Alzheimer disease research in the 21st century: Past and current failures, new perspectives and funding priorities

Oncotarget

Volumn 7, Issue 26, 2016, Pages 38999-39016

  Pistollato, Francesca ^a   Ohayon, Elan L ^a   Lam, Ann ^a,b   Langley, Gillian R ^c   Novak, Thomas J ^d   Pamies, David ^e   Perry, George ^f   Trushina, Eugenia ^g   Williams, Robin S B ^h   Roher, Alex E ^i,j   Hartung, Thomas ^e   Harnad, Stevan ^k   Barnard, Neal ^a   Morris, Martha Clare ^l   Lai, Mei Chun ^a   Merkley, Ryan ^a   Charukeshi Chandrasekera, P ^a  

^a PHYSICIANS COMMITTEE FOR RESPONSIBLE MEDICINE   (United States)

^b Neurolinx Research Institute   (United States)

^c Humane Society International   (United Kingdom)

^d Cellular Dynamics International   (United States)

^e JOHNS HOPKINS BLOOMBERG SCHOOL OF PUBLIC HEALTH   (United States)

^f University of San Antonio   (United States)

^g MAYO CLINIC   (United States)

^h UNIVERSITY OF LONDON   (United Kingdom)

ⁱ MIDWESTERN UNIVERSITY   (United States)

^j BARROW NEUROLOGICAL INSTITUTE   (United States)

^k UNIVERSITÉ DU QUÉBEC À MONTRÉAL   (Canada)

^l RUSH MEDICAL COLLEGE   (United States)

more..

Author keywords

Alzheimer disease; Animal models; Computational models; Gerotarget; Human methods; Induced pluripotent stem cells

Indexed keywords

ALZHEIMER DISEASE; ARTICLE; AUTOPSY; BRAIN TISSUE; DISEASE COURSE; DISEASE MODEL; EPIDEMIOLOGICAL DATA; EXPERIMENTAL STUDY; FINANCIAL MANAGEMENT; GOVERNMENT REGULATION; HUMAN; LIFESTYLE; MAMMAL; MATHEMATICAL COMPUTING; MATHEMATICAL MODEL; MEDICAL RESEARCH; METHODOLOGY; MICROFLUIDICS; NEUROIMAGING; NONHUMAN; PATHOPHYSIOLOGY; RELIABILITY; RESEARCH PRIORITY; RISK ASSESSMENT; RISK FACTOR; ANIMAL; COMPUTER SIMULATION; CYTOLOGY; GENETICS; INDUCED PLURIPOTENT STEM CELL; METABOLISM; NATIONAL HEALTH ORGANIZATION; TRENDS; UNITED STATES;

ALZHEIMER DISEASE; ANIMALS; BIOMEDICAL RESEARCH; COMPUTER SIMULATION; DISEASE MODELS, ANIMAL; HUMANS; INDUCED PLURIPOTENT STEM CELLS; NATIONAL INSTITUTES OF HEALTH (U.S.); NEUROIMAGING; RESEARCH DESIGN; RESEARCH SUPPORT AS TOPIC; RISK FACTORS; UNITED STATES;

EID: 84982924447     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.9175     Document Type: Article

References (127)

1. Alzheimer's Association. 2015 Alzheimer's disease facts and figures. Alzheimer's & dementia. 2015; 11:332-384.
2. Gotz J, Ittner LM and Schonrock N. Alzheimer's disease and frontotemporal dementia: prospects of a tailored therapy? The Medical journal of Australia. 2006; 185:381-384.
3. Hebert LE, Weuve J, Scherr PA and Evans DA. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology. 2013; 80:1778-1783.
4. Bezprozvanny I. The rise and fall of Dimebon. Drug news & perspectives. 2010; 23:518-523.
5. Corbett A and Ballard C. New and emerging treatments for Alzheimer's disease. Expert opinion on emerging drugs. 2012; 17:147-156.
6. Perrin S. Preclinical research: Make mouse studies work. Nature. 2014; 507:423-425.
7. Mak IW, Evaniew N and Ghert M. Lost in translation: animal models and clinical trials in cancer treatment. American journal of translational research. 2014; 6:114-118.
8. Cummings JL, Morstorf T and Zhong K. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimer's research & therapy. 2014; 6:37.
9. Wu YT, Fratiglioni L, Matthews FE, Lobo A, Breteler MM, Skoog I and Brayne C. Dementia in western Europe: epidemiological evidence and implications for policy making. The Lancet Neurology. 2016; 15:116-124.
10. Satizabal CL, Beiser AS, Chouraki V, Chene G, Dufouil C and Seshadri S. Incidence of Dementia over Three Decades in the Framingham Heart Study. The New England journal of medicine. 2016; 374:523-532.
11. Cavanaugh SE, Pippin JJ and Barnard ND. Animal models of Alzheimer disease: historical pitfalls and a path forward. Altex. 2014; 31:279-302.
12. Dodart JC, Mathis C, Bales KR and Paul SM. Does my mouse have Alzheimer's disease? Genes, brain, and behavior. 2002; 1:142-155.
13. Duyckaerts C, Potier MC and Delatour B. Alzheimer disease models and human neuropathology: similarities and differences. Acta neuropathologica. 2008; 115:5-38.
14. Manich G, del Valle J, Cabezon I, Camins A, Pallas M, Pelegri C and Vilaplana J. Presence of a neo-epitope and absence of amyloid beta and tau protein in degenerative hippocampal granules of aged mice. Age. 2014; 36:151-165.
15. Porquet D, Andres-Benito P, Grinan-Ferre C, Camins A, Ferrer I, Canudas AM, Del Valle J and Pallas M. Amyloid and tau pathology of familial Alzheimer's disease APP/PS1 mouse model in a senescence phenotype background (SAMP8). Age. 2015; 37:9747.
16. Sabbagh JJ, Kinney JW and Cummings JL. Animal systems in the development of treatments for Alzheimer's disease: challenges, methods, and implications. Neurobiology of aging. 2013; 34:169-183.
17. Langley GR. Considering a new paradigm for Alzheimer's disease research. Drug discovery today. 2014; 19:1114-1124.
18. Pistollato F, Cavanaugh SE and Chandrasekera PC. A Human-Based Integrated Framework for Alzheimer's Disease Research. Journal of Alzheimer's disease. 2015; 47:857-868.
19. NINDS. (2016). Draft Prioritized Recommendations. Alzheimer's disease and related dementias (ADRD) Summit 2016: NINDS), pp. 1-21.
20. Calitz C, Pollack KM, Millard C and Yach D. National institutes of health funding for behavioral interventions to prevent chronic diseases. American journal of preventive medicine. 2015; 48:462-471.
21. Chai CK. The genetics of Alzheimer's disease. American journal of Alzheimer's disease and other dementias. 2007; 22:37-41.
22. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, Fiske A and Pedersen NL. Role of genes and environments for explaining Alzheimer disease. Archives of general psychiatry. 2006; 63:168-174.
23. Rossor MN, Fox NC, Freeborough PA and Harvey RJ. Clinical features of sporadic and familial Alzheimer's disease. Neurodegeneration. 1996; 5:393-397.
24. Gillette Guyonnet S, Abellan Van Kan G, Andrieu S, Barberger Gateau P, Berr C, Bonnefoy M, Dartigues JF, de Groot L, Ferry M, Galan P, Hercberg S, Jeandel C, Morris MC, Nourhashemi F, Payette H, Poulain JP, et al. IANA task force on nutrition and cognitive decline with aging. The journal of nutrition, health & aging. 2007; 11:132-152.
25. Hernandez SS, Sandreschi PF, da Silva FC, Arancibia BA, da Silva R, Gutierres PJ and Andrade A. What are the Benefits of Exercise for Alzheimer's Disease? A Systematic Review of the Past 10 Years. Journal of aging and physical activity. 2015; 23:659-668.
26. Okonkwo OC, Schultz SA, Oh JM, Larson J, Edwards D, Cook D, Koscik R, Gallagher CL, Dowling NM, Carlsson CM, Bendlin BB, La Rue A, Rowley HA, Christian BT, Asthana S, Hermann BP, et al. Physical activity attenuates age-related biomarker alterations in preclinical AD. Neurology. 2014; 83:1753-1760.
27. Gates NJ and Sachdev P. Is cognitive training an effective treatment for preclinical and early Alzheimer's disease? Journal of Alzheimer's disease. 2014; 42:S551-559.
28. Russ TC, Stamatakis E, Hamer M, Starr JM, Kivimaki M and Batty GD. Socioeconomic status as a risk factor for dementia death: individual participant meta-analysis of 86 508 men and women from the UK. The British journal of psychiatry. 2013; 203:10-17.
29. Sattler C, Toro P, Schonknecht P and Schroder J. Cognitive activity, education and socioeconomic status as preventive factors for mild cognitive impairment and Alzheimer's disease. Psychiatry research. 2012; 196:90-95.
30. Paradise M, Cooper C and Livingston G. Systematic review of the effect of education on survival in Alzheimer's disease. International psychogeriatrics. 2009; 21:25-32.
31. Lim MM, Gerstner JR and Holtzman DM. The sleep-wake cycle and Alzheimer's disease: what do we know? Neurodegenerative disease management. 2014; 4:351-362.
32. Videnovic A, Lazar AS, Barker RA and Overeem S. 'The clocks that time us'-circadian rhythms in neurodegenerative disorders. Nature reviews Neurology. 2014; 10:683-693.
33. Peter-Derex L, Yammine P, Bastuji H and Croisile B. Sleep and Alzheimer's disease. Sleep medicine reviews. 2015; 19:29-38.
34. Lucey BP and Bateman RJ. Amyloid-beta diurnal pattern: possible role of sleep in Alzheimer's disease pathogenesis. Neurobiology of aging. 2014; 35 Suppl 2:S29-34.
35. Ju YE, Lucey BP and Holtzman DM. Sleep and Alzheimer disease pathology-a bidirectional relationship. Nature reviews Neurology. 2014; 10:115-119.
36. Moulton PV and Yang W. Air pollution, oxidative stress, and Alzheimer's disease. Journal of environmental and public health. 2012; 2012:472751.
37. Cataldo JK, Prochaska JJ and Glantz SA. Cigarette smoking is a risk factor for Alzheimer's Disease: an analysis controlling for tobacco industry affiliation. Journal of Alzheimer's disease. 2010; 19:465-480.
38. Shcherbatykh I and Carpenter DO. The role of metals in the etiology of Alzheimer's disease. Journal of Alzheimer's disease. 2007; 11:191-205.
39. Brewer GJ. Copper excess, zinc deficiency, and cognition loss in Alzheimer's disease. BioFactors. 2012; 38:107-113.
40. Tong Y, Yang H, Tian X, Wang H, Zhou T, Zhang S, Yu J, Zhang T, Fan D, Guo X, Tabira T, Kong F, Chen Z, Xiao W and Chui D. High manganese, a risk for Alzheimer's disease: high manganese induces amyloid-beta related cognitive impairment. Journal of Alzheimer's disease. 2014; 42:865-878.
41. Tanner CM, Goldman SM, Ross GW and Grate SJ. The disease intersection of susceptibility and exposure: chemical exposures and neurodegenerative disease risk. Alzheimer's & dementia. 2014; 10:S213-225.
42. Yegambaram M, Manivannan B, Beach TG and Halden RU. Role of environmental contaminants in the etiology of Alzheimer's disease: a review. Current Alzheimer research. 2015; 12:116-146.
43. Rios JA, Cisternas P, Arrese M, Barja S and Inestrosa NC. Is Alzheimer's disease related to metabolic syndrome? A Wnt signaling conundrum. Progress in neurobiology. 2014; 121:125-146.
44. Rosendorff C, Beeri MS and Silverman JM. Cardiovascular risk factors for Alzheimer's disease. The American journal of geriatric cardiology. 2007; 16:143-149.
45. Pistollato F, Sumalla Cano S, Elio I, Masias Vergara M, Giampieri F and Battino M. The Use of Neuroimaging to Assess Associations Among Diet, Nutrients, Metabolic Syndrome, and Alzheimer's Disease. Journal of Alzheimer's disease. 2015; 48:303-318.
46. Gibson JE. An integrated summary of commentary on the National Academy of Sciences report on ''Toxicity testing in the 21st century: a vision and a strategy''. Human & experimental toxicology. 2010; 29:33-35.
47. Poet TS, Timchalk C, Hotchkiss JA and Bartels MJ. Chlorpyrifos PBPK/PD model for multiple routes of exposure. Xenobiotica. 2014; 44:868-881.
48. Santamaria AB. Manganese exposure, essentiality & toxicity. The Indian journal of medical research. 2008; 128:484-500.
49. Muratore CR, Rice HC, Srikanth P, Callahan DG, Shin T, Benjamin LN, Walsh DM, Selkoe DJ and Young-Pearse TL. The familial Alzheimer's disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Human molecular genetics. 2014; 23:3523-3536.
50. Sproul AA, Jacob S, Pre D, Kim SH, Nestor MW, NavarroSobrino M, Santa-Maria I, Zimmer M, Aubry S, Steele JW, Kahler DJ, Dranovsky A, Arancio O, Crary JF, Gandy S and Noggle SA. Characterization and molecular profiling of PSEN1 familial Alzheimer's disease iPSC-derived neural progenitors. PloS one. 2014; 9:e84547.
51. Zhang D, Pekkanen-Mattila M, Shahsavani M, Falk A, Teixeira AI and Herland A. A 3D Alzheimer's disease culture model and the induction of P21-activated kinase mediated sensing in iPSC derived neurons. Biomaterials. 2014; 35:1420-1428.
52. Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, Imamura K, Egawa N, Yahata N, Okita K, Takahashi K, Asaka I, Aoi T, Watanabe A, Watanabe K, Kadoya C, et al. Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell stem cell. 2013; 12:487-496.
53. Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, Hefferan MP, Van Gorp S, Nazor KL, Boscolo FS, Carson CT, Laurent LC, Marsala M, Gage FH, Remes AM, Koo EH, et al. Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature. 2012; 482:216-220.
54. Blasko I, Hinterberger M, Kemmler G, Jungwirth S, Krampla W, Leitha T, Heinz Tragl K and Fischer P. Conversion from mild cognitive impairment to dementia: influence of folic acid and vitamin B12 use in the VITA cohort. The journal of nutrition, health & aging. 2012; 16:687-694.
55. Mosconi L, Murray J, Tsui WH, Li Y, Davies M, Williams S, Pirraglia E, Spector N, Osorio RS, Glodzik L, McHugh P and de Leon MJ. Mediterranean Diet and Magnetic Resonance Imaging-Assessed Brain Atrophy in Cognitively Normal Individuals at Risk for Alzheimer's Disease. The journal of prevention of Alzheimer's disease. 2014; 1:23-32.
56. Titova OE, Ax E, Brooks SJ, Sjogren P, Cederholm T, Kilander L, Kullberg J, Larsson EM, Johansson L, Ahlstrom H, Lind L, Schioth HB and Benedict C. Mediterranean diet habits in older individuals: associations with cognitive functioning and brain volumes. Experimental gerontology. 2013; 48:1443-1448.
57. Frederiksen KS, Sobol N, Beyer N, Hasselbalch S and Waldemar G. Moderate-to-high intensity aerobic exercise in patients with mild to moderate Alzheimer's disease: a pilot study. International journal of geriatric psychiatry. 2014; 29:1242-1248.
58. Paillard T, Rolland Y and de Souto Barreto P. Protective Effects of Physical Exercise in Alzheimer's Disease and Parkinson's Disease: A Narrative Review. Journal of clinical neurology. 2015; 11:212-219.
59. Morris MC, Tangney CC, Wang Y, Sacks FM, Barnes LL, Bennett DA and Aggarwal NT. MIND diet slows cognitive decline with aging. Alzheimer's & dementia. 2015; 11:1015-1022.
60. Williams RS, Boeckeler K, Graf R, Muller-Taubenberger A, Li Z, Isberg RR, Wessels D, Soll DR, Alexander H and Alexander S. Towards a molecular understanding of human diseases using Dictyostelium discoideum. Trends in molecular medicine. 2006; 12:415-424.
61. Ludtmann MH, Otto GP, Schilde C, Chen ZH, Allan CY, Brace S, Beesley PW, Kimmel AR, Fisher P, Killick R and Williams RS. An ancestral non-proteolytic role for presenilin proteins in multicellular development of the social amoeba Dictyostelium discoideum. Journal of cell science. 2014; 127:1576-1584.
62. Ellis KA, Rowe CC, Villemagne VL, Martins RN, Masters CL, Salvado O, Szoeke C, Ames D and group Ar. Addressing population aging and Alzheimer's disease through the Australian imaging biomarkers and lifestyle study: collaboration with the Alzheimer's Disease Neuroimaging Initiative. Alzheimer's & dementia. 2010; 6:291-296.
63. Carrillo MC, Sanders CA and Katz RG. Maximizing the Alzheimer's Disease Neuroimaging Initiative II. Alzheimer's & dementia. 2009; 5:271-275.
64. Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Arauzo-Bravo MJ, Ruau D, Han DW, Zenke M and Scholer HR. Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature. 2008; 454:646-650.
65. Miyazaki S, Yamamoto H, Miyoshi N, Takahashi H, Suzuki Y, Haraguchi N, Ishii H, Doki Y and Mori M. Emerging methods for preparing iPS cells. Japanese journal of clinical oncology. 2012; 42:773-779.
66. Reitz C, Brayne C and Mayeux R. Epidemiology of Alzheimer disease. Nature reviews Neurology. 2011; 7:137-152.
67. Vaskova EA, Stekleneva AE, Medvedev SP and Zakian SM. "Epigenetic memory" phenomenon in induced pluripotent stem cells. Acta naturae. 2013; 5:15-21.
68. Nashun B, Hill PW and Hajkova P. Reprogramming of cell fate: epigenetic memory and the erasure of memories past. The EMBO journal. 2015; 34:1296-1308.
69. Qiang L, Inoue K and Abeliovich A. Instant neurons: directed somatic cell reprogramming models of central nervous system disorders. Biological psychiatry. 2014; 75:945-951.
70. Qiang L, Fujita R and Abeliovich A. Remodeling neurodegeneration: somatic cell reprogramming-based models of adult neurological disorders. Neuron. 2013; 78:957-969.
71. Kim J, Lengner CJ, Kirak O, Hanna J, Cassady JP, Lodato MA, Wu S, Faddah DA, Steine EJ, Gao Q, Fu D, Dawlaty M and Jaenisch R. Reprogramming of postnatal neurons into induced pluripotent stem cells by defined factors. Stem cells. 2011; 29:992-1000.
72. Sproul AA, Vensand LB, Dusenberry CR, Jacob S, Vonsattel JP, Paull DJ, Shelanski ML, Crary JF and Noggle SA. Generation of iPSC lines from archived noncryoprotected biobanked dura mater. Acta neuropathologica communications. 2014; 2:4.
73. Nishino K, Toyoda M, Yamazaki-Inoue M, Fukawatase Y, Chikazawa E, Sakaguchi H, Akutsu H and Umezawa A. DNA methylation dynamics in human induced pluripotent stem cells over time. PLoS genetics. 2011; 7:e1002085.
74. Pistollato F, Bremer-Hoffmann S, Healy L, Young L and Stacey G. Standardization of pluripotent stem cell cultures for toxicity testing. Expert opinion on drug metabolism & toxicology. 2012; 8:239-257.
75. Heininger K. A unifying hypothesis of Alzheimer's disease. IV. Causation and sequence of events. Reviews in the neurosciences. 2000; 11 Spec No:213-328.
76. Young JE and Goldstein LS. Alzheimer's disease in a dish: promises and challenges of human stem cell models. Human molecular genetics. 2012; 21:R82-89.
77. Miller JD, Ganat YM, Kishinevsky S, Bowman RL, Liu B, Tu EY, Mandal PK, Vera E, Shim JW, Kriks S, Taldone T, Fusaki N, Tomishima MJ, Krainc D, Milner TA, Rossi DJ, et al. Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell stem cell. 2013; 13:691-705.
78. Mertens J, Paquola AC, Ku M, Hatch E, Bohnke L, Ladjevardi S, McGrath S, Campbell B, Lee H, Herdy JR, Goncalves JT, Toda T, Kim Y, Winkler J, Yao J, Hetzer MW, et al. Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects. Cell stem cell. 2015; 17:705-718.
79. Mungenast AE, Siegert S and Tsai LH. Modeling Alzheimer's disease with human induced pluripotent stem (iPS) cells. Molecular and cellular neurosciences. 2015:S1044-7431(1015)30037-30033.
80. Byrne SM, Mali P and Church GM. Genome editing in human stem cells. Methods in enzymology. 2014; 546:119-138.
81. Hendriks WT, Warren CR and Cowan CA. Genome Editing in Human Pluripotent Stem Cells: Approaches, Pitfalls, and Solutions. Cell stem cell. 2016; 18:53-65.
82. Sproul AA. Being human: The role of pluripotent stem cells in regenerative medicine and humanizing Alzheimer's disease models. Molecular aspects of medicine. 2015; 43-44:54-65.
83. Pamies D, Hartung T and Hogberg HT. Biological and medical applications of a brain-on-a-chip. Experimental biology and medicine. 2014; 239:1096-1107.
84. Alepee N, Bahinski A, Daneshian M, De Wever B, Fritsche E, Goldberg A, Hansmann J, Hartung T, Haycock J, Hogberg H, Hoelting L, Kelm JM, Kadereit S, McVey E, Landsiedel R, Leist M, et al. State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology. Altex. 2014; 31:441-477.
85. O'Connor MD. The 3R principle: advancing clinical application of human pluripotent stem cells. Stem cell research & therapy. 2013; 4:21.
86. Graul AI. Promoting, improving and accelerating the drug development and approval processes. Drug news & perspectives. 2008; 21:36-43.
87. Beach TG. Alzheimer's disease and the "Valley Of Death": not enough guidance from human brain tissue? Journal of Alzheimer's disease. 2013; 33 Suppl 1:S219-233.
88. Harper L, Fumagalli GG, Barkhof F, Scheltens P, O'Brien JT, Bouwman F, Burton EJ, Rohrer JD, Fox NC, Ridgway GR and Schott JM. MRI visual rating scales in the diagnosis of dementia: evaluation in 184 post-mortem confirmed cases. Brain. 2016; 139:1211-1225.
89. Oka T, Tagawa K, Ito H and Okazawa H. Dynamic changes of the phosphoproteome in postmortem mouse brains. PloS one. 2011; 6:e21405.
90. Beach TG, Adler CH, Sue LI, Serrano G, Shill HA, Walker DG, Lue L, Roher AE, Dugger BN, Maarouf C, Birdsill AC, Intorcia A, Saxon-Labelle M, Pullen J, Scroggins A, Filon J, et al. Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program. Neuropathology. 2015; 35:354-389.
91. Ferrer I, Martinez A, Boluda S, Parchi P and Barrachina M. Brain banks: benefits, limitations and cautions concerning the use of post-mortem brain tissue for molecular studies. Cell and tissue banking. 2008; 9:181-194.
92. Ferrer I, Santpere G, Arzberger T, Bell J, Blanco R, Boluda S, Budka H, Carmona M, Giaccone G, Krebs B, Limido L, Parchi P, Puig B, Strammiello R, Strobel T and Kretzschmar H. Brain protein preservation largely depends on the postmortem storage temperature: implications for study of proteins in human neurologic diseases and management of brain banks: a BrainNet Europe Study. Journal of neuropathology and experimental neurology. 2007; 66:35-46.
93. Sethi P and Lukiw WJ. Micro-RNA abundance and stability in human brain: specific alterations in Alzheimer's disease temporal lobe neocortex. Neuroscience letters. 2009; 459:100-104.
94. Hendrix JA, Finger B, Weiner MW, Frisoni GB, Iwatsubo T, Rowe CC, Kim SY, Guinjoan SM, Sevlever G and Carrillo MC. The Worldwide Alzheimer's Disease Neuroimaging Initiative: An update. Alzheimer's & dementia. 2015; 11:850-859.
95. Kerchner GA. Ultra-high field 7T MRI: a new tool for studying Alzheimer's disease. Journal of Alzheimer's disease. 2011; 26 Suppl 3:91-95.
96. Maruyama M, Shimada H, Suhara T, Shinotoh H, Ji B, Maeda J, Zhang MR, Trojanowski JQ, Lee VM, Ono M, Masamoto K, Takano H, Sahara N, Iwata N, Okamura N, Furumoto S, et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron. 2013; 79:1094-1108.
97. Willette AA, Johnson SC, Birdsill AC, Sager MA, Christian B, Baker LD, Craft S, Oh J, Statz E, Hermann BP, Jonaitis EM, Koscik RL, La Rue A, Asthana S and Bendlin BB. Insulin resistance predicts brain amyloid deposition in late middle-aged adults. Alzheimer's & dementia. 2015; 11:504-510e501.
98. Kenna H, Hoeft F, Kelley R, Wroolie T, DeMuth B, Reiss A and Rasgon N. Fasting plasma insulin and the default mode network in women at risk for Alzheimer's disease. Neurobiology of aging. 2013; 34:641-649.
99. Cherbuin N, Sachdev P and Anstey KJ. Higher normal fasting plasma glucose is associated with hippocampal atrophy: The PATH Study. Neurology. 2012; 79:1019-1026.
100. Pistollato F and Battino M. Role of plant-based diets in the prevention and regression of metabolic syndrome and neurodegenerative diseases. Trends in Food Science & Technology. 2014; 40:62-81.
101. Dai Y and Kamal MA. Fighting Alzheimer's disease and type 2 diabetes: pathological links and treatment strategies. CNS & neurological disorders drug targets. 2014; 13:271-282.
102. de la Monte SM and Tong M. Brain metabolic dysfunction at the core of Alzheimer's disease. Biochemical pharmacology. 2014; 88:548-559.
103. Jbabdi S and Johansen-Berg H. Tractography: where do we go from here? Brain connectivity. 2011; 1:169-183.
104. Gutman B, Leonardo C, Jahanshad N, Hibar D, Eschenburg K, Nir T, Villalon J and Thompson P. Registering cortical surfaces based on whole-brain structural connectivity and continuous connectivity analysis. Medical image computing and computer-assisted intervention. 2014; 17:161-168.
105. Prescott JW, Guidon A, Doraiswamy PM, Roy Choudhury K, Liu C, Petrella JR and Alzheimer's Disease Neuroimaging I. The Alzheimer structural connectome: changes in cortical network topology with increased amyloid plaque burden. Radiology. 2014; 273:175-184.
106. Rhinn H, Fujita R, Qiang L, Cheng R, Lee JH and Abeliovich A. Integrative genomics identifies APOE epsilon4 effectors in Alzheimer's disease. Nature. 2013; 500:45-50.
107. Zahid S, Oellerich M, Asif AR and Ahmed N. Phosphoproteome profiling of substantia nigra and cortex regions of Alzheimer's disease patients. Journal of neurochemistry. 2012; 121:954-963.
108. Graff-Radford J and Kantarci K. Magnetic resonance spectroscopy in Alzheimer's disease. Neuropsychiatric disease and treatment. 2013; 9:687-696.
109. Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD and Rogers J. Epigenetic mechanisms in Alzheimer's disease. Neurobiology of aging. 2011; 32:1161-1180.
110. Millan MJ. The epigenetic dimension of Alzheimer's disease: causal, consequence, or curiosity? Dialogues in clinical neuroscience. 2014; 16:373-393.
111. Trushina E, Dutta T, Persson XM, Mielke MM and Petersen RC. Identification of altered metabolic pathways in plasma and CSF in mild cognitive impairment and Alzheimer's disease using metabolomics. PloS one. 2013; 8:e63644.
112. Chetty M, Rose RH, Abduljalil K, Patel N, Lu G, Cain T, Jamei M and Rostami-Hodjegan A. Applications of linking PBPK and PD models to predict the impact of genotypic variability, formulation differences, differences in target binding capacity and target site drug concentrations on drug responses and variability. Frontiers in pharmacology. 2014; 5:258.
113. Janson J, Eketjall S, Tunblad K, Jeppsson F, Von Berg S, Niva C, Radesater AC, Falting J and Visser SA. Population PKPD modeling of BACE1 inhibitor-induced reduction in Abeta levels in vivo and correlation to in vitro potency in primary cortical neurons from mouse and guinea pig. Pharmaceutical research. 2014; 31:670-683.
114. Rao PP, Mohamed T, Teckwani K and Tin G. Curcumin Binding to Beta Amyloid: A Computational Study. Chem Biol Drug Des. 2015; 86:813-20.
115. Huang HJ, Chen HY, Lee CC and Chen CY. Computational design of apolipoprotein E4 inhibitors for Alzheimer's disease therapy from traditional Chinese medicine. BioMed research international. 2014; 2014:452625.
116. NIH. (2013). NIH to reduce significantly the use of chimpanzees in research. News & Events: NIH).
117. Goodman J. (2012). Public Opinion on Animal Testing.
118. McKernan R and Watt FM. What is the point of large-scale collections of human induced pluripotent stem cells? Nature biotechnology. 2013; 31:875-877.
119. Khachaturian ZS, Petersen RC, Snyder PJ, Khachaturian AS, Aisen P, de Leon M, Greenberg BD, Kukull W, Maruff P, Sperling RA, Stern Y, Touchon J, Vellas B, Andrieu S, Weiner MW, Carrillo MC, et al. Developing a global strategy to prevent Alzheimer's disease: Leon Thal Symposium 2010. Alzheimer's & dementia. 2011; 7:127-132.
120. Khachaturian ZS, Barnes D, Einstein R, Johnson S, Lee V, Roses A, Sager MA, Shankle WR, Snyder PJ, Petersen RC, Schellenberg G, Trojanowski J, Aisen P, Albert MS, Breitner JC, Buckholtz N, et al. Developing a national strategy to prevent dementia: Leon Thal Symposium 2009. Alzheimer's & dementia. 2010; 6:89-97.
121. Devall M, Mill J and Lunnon K. The mitochondrial epigenome: a role in Alzheimer's disease? Epigenomics. 2014; 6:665-675.
122. Baloyannis SJ. Mitochondrial alterations in Alzheimer's disease. Journal of Alzheimer's disease. 2006; 9:119-126.
123. Picone P, Nuzzo D, Caruana L, Scafidi V and Di Carlo M. Mitochondrial dysfunction: different routes to Alzheimer's disease therapy. Oxidative medicine and cellular longevity. 2014; 2014:780179.
124. Heppner FL, Ransohoff RM and Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nature reviews Neuroscience. 2015; 16:358-372.
125. Holbrook JB, Barr KR and Brown KW. We need negative metrics too. Nature. 2013; 497:439.
126. Kaiser J. BIOMEDICAL RESEARCH. Spending bills put NIH on track for biggest raise in 12 years. Science. 2015; 349:12-13.
127. NIH Alzheimer's disease Research Summit 2015: Path to Treatment and Prevention. https://www.nia.nih.gov/about/events/2014/alzheimers-disease-research-summit-2015.