 283, 235-246. (Pubitemid 27438967)
312. Sweeney, J. E., Hohmann, C. F., Moran, T. H. et al. (1988). A long-acting cholinesterase inhibitor reverses spatial memory deficits in mice. Pharmacol Biochem Behav 31, 141-147. (Pubitemid 19271195)
313. Sweeney, J. E., Puttfarcken, P. S. and Coyle, J. T. (1989). Galanthamine, an acetylcholinesterase inhibitor: A time course of the effects on performance and neurochemical parameters in mice. Pharmacol Biochem Behav 34, 129-137. (Pubitemid 20008895)
314. Tai, L. M., Bilousova, T., Jungbauer, L. et al. (2013). Levels of soluble apolipoprotein E/amyloid-beta (Abeta) complex are reduced and oligomeric Abeta increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples. J Biol Chem 288, 5914-5926. http://dx.doi.org/10.1074/jbc.M112.442103
315. Tanemura, K., Murayama, M., Akagi, T. et al. (2002). Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau. J Neurosci 22, 133-141. (Pubitemid 34033491)
316. Tapp, P. D., Siwak, C. T., Estrada, J. et al. (2003). Effects of age on measures of complex working memory span in the beagle dog (Canis familiaris) using two versions of a spatial list learning paradigm. Learn Mem 10, 148-160. http://dx.doi.org/10.1101/lm.56503 (Pubitemid 36418725)
317. Tayeb, H. O., Murray, E. D., Price, B. H. et al. (2013). Bapineuzumab and solanezumab for Alzheimer's disease: Is the 'amyloid cascade hypothesis' still alive? Expert Opin Biol Ther 13, 1075-1084. http://dx.doi.org/10.1517/14712598. 2013.789856
318. Terry, R. D., Masliah, E., Salmon, D. P. et al. (1991). Physical basis of cognitive alterations in Alzheimer's disease: Synapse loss is the major correlate of cognitive impairment. Ann Neurol 30, 572-580. http://dx.doi.org/10. 1002/ana.410300410
319. Thambisetty, M. and Lovestone, S. (2010). Blood-based biomarkers of Alzheimer's disease: Challenging but feasible. Med 4, 65-79.
320. Thyagarajan, T., Totey, S., Danton, M. J. et al. (2003). Genetically altered mouse models: The good, the bad, and the ugly. Crit Rev Oral Biol Med 14, 154-174. (Pubitemid 44560801)
321. Toman, P. D., Pieper, F., Sakai, N. et al. (1999). Production of recombinant human type I procollagen homotrimer in the mammary gland of transgenic mice. Transgenic Res 8, 415-427. (Pubitemid 30170496)
322. Torp, R., Head, E. and Cotman, C. W. (2000). Ultrastructural analyses of beta-amyloid in the aged dog brain: Neuronal beta-amyloid is localized to the plasma membrane. Prog Neuropsychopharmacol Biol Psychiatry 24, 801-810. (Pubitemid 30640160)
323. Urbanc, B., Cruz, L., Le, R. et al. (2002). Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease. Proc Natl Acad Sci U S A 99, 13990-13995. http://dx.doi.org/10.1073/ pnas.222433299 (Pubitemid 35257612)
324. Valla, J., Schneider, L. E., Gonzalez-Lima, F. et al. (2006). Non-progressive transgene-related callosal and hippocampal changes in PDAPP mice. Neuroreport 17, 829-832. http://dx.doi.org/10.1097/01.wnr.0000220140. 91294.15 (Pubitemid 43804763)
325. Van Dam, D., Coen, K. and De Deyn, P. P. (2008). Cognitive evaluation of disease-modifying efficacy of donepezil in the APP23 mouse model for Alzheimer's disease. Psychopharmacology (Berl) 197, 37-43. http://dx.doi.org/10.1007/ s00213-007-1010-x
326. van Gelder, B. M., Tijhuis, M., Kalmijn, S. et al. (2007). Fish consumption, n-3 fatty acids, and subsequent 5-y cognitive decline in elderly men: The Zutphen Elderly study. Am J Clin Nutr 85, 1142-1147. (Pubitemid 46557933)
327. Veerhuis, R. (2011). Histological and direct evidence for the role of complement in the neuroinflammation of AD. Curr Alzheimer Res 8, 34-58.
328. Vellas, B., Black, R., Thal, L. J. et al. (2009). Long-term follow-up of patients immunized with AN1792: Reduced functional decline in antibody responders. Curr Alzheimer Res 6, 144-151.
329. Vellas, B., Sol, O., Snyder, P. J. et al. (2011). EHT0202 in Alzheimer's disease: A 3-month, randomized, placebo-controlled, double-blind study. Curr Alzheimer Res 8, 203-212.
330. Verwey, N. A., van der Flier, W. M., Blennow, K. et al. (2009). A worldwide multicentre comparison of assays for cerebrospinal fluid biomarkers in Alzheimer's disease. Ann Clin Biochem 46, 235-240. http://dx.doi.org/10.1258/ acb.2009.008232
331. Voytko, M. L. (1998). Nonhuman primates as models for aging and Alzheimer's disease. Lab Anim Sci 48, 611-617.
332. Walsh, D. M., Tseng, B. P., Rydel, R. E. et al. (2000). The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. Biochemistry 39, 10831-10839.
333. Walsh, D. M. and Selkoe, D. J. (2007). A beta oligomers - a decade of discovery. J Neurochem 101, 1172-1184. http://dx.doi.org/10.1111/j.1471-4159. 2006.04426.x
334. Wegiel, J., Wisniewski, H. M. and Soltysiak, Z. (1998). Region- and cell-type-specific pattern of tau phosphorylation in dog brain. Brain Res 802, 259-266. (Pubitemid 28392179)
335. Wenk, G. L., Zajaczkowski, W. and Danysz, W. (1997). Neuroprotection of acetylcholinergic basal forebrain neurons by memantine and neurokinin B. Behav Brain Res 83, 129-133. (Pubitemid 27086625)
336. Westerman, M. A., Cooper-Blacketer, D., Mariash, A. et al. (2002). The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease. J Neurosci 22, 1858-1867. (Pubitemid 35386304)
337. Weuve, J., Kang, J. H., Manson, J. E. et al. (2004). Physical activity, including walking, and cognitive function in older women. JAMA 292, 1454-1461. http://dx.doi.org/10.1001/jama.292.12.1454 (Pubitemid 39258338)
338. Wienrich, M., Meier, D., Ensinger, H. A. et al. (2001). Pharmacodynamic profile of the M1 agonist talsaclidine in animals and man. Life Sci 68, 2593-2600. (Pubitemid 32455699)
339. Wiessner, C., Wiederhold, K. H., Tissot, A. C. et al. (2011). The second-generation active Abeta immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects. J Neurosci 31, 9323-9331. http://dx.doi.org/10.1523/JNEUROSCI.0293-11.2011
340. Wilbur, J., Marquez, D. X., Fogg, L. et al. (2012). The relationship between physical activity and cognition in older Latinos. J Gerontol B Psychol Sci Soc Sci 67, 525-534. http://dx.doi.org/10.1093/geronb/gbr137
341. Wilcock, G. K., Lilienfeld, S. and Gaens, E. (2000). Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: Multicentre randomised controlled trial. Galantamine International-1 Study Group. BMJ 321, 1445-1449.
342. Wiley, R. G., Oeltmann, T. N. and Lappi, D. A. (1991). Immunolesioning: Selective destruction of neurons using immunotoxin to rat NGF receptor. Brain Res 562, 149-153.
343. Wilkins, R. H. and Brody, I. A. (1969). Alzheimer's disease. Arch Neurol 21, 109-110.
344. Wolfe, M. S. (2006). The gamma-secretase complex: Membrane-embedded proteolytic ensemble. Biochemistry 45, 7931-7939. http://dx.doi.org/10.1021/ bi060799c
345. Wood, J. G., Mirra, S. S., Pollock, N. J. et al. (1986). Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (tau). Proc Natl Acad Sci U S A 83, 4040-4043. (Pubitemid 16062418)
346. Woodruff-Pak, D. S., Agelan, A. and Del Valle, L. (2007). A rabbit model of Alzheimer's disease: Valid at neuropathological, cognitive, and therapeutic levels. J Alzheimers Dis 11, 371-383. (Pubitemid 47094031)
347. Woodruff-Pak, D. S. (2008). Animal models of Alzheimer's disease: Therapeutic implications. J Alzheimers Dis 15, 507-521.
348. Wu, C. C., Chawla, F., Games, D. et al. (2004). Selective vulnerability of dentate granule cells prior to amyloid deposition in PDAPP mice: Digital morphometric analyses. Proc Natl Acad Sci U S A 101, 7141-7146. http://dx.doi.org/10.1073/pnas.0402147101 (Pubitemid 38596456)
349. Wyss-Coray, T., Masliah, E., Mallory, M. et al. (1997). Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer's disease. Nature 389, 603-606. http://dx.doi.org/10.1038/39321 (Pubitemid 27446177)
350. Yotter, R. A., Doshi, J., Clark, V. et al. (2013). Memory decline shows stronger associations with estimated spatial patterns of amyloid deposition progression than total amyloid burden. Neurobiol Aging 34, 2835-2842. http://dx.doi.org/10.1016/j.neuro-biolaging.2013.05.030
351. Zajaczkowski, W., Quack, G. and Danysz, W. (1996). Infusion of (+) -MK-801 and memantine - contrasting effects on radial maze learning in rats with entorhinal cortex lesion. Eur J Pharmacol 296, 239-246.
352. Zarit, S. H., Reever, K. E. and Bach-Peterson, J. (1980). Relatives of the impaired elderly: Correlates of feelings of burden. Gerontologist 20, 649-655. (Pubitemid 11170845)
353. Zarit, S. H., Todd, P. A. and Zarit, J. M. (1986). Subjective burden of husbands and wives as caregivers: A longitudinal study. Gerontologist 26, 260-266.
354. Zhang, T., Zhang, J., Derreumaux, P. et al. (2013a). Molecular mechanism of the inhibition of EGCG on the Alzheimer Abeta(1-42) dimer. J Phys Chem B 117, 3993-4002. http://dx.doi.org/10.1021/jp312573y
355. Zhang, Y., Pak, C., Han, Y. et al. (2013b). Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron 78, 785-798. http://dx.doi.org/10.1016/j.neuron.2013.05.029