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Longitudinal plasma amyloid beta as a biomarker of Alzheimer’s disease

  • Dementias - Review article
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Abstract

Alzheimer’s disease (AD) affects more than twenty-five million people worldwide and is the most common form of dementia. Symptomatic treatments have been developed, but effective intervention to alter disease progression is needed. Targets have been identified for disease-modifying drugs, but the results of clinical trials have been disappointing. Peripheral biomarkers of disease state may improve clinical trial design and analysis, increasing the likelihood of successful drug development. Amyloid-related measures, presumably reflecting principal pathology of AD, are among the leading cerebrospinal fluid and neuroimaging biomarkers, and measurement of plasma levels of amyloid peptides has been the focus of much investigation. In this review, we discuss recent data on plasma β-amyloid (Aβ) and examine the issues that have arisen in establishing it as a reliable biomarker of AD.

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References

  • Andreasen N, Blennow K (2002) Beta-amyloid (Abeta) protein in cerebrospinal fluid as a biomarker for Alzheimer’s disease. Peptides 23:1205–1214

    Article  PubMed  CAS  Google Scholar 

  • Arai H, Lee VM, Messinger ML, Greenberg BD, Lowery DE, Trojanowski JQ (1991) Expression patterns of beta-amyloid precursor protein (beta-APP) in neural and nonneural human tissues from Alzheimer’s disease and control subjects. Ann Neurol 30:686–693

    Article  PubMed  CAS  Google Scholar 

  • Arvanitakis Z, Lucas JA, Younkin LH, Younkin SG, Graff-Radford NR (2002) Serum creatinine levels correlate with plasma amyloid beta protein. Alzheimer Dis Assoc Disord 16:187–190

    Article  PubMed  CAS  Google Scholar 

  • Bateman RJ, Wen G, Morris JC, Holtzman DM (2007) Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker. Neurology 68:666–669

    Article  PubMed  CAS  Google Scholar 

  • Biere AL, Ostaszewski B, Stimson ER, Hyman BT, Maggio JE, Selkoe DJ (1996) Amyloid beta-peptide is transported on lipoproteins and albumin in human plasma. J Biol Chem 271:32916–32922

    Article  PubMed  CAS  Google Scholar 

  • Blasko I, Jellinger K, Kemmler G, Krampla W, Jungwirth S, Wichart I, Tragl KH, Fischer P (2008) Conversion from cognitive health to mild cognitive impairment and Alzheimer’s disease: prediction by plasma amyloid beta 42, medial temporal lobe atrophy and homocysteine. Neurobiol Aging 29:1–11

    Article  PubMed  CAS  Google Scholar 

  • Cirrito JR, Holtzman DM (2003) Amyloid beta and Alzheimer disease therapeutics: the devil may be in the details. J Clin Invest 112:321–323

    PubMed  CAS  Google Scholar 

  • Coppus AM, Schuur M, Vergeer J, Janssens AC, Oostra BA, Verbeek MM, van Duijn CM (2011) Plasma β amyloid and the risk of Alzheimer’s disease in Down syndrome. Neurobiol Aging [Epub ahead of print]

  • Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt AM, Armstrong DL, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B (2003) RAGE mediates amyloid-beta peptide transport across the blood–brain barrier and accumulation in brain. Nat Med 9:907–913

    Article  PubMed  CAS  Google Scholar 

  • Deane R, Wu ZH, Sagare A, Davis J, Yan SD, Hamm K, Xu F, Parisi M, LaRue B, Hu HW, Spijkers P, Guo H, Song XM, Lenting PJ, Van Nostrand WE, Zlokovic BV (2004a) LRP/amyloid beta-peptide interaction mediates differential brain efflux of A beta isoforms. Neuron 43:333–344

    Article  PubMed  CAS  Google Scholar 

  • Deane R, Wu ZH, Zlokovic BV (2004b) RAGE (Yin) versus LRP (Yang) balance regulates Alzheimer amyloid beta-peptide clearance through transport across the blood–brain barrier. Stroke 35:2628–2631

    Article  PubMed  CAS  Google Scholar 

  • DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM (2002) Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 295:2264–2267

    Article  PubMed  CAS  Google Scholar 

  • Ertekin-Taner N, Graff-Radford N, Younkin LH, Eckman C, Baker M, Adamson J, Ronald J, Blangero J, Hutton M, Younkin SG (2000) Linkage of plasma Abeta42 to a quantitative locus on chromosome 10 in late-onset Alzheimer’s disease pedigrees. Science 290:2303–2304

    Article  PubMed  CAS  Google Scholar 

  • Ertekin-Taner N, Younkin LH, Yager DM, Parfitt F, Baker MC, Asthana S, Hutton ML, Younkin SG, Graff-Radford NR (2008) Plasma amyloid beta protein is elevated in late-onset Alzheimer disease families. Neurology 70:596–606

    Article  PubMed  CAS  Google Scholar 

  • Figurski MJ, Waligorska T, Toledo J, Vanderstichele H, Korecka M, Lee VM-Y, Trojanowski JQ, Shaw LM (2012) Improved protocol for measurement of plasma amyloid-β in longitudinal evaluation of ADNI patients. Alzheimer’s Dementia (in press)

  • Fukumoto H, Tennis M, Locascio JJ, Hyman BT, Growdon JH, Irizarry MC (2003) Age but not diagnosis is the main predictor of plasma amyloid beta-protein levels. Arch Neurol 60:958–964

    Article  PubMed  Google Scholar 

  • Giedraitis V, Sundelof J, Irizarry MC, Garevik N, Hyman BT, Wahlund LO, Ingelsson M, Lannfelt L (2007) The normal equilibrium between CSF and plasma amyloid beta levels is disrupted in Alzheimer’s disease. Neurosci Lett 427:127–131

    Article  PubMed  CAS  Google Scholar 

  • Girouard H, Iadecola C (2006) Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol 100:328–335

    Article  PubMed  CAS  Google Scholar 

  • Graff-Radford NR, Crook JE, Lucas J, Boeve BF, Knopman DS, Ivnik RJ, Smith GE, Younkin LH, Petersen RC, Younkin SG (2007) Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch Neurol 64:354–362

    Article  PubMed  Google Scholar 

  • Gurol ME, Irizarry MC, Smith EE, Raju S, Diaz-Arrastia R, Bottiglieri T, Rosand J, Growdon JH, Greenberg SM (2006) Plasma beta-amyloid and white matter lesions in AD, MCI, and cerebral amyloid angiopathy. Neurology 66:23–29

    Article  PubMed  CAS  Google Scholar 

  • Hampel H, Wilcock G, Andrieu S, Aisen P, Blennow K, Broich K, Carrillo M, Fox NC, Frisoni GB, Isaac M, Lovestone S, Nordberg A, Prvulovic D, Sampaio C, Scheltens P, Weiner M, Winblad B, Coley N, Vellas B (2011) Biomarkers for Alzheimer’s disease therapeutic trials. Prog Neurobiol 95(4):579–593

    Article  PubMed  CAS  Google Scholar 

  • Hansson SF, Andréasson U, Wall M, Skoog I, Andreasen N, Wallin A, Zetterberg H, Blennow K (2009) Reduced levels of amyloid-beta-binding proteins in cerebrospinal fluid from Alzheimer’s disease patients. J Alzheimers Dis 16(2):389–397

    PubMed  CAS  Google Scholar 

  • Head E, Doran E, Nistor M, Hill M, Schmitt FA, Haier RJ, Lott IT (2011) Plasma amyloid-beta as a function of age, level of intellectual disability, and presence of dementia in Down syndrome. J Alzheimers Dis 23:399–409

    PubMed  CAS  Google Scholar 

  • Jensen M, Schroder J, Blomberg M, Engvall B, Pantel J, Ida N, Basun H, Wahlund LO, Werle E, Jauss M, Beyreuther K, Lannfelt L, Hartmann T (1999) Cerebrospinal fluid A beta42 is increased early in sporadic Alzheimer’s disease and declines with disease progression. Ann Neurol 45:504–511

    Article  PubMed  CAS  Google Scholar 

  • Kang JE, Cirrito JR, Dong H, Csernansky JG, Holtzman DM (2007) Acute stress increases interstitial fluid amyloid-beta via corticotropin-releasing factor and neuronal activity. Proc Natl Acad Sci USA 104:10673–10678

    Article  PubMed  CAS  Google Scholar 

  • Kawarabayashi T, Younkin LH, Saido TC, Shoji M, Ashe KH, Younkin SG (2001) Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer’s disease. J Neurosci 21:372–381

    PubMed  CAS  Google Scholar 

  • Koudinov AR, Berezov TT, Kumar A, Koudinova NV (1998) Alzheimer’s amyloid beta interaction with normal human plasma high density lipoprotein: association with apolipoprotein and lipids. Clin Chim Acta 270:75–84

    Article  PubMed  CAS  Google Scholar 

  • Laird FM, Cai H, Savonenko AV, Farah MH, He K, Melnikova T, Wen H, Chiang HC, Xu G, Koliatsos VE, Borchelt DR, Price DL, Lee HK, Wong PC (2005) BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci 25:11693–11709

    Article  PubMed  CAS  Google Scholar 

  • Lee GD, Aruna JH, Barrett PM, Lei DL, Ingram DK, Mouton PR (2005) Stereological analysis of microvascular parameters in a double transgenic model of Alzheimer’s disease. Brain Res Bull 65:317–322

    Article  PubMed  CAS  Google Scholar 

  • Lopez OL, Kuller LH, Mehta PD, Becker JT, Gach HM, Sweet RA, Chang YF, Tracy R, DeKosky ST (2008) Plasma amyloid levels and the risk of AD in normal subjects in the cardiovascular health study. Neurology 70:1664–1671

    Article  PubMed  CAS  Google Scholar 

  • Matsubara E, Ghiso J, Frangione B, Amari M, Tomidokoro Y, Ikeda Y, Harigaya Y, Okamoto K, Shoji M (1999) Lipoprotein-free amyloidogenic peptides in plasma are elevated in patients with sporadic Alzheimer’s disease and Down’s syndrome. Ann Neurol 45:537–541

    Article  PubMed  CAS  Google Scholar 

  • Matsuoka Y, Saito M, LaFrancois J, Gaynor K, Olm V, Wang L, Casey E, Lu Y, Shiratori C, Lemere C, Duff K (2003) Novel therapeutic approach for the treatment of Alzheimer’s disease by peripheral administration of agents with an affinity to beta-amyloid. J Neurosci 23:29–33

    PubMed  CAS  Google Scholar 

  • Matsuoka Y, Andrews HF, Becker AG, Gray AJ, Mehta PD, Sano MC, Dalton AJ, Aisen PS (2009) The relationship of plasma Abeta levels to dementia in aging individuals with Down syndrome. Alzheimer Dis Assoc Disord 23:315–318

    Article  PubMed  CAS  Google Scholar 

  • Mattsson N, Andreasson U, Persson S, Arai H, Batish SD, Bernardini S, Bocchio-Chiavetto L, Blankenstein MA, Carrillo MC, Chalbot S, Coart E, Chiasserini D, Cutler N, Dahlfors G, Duller S, Fagan AM, Forlenza O, Frisoni GB, Galasko D, Galimberti D, Hampel H, Handberg A, Heneka MT, Herskovits AZ, Herukka SK, Holtzman DM, Humpel C, Hyman BT, Iqbal K, Jucker M, Kaeser SA, Kaiser E, Kapaki E, Kidd D, Klivenyi P, Knudsen CS, Kummer MP, Lui J, Llado A, Lewczuk P, Li QX, Martins R, Masters C, McAuliffe J, Mercken M, Moghekar A, Molinuevo JL, Montine TJ, Nowatzke W, O’Brien R, Otto M, Paraskevas GP, Parnetti L, Petersen RC, Prvulovic D, de Reus HP, Rissman RA, Scarpini E, Stefani A, Soininen H, Schroder J, Shaw LM, Skinningsrud A, Skrogstad B, Spreer A, Talib L, Teunissen C, Trojanowski JQ, Tumani H, Umek RM, Van Broeck B, Vanderstichele H, Vecsei L, Verbeek MM, Windisch M, Zhang J, Zetterberg H, Blennow K (2011) The Alzheimer’s association external quality control program for cerebrospinal fluid biomarkers. Alzheimers Dement 7(386–395):e386

    Article  Google Scholar 

  • Mayeux R, Tang MX, Jacobs DM, Manly J, Bell K, Merchant C, Small SA, Stern Y, Wisniewski HM, Mehta PD (1999) Plasma amyloid beta-peptide 1-42 and incipient Alzheimer’s disease. Ann Neurol 46(3):412–416

    Article  PubMed  CAS  Google Scholar 

  • Mayeux R, Honig LS, Tang MX, Manly J, Stern Y, Schupf N, Mehta PD (2003) Plasma A[beta]40 and A[beta]42 and Alzheimer’s disease: relation to age, mortality, and risk. Neurology 61:1185–1190

    Article  PubMed  CAS  Google Scholar 

  • Okereke OI, Xia W, Selkoe DJ, Grodstein F (2009) Ten-year change in plasma amyloid beta levels and late-life cognitive decline. Arch Neurol 66:1247–1253

    Article  PubMed  Google Scholar 

  • Roher AE, Maarouf CL, Sue LI, Hu Y, Wilson J, Beach TG (2009) Proteomics-derived cerebrospinal fluid markers of autopsy-confirmed Alzheimer’s disease. Biomarkers 14(7):493–501

    Article  PubMed  CAS  Google Scholar 

  • Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S (1996) Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 2:864–870

    Article  PubMed  CAS  Google Scholar 

  • Schupf N, Tang MX, Fukuyama H, Manly J, Andrews H, Mehta P, Ravetch J, Mayeux R (2008) Peripheral Abeta subspecies as risk biomarkers of Alzheimer’s disease. Proc Natl Acad Sci USA 105:14052–14057

    Article  PubMed  CAS  Google Scholar 

  • Selkoe DJ (1994) Normal and abnormal biology of the beta-amyloid precursor protein. Annu Rev Neurosci 17:489–517

    Article  PubMed  CAS  Google Scholar 

  • Shaw CA, Li Y, Wiszniewska J, Chasse S, Zaidi SN, Jin W, Dawson B, Wilhelmsen K, Lupski JR, Belmont JW, Doody RS, Szigeti K (2011) Olfactory copy number association with age at onset of Alzheimer disease. Neurology 76:1302–1309

    Article  PubMed  CAS  Google Scholar 

  • Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, Holtzman DM, Miller CA, Strickland DK, Ghiso J, Zlokovic BV (2000) Clearance of Alzheimer’s amyloid-ss(1–40) peptide from brain by LDL receptor-related protein-1 at the blood–brain barrier. J Clin Invest 106:1489–1499

    Article  PubMed  CAS  Google Scholar 

  • Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, Zhao J, McConlogue L, John V (1999) Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402:537–540

    Article  PubMed  CAS  Google Scholar 

  • Sundelöf J, Giedraitis V, Irizarry MC, Sundström J, Ingelsson E, Rönnemaa E, Arnlöv J, Gunnarsson MD, Hyman BT, Basun H, Ingelsson M, Lannfelt L, Kilander L (2008) Plasma beta amyloid and the risk of Alzheimer disease and dementia in elderly men: a prospective, population-based cohort study. Arch Neurol 65(2):256–263

    Article  PubMed  Google Scholar 

  • Takeda S, Sato N, Uchio-Yamada K, Sawada K, Kunieda T, Takeuchi D, Kurinami H, Shinohara M, Rakugi H, Morishita R (2009) Elevation of plasma beta-amyloid level by glucose loading in Alzheimer mouse models. Biochem Biophys Res Commun 385:193–197

    Article  PubMed  CAS  Google Scholar 

  • Tamaki C, Ohtsuki S, Iwatsubo T, Hashimoto T, Yamada K, Yabuki C, Terasaki T (2006) Major involvement of low-density lipoprotein receptor-related protein 1 in the clearance of plasma free amyloid beta-peptide by the liver. Pharm Res 23:1407–1416

    Article  PubMed  CAS  Google Scholar 

  • Tokuda T, Fukushima T, Ikeda S, Sekijima Y, Shoji S, Yanagisawa N, Tamaoka A (1997) Plasma levels of amyloid beta proteins Abeta1-40 and Abeta1-42(43) are elevated in Down’s syndrome. Ann Neurol 41:271–273

    Article  PubMed  CAS  Google Scholar 

  • Toledo JB, Toledo E, Jack CR, Jagust W, Lee VM-Y, Shaw LM, Trojanowski JQ Initiative f.t.A.s.D.N (2011a) Cardiovascular risk factors, cortisol, and amyloid-beta deposition in Alzheimer’s disease neuroimaging initiative. Alzheimer’s Dementia (in press)

  • Toledo JB, Vanderstichele H, Figurski M, Aisen PS, Petersen RC, Weiner MW, Jack CR Jr, Jagust W, Decarli C, Toga AW, Toledo E, Xie SX, Lee VM, Trojanowski JQ, Shaw LM (2011b) Factors affecting Aβ plasma levels and their utility as biomarkers in ADNI. Acta Neuropathol 122(4):401–413

    Article  PubMed  CAS  Google Scholar 

  • Tucker KL, Qiao N, Scott T, Rosenberg I, Spiro A 3rd (2005) High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study. Am J Clin Nutr 82:627–635

    PubMed  CAS  Google Scholar 

  • Van Oijen M, Hofman A, Soares HD, Koudstaal PJ, Breteler MM (2006) Plasma Abeta(1-40) and Abeta(1-42) and the risk of dementia: a prospective case-cohort study. Lancet Neurol 5(8):655–660

    Article  PubMed  CAS  Google Scholar 

  • Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741

    Article  PubMed  CAS  Google Scholar 

  • Yaffe K, Weston A, Graff-Radford NR, Satterfield S, Simonsick EM, Younkin SG, Younkin LH, Kuller L, Ayonayon HN, Ding J, Harris TB (2011) Association of plasma beta-amyloid level and cognitive reserve with subsequent cognitive decline. JAMA 305:261–266

    Article  PubMed  CAS  Google Scholar 

  • Younkin SG (1998) The role of A beta 42 in Alzheimer’s disease. J Physiol Paris 92:289–292

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Seti Moghadam and Kathleen Lao (Rissman lab, ADCS, UCSD) for assistance with manuscript preparation. Supported by NIH/NIA AG010483 (PSA), AG032755 (RAR), the Alzheimer’s Art Quilt Initiative (RAR), the Alzheimer’s Association (RAR), a pilot grant to RAR from the Shiley-Marcos Alzheimer’s Disease Research Center at the UCSD (AG005131), and the Penn Alzheimer Core Center (AG10124) (JQT, LMS).

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  1. Alzheimer’s Disease Cooperative Study, Department of Neurosciences, UCSD School of Medicine, 9500 Gilman Drive, MTF 314 M/C 0624, La Jolla, CA, 92037-0624, USA

    Robert A. Rissman & Paul S. Aisen

  2. Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    John Q. Trojanowski & Leslie M. Shaw

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  1. Robert A. Rissman
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  2. John Q. Trojanowski
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  3. Leslie M. Shaw
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  4. Paul S. Aisen
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Correspondence to Robert A. Rissman.

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Rissman, R.A., Trojanowski, J.Q., Shaw, L.M. et al. Longitudinal plasma amyloid beta as a biomarker of Alzheimer’s disease. J Neural Transm 119, 843–850 (2012). https://doi.org/10.1007/s00702-012-0772-4

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  • DOI: https://doi.org/10.1007/s00702-012-0772-4

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