Current Biomarkers for Alzheimer’s Disease: From CSF to Blood
Abstract
:1. Introduction
2. CSF Markers of AD
2.1. AD Pathogenesis Molecule-Based Biomarkers in CSF
2.1.1. CSF Aβ Markers
2.1.2. CSF t-tau and p-tau Markers
2.1.3. CSF β-Site APP-Cleaving Enzyme 1 (BACE1) Marker
2.2. Neurodegeneration-Based Biomarkers in CSF
3. Blood Markers of AD
3.1. AD Pathogenesis Molecule-Based Biomarkers in Blood
3.1.1. Blood Aβ Markers
3.1.2. Blood p-tau Markers
3.2. Other Biomarkers in Blood
4. Advantages of Blood Biomarkers over CSF Biomarkers
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Scheltens, P.; Blennow, K.; Breteler, M.M.; de Strooper, B.; Frisoni, G.B.; Salloway, S.; Van der Flier, W.M. Alzheimer’s disease. Lancet 2016, 388, 505–517. [Google Scholar] [CrossRef]
- Dubois, B.; Feldman, H.H.; Jacova, C.; Hampel, H.; Molinuevo, J.L.; Blennow, K.; DeKosky, S.T.; Gauthier, S.; Selkoe, D.; Bateman, R.; et al. Advancing research diagnostic criteria for Alzheimer’s disease: The IWG-2 criteria. Lancet Neurol. 2014, 13, 614–629. [Google Scholar] [CrossRef]
- Frisoni, G.B.; Jack, C.R.J.; Bocchetta, M.; Bauer, C.; Frederiksen, K.S.; Liu, Y.; Preboske, G.; Swihart, T.; Blair, M.; Cavedo, E.; et al. The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: Evidence of validity. Alzheimers Dement. 2015, 11, 111–125. [Google Scholar] [CrossRef] [Green Version]
- Frisoni, G.B.; Fox, N.C.; Jack, C.R.J.; Scheltens, P.; Thompson, P.M. The clinical use of structural MRI in Alzheimer disease. Nat. Rev. Neurol. 2010, 6, 67–77. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Herholz, K.; Ebmeier, K. Clinical amyloid imaging in Alzheimer’s disease. Lancet Neurol. 2011, 10, 667–670. [Google Scholar] [CrossRef]
- Selkoe, D.J.; Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 2016, 8, 595–608. [Google Scholar] [CrossRef]
- Dewachter, I.; Van Leuven, F. Secretases as targets for the treatment of Alzheimer’s disease: The prospects. Lancet Neurol. 2002, 1, 409–416. [Google Scholar] [CrossRef]
- Saito, T.; Suemoto, T.; Brouwers, N.; Sleegers, K.; Funamoto, S.; Mihira, N.; Matsuba, Y.; Yamada, K.; Nilsson, P.; Takano, J.; et al. Potent amyloidogenicity and pathogenicity of Abeta43. Nat. Neurosci. 2011, 14, 1023–1032. [Google Scholar] [CrossRef] [Green Version]
- Zou, K.; Liu, J.; Watanabe, A.; Hiraga, S.; Liu, S.; Tanabe, C.; Maeda, T.; Terayama, Y.; Takahashi, S.; Michikawa, M.; et al. Abeta43 is the earliest-depositing Abeta species in APP transgenic mouse brain and is converted to Abeta41 by two active domains of ACE. Am. J. Pathol. 2013, 182, 2322–2331. [Google Scholar] [CrossRef]
- Zou, K.; Gong, J.S.; Yanagisawa, K.; Michikawa, M. A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. J. Neurosci. Off. J. Soc. Neurosci. 2002, 22, 4833–4841. [Google Scholar] [CrossRef] [Green Version]
- Zou, K.; Kim, D.; Kakio, A.; Byun, K.; Gong, J.S.; Kim, J.; Kim, M.; Sawamura, N.; Nishimoto, S.; Matsuzaki, K.; et al. Amyloid beta-protein (Abeta)1-40 protects neurons from damage induced by Abeta1-42 in culture and in rat brain. J. Neurochem. 2003, 87, 609–619. [Google Scholar] [CrossRef] [PubMed]
- Kim, J.; Onstead, L.; Randle, S.; Price, R.; Smithson, L.; Zwizinski, C.; Dickson, D.W.; Golde, T.; McGowan, E. Abeta40 inhibits amyloid deposition In Vivo. J. Neurosci. Off. J. Soc. Neurosci. 2007, 27, 627–633. [Google Scholar]
- Blennow, K.; Zetterberg, H.; Fagan, A.M. Fluid biomarkers in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2012, 2, a006221. [Google Scholar] [CrossRef] [Green Version]
- Karch, C.M.; Goate, A.M. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol. Psychiatry 2015, 77, 43–51. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Walsh, D.M.; Selkoe, D.J. Amyloid beta-protein and beyond: The path forward in Alzheimer’s disease. Curr. Opin. Neurobiol. 2020, 61, 116–124. [Google Scholar] [CrossRef] [PubMed]
- Honig, L.S.; Vellas, B.; Woodward, M.; Boada, M.; Bullock, R.; Borrie, M.; Hager, K.; Andreasen, N.; Scarpini, E.; Liu-Seifert, H.; et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease. N. Engl. J. Med. 2018, 378, 321–330. [Google Scholar] [CrossRef]
- Egan, M.F.; Kost, J.; Tariot, P.N.; Aisen, P.S.; Cummings, J.L.; Vellas, B.; Sur, C.; Mukai, Y.; Voss, T.; Furtek, C.; et al. Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease. N. Engl. J. Med. 2018, 378, 1691–1703. [Google Scholar] [CrossRef]
- Doody, R.S.; Raman, R.; Farlow, M.; Iwatsubo, T.; Vellas, B.; Joffe, S.; Kieburtz, K.; He, F.; Sun, X.; Thomas, R.G.; et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N. Engl. J. Med. 2013, 369, 341–350. [Google Scholar] [CrossRef]
- Zhao, Z.; Nelson, A.R.; Betsholtz, C.; Zlokovic, B.V. Establishment and Dysfunction of the Blood-Brain Barrier. Cell 2015, 163, 1064–1078. [Google Scholar] [CrossRef] [Green Version]
- Shoji, M.; Matsubara, E.; Kanai, M.; Watanabe, M.; Nakamura, T.; Tomidokoro, Y.; Shizuka, M.; Wakabayashi, K.; Igeta, Y.; Ikeda, Y.; et al. Combination assay of CSF tau, A beta 1-40 and A beta 1-42(43) as a biochemical marker of Alzheimer’s disease. J. Neurol. Sci. 1998, 158, 134–140. [Google Scholar] [CrossRef]
- Blennow, K.; Hampel, H.; Weiner, M.; Zetterberg, H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat. Rev. Neurol. 2010, 6, 131–144. [Google Scholar] [CrossRef] [PubMed]
- Blennow, K.; Hampel, H. CSF markers for incipient Alzheimer’s disease. Lancet Neurol. 2003, 2, 605–613. [Google Scholar] [CrossRef]
- Skoog, I.; Davidsson, P.; Aevarsson, O.; Vanderstichele, H.; Vanmechelen, E.; Blennow, K. Cerebrospinal fluid beta-amyloid 42 is reduced before the onset of sporadic dementia: A population-based study in 85-year-olds. Dement. Geriatr. Cogn. Disord. 2003, 15, 169–176. [Google Scholar] [CrossRef] [PubMed]
- Gustafson, D.R.; Skoog, I.; Rosengren, L.; Zetterberg, H.; Blennow, K. Cerebrospinal fluid beta-amyloid 1-42 concentration may predict cognitive decline in older women. J. Neurol. Neurosurg. Psychiatry 2007, 78, 461–464. [Google Scholar] [CrossRef] [Green Version]
- 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. 2007, 24, 118–124. [Google Scholar] [CrossRef]
- Nutu, M.; Zetterberg, H.; Londos, E.; Minthon, L.; Nagga, K.; Blennow, K.; Hansson, O.; Ohrfelt, A. Evaluation of the cerebrospinal fluid amyloid-beta1-42/amyloid-beta1-40 ratio measured by alpha-LISA to distinguish Alzheimer’s disease from other dementia disorders. Dement. Geriatr. Cogn. Disord. 2013, 36, 99–110. [Google Scholar] [CrossRef]
- Janelidze, S.; Zetterberg, H.; Mattsson, N.; Palmqvist, S.; Vanderstichele, H.; Lindberg, O.; van Westen, D.; Stomrud, E.; Minthon, L.; Blennow, K.; et al. CSF Abeta42/Abeta40 and Abeta42/Abeta38 ratios: Better diagnostic markers of Alzheimer disease. Ann. Clin. Transl. Neurol. 2016, 3, 154–165. [Google Scholar] [CrossRef] [Green Version]
- Baldeiras, I.; Santana, I.; Leitao, M.J.; Gens, H.; Pascoal, R.; Tabuas-Pereira, M.; Beato-Coelho, J.; Duro, D.; Almeida, M.R.; Oliveira, C.R. Addition of the Abeta42/40 ratio to the cerebrospinal fluid biomarker profile increases the predictive value for underlying Alzheimer’s disease dementia in mild cognitive impairment. Alzheimers Res. Ther. 2018, 10, 33. [Google Scholar] [CrossRef] [Green Version]
- Bateman, R.J.; Xiong, C.; Benzinger, T.L.; Fagan, A.M.; Goate, A.; Fox, N.C.; Marcus, D.S.; Cairns, N.J.; Xie, X.; Blazey, T.M.; et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 2012, 367, 795–804. [Google Scholar] [CrossRef] [Green Version]
- Walsh, D.M.; Selkoe, D.J. A beta oligomers—A decade of discovery. J. Neurochem. 2007, 101, 1172–1184. [Google Scholar] [CrossRef]
- Fukumoto, H.; Tokuda, T.; Kasai, T.; Ishigami, N.; Hidaka, H.; Kondo, M.; Allsop, D.; Nakagawa, M. High-molecular-weight beta-amyloid oligomers are elevated in cerebrospinal fluid of Alzheimer patients. FASEB J. 2010, 24, 2716–2726. [Google Scholar] [CrossRef] [PubMed]
- Khan, S.S.; Bloom, G.S. Tau: The Center of a Signaling Nexus in Alzheimer’s Disease. Front. Neurosci. 2016, 10, 31. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, V.M.; Brunden, K.R.; Hutton, M.; Trojanowski, J.Q. Developing therapeutic approaches to tau, selected kinases, and related neuronal protein targets. Cold Spring Harb. Perspect. Med. 2011, 1, a006437. [Google Scholar] [CrossRef] [PubMed]
- Lee, V.M.; Balin, B.J.; Otvos, L.J.; Trojanowski, J.Q. A68: A major subunit of paired helical filaments and derivatized forms of normal Tau. Science 1991, 251, 675–678. [Google Scholar] [CrossRef] [PubMed]
- Skillback, T.; Rosen, C.; Asztely, F.; Mattsson, N.; Blennow, K.; Zetterberg, H. Diagnostic performance of cerebrospinal fluid total tau and phosphorylated tau in Creutzfeldt-Jakob disease: Results from the Swedish Mortality Registry. JAMA Neurol. 2014, 71, 476–483. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Van Harten, A.C.; Kester, M.I.; Visser, P.J.; Blankenstein, M.A.; Pijnenburg, Y.A.; van der Flier, W.M.; Scheltens, P. Tau and p-tau as CSF biomarkers in dementia: A meta-analysis. Clin. Chem. Lab. Med. 2011, 49, 353–366. [Google Scholar] [CrossRef] [PubMed]
- Molinuevo, J.L.; Ayton, S.; Batrla, R.; Bednar, M.M.; Bittner, T.; Cummings, J.; Fagan, A.M.; Hampel, H.; Mielke, M.M.; Mikulskis, A.; et al. Current state of Alzheimer’s fluid biomarkers. Acta Neuropathol. 2018, 136, 821–853. [Google Scholar] [CrossRef] [Green Version]
- Blennow, K.; Wallin, A.; Agren, H.; Spenger, C.; Siegfried, J.; Vanmechelen, E. Tau protein in cerebrospinal fluid: A biochemical marker for axonal degeneration in Alzheimer disease? Mol. Chem. Neuropathol. 1995, 26, 231–245. [Google Scholar] [CrossRef]
- Vanmechelen, E.; Vanderstichele, H.; Davidsson, P.; Van Kerschaver, E.; Van Der Perre, B.; Sjogren, M.; Andreasen, N.; Blennow, K. Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: A sandwich ELISA with a synthetic phosphopeptide for standardization. Neurosci. Lett. 2000, 285, 49–52. [Google Scholar] [CrossRef]
- Kohnken, R.; Buerger, K.; Zinkowski, R.; Miller, C.; Kerkman, D.; DeBernardis, J.; Shen, J.; Moller, H.J.; Davies, P.; Hampel, H. Detection of tau phosphorylated at threonine 231 in cerebrospinal fluid of Alzheimer’s disease patients. Neurosci. Lett. 2000, 287, 187–190. [Google Scholar] [CrossRef]
- Olsson, B.; Lautner, R.; Andreasson, U.; Ohrfelt, A.; Portelius, E.; Bjerke, M.; Holtta, M.; Rosen, C.; Olsson, C.; Strobel, G.; et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: A systematic review and meta-analysis. Lancet Neurol. 2016, 15, 673–684. [Google Scholar] [CrossRef]
- Hampel, H.; Vassar, R.; De Strooper, B.; Hardy, J.; Willem, M.; Singh, N.; Zhou, J.; Yan, R.; Vanmechelen, E.; De Vos, A.; et al. The beta-Secretase BACE1 in Alzheimer’s Disease. Biol. Psychiatry 2020. [Google Scholar] [CrossRef] [PubMed]
- Holsinger, R.M.; McLean, C.A.; Collins, S.J.; Masters, C.L.; Evin, G. Increased beta-Secretase activity in cerebrospinal fluid of Alzheimer’s disease subjects. Ann. Neurol. 2004, 55, 898–899. [Google Scholar] [CrossRef]
- Zhong, Z.; Ewers, M.; Teipel, S.; Burger, K.; Wallin, A.; Blennow, K.; He, P.; McAllister, C.; Hampel, H.; Shen, Y. Levels of beta-secretase (BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment. Arch. Gen. Psychiatry 2007, 64, 718–726. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ewers, M.; Zhong, Z.; Burger, K.; Wallin, A.; Blennow, K.; Teipel, S.J.; Shen, Y.; Hampel, H. Increased CSF-BACE 1 activity is associated with ApoE-epsilon 4 genotype in subjects with mild cognitive impairment and Alzheimer’s disease. Brain 2008, 131, 1252–1258. [Google Scholar] [CrossRef] [Green Version]
- Ewers, M.; Cheng, X.; Zhong, Z.; Nural, H.F.; Walsh, C.; Meindl, T.; Teipel, S.J.; Buerger, K.; He, P.; Shen, Y.; et al. Increased CSF-BACE1 activity associated with decreased hippocampus volume in Alzheimer’s disease. J. Alzheimers Dis. 2011, 25, 373–381. [Google Scholar] [CrossRef]
- Park, S.A.; Han, S.M.; Kim, C.E. New fluid biomarkers tracking non-amyloid-beta and non-tau pathology in Alzheimer’s disease. Exp. Mol. Med. 2020, 52, 556–568. [Google Scholar] [CrossRef] [Green Version]
- Yuan, A.; Rao, M.V.; Nixon, R.A. Neurofilaments at a glance. J. Cell Sci. 2012, 125, 3257–3263. [Google Scholar] [CrossRef]
- Zetterberg, H.; Skillback, T.; Mattsson, N.; Trojanowski, J.Q.; Portelius, E.; Shaw, L.M.; Weiner, M.W.; Blennow, K. Alzheimer’s Disease Neuroimaging, I. Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression. JAMA Neurol. 2016, 73, 60–67. [Google Scholar] [CrossRef]
- Sjogren, M.; Rosengren, L.; Minthon, L.; Davidsson, P.; Blennow, K.; Wallin, A. Cytoskeleton proteins in CSF distinguish frontotemporal dementia from AD. Neurology 2000, 54, 1960–1964. [Google Scholar] [CrossRef]
- Sjogren, M.; Blomberg, M.; Jonsson, M.; Wahlund, L.O.; Edman, A.; Lind, K.; Rosengren, L.; Blennow, K.; Wallin, A. Neurofilament protein in cerebrospinal fluid: A marker of white matter changes. J. Neurosci. Res. 2001, 66, 510–516. [Google Scholar] [CrossRef]
- Agren-Wilsson, A.; Lekman, A.; Sjoberg, W.; Rosengren, L.; Blennow, K.; Bergenheim, A.T.; Malm, J. CSF biomarkers in the evaluation of idiopathic normal pressure hydrocephalus. Acta Neurol. Scand. 2007, 116, 333–339. [Google Scholar] [CrossRef] [PubMed]
- Lycke, J.N.; Karlsson, J.E.; Andersen, O.; Rosengren, L.E. Neurofilament protein in cerebrospinal fluid: A potential marker of activity in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 1998, 64, 402–404. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Forgrave, L.M.; Ma, M.; Best, J.R.; DeMarco, M.L. The diagnostic performance of neurofilament light chain in CSF and blood for Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis: A systematic review and meta-analysis. Alzheimers Dement. 2019, 11, 730–743. [Google Scholar] [CrossRef] [PubMed]
- Laterza, O.F.; Modur, V.R.; Crimmins, D.L.; Olander, J.V.; Landt, Y.; Lee, J.M.; Ladenson, J.H. Identification of novel brain biomarkers. Clin. Chem. 2006, 52, 1713–1721. [Google Scholar] [CrossRef]
- Lee, J.M.; Blennow, K.; Andreasen, N.; Laterza, O.; Modur, V.; Olander, J.; Gao, F.; Ohlendorf, M.; Ladenson, J.H. The brain injury biomarker VLP-1 is increased in the cerebrospinal fluid of Alzheimer disease patients. Clin. Chem. 2008, 54, 1617–1623. [Google Scholar] [CrossRef] [Green Version]
- Tarawneh, R.; D’Angelo, G.; Macy, E.; Xiong, C.; Carter, D.; Cairns, N.J.; Fagan, A.M.; Head, D.; Mintun, M.A.; Ladenson, J.H.; et al. Visinin-like protein-1: Diagnostic and prognostic biomarker in Alzheimer disease. Ann. Neurol. 2011, 70, 274–285. [Google Scholar] [CrossRef] [Green Version]
- Tarawneh, R.; Head, D.; Allison, S.; Buckles, V.; Fagan, A.M.; Ladenson, J.H.; Morris, J.C.; Holtzman, D.M. Cerebrospinal Fluid Markers of Neurodegeneration and Rates of Brain Atrophy in Early Alzheimer Disease. JAMA Neurol. 2015, 72, 656–665. [Google Scholar] [CrossRef] [Green Version]
- Mroczko, B.; Groblewska, M.; Zboch, M.; Muszynski, P.; Zajkowska, A.; Borawska, R.; Szmitkowski, M.; Kornhuber, J.; Lewczuk, P. Evaluation of visinin-like protein 1 concentrations in the cerebrospinal fluid of patients with mild cognitive impairment as a dynamic biomarker of Alzheimer’s disease. J. Alzheimers Dis. 2015, 43, 1031–1037. [Google Scholar] [CrossRef]
- Luo, X.; Hou, L.; Shi, H.; Zhong, X.; Zhang, Y.; Zheng, D.; Tan, Y.; Hu, G.; Mu, N.; Chan, J.; et al. CSF levels of the neuronal injury biomarker visinin-like protein-1 in Alzheimer’s disease and dementia with Lewy bodies. J. Neurochem. 2013, 127, 681–690. [Google Scholar] [CrossRef]
- Sutphen, C.L.; McCue, L.; Herries, E.M.; Xiong, C.; Ladenson, J.H.; Holtzman, D.M.; Fagan, A.M.; Adni, O.B.O. Longitudinal decreases in multiple cerebrospinal fluid biomarkers of neuronal injury in symptomatic late onset Alzheimer’s disease. Alzheimers Dement. 2018, 14, 869–879. [Google Scholar] [CrossRef] [PubMed]
- Mavroudis, I.A.; Petridis, F.; Chatzikonstantinou, S.; Karantali, E.; Kazis, D. A meta-analysis on the levels of VILIP-1 in the CSF of Alzheimer’s disease compared to normal controls and other neurodegenerative conditions. Aging Clin. Exp. Res. 2020, 1–8. [Google Scholar] [CrossRef] [PubMed]
- Thorsell, A.; Bjerke, M.; Gobom, J.; Brunhage, E.; Vanmechelen, E.; Andreasen, N.; Hansson, O.; Minthon, L.; Zetterberg, H.; Blennow, K. Neurogranin in cerebrospinal fluid as a marker of synaptic degeneration in Alzheimer’s disease. Brain Res. 2010, 1362, 13–22. [Google Scholar] [CrossRef] [PubMed]
- De Vos, A.; Jacobs, D.; Struyfs, H.; Fransen, E.; Andersson, K.; Portelius, E.; Andreasson, U.; De Surgeloose, D.; Hernalsteen, D.; Sleegers, K.; et al. C-terminal neurogranin is increased in cerebrospinal fluid but unchanged in plasma in Alzheimer’s disease. Alzheimers Dement. 2015, 11, 1461–1469. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kvartsberg, H.; Portelius, E.; Andreasson, U.; Brinkmalm, G.; Hellwig, K.; Lelental, N.; Kornhuber, J.; Hansson, O.; Minthon, L.; Spitzer, P.; et al. Characterization of the postsynaptic protein neurogranin in paired cerebrospinal fluid and plasma samples from Alzheimer’s disease patients and healthy controls. Alzheimers Res. Ther. 2015, 7, 40. [Google Scholar] [CrossRef] [Green Version]
- Lista, S.; Toschi, N.; Baldacci, F.; Zetterberg, H.; Blennow, K.; Kilimann, I.; Teipel, S.J.; Cavedo, E.; Dos Santos, A.M.; Epelbaum, S.; et al. Cerebrospinal Fluid Neurogranin as a Biomarker of Neurodegenerative Diseases: A Cross-Sectional Study. J. Alzheimers Dis. 2017, 59, 1327–1334. [Google Scholar] [CrossRef] [Green Version]
- Kester, M.I.; Teunissen, C.E.; Crimmins, D.L.; Herries, E.M.; Ladenson, J.H.; Scheltens, P.; van der Flier, W.M.; Morris, J.C.; Holtzman, D.M.; Fagan, A.M. Neurogranin as a Cerebrospinal Fluid Biomarker for Synaptic Loss in Symptomatic Alzheimer Disease. JAMA Neurol. 2015, 72, 1275–1280. [Google Scholar] [CrossRef] [Green Version]
- Tarawneh, R.; D’Angelo, G.; Crimmins, D.; Herries, E.; Griest, T.; Fagan, A.M.; Zipfel, G.J.; Ladenson, J.H.; Morris, J.C.; Holtzman, D.M. Diagnostic and Prognostic Utility of the Synaptic Marker Neurogranin in Alzheimer Disease. JAMA Neurol. 2016, 73, 561–571. [Google Scholar] [CrossRef]
- Brinkmalm, A.; Brinkmalm, G.; Honer, W.G.; Frolich, L.; Hausner, L.; Minthon, L.; Hansson, O.; Wallin, A.; Zetterberg, H.; Blennow, K.; et al. SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer’s disease. Mol. Neurodegener. 2014, 9, 53. [Google Scholar] [CrossRef] [Green Version]
- Tible, M.; Sandelius, A.; Hoglund, K.; Brinkmalm, A.; Cognat, E.; Dumurgier, J.; Zetterberg, H.; Hugon, J.; Paquet, C.; Blennow, K. Dissection of synaptic pathways through the CSF biomarkers for predicting Alzheimer’s disease. Neurology 2020. [Google Scholar] [CrossRef]
- Ohrfelt, A.; Brinkmalm, A.; Dumurgier, J.; Brinkmalm, G.; Hansson, O.; Zetterberg, H.; Bouaziz-Amar, E.; Hugon, J.; Paquet, C.; Blennow, K. The pre-synaptic vesicle protein synaptotagmin is a novel biomarker for Alzheimer’s disease. Alzheimers Res. Ther. 2016, 8, 41. [Google Scholar] [CrossRef] [Green Version]
- Mayeux, R.; Honig, L.S.; Tang, M.X.; Manly, J.; Stern, Y.; Schupf, N.; Mehta, P.D. Plasma A[beta]40 and A[beta]42 and Alzheimer’s disease: Relation to age, mortality, and risk. Neurology 2003, 61, 1185–1190. [Google Scholar] [CrossRef] [PubMed]
- Van Oijen, M.; Hofman, A.; Soares, H.D.; Koudstaal, P.J.; Breteler, M.M. Plasma Abeta(1-40) and Abeta(1-42) and the risk of dementia: A prospective case-cohort study. Lancet Neurol. 2006, 5, 655–660. [Google Scholar] [CrossRef]
- Yaffe, K.; Weston, A.; Graff-Radford, N.R.; Satterfield, S.; Simonsick, E.M.; Younkin, S.G.; Younkin, L.H.; Kuller, L.; Ayonayon, H.N.; Ding, J.; et al. Association of plasma beta-amyloid level and cognitive reserve with subsequent cognitive decline. JAMA 2011, 305, 261–266. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nakamura, A.; Kaneko, N.; Villemagne, V.L.; Kato, T.; Doecke, J.; Dore, V.; Fowler, C.; Li, Q.X.; Martins, R.; Rowe, C.; et al. High performance plasma amyloid-beta biomarkers for Alzheimer’s disease. Nature 2018, 554, 249–254. [Google Scholar] [CrossRef] [PubMed]
- Perez-Grijalba, V.; Arbizu, J.; Romero, J.; Prieto, E.; Pesini, P.; Sarasa, L.; Guillen, F.; Monleon, I.; San-Jose, I.; Martinez-Lage, P.; et al. Plasma Abeta42/40 ratio alone or combined with FDG-PET can accurately predict amyloid-PET positivity: A cross-sectional analysis from the AB255 Study. Alzheimers Res. Ther. 2019, 11, 96. [Google Scholar] [CrossRef] [PubMed]
- Perez-Grijalba, V.; Romero, J.; Pesini, P.; Sarasa, L.; Monleon, I.; San-Jose, I.; Arbizu, J.; Martinez-Lage, P.; Munuera, J.; Ruiz, A.; et al. Plasma Abeta42/40 Ratio Detects Early Stages of Alzheimer’s Disease and Correlates with CSF and Neuroimaging Biomarkers in the AB255 Study. J. Prev. Alzheimers Dis. 2019, 6, 34–41. [Google Scholar]
- Kim, K.; Kim, M.J.; Kim, D.W.; Kim, S.Y.; Park, S.; Park, C.B. Clinically accurate diagnosis of Alzheimer’s disease via multiplexed sensing of core biomarkers in human plasma. Nat. Commun. 2020, 11, 119. [Google Scholar] [CrossRef]
- Nabers, A.; Perna, L.; Lange, J.; Mons, U.; Schartner, J.; Guldenhaupt, J.; Saum, K.U.; Janelidze, S.; Holleczek, B.; Rujescu, D.; et al. Amyloid blood biomarker detects Alzheimer’s disease. EMBO Mol. Med. 2018, 10, e8763. [Google Scholar] [CrossRef]
- Zetterberg, H.; Wilson, D.; Andreasson, U.; Minthon, L.; Blennow, K.; Randall, J.; Hansson, O. Plasma tau levels in Alzheimer’s disease. Alzheimers Res. Ther. 2013, 5, 9. [Google Scholar] [CrossRef]
- Mattsson, N.; Zetterberg, H.; Janelidze, S.; Insel, P.S.; Andreasson, U.; Stomrud, E.; Palmqvist, S.; Baker, D.; Tan Hehir, C.A.; Jeromin, A.; et al. Plasma tau in Alzheimer disease. Neurology 2016, 87, 1827–1835. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tatebe, H.; Kasai, T.; Ohmichi, T.; Kishi, Y.; Kakeya, T.; Waragai, M.; Kondo, M.; Allsop, D.; Tokuda, T. Quantification of plasma phosphorylated tau to use as a biomarker for brain Alzheimer pathology: Pilot case-control studies including patients with Alzheimer’s disease and down syndrome. Mol. Neurodegener. 2017, 12, 63. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Karikari, T.K.; Pascoal, T.A.; Ashton, N.J.; Janelidze, S.; Benedet, A.L.; Rodriguez, J.L.; Chamoun, M.; Savard, M.; Kang, M.S.; Therriault, J.; et al. Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: A diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020, 19, 422–433. [Google Scholar] [CrossRef]
- Benussi, A.; Karikari, T.K.; Ashton, N.; Gazzina, S.; Premi, E.; Benussi, L.; Ghidoni, R.; Rodriguez, J.L.; Emersic, A.; Simren, J.; et al. Diagnostic and prognostic value of serum NfL and p-Tau181 in frontotemporal lobar degeneration. J. Neurol. Neurosurg. Psychiatry 2020. [Google Scholar] [CrossRef] [PubMed]
- Rojas, J.C.; Karydas, A.; Bang, J.; Tsai, R.M.; Blennow, K.; Liman, V.; Kramer, J.H.; Rosen, H.; Miller, B.L.; Zetterberg, H.; et al. Plasma neurofilament light chain predicts progression in progressive supranuclear palsy. Ann. Clin. Transl. Neurol. 2016, 3, 216–225. [Google Scholar] [CrossRef] [PubMed]
- Ray, S.; Britschgi, M.; Herbert, C.; Takeda-Uchimura, Y.; Boxer, A.; Blennow, K.; Friedman, L.F.; Galasko, D.R.; Jutel, M.; Karydas, A.; et al. Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins. Nat. Med. 2007, 13, 1359–1362. [Google Scholar] [CrossRef]
- Doecke, J.D.; Laws, S.M.; Faux, N.G.; Wilson, W.; Burnham, S.C.; Lam, C.P.; Mondal, A.; Bedo, J.; Bush, A.I.; Brown, B.; et al. Blood-based protein biomarkers for diagnosis of Alzheimer disease. Arch. Neurol. 2012, 69, 1318–1325. [Google Scholar] [CrossRef] [Green Version]
- Hye, A.; Riddoch-Contreras, J.; Baird, A.L.; Ashton, N.J.; Bazenet, C.; Leung, R.; Westman, E.; Simmons, A.; Dobson, R.; Sattlecker, M.; et al. Plasma proteins predict conversion to dementia from prodromal disease. Alzheimers Dement. 2014, 10, 799–807. [Google Scholar] [CrossRef] [Green Version]
- Mapstone, M.; Cheema, A.K.; Fiandaca, M.S.; Zhong, X.; Mhyre, T.R.; MacArthur, L.H.; Hall, W.J.; Fisher, S.G.; Peterson, D.R.; Haley, J.M.; et al. Plasma phospholipids identify antecedent memory impairment in older adults. Nat. Med. 2014, 20, 415–418. [Google Scholar] [CrossRef]
- Varma, V.R.; Oommen, A.M.; Varma, S.; Casanova, R.; An, Y.; Andrews, R.M.; O’Brien, R.; Pletnikova, O.; Troncoso, J.C.; Toledo, J.; et al. Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study. PLoS ONE Med. 2018, 15, e1002482. [Google Scholar] [CrossRef]
- Abdullah, M.; Kimura, N.; Akatsu, H.; Hashizume, Y.; Ferdous, T.; Tachita, T.; Iida, S.; Zou, K.; Matsubara, E.; Michikawa, M. Flotillin is a Novel Diagnostic Blood Marker of Alzheimer’s Disease. J. Alzheimers Dis. 2019, 72, 1165–1176. [Google Scholar] [CrossRef] [PubMed]
- Abdullah, M.; Takase, H.; Nunome, M.; Enomoto, H.; Ito, J.; Gong, J.S.; Michikawa, M. Amyloid-beta Reduces Exosome Release from Astrocytes by Enhancing JNK Phosphorylation. J. Alzheimers Dis. 2016, 53, 1433–1441. [Google Scholar] [CrossRef] [PubMed]
Biomarker | Relevance in AD | Change in CSF/Blood of AD |
---|---|---|
Aβ42 | Distinguishing AD, mild cognitive impairment (MCI) that developed AD and preclinical AD from normal controls and other neurodegenerative disease | Consistently decreased in CSF, also decreased in blood [20,21,22,23,24,25,26,27,28,29,74,75,76,77,78] |
Aβ40 | Inconsistent results for Aβ40 alone, Aβ42/Aβ40 ratio could be a better biomarker than Aβ42 alone | Aβ42/Aβ40 ratio consistently decreased in CSF, also decreased in blood [20,21,22,23,24,25,26,27,28,29,73] |
Aβ38 | Inconsistent results for Aβ38 alone, Aβ42/Aβ38 ratio could be a better biomarker than Aβ42 alone for discrimination of AD from other dementia | Aβ42/Aβ38 ratio decreased in CSF, very few studies [27] |
Aβ43 | Distinguishing AD from normal controls | Aβ43 increased and Aβ42/Aβ43 ratio decreased in blood, very few studies [9] |
Aβ42/APP669-711 | Distinguishing AD from normal controls and MCI that developed AD | Decreased in blood, one study [75] |
BACE1 | Distinguishing AD and MCI that developed AD from normal controls | Activity and levels increased in CSF, few studies [43,44,45,46] |
β-sheet structure Aβ | Correlated with amyloid-PET and other established CSF AD biomarkers | Increased in blood, one study [79] |
Aβ oligomer | Distinguishing AD and MCI that developed AD from normal controls | Increased in CSF, very few studies [31] |
Flotillin | Distinguishing AD and MCI that developed AD from normal controls and vascular dementia (VaD); single blood marker | Decreased in CSF and blood, very few studies [91] |
p-tau and t-tau | Distinguishing AD and MCI that developed AD from normal controls, p-tau 181 and p-tau 231 discriminates AD from other dementia | Consistently increased in CSF [38,39,40,41]; p-tau 181 increased in blood, several studies [80,81,82,83] |
NF-L | Distinguishing AD from normal controls, but not other dementia; valuable for assessing neuronal injury | Increased in CSF and blood, several studies [41,49,50,51,52,53,54,84,85] |
VILIP-1 | Distinguishing early AD and AD from normal controls, but not other dementia | Increased in CSF, inconsistent and limited results in blood [37,47,55,56,57,58,59,60,61,62] |
Synaptic proteins (neurogranin, SNAP-25, synaptotagmin) | Distinguishing AD and MCI developed to AD from normal controls, but not other dementia | Increased in CSF, inconsistent and limited results in blood [37,47,61,63,64,65,66,67,68,69,70,71] |
18 Signaling proteins | Distinguishing AD and MCI developed to AD from normal controls | Pattern changed in blood, very few studies [86] |
10 plasma proteins | Predicting progression from MCI to AD | Pattern changed in blood, very few studies [87,88] |
10 phospholipids | Detecting preclinical AD from normal controls | Pattern changed in blood, very few studies [89] |
4 sphingolipids | Detecting prodromal and preclinical AD from normal controls | Increased in blood, very few studies [90] |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Zou, K.; Abdullah, M.; Michikawa, M. Current Biomarkers for Alzheimer’s Disease: From CSF to Blood. J. Pers. Med. 2020, 10, 85. https://doi.org/10.3390/jpm10030085
Zou K, Abdullah M, Michikawa M. Current Biomarkers for Alzheimer’s Disease: From CSF to Blood. Journal of Personalized Medicine. 2020; 10(3):85. https://doi.org/10.3390/jpm10030085
Chicago/Turabian StyleZou, Kun, Mohammad Abdullah, and Makoto Michikawa. 2020. "Current Biomarkers for Alzheimer’s Disease: From CSF to Blood" Journal of Personalized Medicine 10, no. 3: 85. https://doi.org/10.3390/jpm10030085