Biomarkers for Alzheimer’s Disease: Imagination or Reality-View and Review!

DOI: 10.4236/jbbs.2013.35040   PDF   HTML   XML   3,128 Downloads   5,025 Views   Citations


The Alzheimers disease (AD) is the most widespread chronic, insidious neurodegenerative disease causing dementia in elderly and leading to a massive burden on AD individuals, their families, and on social and health care systems. Its diagnosis is subjective, definite AD can only be diagnosed after pathological brain specimens are examined by either biopsy or autopsy, and it covers 50%-70% of all dementia cases. It is estimated that, by 2050, the number of people aged 80 years or older will approach 370 million worldwide and that 50 percent of those aged 85 years or older will be afflicted with AD. Causes of the disease are multifactorial; where genetics and environmental risk factors work in harmony to cause the disease. Neuropathological features of AD depend on finding of extracellular deposits of β-amyloid peptides (Aβ) that lead to senile plaque formation and intracellular neurofibrillary tangles of hyperphosphory lated tau. However, increasing evidence has suggested that inflammation may play a critical role in AD pathogenesis as well. In the era of genome and sophisticated technology, AD early diagnosis still indecisive and valid biomarkers for AD to be used in routine clinical practice have met with dissatisfaction. Indeed, the relatively unchanged levels of plasma β-amyloid in AD, and a lack of analytical sensitivity for assays for the axonal damage marker have increased the effort to find an alternative ultra-sensitive assay for pathological markers in peripheral blood. We believe that early presymptomalogical practical inexpensive strategies, for characterizing a potential surrogate marker in blood and CSF for AD is warranted, are of interest because they: 1) confirm diagnosis; 2) enable epidemiological screening; 3) identify distinct groups of patients (predictive testing); 4) monitor progression and response to treatment and aid in design/implementation of optimal therapeutic regimens; 5) further the study of the brain-behaviour relationship underlying neurodegeneration.

Share and Cite:

M. Yassin, Z. Armaly, B. Bisharat and A. Bowirrat, "Biomarkers for Alzheimer’s Disease: Imagination or Reality-View and Review!," Journal of Behavioral and Brain Science, Vol. 3 No. 5, 2013, pp. 393-402. doi: 10.4236/jbbs.2013.35040.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] B. V. Zlokovic, R. Deane, J. Sallstrom N. Chow and J. M. Miano, “Neurovascular Pathways and Alzheimer Amyloid Beta-Peptide,” Brain Pathology, Vol. 15, No. 1, 2005, pp. 78-83. doi:10.1111/j.1750-3639.2005.tb00103.x
[2] J. L. Cummings, H. V. Vinters, G. M. Cole and S. Khachaturian, “Alzheimer’s Disease: Etiologies, Pathophysiology, Cognitive Reserve, and Treatment Opportunities,” Neurology, Vol. 5, No. 1, 1998, pp. S2-S17.
[3] Y. H. Suh, F. Cacabelos, R. Fernández-Novoa and L. Corzo, “Phenotypic Profiles and Functional Genomics in Dementia with a Vascular Component,” Neurology Research, Vol. 26, No. 5, 2004, pp. 459-480.doi:10.1179/016164104225017677
[4] C. L. Lendon, F. Ashall and A. M. Goate, “Exploring the Etiology of Alzheimer Disease Using Molecular Genetics,” JAMA, Vol. 277, No. 10, 1997, pp. 825-831.doi:10.1001/jama.1997.03540340059034
[5] S. Henley, G. P. Bates and S. Tabrizi, “Biomarkers for Neurodegenerative Diseases,” Current Opinion in Neurology, Vol. 18, No. 6, 2005, pp. 698-705.doi:10.1097/01.wco.0000186842.51129.cb
[6] K. Furiea and S. Gisele, “Biomarkers in Neurology,” Clinical Trials in the Neurosciences, Vol. 25, 2009, pp. 55-61. doi:10.1159/000209475
[7] A. Bowirrat, M. Yassin, M. Abir, B. Bisharat and Z. Armaly, “Traditional and Modern Medicine Harmonizing the Two Approaches in the Treatment of Neurodegeneration (Alzheimer’s Disease—AD),” In: S. Marcelo and R. de Medeiros, Eds., Complementary Therapies for the Contemporary Healthcare, InTech Prepress, Novi Sad, 2012, pp. 181-212.
[8] N. G. Frangogiannis, “Biomarkers: Hopes and Challenges in the Path from Discovery to Clinical Practice,” Translational Research, Vol. 159, No. 4, 2012, pp. 197-204.doi:10.1016/j.trsl.2012.01.023
[9] M. Shaw, M. Korecka, C. M. Clark, V. M. Y. Lee and J. Q. Trojanowski, “Biomarkers of Neurodegeneration for Diagnosis and Monitoring Therapeutics,” Nature Reviews Drug Discovery, Vol. 6, No. 4, 2007, pp. 295-303.doi:10.1038/nrd2176
[10] G. Downing, “Biomarkers Definitions Working Group. Biomarkers and Surrogate Endpoints,” Clinical Pharmacology & Therapeutics, Vol. 69, 2001, pp. 89-95.
[11] J. Lee, V. Devanarayan, U. Barrett, R. Weiner, J. Allinson, S. Fountain, S. Keller, I. Weinryb, M. Green and L. Duan, “Fit-for-Purpose Method Development and Validation for Successful Biomarker Measurement,” Pharmaceutical Research, Vol. 23, No. 2, 2006, pp. 312-328.doi:10.1007/s11095-005-9045-3
[12] R. Frank and R. Hargreaves, “Clinical Biomarkers in Drug Discovery and Development,” Nature Reviews Drug Discovery, Vol. 2, No. 7, 2003, pp. 566-580.doi:10.1038/nrd1130
[13] H. Harald, L. Simone and Z. S. Khachaturian, “Development of Biomarkers to Chart All Alzheimer’s Disease Stages: The Royal Road to Cutting the Therapeutic Gordian Knot,” Alzheimer’s & Dementia, Vol. 8, No. 4, 2012, pp. 312-336. doi:10.1016/j.jalz.2012.05.2116
[14] S. M. Dhanasekaran, “Delineation of Prognostic Biomarkers in Prostate Cancer,” Nature, Vol. 412, No. 6849, 2001, pp. 822-826. doi:10.1038/35090585
[15] P. D. Wagner, P. Maruvada and S. Srivastava, “Molecular Diagnostics: A New Frontier in Cancer Prevention,” Expert Review of Molecular Diagnostics, Vol. 4, No. 4, 2004, pp. 503-511.doi:10.1586/14737159.4.4.503
[16] P. Gerde, B. A. Muggenburg, T. Stephens, J. L. Lewis, K. H. Pyon and A. R. Dahl, “A Relevant Dose of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Is Extensively Metabolized and Rapidly Absorbed in the Canine Tracheal Mucosa,” Cancer Research, Vol. 58, No. 7, 1998, pp. 1417-1422.
[17] V. Prashanthi, “Effect of Apolipoprotein E on Biomarkers of Amyloid Load and Neuronal Pathology in Alzheimer Disease,” Annals of Neurology, Vol. 67, No. 3, 2010, pp. 308-316.
[18] J. A. Johnston and M. Hill, “113 The Risk and Gamble We Take with Our Patients on Dopamine Agonists,” Journal of Neurology, Neurosurgery & Psychiatry, Vol. 83, No. 3, 2012, pp. e1-e1.doi:10.1136/jnnp-2011-301993.155
[19] C. H. Golias, “Adhesion Molecules in Cancer Invasion and Metastasis,” Hippokratia, Vol. 9, No. 1, 2005, pp. 106-114.
[20] H. A. Kader, V. T. Tchernev, E. Satyaraj, S. Lejnine, G. Kotler, S. F. Kingsmore and D. Patel, “Protein Microarray Analysis of Disease Activity in Pediatric Inflammatory Bowel Disease Demonstrates Elevated Serum PLGF, IL-7, TGF-β1, and IL-12p40 Levels in Crohn’s Disease and Ulcerative Colitis Patients in Remission versus Active Disease,” The American Journal of Gastroenterology, Vol. 100, No. 2, 2005, pp. 414-423.doi:10.1111/j.1572-0241.2005.40819.x
[21] O. Carrette, I. Demalte, A. Scherl, O. Yalkinoglu, O. Corthals, G. Burkhard and J. C. Sanchez, “A Panel of Cerebrospinal Fluid Potential Biomarkers for the Diagnosis of Alzheimer’s Disease,” Proteomics, Vol. 3, No. 8, 2003, pp. 1486-1494. doi:10.1002/pmic.200300470
[22] B. Ibach, H. Binder, M. Dragon, S. Poljansky, E. Haen, E. Schmitz and G. Hajak, “Cerebrospinal Fluid tau and βAmyloid in Alzheimer Patients, Disease Controls and an Age-Matched Random Sample,” Neurobiology of Aging, Vol. 27, No. 9, 2006, pp. 1202-1211.doi:10.1016/j.neurobiolaging.2005.06.005
[23] M. Davis, S. Hanson and B. Altevogt, “Neuroscience Biomarkers and Biosignatures: Converging Technologies, Emerging Partnerships: Workshop Summary,” National Academies Press, Washington DC, 2008.
[24] N. R. Graff-Radford, J. E. Crook, J. Lucas, B. F. Boeve, D. S. Knopman, R. J. Ivnik and S. G. Younkin, “Association of Low Plasma Abeta42/Abeta40 Ratios with Increased Imminent Risk for Mild Cognitive Impairment and Alzheimer Disease,” Archives of Neurology, Vol. 64, No, 3, 2007, p. 354. doi:10.1001/archneur.64.3.354
[25] D. Butler and B. A. Bahr, “Oxidative Stress and Lysosomes: CNS-Related Consequences and Implications for Lysosomal Enhancement Strategies and Induction of Autophagy,” Antioxidants & Redox Signaling, Vol. 8, No. 1-2, 2006, pp. 185-196.
[26] K. Blennow, E. Vanmechelen and H. Hampel, “CSF Total tau, Ab42 and Phosphorylated tau Protein as Biomarkers for Alzheimer’s Disease” Molecular Neurobiology, Vol. 24, No. 1-3, 2001, pp. 87-97.doi:10.1385/MN:24:1-3:087
[27] A. M. Fagan, M. A. Mintun, R. H. Mach, S. Y. Lee, C. S. Dence, A. R. Shah, G. N. LaRossa, M. L. Spinner, W. E. Klunk, C. A. Mathis, S. T. DeKosky, J. C. Morris and D. M. Holtzman, “Inverse Relation between in Vivo Amyloid Imaging Load and Cerebrospinal Fluid Abeta42 in Humans,” Annals of Neurology, Vol. 59, No. 3, 2006, pp. 512-519. doi:10.1002/ana.20730
[28] A. M. Fagan, C. M. Roe, C. Xiong, M. A. Mintun, J. C. Morris and D. M. Holtzman, “Cerebrospinal Fluid tau/ beta-Amyloid(42) Ratio as a Prediction of Cognitive Decline in Nondemented Older Adults,” Archives of Neurology, Vol. 64, No. 3, 2007, pp. 343-349. doi:10.1001/archneur.64.3.noc60123
[29] M. Sjogren, P. Davidsson and A. Aallin, “Decreased CSF β-Amyloid42 in Alzheimer’s Disease and Amyotrophic Lateral Sclerosis May Reflect Mismetabolism of βAmyloid Induced by separate mechanisms,” Dementia and Geriatric Cognitive Disorders, Vol. 13, 2002, pp. 112-118. doi:10.1159/000048642
[30] D. Strozyk, K. Blennow, L. R. White and L. J. Launer, “CSF Aβ42 Levels Correlate with Amyloid-Neuropathology in a Population-Based Autopsy Study,” Neurology, Vol. 60, No. 4, 2003, pp. 652-656. doi:10.1212/01.WNL.0000046581.81650.D0
[31] M. Morris, S. Maeda, K. Vossel and L. Mucke, “The Many Faces of Tau,” Neuron, Vol. 70, No. 3, 2011, pp. 410-426. doi:10.1016/j.neuron.2011.04.009
[32] L. Buée, T. Bussiere, V. Buee-Scherrer, A. Delacourte and P. R. Hof, “Tau Protein Isoforms, Phosphorylation and Role in Neurodegenerative Disorders,” Brain Research Reviews, Vol. 33, No. 1, 2000, pp. 95-130.doi:10.1016/S0165-0173(00)00019-9
[33] C. Feijoo, D. G. Campbell, R. Jakes, M. Goedert and A. Cuenda, “Evidence That Phosphorylation of the Microtubule-Associated Protein Tau by SAPK4/p38δ at Thr50 Promotes Microtubule Assembly,” Journal of CellScience, Vol. 118, No. 2, 2005, pp. 397-408.doi:10.1242/jcs.01655
[34] K. Boekhoorn, D. Terwel, B. Biemans, P. Borghgraef, O. Wiegert, G. J. Ramakers and P. L. Lucassen, “Improved Long-Term Potentiation and Memory in Young tauP301L Transgenic Mice before Onset of Hyperphosphorylation and Tauopathy,” The Journal of Neuroscience, Vol. 26 No. 13, 006, pp. 3514-3523.
[35] M. Vandermeeren, M. Mercken and E. Vanmechelen, “Detection of τ Proteins in Normal and Alzheimer’s Disease Cerebrospinal Fluid with a Sensitive Sandwich Enzyme-Linked Immunosorbent Assay,” Journal of Neurochemistry, Vol. 61, 1993, pp. 1828-1834.doi:10.1111/j.1471-4159.1993.tb09823.x
[36] O. Hansson, H. Zetterberg, P. Buchhave, E. Londos, K. Blennow and L. Minthon, “Association between CSF Biomarkers and Incipient Alzheimer’s Disease in Patients with Mild Cognitive Impairment: A Follow-Up Study,” The Lancet Neurology, Vol. 5, No. 3, 2006, pp. 228-234doi:10.1016/S1474-4422(06)70355-6
[37] A. Lanari and L. Parnetti, “Cerebrospinal Fluid Biomarkers and Prediction of Conversion in Patients with Mild Cognitive Impairment: 4-Year Follow-Up in a Routine Clinical Setting,” The Scientific World Journal, Vol. 9, 2009, pp. 961-966. doi:10.1100/tsw.2009.106
[38] N. Mattsson, H. Zetterberg, O. Hansson, N. Andreasen, L. Parnetti, M. Jonsson and K. Blennow, “CSF Biomarkers and Incipient Alzheimer Disease in Patients with Mild Cognitive Impairment,” The Journal of the American Medical Association, Vol. 302, No. 4, 2009, pp. 385-393.doi:10.1001/jama.2009.1064
[39] G. Zanusso, M. Fiorini, P. G. Righetti and S. Monaco, “Specific and Surrogate Cerebrospinal Fluid Markers in Creutzfeldt—Jakob Disease,” Advances in Neurobiology, Vol. 2, 2011, pp. 455-467.
[40] P. Formichi, L. Parnetti, E. Radi, G. Cevenini, M. T. Dotti and A. Federico, “CSF Levels of β-Amyloid 1-42, Tau and Phosphorylated Tau Protein in CADASIL,” European Journal of Neurology, Vol. 15, No. 11, 2008, pp. 1252-1255. doi:10.1111/j.1468-1331.2008.02277.x
[41] P. M. Stanford, G. M. Halliday, W. S. Brooks, J. B. Kwok, C. E. Storey, H. Creasey and P. R. Schofield, “Progressive Supranuclear Palsy Pathology Caused by a Novel Silent Mutation in Exon 10 of the Tau Gene Expansion of the Disease Phenotype Caused by Tau Gene Mutations,” Brain, Vol. 123, No. 5, 2011, pp. 880-893.doi:10.1093/brain/123.5.880
[42] D. W. Cleveland, S. Y. Hwo and M. W. Kirschner, “Physical and Chemical Properties of Purified Tau Factor and the Role of Tau in Microtubule Assembly,” Journal of Molecular Biology, Vol. 116, No. 2, pp. 1977, pp. 227-247.
[43] H. Hampel, K. Blennow, L. M. Shaw, Y. C. Hoessler, H. Zetterberg and J. Q. Trojanowski, “Total and Phosphorylated Tau Protein as Biological Markers of Alzheimer’s Disease,” Experimental Gerontology, Vol. 45, No. 1, 2009, pp. 30-40. doi:10.1016/j.exger.2009.10.010
[44] K. J. Reinikainen, H. Soininen and P. J. Riekkinen, “Neurotransmitter Changes in Alzheimer’s Disease: Implications to Diagnostics and Therapy,” Journal of Neuroscience Research, Vol. 27, No. 4, 1990, pp. 576-586.doi:10.1002/jnr.490270419
[45] S. T. DeKosky and S. W. Scheff, “Synapse Loss in Frontal Cortex Biopsies in Alzheimer’s Disease: Correlation with Cognitive Severity,” Annals of Neurology, Vol. 27, No. 5, 1990, pp. 457-464. doi:10.1002/ana.410270502
[46] M. G. Giovannini, A. Rakovska, R. S. Benton, M. Pazzagli, L. Bianchi and G. Pepeu, “Effects of Novelty and Habituation on Acetylcholine, GABA, and Glutamate Release from the Frontal Cortex and Hippocampus of Freely Moving Rats,” Neuroscience, Vol. 106, No. 1, 2001, pp. 43-53.doi:10.1016/S0306-4522(01)00266-4
[47] A. Schousboe, “Transport and Metabolism of Glutamate and GABA in Neurons are Glial Cells,” International Review of Neurobiology, Vol. 22, No. 1, 1981, pp. 1-45.
[48] L. Hertz and H. R. Zielke, “Astrocytic Control of Glutamatergic Activity: Astrocytes as Stars of the Show,” Trends in Neurosciences, Vol. 27, No. 12, 2004, pp. 735-743. doi:10.1016/j.tins.2004.10.008
[49] J. T. Greenamyre, “The Role of Glutamate in Neurotransmission and in Neurologic Disease,” Archives of neurology, Vol. 43, No. 10, 1986, pp. 1058-1063.doi:10.1001/archneur.1986.00520100062016
[50] P. G. Haydon, “GLIA: Listening and Talking to the Synapse,” Nature Reviews Neuroscience, Vol. 2, No. 3, 2001, pp. 185-193.
[51] P. T. Francis, “The Interplay of Neurotransmitters in Alzheimer’s Disease,” CNS Spectrums, Vol. 10, Suppl. 18, 2005, pp. 6-20.
[52] M. R. Farlow, “NMDA Receptor Antagonists,” Geriatrics, Vol. 59, No. 6, 2004, pp. 22-27.
[53] J. D. Rothstein, L. J. Martin and R. W. Kuncl, “Decreased Glutamate Transport by the Brain and Spinal Cord in Amyotrophic Lateral Sclerosis,” New England Journal of Medicine, Vol. 326, No. 22, 1992, pp. 1464-1468.doi:10.1056/NEJM199205283262204
[54] J. Masson, C. Sagne, M. Hamon and S. El Mestikawy, “Neurotransmitter Transporters in the Central Nervous System,” Pharmacological Reviews, Vol. 51, No. 3, 1999, pp. 439-464.
[55] J. P. Hornung, “The Human Raphe Nuclei and the Serotonergic System,” Journal of Chemical Neuroanatomy, Vol. 26, No. 4, 2003, pp. 331-343.doi:10.1016/j.jchemneu.2003.10.002
[56] R. Mossner, A. Schmitt, Y. Syagailo, M. Gerlach, P. Riederer and K. P. Lesch, “The Serotonin Transporter in Alzheimer’s and Parkinson’s Disease,” Advances in Research on Neurodegeneration, Vol. 60, 2000, pp 345-350.
[57] W. J. Geldenhuys and C. J. Van der Schyf, “Serotonin 5-HT6 Receptor Antagonists for the Treatment of Alzheimer’s Disease,” Current Topics in Medicinal Chemistry, Vol. 8, No. 12, 2008, pp. 1035-1048.doi:10.2174/156802608785161420
[58] G. Downing (Biomarkers Definitions Working Group), “Biomarkers and Surrogate Endpoints,” Clinical Pharmacology and Therapeutics, Vol. 69, No. 3, 2001, pp. 89-95.
[59] J. Lee, V. Devanarayan, U. Barrett, R. Weiner, J. Allinson, S. Fountain, S. Keller, I. Weinryb, M. Green and L. Duan, “Fit-for-Purpose Method Development and Validation for Successful Biomarker Measurement,” Pharmaceutical Research, Vol. 23, No. 2, 2006, pp. 312-328.doi:10.1007/s11095-005-9045-3
[60] N. S. M. Schoonenboom, F. E. Reesink, N. A. Verwey, M. I. Kester, C. E. Teunissen, P. M. van de Ven, Y. A. L. Pijnenburg, M. A. Blankenstein, A. J. Rozemuller, P. Scheltens and W. M. van de Flier, “Cerebrospinal Fluid Markers for Differential Dementia Diagnosis in a Large Memory Clinic Cohort,” Neurology, Vol. 78, No. 1, 2012, pp. 47-54. doi:10.1212/WNL.0b013e31823ed0f0
[61] C. Humpel, “Identifying and Validating Biomarkers for Alzheimer’s Disease,” Trends in Biotechnology, Vol. 29, No. 1, 2011, pp. 26-32. doi:10.1016/j.tibtech.2010.09.007
[62] K. Buerger, E. M. Pirttila, R. Zinkowski, I. Alafuzoff, S. J. Teipel, J. DeBernardis, D. Kerkman, C. McCulloch, H. Soininen and H. Hampel, “CSF Phosphorylated Tau Protein Correlates with Neocortical Neurofibrillary Pathology in Alzheimer’s Disease,” Brain, Vol. 129, No. 11, 2006, pp. 3035-3041. doi:10.1093/brain/awl269
[63] S. Engelborghs, K. Sleegers, P. Cras, N. Brouwers, S. Serneels, E. De Leenheir, J. J. Martin, E. Vanmechelen, C. Van Broeckhoven and P. P. De Deyn, “No Association of CSF Biomarkers with APOE e4, Plaque and Tangle Burden in Definite Alzheimer’s Disease,” Brain, Vol. 130, No. 9, 2007, pp. 2320-2326. doi:10.1093/brain/awm136
[64] K. Buerger, I. Alafuzoff, M. Ewers, T. Pirttila, R. Zinkowski and H. Hampel, “No Correlation between CSF Tau Protein Phosphorylated at Threonine 181 with Neocortical Neurofibrillary Pathology in Alzheimer’s Disease,” Brain, Vol. 130, No. 10, 2007, p. e82.doi:10.1093/brain/awm140
[65] M. C. Irizarry, “Biomarkers of Alzheimer Disease in Plasma,” NeuroRX, Vol. 1, No. 2, 2004, pp. 226-234.doi:10.1602/neurorx.1.2.226
[66] N. Rosier, I. Wichart and K. A. Jellinger, “Current Clinical Neurochemical Diagnosis of Alzheimer’s Disease,” Laboratoriums Medizin, Vol. 26, No. 3-4, 2002, pp. 139-148. doi:10.1046/j.1439-0477.2002.02031.x
[67] R. Mayeux, L. S. Honig and M. X. Tang, “Plasma A[beta]40 and A[beta]42 and Alzheimer’s Disease: Relation to Age, Mortality, and Risk,” Neurology, Vol. 61, No. 9, 2003, pp. 1185-1190.doi:10.1212/01.WNL.0000091890.32140.8F
[68] P. M. Mehta, T. Pirttila and B. A. Patrick, “Amyloid Beta Protein 1-40 and 1-42 Levels in Matched Cerebrospinal Fluid and Plasma from Patients with Alzheimer Disease,” Neuroscience Letters, Vol. 304, No. 1-2, 2001, pp. 102-106. doi:10.1016/S0304-3940(01)01754-2
[69] J. D. Doecke, S. M. Laws, N. G. Faux, W. Wilson, S. C. Burnham, C. P. Lam, A. Mondal, J. Bedo, et al., “Blood-Based Protein Biomarkers for Diagnosis of Alzheimer Disease,” Archives of Neurology, Vol. 69, No. 10, 2012, pp. 1318-1325. doi:10.1001/archneurol.2012.1282
[70] H. D. Soares, W. Z. Potter, E. Pickering, M. Kuhn, F. W. Immermann, D. M. Shera, M. Ferm, R. A. Dean, A. J. Simon, F. Swenson, J. A. Siuciak, J. Kaplow, M. Thambisetty, et al., “Biomarkers Consortium Alzheimer’s Disease Plasma Proteomics Project. Plasma Biomarkers Associated with the Apolipoprotein E Genotype and Alzheimer Disease,” Archives of Neurology, Vol. 69, No. 10, 2012, pp. 1310-1317.
[71] J. B. Toledo, X. Da, P. Bhatt, D. A. Wolk, S. E. Arnold, L. M. Shaw, J. Q. Trojanowski and C. Davatzikos, “Relationship between Plasma Analytes and SPARE-AD Defined Brain Atrophy Patterns in ADNI,” PLoS One, Vol. 8, No. 2, 2013, Article ID: e55531.doi:10.1371/journal.pone.0055531
[72] R. Mayeux, A. M. Saunders, S. Shea, S. Mirra, D. Evans, A. D. Roses, B. T. Hyman, B. Crain, M. X. Tang and C. H. Phelps, “Utility of the Apolipoprotein E Genotype in the Diagnosis of Alzheimer’s Disease,” New England Journal of Medicine, Vol. 338, 1998, pp. 506-511.doi:10.1056/NEJM199802193380804
[73] R. S Britschgi, C. Herbert, Y. Takeda-Uchimura, A. Boxer, K. Blennow, L. F. Friedman, D. R. Galasko, M. Jutel, A. Karydas, A. Kaye and J. Leszek, “Classification and Prediction of Clinical Alzheimer’s Diagnosis Based on Plasma Signaling Proteins,” Nature Medicine, Vol. 13, 2007, pp. 1359-1362.
[74] P. Sebastiani, N. Solovieff, A. T. DeWan, K. M. Walsh, A. P. Stephen, H. Efthymia, M. S. Andersen, D. A. Dworkis, J. B. Wilk, R. H. Myers and M. H. Steinberg, “Perls Genetic Signatures of Exceptional Longevity in Humans,” PloS One, Vol. 7, No. 1, 2012, p. e29848.doi:10.1371/journal.pone.0029848
[75] S. L. Andersen, P. Sebastiani, L. Feldman, “Health Span Approximates Life Span Amongmany Supercentenarians: Compression of Morbidity at the Approximate Limit of Life Span,” The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, Vol. 67, No. 4, 2012, pp. 395-405.
[76] A. B. Newman, N. W. Glynn, C. A. Taylor, P. Sebastiani, T. T. Perls, R. Mayeux, K. Christensen, J. M. Zmuda, S. Barral, J. H. Lee and E. M. Simonsick, “Health and Function of Participants in the Long Life Family Study: A Comparison with Other Cohorts,” Aging (Albany NY), Vol. 3, No. 1, 2011, pp. 63-76.
[77] T. Perls and N. Barzilai, “100 Semi-Supercentenarians and Older as a Proposed Sample Set for the Archon Genomics X PRIZE Validation Protocol,” Nature Precedings, 2011, in press. doi:10.1038/npre.2011.5756.1

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.