Preventing Alzheimer's disease by means of natural selection

Journal of the Royal Society Interface

Volumn 12, Issue 102, 2015, Pages

  Demetrius, Lloyd A ^a,b   Driver, Jane A ^c,d  

^a HARVARD UNIVERSITY   (United States)

^b MAX PLANCK INSTITUTE FOR MOLECULAR GENETICS   (Germany)

^c BOSTON MEDICAL CENTER   (United States)

^d BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

Alzheimer's disease; Natural selection; Neuroenergetics

Indexed keywords

GLYCOPROTEINS; METABOLISM; NEURONS; STREAM FLOW; SUBSTRATES;

ALZHEIMER'S DISEASE; CLINICAL TRIAL; EMPIRICAL DATA; ENERGY PRODUCTIONS; NATURAL SELECTION; NEUROENERGETICS; OXIDATIVE PHOSPHORYLATION; THERAPEUTIC STRATEGY;

NEURODEGENERATIVE DISEASES;

AMYLOID;

AGE; AGING; ALZHEIMER DISEASE; ARTICLE; ARTIFICIAL NEURAL NETWORK; CELL SURVIVAL; CLINICAL TRIAL (TOPIC); ENERGY METABOLISM; ENERGY TRANSFER; ENERGY YIELD; ENTROPY; EVOLUTIONARY DEVELOPMENTAL BIOLOGY; EVOLUTIONARY ENTROPY; EXPERIMENTAL STUDY; HUMAN; NATURAL SCIENCE; NATURAL SELECTION; NUCLEAR REPROGRAMMING; OXIDATIVE PHOSPHORYLATION; PHYSIOLOGICAL PROCESS; PROTEIN DOMAIN; QUANTITATIVE ANALYSIS; SURVIVAL RATE; THERAPY EFFECT; THERMODYNAMICS; UPREGULATION; WARBURG EFFECT;

EID: 84915756478     PISSN: 17425689     EISSN: 17425662     Source Type: Journal    
DOI: 10.1098/rsif.2014.0919     Document Type: Article

References (103)

1. Goate A et al. 1991 Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704-706. (doi:10.1038/349704a0)
2. Gooch MD, Stennett DJ. 1996 Molecular basis of Alzheimer's disease. Am. J. Health Syst. Pharm. 53, 1545-1557; quiz 603-604.
3. Hardy J, Selkoe DJ. 2002 The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353-356. (doi:10.1126/science.1072994)
4. Hardy J. 2006 Alzheimer's disease: the amyloid cascade hypothesis: an update and reappraisal. J. Alzheimer's Dis. 9(Suppl. 3), 151-153.
5. Rao VS, van Duijn CM, Connor-Lacke L, Cupples LA, Growdon JH, Farrer LA. 1994 Multiple etiologies for Alzheimer disease are revealed by segregation analysis. Am. J. Hum. Genet. 55, 991-1000.
6. Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee J-M, Holtzman DM. 2011 Neuronal activity regulates the regional vulnerability to amyloid-beta deposition. Nat. Neurosci. 14, 750-756. (doi:10.1038/nn.2801)
7. Davies L, Wolska B, Hilbich C, Multhaup G, Martins R, Simms G, Beyreuther K, Masters CL. 1988 A4 amyloid protein deposition and the diagnosis of Alzheimer's disease: prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques. Neurology 38, 1688-1693. (doi:10.1212/WNL.38.11.1688)
8. Bulbarelli A, Lonati E, Brambilla A, Orlando A, Cazzaniga E, Piazza F, Ferrarese C, Masserini M, Sancini G. 2012 Aβ42 production in brain capillary endothelial cells after oxygen and glucose deprivation. Mol. Cell. Neurosci. 49, 415-422. (doi:10.1016/j.mcn.2012.01.007)
9. Daulatzai MA. 2013 Death by a thousand cuts in Alzheimer's disease: hypoxia-the prodrome. Neurotox. Res. 24, 216-243. (doi:10.1007/s12640-013-9379-2)
10. Pimentel-Coelho PM, Rivest S. 2012 The early contribution of cerebrovascular factors to the pathogenesis of Alzheimer's disease. Eur. J. Neurosci. 35, 1917-1937. (doi:10.1111/j.1460-9568.2012.08126.x)
11. Roberts GW, Gentleman SM, Lynch A, Murray L, Landon M, Graham DI. 1994 Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 57, 419-425. (doi:10.1136/jnnp.57.4.419)
12. Klunk WE et al. 2004 Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann. Neurol. 55, 306-319. (doi:10.1002/ana.20009)
13. Schmitt FA, Davis DG, Wekstein DR, Smith CD, Ashford JW, Markesbery WR. 2000 'Preclinical' AD revisited: neuropathology of cognitively normal older adults. Neurology 55, 370-376. (doi:10.1212/ WNL.55.3.370)
14. Doody RS et al. 2014 Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl. J. Med. 370, 311-321. (doi:10.1056/ NEJMoa1312889)
15. Fleisher AS et al. 2008 Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease. Arch. Neurol. 65, 1031-1038. (doi:10.1001/archneur.65.8.1031)
16. Green RC et al. 2009 Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. J. Am. Med. Assoc. 302, 2557-2564. (doi:10.1001/jama.2009.1866)
17. Holmes C et al. 2008 Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372, 216-223. (doi:10.1016/S0140-6736(08)61075-2)
18. Salloway S et al. 2014 Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl. J. Med. 370, 322-333. (doi:10.1056/NEJMoa1304839)
19. Pimplikar SW. 2009 Reassessing the amyloid cascade hypothesis of Alzheimer's disease. Int. J. Biochem. Cell Biol. 41, 1261-1268. (doi:10.1016/j.biocel.2008.12.015)
20. Struble RG, Ala T, Patrylo PR, Brewer GJ, Yan XX. 2010 Is brain amyloid production a cause or a result of dementia of the Alzheimer's type? J. Alzheimer's Dis. 22, 393-399.
21. Choi SH et al. 2014 A three-dimensional human neural cell culture model of Alzheimer's disease. Nature 515, 274-278. (doi:10.1038/nature13800)
22. Haroutunian V et al. 2008 Role of the neuropathology of Alzheimer disease in dementia in the oldest-old. Arch. Neurol. 65, 1211-1217. (doi:10.1001/archneur.65.9.1211)
23. Prohovnik I, Perl DP, Davis KL, Libow L, Lesser G, Haroutunian V. 2006 Dissociation of neuropathology from severity of dementia in late-onset Alzheimer disease. Neurology 66, 49-55. (doi:10.1212/01.wnl.0000191298.68045.50)
24. Hayflick L. 2007 Entropy explains aging, genetic determinism explains longevity, and undefined terminology explains misunderstanding both. PLOS Genet. 3, e220. (doi:10.1371/journal.pgen.0030220)
25. Demetrius LA, Simon DK. 2012 An inverse-Warburg effect and the origin of Alzheimer's disease. Biogerontology 13, 583-594. (doi:10.1007/s10522-012-9403-6)
26. Demetrius LA, Driver J. 2013 Alzheimer's as a metabolic disease. Biogerontology 14, 641-649. (doi:10.1007/s10522-013-9479-7)
27. Demetrius LA, Simon DK. 2013 The inverse association of cancer and Alzheimer's: a bioenergetic mechanism. J. R. Soc. Interface 10, 20130006. (doi:10.1098/rsif.2013.0006)
28. Mattson MP, Magnus T. 2006 Ageing and neuronal vulnerability. Nat. Rev. Neurosci. 7, 278-294. (doi:10.1038/nrn1886)
29. Driver JA, Beiser A, Au R, Kreger BE, Splansky GL, Kurth T, Kiel DP, Lu KP, Seshadri S. 2012 Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study. Br. Med. J. 344, e1442. (doi:10.1136/bmj.e1442)
30. Tabares-Seisdedos R, Rubenstein JL. 2013 Inverse cancer comorbidity: a serendipitous opportunity to gain insight into CNS disorders. Nat. Rev. Neurosci. 14, 293-304. (doi:10.1038/nrn3464)
31. Demetrius L, Legendre S. 2013 Evolutionary entropy predicts the outcome of selection: competition for resources that vary in abundance and diversity. Theor. Popul. Biol. 83, 39-54. (doi:10.1016/j.tpb.2012.10.004)
32. Demetrius L. 1974 Demographic parameters and natural selection. Proc. Natl Acad. Sci. USA 71, 4645-4647. (doi:10.1073/pnas.71.12.4645)
33. Demetrius L. 2013 Boltzmann, Darwin and directionality theory. Phys. Rep. 530, 1-85. (doi:10.1016/j.physrep.2013.04.001)
34. Demetrius L. 1997 Directionality principles in thermodynamics and evolution. Proc. Natl Acad. Sci. USA 94, 3491-3498. (doi:10.1073/pnas.94.8.3491)
35. Beal MF. 1995 Aging, energy, and oxidative stress in neurodegenerative diseases. Ann. Neurol. 38, 357-366. (doi:10.1002/ana.410380304)
36. Drachman DA. 2006 Aging of the brain, entropy, and Alzheimer disease. Neurology 67, 1340-1352. (doi:10.1212/01.wnl.0000240127.89601.83)
37. Schmitt K, Grimm A, Kazmierczak A, Strosznajder JB, Gotz J, Eckert A. 2012 Insights into mitochondrial dysfunction: aging, amyloid-beta, and tau-A deleterious trio. Antioxid. Redox Signal. 16, 1456-1466. (doi:10.1089/ars.2011.4400)
38. Swerdlow RH. 2012 Mitochondria and cell bioenergetics: increasingly recognized components and a possible etiologic cause of Alzheimer's disease. Antioxid. Redox Signal. 16, 1434-1455. (doi:10.1089/ars.2011.4149)
39. Wallace DC, Fan W, Procaccio V. 2010 Mitochondrial energetics and therapeutics. Annu. Rev. Pathol. 5, 297-348. (doi:10.1146/annurev.pathol.4.110807.092314)
40. Wallace DC. 1992 Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 256, 628-632. (doi:10.1126/science.1533953)
41. Bakkour A, Morris JC, Dickerson BC. 2009 The cortical signature of prodromal AD: regional thinning predicts mild AD dementia. Neurology 72, 1048-1055. (doi:10.1212/01.wnl.0000340981.97664.2f)
42. Dickerson BC et al. 2009 The cortical signature of Alzheimer's disease: regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloid-positive individuals. Cereb. Cortex. 19, 497-510. (doi:10.1093/cercor/bhn113)
43. LaManna JC, Harik SI. 1985 Regional comparisons of brain glucose influx. Brain Res. 326, 299-305. (doi:10.1016/0006-8993(85)90039-3)
44. Kapogiannis D, Mattson MP. 2011 Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. Lancet Neurol. 10, 187-198. (doi:10.1016/S1474-4422(10)70277-5)
45. Swerdlow RH, Burns JM, Khan SM. 2010 The Alzheimer's disease mitochondrial cascade hypothesis. J. Alzheimer's Dis. 20(Suppl. 2), S265-S279.
46. Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW. 1991 The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cereb. Cortex 1, 103-116. (doi:10.1093/cercor/1.1.103)
47. Buckner RL et al. 2009 Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer's disease. J. Neurosci. 29, 1860-1873. (doi:10.1523/ JNEUROSCI.5062-08.2009)
48. Dickerson BC et al. 2004 Medial temporal lobe function and structure in mild cognitive impairment. Ann. Neurol. 56, 27-35. (doi:10.1002/ana.20163)
49. Jacobs HI, Van Boxtel MP, Heinecke A, Gronenschild EH, Backes WH, Ramakers IH, Jolles J, Verhey FRJ. 2012 Functional integration of parietal lobe activity in early Alzheimer disease. Neurology 78, 352-360. (doi:10.1212/WNL.0b013e318245287d)
50. Nichols LM et al. 2012 Interactive effect of apolipoprotein E genotype and age on hippocampal activation during memory processing in healthy adults. Arch. Gen. Psychiatry 69, 804-813. (doi:10.1001/archgenpsychiatry.2011.1893)
51. Oh H, Habeck C, Madison C, Jagust W. 2014 Covarying alterations in Aβ deposition, glucose metabolism, and gray matter volume in cognitively normal elderly. Hum. Brain Mapp. 35, 297-308. (doi:10.1002/hbm.22173)
52. Benzinger TL et al. 2013 Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease. Proc. Natl Acad. Sci. USA 110, E4502-E4509. (doi:10.1073/pnas.1317918110)
53. Cirrito JR et al. 2005 Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 48, 913-922. (doi:10.1016/j.neuron.2005.10.028)
54. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K. 1987 The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733-736. (doi:10.1038/325733a0)
55. Hayflick L. 2007 Biological aging is no longer an unsolved problem. Ann. NY Acad. Sci. 1100, 1-13. (doi:10.1196/annals.1395.001)
56. Demetrius L. 2002 Thermodynamics and kinetics of protein folding: an evolutionary perspective. J. Theor. Biol. 217, 397-411. (doi:10.1006/jtbi.2002.3006)
57. Csermely P. 2001 Chaperone overload is a possible contributor to 'civilization diseases'. Trends Genet. 17, 701-704. (doi:10.1016/S0168-9525(01)02495-7)
58. Chiti F, Dobson CM. 2006 Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem. 75, 333-366. (doi:10.1146/annurev. biochem.75.101304.123901)
59. Birsoy K et al. 2014 Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature 508, 108-112. (doi:10.1038/ nature13110)
60. Pfeiffer T, Bonhoeffer S. 2002 Evolutionary consequences of tradeoffs between yield and rate of ATP production. Z. Physikalische Chemie 216, 51-63. (doi:10.1524/zpch.2002.216.1.051)
61. Koopman WJ, Distelmaier F, Smeitink JA, Willems PH. 2013 OXPHOS mutations and neurodegeneration. EMBO J. 32, 9-29. (doi:10.1038/emboj.2012.300)
62. Vander Heiden MG, Cantley LC, Thompson CB. 2009 Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029-1033. (doi:10.1126/science.1160809)
63. Warburg O. 1956 On the origin of cancer cells. Science 123, 309-314. (doi:10.1126/science.123.3191.309)
64. Lunt SY, Vander Heiden MG. 2011 Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol. 27, 441-464. (doi:10.1146/annurev-cellbio-092910-154237)
65. Zhao Y, Butler EB, Tan M. 2013 Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis. 4, e532. (doi:10.1038/cddis.2013.60)
66. Bauernfeind AL, Barks SK, Duka T, Grossman LI, Hof PR, Sherwood CC. 2013 Aerobic glycolysis in the primate brain: reconsidering the implications for growth and maintenance. Brain Struct. Funct. 219, 1149-1167. (doi:10.1007/s00429-013-0662-z)
67. Goyal MS, Hawrylycz M, Miller JA, Snyder AZ, Raichle ME. 2014 Aerobic glycolysis in the human brain is associated with development and neotenous gene expression. Cell Metab. 19, 49-57. (doi:10.1016/j.cmet.2013.11.020)
68. Magistretti PJ. 2006 Neuron-glia metabolic coupling and plasticity. J. Exp. Biol. 209, 2304-2311. (doi:10.1242/jeb.02208)
69. Nicholls DG. 2002 Mitochondrial function and dysfunction in the cell: its relevance to aging and aging-related disease. Int. J. Biochem. Cell Biol. 34, 1372-1381. (doi:10.1016/S1357-2725(02)00077-8)
70. Hu Y, Wilson GS. 1997 A temporary local energy pool coupled to neuronal activity: fluctuations of extracellular lactate levels in rat brain monitored with rapid-response enzyme-based sensor. J. Neurochem. 69, 1484-1490. (doi:10.1046/j.1471-4159.1997.69041484.x)
71. Stobart JL, Anderson CM. 2013 Multifunctional role of astrocytes as gatekeepers of neuronal energy supply. Front. Cell. Neurosci. 7, 38. (doi:10.3389/ fncel.2013.00038)
72. de la Monte SM, Luong T, Neely TR, Robinson D, Wands JR. 2000 Mitochondrial DNA damage as a mechanism of cell loss in Alzheimer's disease. Lab. Invest. J. Tech. Methods Pathol. 80, 1323-1335. (doi:10.1038/labinvest.3780140)
73. Manczak M, Park BS, Jung Y, Reddy PH. 2004 Differential expression of oxidative phosphorylation genes in patients with Alzheimer's disease: implications for early mitochondrial dysfunction and oxidative damage. Neuromol. Med. 5, 147-162. (doi:10.1385/NMM:5:2:147)
74. Nagy Z, Esiri MM, LeGris M, Matthews PM. 1999 Mitochondrial enzyme expression in the hippocampus in relation to Alzheimer-type pathology. Acta Neuropathol. 97, 346-354. (doi:10.1007/s004010050997)
75. Youle RJ, van der Bliek AM. 2012 Mitochondrial fission, fusion, and stress. Science 337, 1062-1065. (doi:10.1126/science.1219855)
76. de la Torre JC. 2008 Pathophysiology of neuronal energy crisis in Alzheimer's disease. Neuro-Degener. Dis. 5, 126-132. (doi:10.1159/000113681)
77. Breteler MM. 2000 Vascular risk factors for Alzheimer's disease: an epidemiologic perspective. Neurobiol. Aging 21, 153-160. (doi:10.1016/S0197-4580(99)00110-4)
78. Elias MF, Wolf PA, D'Agostino RB, Cobb J, White LR. 1993 Untreated blood pressure level is inversely related to cognitive functioning: the Framingham Study. Am. J. Epidemiol. 138, 353-364.
79. Ivan CS, Seshadri S, Beiser A, Au R, Kase CS, Kelly-Hayes M, Kelly-Hayes M, Wolf PA. 2004 Dementia after stroke: the Framingham Study. Stroke J. Cereb. Circulation 35, 1264-1268. (doi:10.1161/01.STR.0000127810.92616.78)
80. Ruitenberg A, den Heijer T, Bakker SL, van Swieten JC, Koudstaal PJ, Hofman A, Breteler MMB. 2005 Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study. Ann. Neurol. 57, 789-794. (doi:10.1002/ana.20493)
81. Coyle JT, Puttfarcken P. 1993 Oxidative stress, glutamate, and neurodegenerative disorders. Science 262, 689-695. (doi:10.1126/science.7901908)
82. Folch J, Junyent F, Verdaguer E, Auladell C, Pizarro JG, Beas-Zarate C, Camins A. 2012 Role of cell cycle re-entry in neurons: a common apoptotic mechanism of neuronal cell death. Neurotox. Res. 22, 195-207. (doi:10.1007/s12640-011-9277-4)
83. Baker LD et al. 2010 Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch. Neurol. 67, 71-79. (doi:10.1001/archneurol.2009.307)
84. Etgen T, Sander D, Huntgeburth U, Poppert H, Forstl H, Bickel H. 2010 Physical activity and incident cognitive impairment in elderly persons: the INVADE study. Arch. Intern. Med. 170, 186-193. (doi:10.1001/archinternmed.2009.498)
85. Geda YE et al. 2010 Physical exercise, aging, and mild cognitive impairment: a population-based study. Arch. Neurol. 67, 80-86. (doi:10.1001/ archneurol.2009.297)
86. Brix B, Mesters JR, Pellerin L, Johren O. 2012 Endothelial cell-derived nitric oxide enhances aerobic glycolysis in astrocytes via HIF-1alphamediated target gene activation. J. Neurosci. 32, 9727-9735. (doi:10.1523/JNEUROSCI.0879-12.2012)
87. Roig M, Skriver K, Lundbye-Jensen J, Kiens B, Nielsen JB. 2012 A single bout of exercise improves motor memory. PLoS ONE 7, e44594. (doi:10.1371/ journal.pone.0044594)
88. Berthet C, Castillo X, Magistretti PJ, Hirt L. 2012 New evidence of neuroprotection by lactate after transient focal cerebral ischaemia: extended benefit after intracerebroventricular injection and efficacy of intravenous administration. Cerebrovasc. Dis. 34, 329-335. (doi:10.1159/000343657)
89. Coco M, Caggia S, Musumeci G, Perciavalle V, Graziano AC, Pannuzzo G, Cardile V. 2013 Sodium L-lactate differently affects brain-derived neurothrophic factor, inducible nitric oxide synthase, and heat shock protein 70 kDa production in human astrocytes and SH-SY5Y cultures. J. Neurosci. Res. 91, 313-320. (doi:10.1002/jnr.23154)
90. Newington JT, Pitts A, Chien A, Arseneault R, Schubert D, Cumming RC. 2011 Amyloid beta resistance in nerve cell lines is mediated by the Warburg effect. PLoS ONE 6, e19191. (doi:10.1371/ journal.pone.0019191)
91. Soucek T, Cumming R, Dargusch R, Maher P, Schubert D. 2003 The regulation of glucose metabolism by HIF-1 mediates a neuroprotective response to amyloid beta peptide. Neuron 39, 43-56. (doi:10.1016/S0896-6273(03)00367-2)
92. Maalouf M, Sullivan PG, Davis L, Kim DY, Rho JM. 2007 Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience 145, 256-264. (doi:10.1016/j.neuroscience.2006.11.065)
93. Sato K et al . 1995 Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J. 9, 651-658.
94. Costantini LC, Barr LJ, Vogel JL, Henderson ST. 2008 Hypometabolism as a therapeutic target in Alzheimer's disease. BMC Neurosci. 9(Suppl. 2), S16. (doi:10.1186/1471-2202-9-S2-S16)
95. Fuller S, Munch G, Steele M. 2009 Activated astrocytes: a therapeutic target in Alzheimer's disease? Expert Rev. Neurother. 9, 1585-1594. (doi:10.1586/ern.09.111)
96. Adair JC, Knoefel JE, Morgan N. 2001 Controlled trial of N-acetylcysteine for patients with probable Alzheimer's disease. Neurology 57, 1515-1517. (doi:10.1212/WNL.57.8.1515)
97. Begni B et al. 2004 Oxidative stress impairs glutamate uptake in fibroblasts from patients with Alzheimer's disease. Free Rad. Biol. Med. 37, 892-901. (doi:10.1016/j.freeradbiomed.2004.05.028)
98. Benedict C, Kern W, Schultes B, Born J, Hallschmid M. 2008 Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin. J. Clin. Endocrinol. Metabol. 93,1339-1344. (doi:10.1210/jc.2007-2606)
99. Craft S et al. 2012 Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch. Neurol. 69, 29-38. (doi:10.1001/archneurol.2011.233)
100. Shemesh E, Rudich A, Harman-Boehm I, Cukierman-Yaffe T. 2012 Effect of intranasal insulin on cognitive function: a systematic review. J. Clin. Endocrinol. Metab. 97, 366-376. (doi:10.1210/jc.2011-1802)
101. Hölscher C. 2013 Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases. J. Endocrinol. 221, T31-T41. (doi:10.1530/JOE-13-0221)
102. Watson JD. 2009 To fight cancer, know the enemy. New York Times. 6 August 2009, p. A29. See http://www.nytimes.com/2009/08/06/opinion/06watson. html?pagewanted=all&-r=0.
103. Kennedy SR, Loeb LA, Herr AJ. 2012 Somatic mutations in aging, cancer and neurodegeneration. Mech. Ageing Dev. 133, 118-126. (doi:10.1016/j. mad.2011.10.009)