CoChat
Sign Up
Cited by 60Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Increased Number of Plasma B Cells Producing Autoantibodies Against Aβ 42 Protofibrils in Alzheimer’s Disease

Open access
Söllvander, Sofia, Ekholm-Pettersson, Frida, Brundin, Rose-Marie, Westman, Gabriel, Kilander, Lena, Paulie, Staffan, Lannfelt, Lars, Sehlin, Dag·2015·Journal of Alzheimer’s Disease
DOI 10.3233/jad-150236PMC PMC4923756
Open this paper in CoChat — free accountOpen PDF

Abstract

The Alzheimer’s disease (AD)-related peptide amyloid-β (Aβ) has a propensity to aggregate into various assemblies including toxic soluble Aβ protofibrils. Several studies have reported the existence of anti-Aβ antibodies in humans. However, it is still debated whether levels of anti-Aβ antibodies are altered in AD patients compared to healthy individuals. Formation of immune complexes with plasma Aβ makes it difficult to reliably measure the concentration of circulating anti-Aβ antibodies with certain immunoassays, potentially leading to an underestimation. Here we have investigated anti-Aβ antibody production on a cellular level by measuring the amount of anti-Aβ antibody producing cells instead of the plasma level of anti-Aβ antibodies. To our knowledge, this is the first time the anti-Aβ antibody response in plasma has been compared in AD patients and age-matched healthy individuals using the enzyme-linked immunospot (ELISpot) technique. Both AD patients and healthy individuals had low levels of B cells producing antibodies binding Aβ 40 monomers, whereas the number of cells producing antibodies toward Aβ 42 protofibrils was higher overall and significantly higher in AD compared to healthy controls. This study shows, by an alternative and reliable method, that there is a specific immune response to the toxic Aβ protofibrils, which is significantly increased in AD patients.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3233/jad-150236

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Recruitment of adaptive immune cells, particularly T and B lymphocytes, can exacerbate neurodegeneration through sustained cytokine production.

    “In parallel, recruitment of adaptive immune cells—particularly T and B lymphocytes—can further exacerbate neurodegeneration through sustained cytokine production despite their initial roles in aggregate clearance [37–41].”

    From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [40]

    The Discussion (page unavailable) reports increased numbers of B cells producing Aβ42-protofibril antibodies in Alzheimer’s patients and suggests that dysregulated immune responses may play a role in the disease. It does not establish recruitment of T or B cells into the brain or show that sustained cytokine production by those cells exacerbates neurodegeneration. (LLM, conf=0.79)

    Experimental — accuracy not yet measured

  • Circulating plasmocytes producing anti-Aβ42 antibodies are elevated in AD patients compared to age-matched healthy individuals.

    “circulating plasmocytes producing anti-A β 42 antibodies are elevated in AD patients compared to agematched healthy individuals”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [95]

    The Results report significantly more circulating plasma B cells secreting antibodies to Aβ42 protofibrils in AD patients than in age-matched healthy controls. The claim omits the protofibril qualifier; the study does not establish an increase in cells producing antibodies to Aβ42 in all forms. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • B cells respond specifically to toxic Aβ peptides.

    “suggesting that B cells respond specif­ ically to toxic A β peptides [95,96].”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [95]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 54

  1. [1]Klyubin I Cullen WK Hu NW Rowan MJ 2012 Alzheimer’s disease Abeta assemblies mediating rapid disruption of synaptic plasticity and memory Mol Brain 5 25 22805374 PMC3502131
  2. [2]Klyubin I Walsh DM Cullen WK Fadeeva JV Anwyl R Selkoe DJ Rowan MJ 2004 Soluble Arctic amyloid beta protein inhibits hippocampal long-term potentiation in vivo Eur J Neurosci 19 2839 2846 15147317
  3. [3]Walsh DM Klyubin I Fadeeva JV Cullen WK Anwyl R Wolfe MS Rowan MJ Selkoe DJ 2002 Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo Nature 416 535 539 11932745
  4. [4]Hartley DM Walsh DM Ye CP Diehl T Vasquez S Vassilev PM Teplow DB Selkoe DJ 1999 Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons J Neurosci 19 8876 8884 10516307 PMC6782787
  5. [6]Nilsberth C Westlind-Danielsson A Eckman CB Condron MM Axelman K Forsell C Stenh C Luthman J Teplow DB Younkin SG Naslund J Lannfelt L 2001 The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation Nat Neurosci 4 887 893 11528419
  6. [7]Fukumoto H Tokuda T Kasai T Ishigami N Hidaka H Kondo M Allsop D Nakagawa M 2010 High-molecular-weight beta-amyloid oligomers are elevated in cerebrospinal fluid of Alzheimer patients FASEB J 24 2716 2726 20339023
  7. [8]Santos AN Ewers M Minthon L Simm A Silber RE Blennow K Prvulovic D Hansson O Hampel H 2012 Amyloid-beta oligomers in cerebrospinal fluid are associated with cognitive decline in patients with Alzheimer’s disease J Alzheimers Dis 29 171 176 22214781
  8. [10]Savage MJ Kalinina J Wolfe A Tugusheva K Korn R Cash-Mason T Maxwell JW Hatcher NG Haugabook SJ Wu G Howell BJ Renger JJ Shughrue PJ McCampbell A 2014 A sensitive abeta oligomer assay discriminates Alzheimer’s and aged control cerebrospinal fluid J Neurosci 34 2884 2897 24553930 PMC6608513
  9. [11]Gold M Pul R Bach JP Stangel M Dodel R 2012 Pathogenic and physiological autoantibodies in the central nervous system Immunol Rev 248 68 86 22725955
  10. [12]Du Y Dodel R Hampel H Buerger K Lin S Eastwood B Bales K Gao F Moeller HJ Oertel W Farlow M Paul S 2001 Reduced levels of amyloid beta-peptide antibody in Alzheimer disease Neurology 57 801 805 11552007
  11. [13]Weksler ME Relkin N Turkenich R LaRusse S Zhou L Szabo P 2002 Patients with Alzheimer disease have lower levels of serum anti-amyloid peptide antibodies than healthy elderly individuals Exp Gerontol 37 943 948 12086704
  12. [14]Dodel R Balakrishnan K Keyvani K Deuster O Neff F Andrei-Selmer LC Roskam S Stuer C Al-Abed Y Noelker C Balzer-Geldsetzer M Oertel W Du Y Bacher M 2011 Naturally occurring autoantibodies against beta-amyloid: Investigating their role in transgenic animal and in vitro models of Alzheimer’s disease J Neurosci 31 5847 5854 21490226 PMC6622820
  13. [15]O’Nuallain B Acero L Williams AD Koeppen HP Weber A Schwarz HP Wall JS Weiss DT Solomon A 2008 Human plasma contains cross-reactive Abeta conformer-specific IgG antibodies Biochemistry 47 12254 12256 18956886
  14. [16]Di Malta C Fryer JD Settembre C Ballabio A 2012 Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder Proc Natl Acad Sci U S A 109 E2334 E2342 22826245 PMC3435187
  15. [17]Szabo P Mujalli DM Rotondi ML Sharma R Weber A Schwarz HP Weksler ME Relkin N 2010 Measurement of anti-beta amyloid antibodies in human blood J Neuroimmunol 227 167 174 20638733
  16. [18]Sehlin D Englund H Simu B Karlsson M Ingelsson M Nikolajeff F Lannfelt L Pettersson FE 2012 Large aggregates are the major soluble Abeta species in AD brain fractionated with density gradient ultracentrifugation PLoS One 7 e32014 22355408 PMC3280222
  17. [19]Du Y Wei X Dodel R Sommer N Hampel H Gao F Ma Z Zhao L Oertel WH Farlow M 2003 Human anti-beta-amyloid antibodies block beta-amyloid fibril formation and prevent beta-amyloid-induced neurotoxicity Brain 126 1935 1939 12821522
  18. [20]St-Amour I Pare I Tremblay C Coulombe K Bazin R Calon F 2014 IVIg protects the 3xTg-AD mouse model of Alzheimer’s disease from memory deficit and Abeta pathology J Neuroinflammation 11 54 24655894 PMC3997966
  19. [21]Morgan D 2010 Immunotherapy for Alzheimer’s disease J Intern Med 269 54 63 21158978 PMC3074967
  20. [22]Taguchi H Planque S Nishiyama Y Symersky J Boivin S Szabo P Friedland RP Ramsland PA Edmundson AB Weksler ME Paul S 2008 Autoantibody-catalyzed hydrolysis of amyloid beta peptide J Biol Chem 283 4714 4722 18086674
  21. [23]Relkin NR Szabo P Adamiak B Burgut T Monthe C Lent RW Younkin S Younkin L Schiff R Weksler ME 2009 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease Neurobiol Aging 30 1728 1736 18294736
  22. [24]Dodel R Rominger A Bartenstein P Barkhof F Blennow K Forster S Winter Y Bach JP Popp J Alferink J Wiltfang J Buerger K Otto M Antuono P Jacoby M Richter R Stevens J Melamed I Goldstein J Haag S Wietek S Farlow M Jessen F 2013 Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer’s disease: A phase 2, randomised, double-blind, placebo-controlled, dose-finding trial Lancet Neurol 12 233 243 23375965 PMC4986921
  23. [25]Relkin N 2014 Clinical trials of intravenous immunoglobulin for Alzheimer’s disease J Clin Immunol 34 Suppl 1 S74 S79 24760112
  24. [27]Brettschneider S Morgenthaler NG Teipel SJ Fischer-Schulz C Burger K Dodel R Du Y Moller HJ Bergmann A Hampel H 2005 Decreased serum amyloid beta(1-42) autoantibody levels in Alzheimer’s disease, determined by a newly developed immuno-precipitation assay with radiolabeled amyloid beta(1-42) peptide Biol Psychiatry 57 813 816 15820240
  25. [28]Moir RD Tseitlin KA Soscia S Hyman BT Irizarry MC Tanzi RE 2005 Autoantibodies to redox-modified oligomeric Abeta are attenuated in the plasma of Alzheimer’s disease patients J Biol Chem 280 17458 17463 15728175
  26. [29]Gustaw KA Garrett MR Lee HG Castellani RJ Zagorski MG Prakasam A Siedlak SL Zhu X Perry G Petersen RB Friedland RP Smith MA 2008 Antigen-antibody dissociation in Alzheimer disease: A novel approach to diagnosis J Neurochem 106 1350 1356 18485104 PMC2575068
  27. [30]Gustaw-Rothenberg KA Siedlak SL Bonda DJ Lerner A Tabaton M Perry G Smith MA 2010 Dissociated amyloid-beta antibody levels as a serum biomarker for the progression of Alzheimer’s disease: A population-based study Exp Gerontol 45 47 52 19819324 PMC2815174
  28. [31]Qu BX Gong Y Moore C Fu M German DC Chang LY Rosenberg R Diaz-Arrastia R 2014 Beta-amyloid auto-antibodies are reduced in Alzheimer’s disease J Neuroimmunol 274 168 173 25022335 PMC4410718
  29. [32]Mruthinti S Buccafusco JJ Hill WD Waller JL Jackson TW Zamrini EY Schade RF 2004 Autoimmunity in Alzheimer’s disease: Increased levels of circulating IgGs binding Abeta and RAGE peptides Neurobiol Aging 25 1023 1032 15212827
  30. [33]Storace D Cammarata S Borghi R Sanguineti R Giliberto L Piccini A Pollero V Novello C Caltagirone C Smith MA Bossu P Perry G Odetti P Tabaton M 2010 Elevation of beta-amyloid 1-42 autoantibodies in the blood of amnestic patients with mild cognitive impairment Arch Neurol 67 867 872 20625095
  31. [34]Hyman BT Smith C Buldyrev I Whelan C Brown H Tang MX Mayeux R 2001 Autoantibodies to amyloid-beta and Alzheimer’s disease Ann Neurol 49 808 810 11409436
  32. [35]Klaver AC Coffey MP Smith LM Bennett DA Finke JM Dang L Loeffler DA 2011 ELISA measurement of specific non-antigen-bound antibodies to Abeta1-42 monomer and soluble oligomers in sera from Alzheimer’s disease, mild cognitively impaired, and noncognitively impaired subjects J Neuroinflammation 8 93 21827691 PMC3162899
  33. [36]Conti E Galimberti G Piazza F Raggi ME Ferrarese C 2010 Increased soluble APPalpha, Abeta 1-42, and anti-Abeta 1-42 antibodies in plasma from down syndrome patients Alzheimer Dis Assoc Disord 24 96 100 19571731
  34. [37]Boncoraglio GB Piazza F Savoiardo M Farina L DiFrancesco JC Prioni S Tagliavini F Parati EA Giaccone G 2015 Prodromal Alzheimer’s disease presenting as cerebral amyloid angiopathy-related inflammation with spontaneous amyloid-related imaging abnormalities and high cerebrospinal fluid anti-abeta autoantibodies J Alzheimers Dis 45 363 367 25537009
  35. [38]Piazza F Greenberg SM Savoiardo M Gardinetti M Chiapparini L Raicher I Nitrini R Sakaguchi H Brioschi M Billo G Colombo A Lanzani F Piscosquito G Carriero MR Giaccone G Tagliavini F Ferrarese C DiFrancesco JC 2013 Anti-amyloid beta autoantibodies in cerebral amyloid angiopathy-related inflammation: Implications for amyloid-modifying therapies Ann Neurol 73 449 458 23625526
  36. [39]Czerkinsky CC Nilsson LA Nygren H Ouchterlony O Tarkowski A 1983 A solid-phase enzyme-linked immunospot (ELISPOT) assay for enumeration of specific antibody-secreting cells J Immunol Methods 65 109 121 6361139
  37. [40]Sehlin D Sollvander S Paulie S Brundin R Ingelsson M Lannfelt L Pettersson FE Englund H 2010 Interference from heterophilic antibodies in amyloid-beta oligomer ELISAs J Alzheimers Dis 21 1295 1301 21504116
  38. [41]Magnusson K Sehlin D Syvanen S Svedberg MM Philipson O Soderberg L Tegerstedt K Holmquist M Gellerfors P Tolmachev V Antoni G Lannfelt L Hall H Nilsson LN 2013 Specific uptake of an amyloid-beta protofibril-binding antibody-tracer in AbetaPP transgenic mouse brain J Alzheimers Dis 37 29 40 23780660
  39. [42]Englund H Sehlin D Johansson AS Nilsson LN Gellerfors P Paulie S Lannfelt L Pettersson FE 2007 Sensitive ELISA detection of amyloid-beta protofibrils in biological samples J Neurochem 103 334 345 17623042
  40. [43]Baril L Nicolas L Croisile B Crozier P Hessler C Sassolas A McCormick JB Trannoy E 2004 Immune response to Abeta-peptides in peripheral blood from patients with Alzheimer’s disease and control subjects Neurosci Lett 355 226 230 14732472
  41. [44]Gruden MA Davudova TB Malisauskas M Zamotin VV Sewell RD Voskresenskaya NI Kostanyan IA Sherstnev VV Morozova-Roche LA 2004 Autoimmune responses to amyloid structures of Abeta(25-35) peptide and human lysozyme in the serum of patients with progressive Alzheimer’s disease Dement Geriatr Cogn Disord 18 165 171 15211072
  42. [45]Nath A Hall E Tuzova M Dobbs M Jons M Anderson C Woodward J Guo Z Fu W Kryscio R Wekstein D Smith C Markesbery WR Mattson MP 2003 Autoantibodies to amyloid beta-peptide (Abeta) are increased in Alzheimer’s disease patients and Abeta antibodies can enhance Abeta neurotoxicity: Implications for disease pathogenesis and vaccine development Neuromolecular Med 3 29 39 12665674
  43. [46]Sohn JH So JO Hong HJ Kim JW Na DR Kim M Kim H Nam E Ha HJ Kim YH Mook-Jung I 2009 Identification of autoantibody against beta-amyloid peptide in the serum of elderly Front Biosci 14 3879 3883 19273318
  44. [47]Song MS Mook-Jung I Lee HJ Min JY Park MH 2007 Serum anti-amyloid-beta antibodies and Alzheimer’s disease in elderly Korean patients J Int Med Res 35 301 306 17593857
  45. [48]Jianping L Zhibing Y Wei Q Zhikai C Jie X Jinbiao L 2006 Low avidity and level of serum anti-Abeta antibodies in Alzheimer disease Alzheimer Dis Assoc Disord 20 127 132 16917180
  46. [49]Stenh C Englund H Lord A Johansson AS Almeida CG Gellerfors P Greengard P Gouras GK Lannfelt L Nilsson LN 2005 Amyloid-beta oligomers are inefficiently measured by enzyme-linked immunosorbent assay Ann Neurol 58 147 150 15984012
  47. [50]Englund H Degerman Gunnarsson M Brundin RM Hedlund M Kilander L Lannfelt L Pettersson FE 2009 Oligomerization partially explains the lowering of Abeta42 in Alzheimer’s disease cerebrospinal fluid Neurodegener Dis 6 139 147 19521063
  48. [51]Pellicano M Bulati M Buffa S Barbagallo M Di Prima A Misiano G Picone P Di Carlo M Nuzzo D Candore G Vasto S Lio D Caruso C Colonna-Romano G 2010 Systemic immune responses in Alzheimer’s disease: In vitro mononuclear cell activation and cytokine production J Alzheimers Dis 21 181 192 20413861
  49. [52]Speciale L Calabrese E Saresella M Tinelli C Mariani C Sanvito L Longhi R Ferrante P 2007 Lymphocyte subset patterns and cytokine production in Alzheimer’s disease patients Neurobiol Aging 28 1163 1169 16814429
  50. [54]Xue SR Xu DH Yang XX Dong WL 2009 Alterations in lymphocyte subset patterns and co-stimulatory molecules in patients with Alzheimer disease Chin Med J (Engl) 122 1469 1472 19567174
  51. [55]O’Nuallain B Wetzel R 2002 Conformational Abs recognizing a generic amyloid fibril epitope Proc Natl Acad Sci U S A 99 1485 1490 11818542 PMC122217
  52. [56]Britschgi M Wyss-Coray T 2007 Systemic and acquired immune responses in Alzheimer’s disease Int Rev Neurobiol 82 205 233 17678963
  53. [57]Conti E Galimberti G Tremolizzo L Masetto A Cereda D Zanchi C Piazza F Casati M Isella V Appollonio I Ferrarese C 2010 Cholinesterase inhibitor use is associated with increased plasma levels of anti-Abeta 1-42 antibodies in Alzheimer’s disease patients Neurosci Lett 486 193 196 20869427
  54. [58]Reale M Iarlori C Gambi F Feliciani C Isabella L Gambi D 2006 The acetylcholinesterase inhibitor, Donepezil, regulates a Th2 bias in Alzheimer’s disease patients Neuropharmacology 50 606 613 16445950

Cited by

Sorted by citations

Authors
Söllvander, S., Ekholm-Pettersson, F., Brundin, R.-M., Westman, G., Kilander, L., Paulie, S., Lannfelt, L., & Sehlin, D.
Affiliations
  • Uppsala University (SE)
  • Department of Public Health & Caring Sciences/Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
  • Mabtech (Sweden) (SE)
Corresponding author
Sehlin, Dag
ORCID
Venue
Journal of Alzheimer’s Disease
Publisher
SAGE Publications
Published
2015-08-28
Volume
48
Issue
1
Pages
63-72
ISSN
  • 1387-2877 (ISSN-L)
  • 1875-8908
DOI
10.3233/jad-150236
PMC
PMC4923756
OpenAlex
W2206815046
Cited by
60
References
3
Citations by year
2026: 6 · 2025: 11 · 2024: 5 · 2023: 4 · 2022: 11 · 2021: 8 · 2020: 6 · 2019: 5 · 2018: 1 · 2017: 1 · 2016: 2
FWCI
0.98
Type
journal article
Language
en
Open access
Licence
journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations
  • Journal of Alzheimer s Disease (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
Funders
  • Vetenskapsrådet (#2012-2172)
  • Alzheimerfonden
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, amyloid-beta
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Autoantibodies, B-Lymphocytes, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Humans, Male, Mental Status Schedule, Peptide Fragments, Case-Control Studies, Amyloid beta-Peptides, Biotinylation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review