Abstract
Intense multidisciplinary research has provided detailed knowledge of the molecular pathogenesis of Alzheimer disease (AD). This knowledge has been translated into new therapeutic strategies with putative disease-modifying effects. Several of the most promising approaches, such as amyloid-β immunotherapy and secretase inhibition, are now being tested in clinical trials. Disease-modifying treatments might be at their most effective when initiated very early in the course of AD, before amyloid plaques and neurodegeneration become too widespread. Thus, biomarkers are needed that can detect AD in the predementia phase or, ideally, in presymptomatic individuals. In this Review, we present the rationales behind and the diagnostic performances of the core cerebrospinal fluid (CSF) biomarkers for AD, namely total tau, phosphorylated tau and the 42 amino acid form of amyloid-β. These biomarkers reflect AD pathology, and are candidate markers for predicting future cognitive decline in healthy individuals and the progression to dementia in patients who are cognitively impaired. We also discuss emerging plasma and CSF biomarkers, and explore new proteomics-based strategies for identifying additional CSF markers. Furthermore, we outline the roles of CSF biomarkers in drug discovery and clinical trials, and provide perspectives on AD biomarker discovery and the validation of such markers for use in the clinic.
Key Points
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Current clinical diagnostic criteria for Alzheimer disease (AD) require a patient to have dementia before a diagnosis can be made, and are largely based on the exclusion of other disorders
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Disease-modifying drugs for AD, when they become available, will need to be administered very early in the course of the disease, before neurodegeneration is too severe and widespread
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No clinical method is available for identifying prodromal AD in patients with mild cognitive impairment (MCI), as such individuals have only mild disturbances in episodic memory
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The cerebrospinal fluid (CSF) biomarkers total tau, phosphorylated tau (p-tau181 and p-tau231) and β-amyloid1–42 have a high diagnostic accuracy for AD, and for prodromal AD in patients with MCI
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CSF biomarkers are increasingly being used in the clinic for diagnosing AD, and will also be valuable in clinical trials, allowing enrichment of patient populations with pure AD cases
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Biomarker evidence that a candidate drug affects the central disease processes in AD will, together with a beneficial effect on cognition, be essential for labeling the drug as disease modifying
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References
Alzheimer, A., Stelzmann, R. A., Schnitzlein, H. N. & Murtagh, F. R. An English translation of Alzheimer's 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin. Anat. 8, 429–431 (1995).
Masters, C. L. et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl Acad. Sci. USA 82, 4245–4249 (1985).
Kang, J. et al. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733–736 (1987).
Grundke-Iqbal, I. et al. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc. Natl Acad. Sci. USA 83, 4913–4917 (1986).
Blennow, K., de Leon, M. J. & Zetterberg, H. Alzheimer's disease. Lancet 368, 387–403 (2006).
Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).
Garcia-Alloza, M. et al. Existing plaques and neuritic abnormalities in APP:PS1 mice are not affected by administration of the gamma-secretase inhibitor LY-411575. Mol. Neurodegener. 4, 19 (2009).
Das, P., Murphy, M. P., Younkin, L. H., Younkin, S. G. & Golde, T. E. Reduced effectiveness of Aβ1–42 immunization in APP transgenic mice with significant amyloid deposition. Neurobiol. Aging 22, 721–727 (2001).
Levites, Y. et al. Anti-Aβ42- and anti-Aβ40-specific mAbs attenuate amyloid deposition in an Alzheimer disease mouse model. J. Clin. Invest. 116, 193–201 (2006).
Siemers, E. R. How can we recognize “disease modification” effects? J. Nutr. Health Aging 13, 341–343 (2009).
Tibbling, G., Link, H. & Ohman, S. Principles of albumin and IgG analyses in neurological disorders. I. Establishment of reference values. Scand. J. Clin. Lab. Invest. 37, 385–390 (1977).
Blennow, K. et al. Blood–brain barrier disturbance in patients with Alzheimer's disease is related to vascular factors. Acta Neurol. Scand. 81, 323–326 (1990).
Andersson, M. et al. Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J. Neurol. Neurosurg. Psychiatry 57, 897–902 (1994).
[No authors listed] Consensus report of the Working Group on: “Molecular and Biochemical Markers of Alzheimer's Disease”. The Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group. Neurobiol. Aging 19, 109–116 (1998).
Strozyk, D., Blennow, K., White, L. R. & Launer, L. J. CSF Aβ 42 levels correlate with amyloid-neuropathology in a population-based autopsy study. Neurology 60, 652–656 (2003).
Tapiola, T. et al. Cerebrospinal fluid β-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch. Neurol. 66, 382–389 (2009).
Fagan, A. M. et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans. Ann. Neurol. 59, 512–519 (2006).
Forsberg, A. et al. PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol. Aging 29, 1456–1465 (2008).
Hesse, C. et al. Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke. Neurosci. Lett. 297, 187–190 (2001).
Ost, M. et al. Initial CSF total tau correlates with 1-year outcome in patients with traumatic brain injury. Neurology 67, 1600–1604 (2006).
Zetterberg, H. et al. Neurochemical aftermath of amateur boxing. Arch. Neurol. 63, 1277–1280 (2006).
Blom, E. S. et al. Rapid progression from mild cognitive impairment to Alzheimer's disease in subjects with elevated levels of tau in cerebrospinal fluid and the APOE ε4/ε4 genotype. Dement. Geriatr. Cogn. Disord. 27, 458–464 (2009).
Samgard, K. et al. Cerebrospinal fluid total tau as a marker of Alzheimer's disease intensity. Int. J. Geriatr. Psychiatry doi:10.1002/gps.2353.
Wallin, A. K., Hansson, O., Blennow, K., Londos, E. & Minthon, L. Can CSF biomarkers or pre-treatment progression rate predict response to cholinesterase inhibitor treatment in Alzheimer's disease? Int. J. Geriatr. Psychiatry 24, 638–647 (2009).
Otto, M. et al. Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt–Jakob disease. Neurosci. Lett. 225, 210–212 (1997).
Buerger, K. et al. CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease. Brain 129, 3035–3041 (2006).
Hampel, H. et al. Correlation of cerebrospinal fluid levels of tau protein phosphorylated at threonine 231 with rates of hippocampal atrophy in Alzheimer disease. Arch. Neurol. 62, 770–773 (2005).
Blennow, K. et al. Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? Mol. Chem. Neuropathol. 26, 231–245 (1995).
Sjögren, M. et al. Both total and phosphorylated tau are increased in Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 70, 624–630 (2001).
Riemenschneider, M. et al. Phospho-tau/total tau ratio in cerebrospinal fluid discriminates Creutzfeldt–Jakob disease from other dementias. Mol. Psychiatry 8, 343–347 (2003).
Hampel, H. et al. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch. Gen. Psychiatry 61, 95–102 (2004).
Kapaki, E. N. et al. Cerebrospinal fluid tau, phospho-tau181 and β-amyloid1–42 in idiopathic normal pressure hydrocephalus: a discrimination from Alzheimer's disease. Eur. J. Neurol. 14, 168–173 (2007).
Koopman, K. et al. Improved discrimination of autopsy-confirmed Alzheimer's disease (AD) from non-AD dementias using CSF P-tau181P . Neurochem. Int. 55, 214–218 (2009).
Seubert, P. et al. Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids. Nature 359, 325–327 (1992).
Jarrett, J. T., Berger, E. P. & Lansbury, P. T. Jr. The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry 32, 4693–4697 (1993).
Blennow, K. Cerebrospinal fluid protein biomarkers for Alzheimer's disease. NeuroRx 1, 213–225 (2004).
Kohnken, R. et al. Detection of tau phosphorylated at threonine 231 in cerebrospinal fluid of Alzheimer's disease patients. Neurosci. Lett. 287, 187–190 (2000).
Vanmechelen, E. et al. Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: a sandwich ELISA with a synthetic phosphopeptide for standardization. Neurosci. Lett. 285, 49–52 (2000).
Hansson, O. et al. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 5, 228–234 (2006).
Maddalena, A. et al. Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to β-amyloid peptide42 . Arch. Neurol. 60, 1202–1206 (2003).
Riemenschneider, M. et al. Cerebrospinal fluid tau and β-amyloid 42 proteins identify Alzheimer disease in subjects with mild cognitive impairment. Arch. Neurol. 59, 1729–1734 (2002).
Zetterberg, H., Wahlund, L. O. & Blennow, K. Cerebrospinal fluid markers for prediction of Alzheimer's disease. Neurosci. Lett. 352, 67–69 (2003).
Olsson, A. et al. Simultaneous measurement of β-amyloid(1–42), total tau, and phosphorylated tau (Thr181) in cerebrospinal fluid by the xMAP technology. Clin. Chem. 51, 336–345 (2005).
Mattsson, N. et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 302, 385–393 (2009).
Shaw, L. M. et al. Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann. Neurol. 65, 403–413 (2009).
Blennow, K. & Hampel, H. CSF markers for incipient Alzheimer's disease. Lancet Neurol. 2, 605–613 (2003).
Blennow, K. CSF biomarkers for Alzheimer's disease: use in early diagnosis and evaluation of drug treatment. Expert Rev. Mol. Diagn. 5, 661–672 (2005).
Engelborghs, S. et al. Diagnostic performance of a CSF-biomarker panel in autopsy-confirmed dementia. Neurobiol. Aging 29, 1143–1159 (2008).
Forman, M. S. et al. Frontotemporal dementia: clinicopathological correlations. Ann. Neurol. 59, 952–962 (2006).
Snowdon, D. A. Aging and Alzheimer's disease: lessons from the Nun Study. Gerontologist 37, 150–156 (1997).
Price, J. L. & Morris, J. C. Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease. Ann. Neurol. 45, 358–368 (1999).
Kotzbauer, P. T., Trojanowski, J. Q. & Lee, V. M. Lewy body pathology in Alzheimer's disease. J. Mol. Neurosci. 17, 225–232 (2001).
Jellinger, K. A. Diagnostic accuracy of Alzheimer's disease: a clinicopathological study. Acta Neuropathol. (Berl.) 91, 219–220 (1996).
Schneider, J. A., Arvanitakis, Z., Leurgans, S. E. & Bennett, D. A. The neuropathology of probable alzheimer's disease and mild cognitive impairment. Ann. Neurol. 66, 200–208 (2009).
Visser, P. J. et al. Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study. Lancet Neurol. 8, 619–627 (2009).
Skoog, I. et al. Cerebrospinal fluid β-amyloid 42 is reduced before the onset of sporadic dementia: a population-based study in 85-year-olds. Dement. Geriatr. Cogn. Disord. 15, 169–176 (2003).
Gustafson, D. R., Skoog, I., Rosengren, L., Zetterberg, H. & Blennow, K. Cerebrospinal fluid β-amyloid 1–42 concentration may predict cognitive decline in older women. J. Neurol. Neurosurg. Psychiatry 78, 461–464 (2007).
Stomrud, E., Hansson, O., Blennow, K., Minthon, L. & Londos, E. Cerebrospinal fluid biomarkers predict decline in subjective cognitive function over 3 years in healthy elderly. Dement. Geriatr. Cogn. Disord. 24, 118–124 (2007).
Moonis, M. et al. Familial Alzheimer disease: decreases in CSF Aβ42 levels precede cognitive decline. Neurology 65, 323–325 (2005).
Ringman, J. M. et al. Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology 71, 85–92 (2008).
Götz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Aβ42 fibrils. Science 293, 1491–1495 (2001).
Lewis, J. et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491 (2001).
Fagan, A. M. et al. Cerebrospinal fluid tau and ptau181 increase with cortical amyloid deposition in cognitively normal individuals: Implications for future clinical trials of Alzheimer's disease. EMBO Mol. Med. 1, 371–380 (2009).
Cairns, N. et al. Absence of Pittsburgh compound B detection of cerebral amyloid β in a patient with clinical, cognitive, and cerebrospinal fluid markers of Alzheimer disease: a case report. Arch. Neurol. 66, 1557–1562 (2009).
Clark, C. M. et al. Cerebrospinal fluid tau and β-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses? Arch. Neurol. 60, 1696–1702 (2003).
Bian, H. et al. CSF biomarkers in frontotemporal lobar degeneration with known pathology. Neurology 70, 1827–1835 (2008).
Sunderland, T. et al. Decreased β-amyloid1–42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA 289, 2094–2103 (2003).
Fukumoto, H., Cheung, B. S., Hyman, B. T. & Irizarry, M. C. β-Secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch. Neurol. 59, 1381–1389 (2002).
Yang, L. B. et al. Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat. Med. 9, 3–4 (2003).
Holsinger, R. M., McLean, C. A., Collins, S. J., Masters, C. L. & Evin, G. Increased β-secretase activity in cerebrospinal fluid of Alzheimer's disease subjects. Ann. Neurol. 55, 898–899 (2004).
Zetterberg, H. et al. Elevated cerebrospinal fluid BACE1 activity in incipient Alzheimer disease. Arch. Neurol. 65, 1102–1107 (2008).
Zhong, Z. et al. Levels of β-secretase (BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment. Arch. Gen. Psychiatry 64, 718–726 (2007).
Olsson, A. et al. Measurement of α- and β-secretase cleaved amyloid precursor protein in cerebrospinal fluid from Alzheimer patients. Exp. Neurol. 183, 74–80 (2003).
Lewczuk, P. et al. Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study. Mol. Psychiatry doi:10.1038/mp.2008.84.
Portelius, E., Westman-Brinkmalm, A., Zetterberg, H. & Blennow, K. Determination of β-amyloid peptide signatures in cerebrospinal fluid using immunoprecipitation–mass spectrometry. J. Proteome Res. 5, 1010–1016 (2006).
Mehta, P. D. et al. Plasma and cerebrospinal fluid levels of amyloid β proteins 1–40 and 1–42 in Alzheimer disease. Arch. Neurol. 57, 100–105 (2000).
Hansson, O. et al. Prediction of Alzheimer's disease using the CSF Aβ42/Aβ40 ratio in patients with mild cognitive impairment. Dement. Geriatr. Cogn. Disord. 23, 316–320 (2007).
Lewczuk, P. et al. The amyloid-β (Aβ) peptide pattern in cerebrospinal fluid in Alzheimer's disease: evidence of a novel carboxyterminally elongated Aβ peptide. Rapid Commun. Mass Spectrom. 17, 1291–1296 (2003).
Schoonenboom, N. S. et al. Amyloid β 38, 40, and 42 species in cerebrospinal fluid: more of the same? Ann. Neurol. 58, 139–142 (2005).
Portelius, E. et al. An Alzheimer's disease-specific β-amyloid fragment signature in cerebrospinal fluid. Neurosci. Lett. 409, 215–219 (2006).
Portelius, E. et al. A novel pathway for amyloid precursor protein processing. Neurobiol. Aging doi:10.1016/j.neurobiolaging.2009.06.002.
Walsh, D. M. & Selkoe, D. J. Aβ oligomers—a decade of discovery. J. Neurochem. 101, 1172–1184 (2007).
Georganopoulou, D. G. et al. Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer's disease. Proc. Natl Acad. Sci. USA 102, 2273–2276 (2005).
Santos, A. N. et al. Detection of amyloid-β oligomers in human cerebrospinal fluid by flow cytometry and fluorescence resonance energy transfer. J. Alzheimers Dis. 11, 117–125 (2007).
Klyubin, I. et al. Amyloid β protein dimer-containing human CSF disrupts synaptic plasticity: prevention by systemic passive immunization. J. Neurosci. 28, 4231–4237 (2008).
Mruthinti, S. et al. Autoimmunity in Alzheimer's disease: increased levels of circulating IgGs binding Aβ and RAGE peptides. Neurobiol. Aging 25, 1023–1032 (2004).
Nath, A. et al. Autoantibodies to amyloid β-peptide (Aβ) are increased in Alzheimer's disease patients and Aβ antibodies can enhance Aβ neurotoxicity: implications for disease pathogenesis and vaccine development. Neuromolecular Med. 3, 29–39 (2003).
Brettschneider, S. et al. Decreased serum amyloid β1–42 autoantibody levels in Alzheimer's disease, determined by a newly developed immuno-precipitation assay with radiolabeled amyloid β1–42 peptide. Biol. Psychiatry 57, 813–816 (2005).
Du, Y. et al. Reduced levels of amyloid β-peptide antibody in Alzheimer disease. Neurology 57, 801–805 (2001).
Hyman, B. T. et al. Autoantibodies to amyloid-β and Alzheimer's disease. Ann. Neurol. 49, 808–810 (2001).
Britschgi, M. et al. Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease. Proc. Natl Acad. Sci. USA 106, 12145–12150 (2009).
Laterza, O. F. et al. Identification of novel brain biomarkers. Clin. Chem. 52, 1713–1721 (2006).
Lee, J. M. et al. The brain injury biomarker VLP-1 is increased in the cerebrospinal fluid of Alzheimer disease patients. Clin. Chem. 54, 1617–1623 (2008).
Friede, R. L. & Samorajski, T. Axon caliber related to neurofilaments and microtubules in sciatic nerve fibers of rats and mice. Anat. Rec. 167, 379–387 (1970).
Sjögren, M. et al. Neurofilament protein in cerebrospinal fluid: a marker of white matter changes. J. Neurosci. Res. 66, 510–516 (2001).
Agren-Wilsson, A. et al. CSF biomarkers in the evaluation of idiopathic normal pressure hydrocephalus. Acta Neurol. Scand. 116, 333–339 (2007).
Sjögren, M. et al. Cytoskeleton proteins in CSF distinguish frontotemporal dementia from AD. Neurology 54, 1960–1964 (2000).
Davidsson, P., Puchades, M. & Blennow, K. Identification of synaptic vesicle, pre- and postsynaptic proteins in human cerebrospinal fluid using liquid-phase isoelectric focusing. Electrophoresis 20, 431–437 (1999).
Sjögren, M. et al. The cerebrospinal fluid levels of tau, growth-associated protein-43 and soluble amyloid precursor protein correlate in Alzheimer's disease, reflecting a common pathophysiological process. Dement. Geriatr. Cogn. Disord. 12, 257–264 (2001).
Montine, T. J., Quinn, J., Kaye, J. & Morrow, J. D. F2-isoprostanes as biomarkers of late-onset Alzheimer's disease. J. Mol. Neurosci. 33, 114–119 (2007).
Brys, M. et al. Prediction and longitudinal study of CSF biomarkers in mild cognitive impairment. Neurobiol. Aging 30, 682–690.
Knopman, D. S. et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56, 1143–1153 (2001).
Visser, P. J., Scheltens, P. & Verhey, F. R. Do MCI criteria in drug trials accurately identify subjects with predementia Alzheimer's disease? J. Neurol. Neurosurg. Psychiatry 76, 1348–1354 (2005).
Ganguli, M. et al. Detection and management of cognitive impairment in primary care: The Steel Valley Seniors Survey. J. Am. Geriatr. Soc. 52, 1668–1675 (2004).
Raschetti, R., Albanese, E., Vanacore, N. & Maggini, M. Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials. PLoS Med. 4, e338 (2007).
Cummings, J. L., Doody, R. & Clark, C. Disease-modifying therapies for Alzheimer disease: challenges to early intervention. Neurology 69, 1622–1634 (2007).
Salloway, S. et al. A phase 2 trial of bapineuzumab in mild to moderate Alzheimer's disease. Neurology doi:10.1212/WNL.0b013e3181c67808.
Orgogozo, J. M. et al. Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization. Neurology 61, 46–54 (2003).
Blennow, K. et al. Longitudinal stability of CSF biomarkers in Alzheimer's disease. Neurosci. Lett. 419, 18–22 (2007).
Zetterberg, H. et al. Intra-individual stability of CSF biomarkers for Alzheimer's disease over two years. J. Alzheimers Dis. 12, 255–260 (2007).
Vellas, B. Use of biomarkers in Alzheimer's trials. J. Nutr. Health Aging 13, 331 (2009).
Hampel, H. et al. Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J. Clin. Psychiatry 70, 922–931 (2009).
Anderson, J. J. et al. Reductions in β-amyloid concentrations in vivo by the γ-secretase inhibitors BMS-289948 and BMS-299897. Biochem. Pharmacol. 69, 689–698 (2005).
Lanz, T. A., Hosley, J. D., Adams, W. J. & Merchant, K. M. Studies of Aβ pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free) Tg2576 mice using the γ-secretase inhibitor N2-[(2S)-2-(3, 5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo -6, 7-dihydro-5H-dibenzo[b, d]azepin-7-yl]-L-alaninamide (LY-411575). J. Pharmacol. Exp. Ther. 309, 49–55 (2004).
Sankaranarayanan, S. et al. First demonstration of cerebrospinal fluid and plasma Aβ lowering with oral administration of a β-site amyloid precursor protein-cleaving enzyme 1 inhibitor in nonhuman primates. J. Pharmacol. Exp. Ther. 328, 131–140 (2009).
Lannfelt, L. et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 7, 779–786 (2008).
Kadir, A. et al. Effect of phenserine treatment on brain functional activity and amyloid in Alzheimer's disease. Ann. Neurol. 63, 621–631 (2008).
Gilman, S. et al. Clinical effects of Aβ immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64, 1553–1562 (2005).
Fleisher, A. S. et al. Phase 2 safety trial targeting amyloid β production with a γ-secretase inhibitor in Alzheimer disease. Arch. Neurol. 65, 1031–1038 (2008).
Bateman, R. J. et al. A γ-secretase inhibitor decreases amyloid-β production in the central nervous system. Ann. Neurol. 66, 48–54 (2009).
Irizarry, M. C. Biomarkers of Alzheimer disease in plasma. NeuroRx 1, 226–234 (2004).
Mayeux, R. et al. Plasma Aβ40 and Aβ42 and Alzheimer's disease: relation to age, mortality, and risk. Neurology 61, 1185–1190 (2003).
Pomara, N., Willoughby, L. M., Sidtis, J. J. & Mehta, P. D. Selective reductions in plasma Aβ 1–42 in healthy elderly subjects during longitudinal follow-up: a preliminary report. Am. J. Geriatr. Psychiatry 13, 914–917 (2005).
van Oijen, M., Hofman, A., Soares, H. D., Koudstaal, P. J. & Breteler, M. M. Plasma Aβ1–40 and Aβ1–42 and the risk of dementia: a prospective case-cohort study. Lancet Neurol. 5, 655–660 (2006).
Graff-Radford, N. R. et al. Association of low plasma Aβ42/Aβ40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch. Neurol. 64, 354–362 (2007).
Kuo, Y. M. et al. High levels of circulating Aβ42 are sequestered by plasma proteins in Alzheimer's disease. Biochem. Biophys. Res. Commun. 257, 787–791 (1999).
Ray, S. et al. Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat. Med. 13, 1359–1362 (2007).
Hye, A. et al. Proteome-based plasma biomarkers for Alzheimer's disease. Brain 129, 3042–3050 (2006).
Buerger, K. et al. Blood-based microcirculation markers in Alzheimer's disease-diagnostic value of midregional pro-atrial natriuretic peptide/C-terminal endothelin-1 precursor fragment ratio. Biol. Psychiatry 65, 979–984 (2009).
Brys, M. et al. Magnetic resonance imaging improves cerebrospinal fluid biomarkers in the early detection of Alzheimer's disease. J. Alzheimers Dis. 16, 351–362 (2009).
Zhang, Y. et al. Usefulness of computed tomography linear measurements in diagnosing Alzheimer's disease. Acta Radiol. 49, 91–97 (2008).
Schoonenboom, N. S. et al. CSF and MRI markers independently contribute to the diagnosis of Alzheimer's disease. Neurobiol. Aging 29, 669–675 (2008).
Vemuri, P. et al. MRI and CSF biomarkers in normal, MCI, and AD subjects: diagnostic discrimination and cognitive correlations. Neurology 73, 287–293 (2009).
Okamura, N. et al. Combined analysis of CSF tau levels and [123I]iodoamphetamine SPECT in mild cognitive impairment: implications for a novel predictor of Alzheimer's disease. Am. J. Psychiatry 159, 474–476 (2002).
Hansson, O. et al. Combined rCBF and CSF biomarkers predict progression from mild cognitive impairment to Alzheimer's disease. Neurobiol. Aging 30, 165–173 (2007).
Nyberg, S. et al. Detection of amyloid in Alzheimer's disease with positron emission tomography using [11C]AZD2184. Eur. J. Nucl. Med. Mol. Imaging 36, 1859–1863 (2009).
McKhann, G. et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS–ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34, 939–944 (1984).
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR (American Psychiatric Association, Washington DC, 2000).
WHO. ICD-10: International Statistical Classification of Diseases and Related Health Problems 10th Revision (WHO, Geneva, 1992).
Dubois, B. et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS–ADRDA criteria. Lancet Neurol. 6, 734–746 (2007).
Frisoni, G. B. et al. Markers of Alzheimer's disease in a population attending a memory clinic. Alzheimers Dement. 5, 307–317 (2009).
Vanderstichele, H. et al. Standardization of measurement of β-amyloid1–42 in cerebrospinal fluid and plasma. Amyloid 7, 245–258 (2000).
Vanderstichele, H. et al. Analytical performance and clinical utility of the INNOTEST PHOSPHO-TAU181P assay for discrimination between Alzheimer's disease and dementia with Lewy bodies. Clin. Chem. Lab. Med. 44, 1472–1480 (2006).
Verwey, N. A. et al. A worldwide multicentre comparison of assays for cerebrospinal fluid biomarkers in Alzheimer's disease. Ann. Clin. Biochem. 46, 235–240 (2009).
Beher, D., Wrigley, J. D., Owens, A. P. & Shearman, M. S. Generation of C-terminally truncated amyloid-β peptides is dependent on γ-secretase activity. J. Neurochem. 82, 563–575 (2002).
Vassar, R. et al. β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741 (1999).
Selkoe, D. J. & Wolfe, M. S. Presenilin: running with scissors in the membrane. Cell 131, 215–221 (2007).
Lammich, S. et al. Constitutive and regulated α-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl Acad. Sci. USA 96, 3922–3927 (1999).
Haass, C. et al. Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature 359, 322–325 (1992).
Bibl, M. et al. Cerebrospinal fluid amyloid β peptide patterns in Alzheimer's disease patients and nondemented controls depend on sample pretreatment: indication of carrier-mediated epitope masking of amyloid beta peptides. Electrophoresis 25, 2912–2918 (2004).
Trojanowski, J. Q., Schuck, T., Schmidt, M. L. & Lee, V. M. Distribution of tau proteins in the normal human central and peripheral nervous system. J. Histochem. Cytochem. 37, 209–215 (1989).
Goedert, M. Tau protein and the neurofibrillary pathology of Alzheimer's disease. Trends Neurosci. 16, 460–465 (1993).
Iqbal, K. et al. Tau pathology in Alzheimer disease and other tauopathies. Biochim. Biophys. Acta 1739, 198–210 (2005).
McLean, C. A. et al. Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann. Neurol. 46, 860–866 (1999).
Blennow, K., Rybo, E., Wallin, A., Gottfries, C. G. & Svennerholm, L. Cerebrospinal fluid cytology in Alzheimer's disease. Dementia 2, 25–29 (1991).
Blennow, K. et al. Intrathecal synthesis of immunoglobulins in patients with Alzheimer's disease. Eur. Neuropsychopharmacol. 1, 79–81 (1990).
Mollenhauer, B. et al. Tau protein, Aβ42 and S-100B protein in cerebrospinal fluid of patients with dementia with Lewy bodies. Dement. Geriatr. Cogn. Disord. 19, 164–170 (2005).
Grimes, D. A. & Schulz, K. F. Uses and abuses of screening tests. Lancet 359, 881–884 (2002).
Birks, J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database of Systematic Reviews, Issue 1 Art. No.:CD005593. doi:10.1002/14651858.CD005593 (2006).
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K. Blennow and M. Weiner have received research support from Innogenetics. H. Hampel has acted as a consultant for and received research support from BRAHMS AG. He also holds a patent with this company. H. Zetterberg declares no competing interests.
Supplementary information
Supplementary Figure 1
Lumbar puncture with the patient in the sitting position (DOC 1791 kb)
Supplementary Figure 2
CSF biomarkers for Alzheimer disease (DOC 607 kb)
Supplementary Figure 3
Intrathecal immunoglobulin production (DOC 1567 kb)
Supplementary Table 1
Flow chart for LP and CSF biomarker analyses (DOC 44 kb)
Supplementary Table 2
Criteria for an ideal biomarker for AD (DOC 53 kb)
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Blennow, K., Hampel, H., Weiner, M. et al. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6, 131–144 (2010). https://doi.org/10.1038/nrneurol.2010.4
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DOI: https://doi.org/10.1038/nrneurol.2010.4
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