Is there a role for B cells in Alzheimer's disease?

Probably not a substantial claim: may not pass S3 (load-bearing).

GWAS have identified over 80 independent genetic loci associated with AD risk.

“Over the past two decades, GWAS have identified over 80 independent genetic loci asso­ ciated with AD risk [19,20].”

• cites [19] [19] [C. Bellenguez, F. Kucukali, I.E. Jansen, L. Kleineidam, S. Moreno-Grau, N. Amin, A.C. Naj, R. Campos-Martin, B. Grenier-Boley, V. Andrade, P.A. Holmans, A. Boland, V. Damotte, S.J. van der Lee, M.R. Costa, T. Kuulasmaa, Q. Yang, I. de Rojas, J.C. Bis, A. Yaqub, I. Prokic, J. Chapuis, S. Ahmad, V. Giedraitis, D. Aarsland, P. Garcia-Gonzalez, C. Abdelnour, E. Alarcon-Martin, D. Alcolea, M. Alegret, I. Alvarez, V. Alvarez, N.J. Armstrong, A. Tsolaki, C. Antunez, I. Appollonio, M. Arcaro, S. Archetti, A.A. Pastor, B. Arosio, L. Athanasiu, H. Bailly, N. Banaj, M. Baquero, S. Barral, A. Beiser sourceDisputed

  The Discussion reports 75 independent loci for Alzheimer’s disease and related dementias (ADD): 33 previously reported and 42 new. That is contrary to the attributed figure of over 80, though the paper’s outcome is ADD rather than AD alone. (LLM, conf=0.87)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [20] [20] [J.C. Lambert, A. Ramirez, B. Grenier-Boley, C. Bellenguez, Step by step: towards a better understanding of the genetic architecture of Alzheimer ' s disease, Mol. Psychiatry (2023) 2716 -2727.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0100) - sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The proportion of Bregs ranges from 1 to 3% of total B cells in the spleen and peritoneal cavity of healthy mice, whereas in humans Bregs typically constitute 1-4% of circulating B cells under homeostatic conditions.

“The proportion of Bregs ranges from 1 to 3% of total B cells in the spleen and peritoneal cavity of healthy mice, whereas in humans, Bregs typically constitute 1 -4% of circulating B cells under homeostatic conditions [57,59,60].”

• cites [57] [57] [P.A. Blair, L.Y. Norena, F. Flores-Borja, D.J. Rawlings, D.A. Isenberg, M. R. Ehrenstein, C. Mauri, CD19( + )CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients, Immunity (2010) 129 -140.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0285) - sourcePartly supported

  The Results identify regulatory CD19+CD24hiCD38hi B cells in the peripheral blood of healthy human donors. The passages do not give the claimed 1–4% frequency in humans or the 1–3% frequency in the spleen and peritoneal cavity of healthy mice; searches for those ranges and sites found no supporting passage. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [59] [59] [T. Matsushita, M. Horikawa, Y. Iwata, T.F. Tedder, Regulatory B cells (B10 cells) and regulatory T cells have independent roles in controlling experimental autoimmune encephalomyelitis initiation and late-phase immunopathogenesis, J. Immunol. (2010) 2240 -2252.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0295) - sourcePartly supported

  The Introduction (page unavailable) says B10 cells normally represent 1–2% of mouse spleen B cells, supporting the spleen portion of the stated range. Our copy does not establish a 1–3% range for the peritoneal cavity or the claimed 1–4% of circulating B cells in healthy humans; searches for those populations and percentages found no supporting passage. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [60] [60] [D. Maseda, K.M. Candando, S.H. Smith, I. Kalampokis, C.T. Weaver, S.E. Plevy, J. C. Poe, T.F. Tedder, Peritoneal cavity regulatory B cells (B10 cells) modulate IFNgamma + CD4 + T cell numbers during colitis development in mice, J. Immunol. 191 (2013) 2780 -2795.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0300) sourceDisputed

  The Introduction reports B10 cells at 1–5% of spleen B cells in naïve mice, rather than the claimed 1–3%. More decisively, the Results section on IL-10-competent B cells reports about 40% in the peritoneal cavity, contrary to the claimed 1–3%. The passages found do not establish the stated 1–4% figure for circulating human B cells; page numbers were not available in our copy. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

May combine two claims.

TIM express several markers of exhausted cells and have an altered capability to phagocytose Aβ.

“Functional ex vivo studies on TIM indicate they express several markers of exhausted cells and have an altered capability to phagocytose A β .”

• cites [38] [38] [A. Millet, J.H. Ledo, S.F., Tavazoie, an exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer ' s brains, Immunity 57 (2024) 153 -170 e156.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0190) - sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

B cells produce cytokines and contribute to T cell activation through antigen presentation, which can shape overall immune responses.

“In addition, B cells produce cytokines and contribute to T cell activation through antigen presentation which can shape the overall immune responses [41,42].”

• cites [41] [41] [P. Shen, S. Fillatreau, Antibody-independent functions of B cells: a focus on cytokines, Nat. Rev. Immunol. (2015) 441 -451.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0205) - sourceNot checked — no full text of the source
• cites [42] [42] [I. Rastogi, D. Jeon, J.E. Moseman, A. Muralidhar, H.K. Potluri, D.G. McNeel, Role of B cells as antigen presenting cells, Front. Immunol. 13 (2022) 954936.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0210) - sourceSupported

May combine two claims.

IGHG1 is less well established as a causal AD gene and is more accurately described as residing within an AD associated locus rather than as a validated risk gene.

“IGHG1 , in contrast, is less well established as a causal AD gene and is more accurately described as residing within an AD associated locus rather than as a validated risk gene.”

• cites [26] [26] [P. Draber, I. Vonkova, O. Stepanek, M. Hrdinka, M. Kucova, T. Skopcova, P. Otahal, P. Angelisova, V. Horejsi, M. Yeung, A. Weiss, T. Brdicka, SCIMP, a transmembrane adaptor protein involved in major histocompatibility complex class II signaling, Mol. Cell. Biol. (2011) 4550 -4562.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0130) E.-L. Charavner et al. - sourceCould not verify

  The Introduction, Results, and Discussion passages address SCIMP and MHC-II signaling, not IGHG1 or Alzheimer’s disease. Searches for IGHG1, Alzheimer’s disease, and an AD-associated genetic locus found no passage addressing whether IGHG1 is a causal or validated risk gene. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [27] [27] [I.E. Jansen, J.E. Savage, K. Watanabe, J. Bryois, D.M. Williams, S. Steinberg, J. Sealock, I.K. Karlsson, S. Hagg, L. Athanasiu, N. Voyle, P. Proitsi, A. Witoelar, S. Stringer, D. Aarsland, I.S. Almdahl, F. Andersen, S. Bergh, F. Bettella, S. Bjornsson, A. Braekhus, G. Brathen, C. de Leeuw, R.S. Desikan, S. Djurovic, L. Dumitrescu, T. Fladby, T.J. Hohman, P.V. Jonsson, S.J. Kiddle, A. Rongve, I. Saltvedt, S.B. Sando, G. Selbaek, M. Shoai, N.G. Skene, J. Snaedal, E. Stordal, I. D. Ulstein, Y. Wang, L.R. White, J. Hardy, J. Hjerling-Leffler, P.F. Sullivan, W. M. van der Flier, R. Dobson, L sourceCould not verify

  The Results sections on implicated genes and AD-associated loci distinguish putative causal genes from locus-level associations, but they do not identify IGHG1 or place it within an AD-associated locus. Searches for IGHG1 and the immunoglobulin heavy-chain locus found no passage addressing its status as an AD risk gene. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [28] [28] [J.C. Lambert, C.A. Ibrahim-Verbaas, D. Harold, A.C. Naj, R. Sims, C. Bellenguez,](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0140) [A.L. DeStafano, J.C. Bis, G.W. Beecham, B. Grenier-Boley, G. Russo, T.A. Thorton-](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0140) [Wells, N. Jones, A.V. Smith, V. Chouraki, C. Thomas, M.A. Ikram, D. Zelenika, B.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0140) [N. Vardarajan, Y. Kamatani, C.F. Lin, A. Gerrish, H. Schmidt, B. Kunkle, M.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0140) - L. [Dunstan, A. Ruiz, M.T. Bihoreau, Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [29] [29] [J. Schwartzentruber, S. Cooper, J.Z. Liu, I. Barrio-Hernandez, E. Bello, N. Kumasaka, A.M.H. Young, R.J.M. Franklin, T. Johnson, K. Estrada, D. J. Gaffney, P. Beltrao, A. Bassett, Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer ' s disease risk genes, Nat. Genet. (2021) 392 -402.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0145) - sourceSupported
• cites [30] [30] [M. Hikida, S. Casola, N. Takahashi, T. Kaji, T. Takemori, K. Rajewsky, T. Kurosaki, PLC-gamma2 is essential for formation and maintenance of memory B cells, J. Exp. Med. (2009) 681 -689.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0150) - sourceCould not verify

  The Results discuss IgG1-positive B cells and PLC-γ2 in immunized mice, not IGHG1 as an Alzheimer’s disease risk gene. Searches for IGHG1, Alzheimer’s disease, and an AD-associated locus found no passage in our copy addressing the claim. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [31] [31] [L. Capitani, S.M. Carpanini, HLA ' s hidden hand in Alzheimer ' s disease-five research questions en route to an answer, Brain Commun. 7 (6) (2025) fcaf438.](http://refhub.elsevier.com/S0008-8749(26)00095-X/h9015) - sourceCould not verify

  The Introduction’s “HLA allele associations—which of the many?” section discusses AD-associated variants in the HLA locus and cautions that linkage can make causative genes difficult to identify (page unavailable). Searches for IGHG1 and its expanded gene name found no passage addressing whether IGHG1 lies in an AD-associated locus or is a validated risk gene. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [32] [32] [C. Fu, C.W. Turck, T. Kurosaki, A.C. Chan, BLNK: a central linker protein in B cell activation, Immunity (1998) 93 -103.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0160) - sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

B cells are a crucial component of the adaptive immune system, responsible for producing antibodies and providing defense against infectious agents.

“B cells are a crucial component of the adaptive immune system, responsible for producing antibodies, providing an important line of defense against infectious agents.”

• cites [41] [41] [P. Shen, S. Fillatreau, Antibody-independent functions of B cells: a focus on cytokines, Nat. Rev. Immunol. (2015) 441 -451.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0205) - sourceNot checked — no full text of the source
• cites [42] [42] [I. Rastogi, D. Jeon, J.E. Moseman, A. Muralidhar, H.K. Potluri, D.G. McNeel, Role of B cells as antigen presenting cells, Front. Immunol. 13 (2022) 954936.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0210) - sourceSupported

May combine two claims.

A substantial proportion of AD-associated risk alleles regulate enhancers specifically in microglia, and approximately 25% of candidate AD risk genes are highly or exclusively expressed by microglia or functionally tied to immune responses.

“Notably, a sub­ stantial proportion of AD-associated risk alleles have been shown to regulate enhancers specifically in microglia, and approximately 25% of candidate AD risk genes are highly or exclusively expressed by microglia or functionally tied to immune responses [21,22].”

• cites [21] [21] [E. Gjoneska, A.R. Pfenning, H. Mathys, G. Quon, A. Kundaje, L.H. Tsai, M. Kellis, Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease, Nature (2015) 365 -369.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0105) - sourcePartly supported

  The passages labeled Abstract (Figs. 2c and 3d; no page given) report enrichment of AD-associated variants in immune-related enhancers and show that one AD-associated variant increases enhancer activity in a microglial cell line. They do not establish that a substantial proportion of risk alleles regulate enhancers specifically in microglia, nor do they report that approximately 25% of candidate AD risk genes have the stated expression or immune-function characteristics. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [22] [22] [A.K. Hodges, T.M. Piers, D. Collier, O. Cousins, J.M. Pocock, Pathways linking Alzheimer's disease risk genes expressed highly in microglia, Neuroimmunol. Neuroinflammat. 8 (2021) 245.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0110) - sourcePartly supported

  The Abstract states that around 25% of approximately 84 AD risk genes have enriched or exclusive expression in microglia and/or are linked to immune function; the Introduction similarly reports 20 of 84 genes with enriched or exclusive microglial expression. The passages found for “enhancer” and microglial regulatory variants do not state that a substantial proportion of AD risk alleles regulate enhancers specifically in microglia, so that part is unsupported by our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

TIM are detected in human AD single nucleus RNAseq datasets, suggesting similar patterns of microglia transcriptional states exist in AD.

“Remarkably, TIM are also detected in human AD single nucleus RNAseq datasets, suggesting that similar patterns of microglia transcriptional states exist in AD [38].”

• cites [38] [38] [A. Millet, J.H. Ledo, S.F., Tavazoie, an exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer ' s brains, Immunity 57 (2024) 153 -170 e156.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0190) - sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

A longitudinal single-cell RNAseq atlas defined DAM states as a transitional profile leading to a terminally inflammatory microglia (TIM) state, enriched in stress and inflammatory genes and devoid of homeostatic gene expression.

“More recently, a longitudinal single-cell RNAseq atlas of microglial cells during experimental AD has defined DAM states as a transitional profile that ultimately leads to a terminally inflammatory microglia (TIM) state, which is enriched in stress and inflammatory genes, and is devoid of homeostatic genes expression [38].”

• cites [38] [38] [A. Millet, J.H. Ledo, S.F., Tavazoie, an exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer ' s brains, Immunity 57 (2024) 153 -170 e156.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0190) - sourcePartly supported

  In Results, the single-cell RNA-sequencing section reports a modeled flow from homeostatic microglia through inflammatory clusters to TIMs; the Discussion describes TIMs as expressing inflammatory markers and stress signatures. The passages do not identify DAMs specifically as the transitional stage or establish that TIMs lack all homeostatic gene expression. The Results also describe TIMs as less inflammatory than DAMs in their predicted cell interactions. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Lecanemab and donanemab clear Aβ plaque deposits and slow cognitive decline by 25 to 30%.

“More recently, lecanemab (approved in 2023) and donanemab (approved in 2024) have demonstrated the ability to clear A β plaque deposits and slow cognitive decline by 25 to 30%”

• cites [11] [11] [C.H. van Dyck, C.J. Swanson, P. Aisen, R.J. Bateman, C. Chen, M. Gee, M. Kanekiyo, D. Li, L. Reyderman, S. Cohen, L. Froelich, S. Katayama, M. Sabbagh, B. Vellas, D. Watson, S. Dhadda, M. Irizarry, L.D. Kramer, T. Iwatsubo, Lecanemab in early Alzheimer ' s disease, N. Engl. J. Med. 388 (2023) 9 -21.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0055) - sourcePartly supported

  The End-Point Results report that lecanemab reduced brain amyloid burden and that CDR-SB worsening at 18 months was 1.21 versus 1.66 with placebo—approximately 27% less decline on that measure. The paper does not establish the claimed effects for donanemab or substantiate the stated approval dates. (LLM, conf=0.91)

  Experimental — accuracy not yet measured
• cites [12] [12] [J.R. Sims, J.A. Zimmer, C.D. Evans, M. Lu, P. Ardayfio, J. Sparks, A.M. Wessels, S. Shcherbinin, H. Wang, E.S. Monkul Nery, E.C. Collins, P. Solomon, S. Salloway, L.G. Apostolova, O. Hansson, C. Ritchie, D.A. Brooks, M. Mintun, D. M. Skovronsky, Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial, JAMA (2023) 512 -527.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0060) - sourcePartly supported

  The Clinical Assessments section reports amyloid clearance with donanemab and 28.9% slower clinical progression on the CDR-SB scale in the combined population. The paper describes promising plaque clearance with lecanemab, but does not give a 25–30% slowing figure for it or substantiate the approval years in the citing sentence. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

SCIMP is expressed across myeloid and B cell lineages and has been identified as an AD-associated locus.

“SCIMP is expressed accross myeloid and B cell lineages and has been identified as an AD-associated locus.”

• cites [26] [26] [P. Draber, I. Vonkova, O. Stepanek, M. Hrdinka, M. Kucova, T. Skopcova, P. Otahal, P. Angelisova, V. Horejsi, M. Yeung, A. Weiss, T. Brdicka, SCIMP, a transmembrane adaptor protein involved in major histocompatibility complex class II signaling, Mol. Cell. Biol. (2011) 4550 -4562.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0130) E.-L. Charavner et al. - sourcePartly supported

  The Results (page not provided) report SCIMP expression in B cells, monocytes, and monocyte-derived dendritic cells, supporting the expression claim. The passages from our copy do not identify SCIMP as an AD-associated locus; a search for that association found no supporting passage. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [27] [27] [I.E. Jansen, J.E. Savage, K. Watanabe, J. Bryois, D.M. Williams, S. Steinberg, J. Sealock, I.K. Karlsson, S. Hagg, L. Athanasiu, N. Voyle, P. Proitsi, A. Witoelar, S. Stringer, D. Aarsland, I.S. Almdahl, F. Andersen, S. Bergh, F. Bettella, S. Bjornsson, A. Braekhus, G. Brathen, C. de Leeuw, R.S. Desikan, S. Djurovic, L. Dumitrescu, T. Fladby, T.J. Hohman, P.V. Jonsson, S.J. Kiddle, A. Rongve, I. Saltvedt, S.B. Sando, G. Selbaek, M. Shoai, N.G. Skene, J. Snaedal, E. Stordal, I. D. Ulstein, Y. Wang, L.R. White, J. Hardy, J. Hjerling-Leffler, P.F. Sullivan, W. M. van der Flier, R. Dobson, L sourcePartly supported

  The Results section (‘Genome-wide meta-analysis for AD status’; page unavailable) identifies SCIMP among loci previously discovered in AD genetic studies. Our copy does not state that SCIMP is expressed across myeloid and B-cell lineages; its cell-expression discussion does not establish that gene-specific claim. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [28] [28] [J.C. Lambert, C.A. Ibrahim-Verbaas, D. Harold, A.C. Naj, R. Sims, C. Bellenguez,](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0140) [A.L. DeStafano, J.C. Bis, G.W. Beecham, B. Grenier-Boley, G. Russo, T.A. Thorton-](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0140) [Wells, N. Jones, A.V. Smith, V. Chouraki, C. Thomas, M.A. Ikram, D. Zelenika, B.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0140) [N. Vardarajan, Y. Kamatani, C.F. Lin, A. Gerrish, H. Schmidt, B. Kunkle, M.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0140) - L. [Dunstan, A. Ruiz, M.T. Bihoreau, Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [29] [29] [J. Schwartzentruber, S. Cooper, J.Z. Liu, I. Barrio-Hernandez, E. Bello, N. Kumasaka, A.M.H. Young, R.J.M. Franklin, T. Johnson, K. Estrada, D. J. Gaffney, P. Beltrao, A. Bassett, Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer ' s disease risk genes, Nat. Genet. (2021) 392 -402.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0145) - sourceCould not verify

  The Results sections on AD risk loci and gene-expression colocalization discuss other genes, but the passages found do not identify SCIMP as an AD-associated locus or describe its expression in myeloid and B-cell lineages. Searches for “SCIMP” and for those cell lineages found no passage addressing the claim. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [30] [30] [M. Hikida, S. Casola, N. Takahashi, T. Kaji, T. Takemori, K. Rajewsky, T. Kurosaki, PLC-gamma2 is essential for formation and maintenance of memory B cells, J. Exp. Med. (2009) 681 -689.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0150) - sourceCould not verify

  The Results and Materials and Methods passages concern PLC-γ2 and memory B cells, not SCIMP. Searches for SCIMP expression across myeloid and B cell lineages and for an AD-associated locus found no passage addressing either claim in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [31] [31] [L. Capitani, S.M. Carpanini, HLA ' s hidden hand in Alzheimer ' s disease-five research questions en route to an answer, Brain Commun. 7 (6) (2025) fcaf438.](http://refhub.elsevier.com/S0008-8749(26)00095-X/h9015) - sourceCould not verify

  The Introduction discusses AD-associated HLA variants and expression of MHC-II in microglia, but neither passage addresses SCIMP. Searches of our copy for “SCIMP” and for myeloid and B-cell lineages found no passage establishing SCIMP expression or its identification as an AD-associated locus. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [32] [32] [C. Fu, C.W. Turck, T. Kurosaki, A.C. Chan, BLNK: a central linker protein in B cell activation, Immunity (1998) 93 -103.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0160) - sourceNot checked — no full text of the source

May combine two claims.

BLNK is a central adaptor downstream of BCR, and PLCG2 is a major BCR proximal signaling node implicated in germinal center and memory B cell formation.

“Two further loci provide more direct mechanistic links to B cell receptor (BCR) signaling: BLNK is a central adaptor downstream of the BCR, and PLCG2 is a major BCR proximal signaling node implicated in germinal center and memory B cell formation.”

• cites [26] [26] [P. Draber, I. Vonkova, O. Stepanek, M. Hrdinka, M. Kucova, T. Skopcova, P. Otahal, P. Angelisova, V. Horejsi, M. Yeung, A. Weiss, T. Brdicka, SCIMP, a transmembrane adaptor protein involved in major histocompatibility complex class II signaling, Mol. Cell. Biol. (2011) 4550 -4562.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0130) E.-L. Charavner et al. - sourcePartly supported

  The Introduction identifies SLP65 as BLNK and describes its role in BCR signal transduction, including its association with PLC-γ2. The Discussion also reports PLC-γ2 phosphorylation in a SCIMP signaling experiment. Neither passage links PLC-γ2 to germinal center or memory B cell formation. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [27] [27] [I.E. Jansen, J.E. Savage, K. Watanabe, J. Bryois, D.M. Williams, S. Steinberg, J. Sealock, I.K. Karlsson, S. Hagg, L. Athanasiu, N. Voyle, P. Proitsi, A. Witoelar, S. Stringer, D. Aarsland, I.S. Almdahl, F. Andersen, S. Bergh, F. Bettella, S. Bjornsson, A. Braekhus, G. Brathen, C. de Leeuw, R.S. Desikan, S. Djurovic, L. Dumitrescu, T. Fladby, T.J. Hohman, P.V. Jonsson, S.J. Kiddle, A. Rongve, I. Saltvedt, S.B. Sando, G. Selbaek, M. Shoai, N.G. Skene, J. Snaedal, E. Stordal, I. D. Ulstein, Y. Wang, L.R. White, J. Hardy, J. Hjerling-Leffler, P.F. Sullivan, W. M. van der Flier, R. Dobson, L sourceCould not verify

  The Results section on Alzheimer’s disease loci names CLNK, not BLNK, and the Discussion describes broad immune-system involvement. Searches for BLNK, PLCG2, B-cell receptor signaling, and germinal-center or memory B-cell formation found no passage in our copy addressing the claimed roles of BLNK or PLCG2. No page numbers were available for these passages. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [28] [28] [J.C. Lambert, C.A. Ibrahim-Verbaas, D. Harold, A.C. Naj, R. Sims, C. Bellenguez,](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0140) [A.L. DeStafano, J.C. Bis, G.W. Beecham, B. Grenier-Boley, G. Russo, T.A. Thorton-](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0140) [Wells, N. Jones, A.V. Smith, V. Chouraki, C. Thomas, M.A. Ikram, D. Zelenika, B.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0140) [N. Vardarajan, Y. Kamatani, C.F. Lin, A. Gerrish, H. Schmidt, B. Kunkle, M.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0140) - L. [Dunstan, A. Ruiz, M.T. Bihoreau, Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [29] [29] [J. Schwartzentruber, S. Cooper, J.Z. Liu, I. Barrio-Hernandez, E. Bello, N. Kumasaka, A.M.H. Young, R.J.M. Franklin, T. Johnson, K. Estrada, D. J. Gaffney, P. Beltrao, A. Bassett, Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer ' s disease risk genes, Nat. Genet. (2021) 392 -402.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0145) - sourceCould not verify

  The Results section on network evidence names PLCG2 as an Alzheimer’s disease gene with a high network score, but does not describe its role in B-cell receptor signaling. Searches for BLNK, BCR signaling, and germinal-center or memory B-cell formation found no passage addressing the claimed mechanisms in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [30] [30] [M. Hikida, S. Casola, N. Takahashi, T. Kaji, T. Takemori, K. Rajewsky, T. Kurosaki, PLC-gamma2 is essential for formation and maintenance of memory B cells, J. Exp. Med. (2009) 681 -689.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0150) - sourcePartly supported

  The paper’s Abstract identifies PLC-γ2 as an important BCR-signaling component and reports that it is required for efficient germinal-center and memory B-cell formation. The Discussion mentions BLNK-deficient mice, but does not describe BLNK as a central adaptor downstream of the BCR. That part of the sentence is therefore unsupported by this source. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [31] [31] [L. Capitani, S.M. Carpanini, HLA ' s hidden hand in Alzheimer ' s disease-five research questions en route to an answer, Brain Commun. 7 (6) (2025) fcaf438.](http://refhub.elsevier.com/S0008-8749(26)00095-X/h9015) - sourceCould not verify

  The Introduction discusses HLA-mediated antigen presentation and T-cell responses in Alzheimer’s disease, but the passages in our copy do not address BLNK, PLCG2, BCR signaling, or germinal-center and memory B-cell formation. Searches for both gene names and those B-cell processes found no passage supporting the attributed mechanisms. (LLM, conf=0.75)

  Experimental — accuracy not yet measured
• cites [32] [32] [C. Fu, C.W. Turck, T. Kurosaki, A.C. Chan, BLNK: a central linker protein in B cell activation, Immunity (1998) 93 -103.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0160) - sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

APOE ε4 allele is the highest genetic risk factor for LOAD.

“Among these genes, apolipoprotein E ( APOE ; especially the APOE ε 4 allele) is the highest genetic risk factor for LOAD [23,24].”

• cites [23] [23] [A.M. Saunders, W.J. Strittmatter, D. Schmechel, P.H. George-Hyslop, M. A. Pericak-Vance, S.H. Joo, B.L. Rosi, J.F. Gusella, D.R. Crapper-MacLachlan, M. J. Alberts, et al., Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease, Neurology 43 (1993) 1467 -1472.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0115) - sourcePartly supported

  The Abstract and Statistical analysis section report an association between APOE ε4 and late-onset familial and sporadic Alzheimer’s disease, and describe ε4 as a possible susceptibility gene or risk factor. They do not establish that it is the highest genetic risk factor relative to other genes. Page numbers are not available in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [24] [24] [W.J. Strittmatter, A.M. Saunders, D. Schmechel, M. Pericak-Vance, J. Enghild, G. S. Salvesen, A.D. Roses, Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease, Proc. Natl. Acad. Sci. USA 90 (1993) 1977 -1981.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0120) - sourcePartly supported

  The allele-association passage (section labeled Materials and Methods; page unavailable) reports that APOE ε4 was significantly more frequent in patients with late-onset familial Alzheimer disease than in controls. It does not compare APOE ε4 with other genetic risk factors or establish that it is the highest risk factor for LOAD generally; the paper says sporadic disease will be addressed in another report. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

CD4+ and CD8+ T cells have been most extensively studied, with evidence of their presence in brain parenchyma and CSF of AD patients, where they modulate neuroinflammation and contribute to neurodegeneration.

“Among these, CD4 + and CD8 + T cells have been the most extensively studied, with compelling evidence of their presence in the brain parenchyma and cerebrospinal fluid (CSF) of AD patients, where they have been shown to modulate neuroinflammation and contribute to neurodegeneration (reviewed in [40]).”

• cites [40] [40] [B.M. Bettcher, M.G. Tansey, G. Dorothee, M.T. Heneka, Peripheral and central immune system crosstalk in Alzheimer disease - a research prospectus, Nat. Rev. Neurol. 17 (2021) 689 -701.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0200) - sourcePartly supported

  The Clinical studies of immune dysregulation section reports CD8+ T cells in the CSF and hippocampi of patients with AD, and the Mechanistic insight from animal studies section reports T-cell infiltration in AD brain parenchyma. But the review does not establish that both CD4+ and CD8+ cells are present in both locations or that they have been shown to cause neurodegeneration in patients. It says their functional significance needs further study, while mouse studies show both beneficial and detrimental effects. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

HLA class II locus encompassing HLA-DRB1/HLA-DQA1 is a well established AD risk locus, although extensive linkage disequilibrium makes it difficult to pin down the specific causal gene.

“The HLA class II locus encom­ passing HLA-DRB1/HLA-DQA1 is also a well established AD risk locus, although extensive linkage disequilibrium across this region makes it difficult to pin down the specific causal gene.”

• cites [26] [26] [P. Draber, I. Vonkova, O. Stepanek, M. Hrdinka, M. Kucova, T. Skopcova, P. Otahal, P. Angelisova, V. Horejsi, M. Yeung, A. Weiss, T. Brdicka, SCIMP, a transmembrane adaptor protein involved in major histocompatibility complex class II signaling, Mol. Cell. Biol. (2011) 4550 -4562.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0130) E.-L. Charavner et al. - sourceCould not verify

  The Introduction and Discussion discuss MHC class II signaling and SCIMP, not Alzheimer’s disease genetics. Searches for HLA-DRB1/HLA-DQA1, an AD risk locus, and linkage disequilibrium found no passage addressing the claimed association or difficulty identifying a causal gene; the retrieved Methods and References passages do not address it either. No page numbers were available in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [27] [27] [I.E. Jansen, J.E. Savage, K. Watanabe, J. Bryois, D.M. Williams, S. Steinberg, J. Sealock, I.K. Karlsson, S. Hagg, L. Athanasiu, N. Voyle, P. Proitsi, A. Witoelar, S. Stringer, D. Aarsland, I.S. Almdahl, F. Andersen, S. Bergh, F. Bettella, S. Bjornsson, A. Braekhus, G. Brathen, C. de Leeuw, R.S. Desikan, S. Djurovic, L. Dumitrescu, T. Fladby, T.J. Hohman, P.V. Jonsson, S.J. Kiddle, A. Rongve, I. Saltvedt, S.B. Sando, G. Selbaek, M. Shoai, N.G. Skene, J. Snaedal, E. Stordal, I. D. Ulstein, Y. Wang, L.R. White, J. Hardy, J. Hjerling-Leffler, P.F. Sullivan, W. M. van der Flier, R. Dobson, L sourcePartly supported

  The Results sections on functional interpretation and implicated genes identify an AD-associated HLA-DRB1 locus, list HLA-DRB1 and HLA-DQA among implicated genes, and nominate 345 of 434 variants there as plausible causal SNPs. This supports difficulty resolving the causal signal, but the passages do not specifically say that extensive linkage disequilibrium across the HLA region prevents identification of the causal gene. Page numbers are unavailable in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [28] [28] [J.C. Lambert, C.A. Ibrahim-Verbaas, D. Harold, A.C. Naj, R. Sims, C. Bellenguez,](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0140) [A.L. DeStafano, J.C. Bis, G.W. Beecham, B. Grenier-Boley, G. Russo, T.A. Thorton-](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0140) [Wells, N. Jones, A.V. Smith, V. Chouraki, C. Thomas, M.A. Ikram, D. Zelenika, B.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0140) [N. Vardarajan, Y. Kamatani, C.F. Lin, A. Gerrish, H. Schmidt, B. Kunkle, M.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0140) - L. [Dunstan, A. Ruiz, M.T. Bihoreau, Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [29] [29] [J. Schwartzentruber, S. Cooper, J.Z. Liu, I. Barrio-Hernandez, E. Bello, N. Kumasaka, A.M.H. Young, R.J.M. Franklin, T. Johnson, K. Estrada, D. J. Gaffney, P. Beltrao, A. Bassett, Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer ' s disease risk genes, Nat. Genet. (2021) 392 -402.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0145) - sourcePartly supported

  The Online Methods treat HLA as an AD risk locus, and Extended Data Fig. 2 cautions that its fine-mapping results should be interpreted carefully. But our copy does not identify the locus as encompassing HLA-DRB1/HLA-DQA1 or say that extensive LD across that region prevents identification of the causal gene; the fine-mapping discussion instead points to sensitivity to the reference panel. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [30] [30] [M. Hikida, S. Casola, N. Takahashi, T. Kaji, T. Takemori, K. Rajewsky, T. Kurosaki, PLC-gamma2 is essential for formation and maintenance of memory B cells, J. Exp. Med. (2009) 681 -689.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0150) - sourceCould not verify

  The Discussion addresses PLC-γ2 signaling and memory B-cell maintenance, not Alzheimer’s disease risk. Searches for HLA-DRB1/HLA-DQA1, the HLA class II locus, and linkage disequilibrium found no passage addressing the claimed risk locus or difficulty identifying a causal gene. Page numbers were not available in our copy. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [31] [31] [L. Capitani, S.M. Carpanini, HLA ' s hidden hand in Alzheimer ' s disease-five research questions en route to an answer, Brain Commun. 7 (6) (2025) fcaf438.](http://refhub.elsevier.com/S0008-8749(26)00095-X/h9015) - sourceSupported
• cites [32] [32] [C. Fu, C.W. Turck, T. Kurosaki, A.C. Chan, BLNK: a central linker protein in B cell activation, Immunity (1998) 93 -103.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0160) - sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Microglial cells are the main innate immune population residing in the CNS and play a critical role in CNS immune surveillance and tissue homeostasis through clearance of pathogens, dead cells, and protein aggregates such as Aβ.

“Microglial cells represent the main innate immune population residing in the central nervous system (CNS). Through the clearance of pathogens, dead cells, and protein aggregates such as A β , they play a critical role in CNS immune surveillance and the preservation of tissue homeostasis [33,34].”

• cites [33] [33] [A. Nimmerjahn, F. Kirchhoff, F. Helmchen, Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo, Science 308 (2005) 1314 -1318.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0165) - sourceNot checked — no full text of the source
• cites [34] [34] [D.V. Hansen, J.E. Hanson, M. Sheng, Microglia in Alzheimer ' s disease, J. Cell Biol. 217 (2018) 459 -472.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0170) - sourceSupported

May combine two claims.

In an in vitro 3D model recreating interactions between AD cerebral tissue and the immune system, B cells do not preferentially infiltrate AD 3D cultures compared to control cultures; instead B cell infiltration was significantly reduced, particularly in the presence of microglia.

“The results revealed that B cells do not preferentially infiltrate AD 3D cultures compared to control cultures. Instead, B cell infiltration was significantly reduced, particularly in the presence of microglia [83].”

• cites [83] [83] M. Jorfi, J. Park, C.K. Hall, C.J. Lin, M. Chen, D. von Maydell, J.M. Kruskop, B. Kang, Y. Choi, D. Prokopenko, D. Irimia, D.Y. Kim, R.E. Tanzi, Infiltrating CD8( + ) T cells exacerbate Alzheimer ' s disease pathology in a 3D human neuroimmune axis model, Nat. Neurosci. 26 (2023) 1489 -1504. - sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Upon migration to the spleen, transitional B cells differentiate into follicular (naïve) B cells and marginal zone B cells.

“Upon migration to the spleen, transitional B cells differentiate into two subsets of B2 B cells: follicular (e.g. naïve) B cells and marginal zone B cells (MZB).”

• cites [51] [51] [M. Zouali, Y. Richard, Marginal zone B-cells, a gatekeeper of innate immunity, Front. Immunol. 2 (2011) 63.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0255) - sourcePartly supported

  The Marginal Zone B-Cells section distinguishes follicular and marginal zone B cells as mature populations, and the paper describes them as two specialized B-cell populations. Our copy does not state that transitional B cells migrate to the spleen and differentiate into these populations, or identify both as B2 subsets (no page numbers provided). (LLM, conf=0.78)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

In mice, Bregs can arise from various developmental stages including B1 B cells, transitional B cells, marginal zone B cells, follicular B cells and plasmocytes.

“In mice, Bregs can arise from various developmental stages, including B1 B cells, transitional B cells, marginal zone B cells, follicular B cells and plasmocytes [62].”

• cites [62] [62] [E.C. Rosser, C. Mauri, Regulatory B cells: origin, phenotype, and function, Immunity 42 (2015) 607 -612.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0310) - sourcePartly supported

  The Introduction (page unavailable) says that immature and mature B cells and plasmablasts can differentiate into IL-10-producing Breg cells in mice, and it describes transitional marginal-zone precursor cells and regulatory plasma cells. It does not specifically establish B1, follicular, and marginal-zone B cells as separate origins in the claimed list; it also says the developmental links among Breg subsets remain unknown. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

Although B cells infiltrated the in vitro 3D model of AD brain in very low numbers, they significantly elevated protein levels of complement proteins and chemokines compared to cultures lacking B cells.

“Although B cells infiltrated the in vitro 3D model of AD brain in very low numbers, they significantly elevated protein levels of complement proteins and chemokines compared to cultures lacking B cells [83].”

• cites [83] [83] M. Jorfi, J. Park, C.K. Hall, C.J. Lin, M. Chen, D. von Maydell, J.M. Kruskop, B. Kang, Y. Choi, D. Prokopenko, D. Irimia, D.Y. Kim, R.E. Tanzi, Infiltrating CD8( + ) T cells exacerbate Alzheimer ' s disease pathology in a 3D human neuroimmune axis model, Nat. Neurosci. 26 (2023) 1489 -1504. - sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Bregs are B cells with regulatory and immunosuppressive functions that maintain immunological homeostasis by producing IL-10, IL-35, and TGFβ, thereby suppressing immunopathology.

“Bregs is a generic term used to define B cells endowed with regulatory and immunosuppressive functions. They play a crucial role in maintain­ ing immunological homeostasis by producing anti-inflammatory cyto­ kines such as interleukin-10 (IL-10), IL-35, and transforming growth factor-beta (TGFβ ), thereby suppressing immunopathology.”

• cites [53] [53] [S.D. Wolf, B.N. Dittel, F. Hardardottir, C.A. Janeway Jr., Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice, J. Exp. Med. 184 (1996) 2271 -2278.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0265) - sourcePartly supported

  The Discussion proposes that B cells may help regulate immune responses during EAE, which supports the broad regulatory role attributed to them. It does not define Bregs or show that B cells produce IL-10, IL-35, or TGFβ; it identifies T cells as producers of IL-10 and TGF-β1 and does not mention IL-35. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [54] [54] [S. Fillatreau, C.H. Sweenie, M.J. McGeachy, D. Gray, S.M. Anderton, B cells regulate autoimmunity by provision of IL-10, Nat. Immunol. 3 (2002) 944 -950.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0270) - sourceNot checked — no full text of the source
• cites [55] [55] [P. Shen, T. Roch, V. Lampropoulou, R.A. O'Connor, U. Stervbo, E. Hilgenberg, S. Ries, V.D. Dang, Y. Jaimes, C. Daridon, R. Li, L. Jouneau, P. Boudinot, S. Wilantri, I. Sakwa, Y. Miyazaki, M.D. Leech, R.C. McPherson, S. Wirtz, M. Neurath, K. Hoehlig, E. Meinl, A. Grutzkau, J.R. Grun, K. Horn, A.A. Kuhl, T. Dorner, A. Bar-Or, S.H.E. Kaufmann, S.M. Anderton, S. Fillatreau, IL-35producing B cells are critical regulators of immunity during autoimmune and infectious diseases, Nature 507 (2014) 366 -370.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0275) - sourcePartly supported

  The Results & Discussion section describes B-cell suppression of autoimmune inflammation through IL-10 and identifies IL-35-producing B cells as regulators of immunity. It does not identify TGFβ as a cytokine produced by these regulatory B cells, so the three-cytokine account is only partly supported. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [56] [56] [Q. Ding, M. Yeung, G. Camirand, Q. Zeng, H. Akiba, H. Yagita, G. Chalasani, M. H. Sayegh, N. Najafian, D.M. Rothstein, Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice, J. Clin. Invest. 121 (2011) 3645 -3656.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0280) - sourcePartly supported

  The Introduction describes regulatory B cells that inhibit inflammation in an IL-10-dependent manner, and the Discussion says Bregs promote tolerance in several mouse models. These passages support the regulatory function and IL-10 portion of the claim, but the paper does not identify IL-35 or TGFβ as cytokines produced by Bregs. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [57] [57] [P.A. Blair, L.Y. Norena, F. Flores-Borja, D.J. Rawlings, D.A. Isenberg, M. R. Ehrenstein, C. Mauri, CD19( + )CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients, Immunity (2010) 129 -140.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0285) - sourcePartly supported

  The Results report that human regulatory B cells suppress CD4+ T-cell inflammatory responses partly through IL-10, supporting their regulatory function. But the same section finds suppression is not dependent on TGF-β, and the passages found do not identify IL-35 as a mediator. The paper therefore does not support the full three-cytokine account. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [58] [58] [V. Lampropoulou, K. Hoehlig, T. Roch, P. Neves, E. Calderon Gomez, C. H. Sweenie, Y. Hao, A.A. Freitas, U. Steinhoff, S.M. Anderton, S. Fillatreau, TLRactivated B cells suppress T cell-mediated autoimmunity, J. Immunol. (2008) 4763 -4773.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0290) - sourceNot checked — no full text of the source

May combine two claims.

B cell production and/or maturation are affected by AD.

“suggest that B cell production and/or maturation are affected by AD [78,93].”

• cites [78] [78] [M. Bulati, S. Buffa, A. Martorana, F. Gervasi, C. Camarda, D.M. Azzarello, R. Monastero, C. Caruso, G. Colonna-Romano, Double negative (IgG + IgD-CD27-) B cells are increased in a cohort of moderate-severe Alzheimer ' s disease patients and show a pro-inflammatory trafficking receptor phenotype, J. Alzheimer ' s Dis 44 (2015) 1241 -1251.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0390) - sourceNot checked — no full text of the source
• cites [93] [93] [S. Humblet-Baron, Y. Feng, R. Veiga, J. Neumann, T. Prezzemolo, E. Pasciuto, R. Vandenberghe, L. Yshii, A. Liston, A systems immunology analysis of Alzheimer ' s disease reveals an age- and environmental exposure-independent disturbance in B cell maturation, Alzheimers Dement. 21 (11) (2025) e70952.](http://refhub.elsevier.com/S0008-8749(26)00095-X/h9005) - sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Breg differentiation is influenced by signals such as CD40 ligation, TLR stimulation, and cytokine exposure.

“Their differentiation is influenced by signals such as CD40 ligation, TLR stimulation, and cytokine exposure [58,63,64].”

• cites [58] [58] [V. Lampropoulou, K. Hoehlig, T. Roch, P. Neves, E. Calderon Gomez, C. H. Sweenie, Y. Hao, A.A. Freitas, U. Steinhoff, S.M. Anderton, S. Fillatreau, TLRactivated B cells suppress T cell-mediated autoimmunity, J. Immunol. (2008) 4763 -4773.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0290) - sourceNot checked — no full text of the source
• cites [63] [63] [V. Lampropoulou, E. Calderon-Gomez, T. Roch, P. Neves, P. Shen, U. Stervbo, P. Boudinot, S.M. Anderton, S. Fillatreau, Suppressive functions of activated B cells in autoimmune diseases reveal the dual roles of toll-like receptors in immunity, Immunol. Rev. (2010) 146 -161.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0315) - sourceNot checked — no full text of the source
• cites [64] [64] [K. Yanaba, J.D. Bouaziz, T. Matsushita, T. Tsubata, T.F. Tedder, The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals, J. Immunol. (2009) 7459 -7472.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0320) - sourcePartly supported

  The Discussion (page not provided) says CD40 signals may facilitate B10-cell maturation and that TLR signaling is critical for B10-cell effector function. It does not establish cytokine exposure as an influence on differentiation; it also says CD40 is not required for normal B10-cell development in vivo. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

During ageing, remodelling of peripheral B cell subsets occurs with a decline in B cell production in the bone marrow and expansion of atypical B cell subsets such as ABCs and DN B cells.

“During ageing, a remodelling of peripheral B cell subsets occurs with a decline in B cell production in the bone marrow and the expansion of atypical B cell subsets, such as age-associated B cells (ABCs) and double-negative (DN) B cells.”

• cites [65] [65] [M.P. Cancro, Y. Hao, J.L. Scholz, R.L. Riley, D. Frasca, D.K. Dunn-Walters, B.B. B. lomberg, B cells and aging: molecules and mechanisms, Trends Immunol. (2009) 313 -318.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0325) - sourcePartly supported

  The sections “B-cell production wanes with age” and “Homeostatic relationships shift with age” report reduced bone-marrow B-cell output and age-related changes in mature B-cell subsets. They discuss B1 and marginal-zone B cells, but do not identify an expansion of age-associated B cells (ABCs) or double-negative (DN) B cells. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [66] [66] [D. Frasca, B.B.B. lomberg, Aging induces B cell defects and decreased antibody responses to influenza infection and vaccination, Immun. Ageing (2020) 37.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0330) - sourcePartly supported

  The “Age effects on B cell subsets” section describes age-related redistribution of peripheral B cell subsets and a significant expansion of DN B cells; it also identifies DN B cells as the human equivalent of mouse ABCs. It does not state that B cell production in the bone marrow declines with age, so that part of the claim is unsupported by our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [67] [67] K.L. Gibson, Y.C. Wu, Y. Barnett, O. Duggan, R. Vaughan, E. Kondeatis, B. O. Nilsson, A. Wikby, D. Kipling, D.K. Dunn-Walters, B-cell diversity decreases in old age and is correlated with poor health status, Aging Cell (2009) 18 -25. sourcePartly supported

  The Discussion (page not provided) reports an age-related increase in the proportion of memory B cells in mice and humans, supporting a change in peripheral B-cell composition. It says reduced bone-marrow B-cell output has been shown in mice but is not known in older humans, and it does not identify expanding age-associated B cells (ABCs) or double-negative (DN) B cells. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [68] [68] M.E. Weksler, P. Szabo, The effect of age on the B-cell repertoire, J. Clin. Immunol. 20 (2000) 240 -249. - sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

ABCs are characterized by distinct gene expression profiles with expression of transcription factors T-BET, IRF5, and ZEB2.

“ABCs are characterized by their distinct gene expression profiles with the expression of a set a transcription factor including T-BET, IRF5, and ZEB2 [73 -75].”

• cites [73] [73] [D. Dai, S. Gu, X. Han, H. Ding, Y. Jiang, X. Zhang, C. Yao, S. Hong, J. Zhang, Y. Shen, G. Hou, B. Qu, H. Zhou, Y. Qin, Y. He, J. Ma, Z. Yin, Z. Ye, J. Qian, Q. Jiang, L. Wu, Q. Guo, S. Chen, C. Huang, L.C. Kottyan, M.T. Weirauch, C. G. Vinuesa, N. Shen, The transcription factor ZEB2 drives the formation of ageassociated B cells, Science 383 (2024) 413 -421.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0365) - sourceSupported
• cites [74] [74] [M. Manni, S. Gupta, E. Ricker, Y. Chinenov, S.H. Park, M. Shi, T. Pannellini, R. Jessberger, L.B. Ivashkiv, A.B. Pernis, Regulation of age-associated B cells by IRF5 in systemic autoimmunity, Nat. Immunol. (2018) 407 -419.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0370) - sourcePartly supported

  The Results sections on distinctive transcriptional programs and chromatin landscape (page unavailable) report a distinctive profile in autoimmune-prone DKO ABCs, Tbx21 expression, and enrichment of T-bet and IRF binding motifs. The paper also identifies IRF5 as a regulator of these ABCs. It does not establish that ABCs generally express all three named factors: Zeb2 appears as a control locus in the Results and ChIP methods, not as evidence of ZEB2 expression in ABCs. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites [75] [75] [E. Zumaquero, S.L. Stone, C.D. Scharer, S.A. Jenks, A. Nellore, B. Mousseau, A. Rosal-Vela, D. Botta, J.E. Bradley, W. Wojciechowski, T. Ptacek, M.I. Danila, J. C. Edberg, S.L. Bridges Jr., R.P. Kimberly, W.W. Chatham, T.R. Schoeb, A. F. Rosenberg, J.M. Boss, I. Sanz, F.E. Lund, IFNgamma induces epigenetic programming of human T-Bet(Hi) B cells and promotes TLR7/8 and IL-21 induced differentiation, Elife 8 (2019) e41641.](http://refhub.elsevier.com/S0008-8749(26)00095-X/h9000) - sourcePartly supported

  The Results section on T-bet-high B cells reports a distinct gene-expression profile and higher TBX21 (T-BET) expression; page numbers are unavailable in our copy. It does not establish IRF5 or ZEB2 expression as features of these cells. Searches for both factors found no supporting passage. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

MZB cells located in the spleen's marginal zone are the first responders to blood-borne infectious agents due to their strategic location.

“MZB cells, located in the spleen's marginal zone, are the first responders to blood-borne infectious agents due to their strategic loca­ tion [51].”

• cites [51] [51] [M. Zouali, Y. Richard, Marginal zone B-cells, a gatekeeper of innate immunity, Front. Immunol. 2 (2011) 63.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0255) - sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

ABCs are characterized in mice by the surface phenotype CD19+, CD11c+, T-bet+, CD11b+, CD21-, CD23-, CD86+, MHCII+, and in humans by CD11c+, T-bet+, CD27-, IgD-, CD38-, CD21-.

“They are charac­ terized in mice by the surface phenotype CD19 + , CD11c + , T-bet + , CD11b + , CD21 , CD23 , CD86 + , MHCII + , and in humans by CD11c + , Tbet + , CD27 , IgD , CD38 , CD21 [69 -72].”

• cites [69] [69] [Y. Hao, P. O'Neill, M.S. Naradikian, J.L. Scholz, M.P. Cancro, A B-cell subset uniquely responsive to innate stimuli accumulates in aged mice, Blood (2011) 1294 -1304.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0345) - sourceNot checked — no full text of the source
• cites [70] [70] [S.A. Jenks, K.S. Cashman, E. Zumaquero, U.M. Marigorta, A.V. Patel, X. Wang, D. Tomar, M.C. Woodruff, Z. Simon, R. Bugrovsky, E.L. Blalock, C.D. Scharer, C. M. Tipton, C. Wei, S.S. Lim, M. Petri, T.B. Niewold, J.H. Anolik, G. Gibson, F. E. Lee, J.M. Boss, F.E. Lund, I. Sanz, Distinct effector B cells induced by](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0350) E.-L. Charavner et al. - [unregulated toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus, Immunity 49 (2018) 725 -739, e726.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0350) - sourcePartly supported

  The Results sections on DN2 cells describe the human phenotype: CD11c+, T-bet+, CD27−, IgD−, CD21−, and low or absent CD38. The Discussion says human DN2 cells share a T-bet+ CD11c-bright phenotype with mouse ABCs, but our copy does not establish the rest of the claimed mouse marker panel (CD19, CD11b, CD21, CD23, CD86, and MHCII). Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [71] [71] [A.V. Rubtsov, K. Rubtsova, A. Fischer, R.T. Meehan, J.Z. Gillis, J.W. Kappler, P. Marrack, Toll-like receptor 7 (TLR7)-driven accumulation of a novel CD11c( + ) B-cell population is important for the development of autoimmunity, Blood (2011) 1305 -1315.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0355) - sourcePartly supported

  The mouse-characterization and gene-expression sections support most of the listed mouse markers, including CD19, CD11c, CD11b, CD21 negativity, CD86, MHCII, and T-bet. The human-patient section supports CD11c positivity, CD21 negativity, and IgD negativity, but describes the cells as CD27-high and CD38-low, not CD27-negative and CD38-negative; it does not establish T-bet expression in human cells. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [72] [72] [S. Wang, J. Wang, V. Kumar, J.L. Karnell, B. Naiman, P.S. Gross, S. Rahman, K. Zerrouki, R. Hanna, C. Morehouse, N. Holoweckyj, H. Liu, Z. Manna, R. Goldbach-Mansky, S. Hasni, R. Siegel, M. Sanjuan, K. Streicher, M.P. Cancro, R. Kolbeck, R. Ettinger, IL-21 drives expansion and plasma cell differentiation of autoreactive CD11c(Hi)T-Bet( + ) B cells in SLE, Nat. Commun. 9 (2018) 1758.](http://refhub.elsevier.com/S0008-8749(26)00095-X/h9025) - sourcePartly supported

  The Introduction and Results (Phenotypes of CD11chi B cells from SLE patients; page unavailable) support several listed markers: murine ABCs express CD11c and T-bet, and the paper describes murine CD11b+CD21−CD23− cells and human CD11chiT-bet+CD21− cells with low CD27 and CD38. But it does not establish the full murine surface-marker list, including CD86+ and MHCII+, and it explicitly reports that a fraction of the human cells express IgD rather than being uniformly IgD−. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Bregs numbers and their suppressive abilities are often increased in response to chronic inflammation or autoimmune diseases.

“Bregs numbers and their suppressive abilities are often increased in response to chronic inflammation or autoimmune diseases [59,61].”

• cites [59] [59] [T. Matsushita, M. Horikawa, Y. Iwata, T.F. Tedder, Regulatory B cells (B10 cells) and regulatory T cells have independent roles in controlling experimental autoimmune encephalomyelitis initiation and late-phase immunopathogenesis, J. Immunol. (2010) 2240 -2252.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0295) - sourcePartly supported

  The Results section (‘B10 and Treg cell expansion during EAE’; page unavailable) reports increased B10 cell numbers and IL-10 production during experimental autoimmune encephalomyelitis in mice. The Discussion also reports that B10 cells from mice with EAE suppressed disease after transfer. These findings do not establish that Breg numbers and suppressive abilities are often increased across chronic inflammation or autoimmune diseases generally. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [61] [61] [A. Mizoguchi, E. Mizoguchi, H. Takedatsu, R.S. Blumberg, A.K. Bhan, Chronic](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0305) [intestinal inflammatory condition generates IL-10-producing regulatory B cell](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0305) [subset characterized by CD1d upregulation, Immunity 16 (2002) 219](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0305) [-](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0305) [230.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0305) - sourcePartly supported

  The Results (page unavailable) show that gut-associated B cells upregulated CD1d in mice with colitis, and transfer experiments show that these cells suppressed intestinal inflammation. The paper does not establish that Breg numbers and suppressive abilities are often increased across chronic inflammatory or autoimmune diseases; it reports no difference in the number of splenic CD1d-high B cells between diseased and control mice. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

Advancing age is accompanied by profound qualitative changes in the peripheral B cell repertoire with reduced clonotypic diversity and a shift towards autoreactive specificities.

“Advancing age is accompanied by profound qualitative changes in the peripheral B cell repertoire with reduced clonotypic diversity and a shift towards autoreactive specificities [65 -68].”

• cites [65] [65] [M.P. Cancro, Y. Hao, J.L. Scholz, R.L. Riley, D. Frasca, D.K. Dunn-Walters, B.B. B. lomberg, B cells and aging: molecules and mechanisms, Trends Immunol. (2009) 313 -318.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0325) - sourcePartly supported

  The “BCR diversity truncates with age” section reports a significant loss of peripheral-blood B-cell diversity in some older subjects, not all older people. “Homeostatic relationships shift with age” says autoreactive cells might enter the primary repertoire and notes age-associated autoreactive antibodies in mouse strains, but it does not establish a general shift of the peripheral B-cell repertoire toward autoreactive specificities. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [66] [66] [D. Frasca, B.B.B. lomberg, Aging induces B cell defects and decreased antibody responses to influenza infection and vaccination, Immun. Ageing (2020) 37.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0330) - sourceSupported
• cites [67] [67] K.L. Gibson, Y.C. Wu, Y. Barnett, O. Duggan, R. Vaughan, E. Kondeatis, B. O. Nilsson, A. Wikby, D. Kipling, D.K. Dunn-Walters, B-cell diversity decreases in old age and is correlated with poor health status, Aging Cell (2009) 18 -25. sourcePartly supported

  The Results report clonal expansions in older donors with distorted peripheral B-cell repertoires, supporting reduced clonotypic diversity in some older individuals. The paper does not show a shift toward autoreactive specificities; its Introduction mentions autoimmune disease only in discussing a possible regulatory role of B cells. The finding is also narrower than a change accompanying age generally. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [68] [68] M.E. Weksler, P. Szabo, The effect of age on the B-cell repertoire, J. Clin. Immunol. 20 (2000) 240 -249. - sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

B1 B cells are important producers of IL-10 after innate immune activation and are crucial in controlling lethal TLR-mediated inflammation by dampening excessive inflammation in an IL-10-dependent manner.

“In addition, B1 B cells are important producers of IL-10 after innate immune activation and are crucial in controlling lethal Toll-Like Re­ ceptor (TLR)-mediated inflammation by dampening excessive inflam­ mation in an IL-10-dependent manner [47,48].”

• cites [47] [47] [X. Zhang, E. Deriaud, X. Jiao, D. Braun, C. Leclerc, R. Lo-Man, Type I interferons protect neonates from acute inflammation through interleukin 10-producing B cells, J. Exp. Med. (2007) 1107 -1118.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0235) - sourcePartly supported

  The Results sections report that neonatal CD5+CD23− B cells produce IL-10 after TLR stimulation and that their IL-10 protects neonatal mice from lethal CpG-induced inflammation. The claim extends this finding to B1 B cells generally, whereas the demonstrated protection is specific to neonatal mice and the CD5+CD23− subset. The supplied passages do not give page numbers. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [48] [48] [A. O ' Garra, M. Howard, IL-10 production by CD5 B cells, Ann. N. Y. Acad. Sci. 651 (1992) 182 -199.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0240) - sourceNot checked — no full text of the source

May combine two claims.

These DN B cells have been associated with several inflammatory chronic disorders, which suggests they might be involved in the inflammatory component of AD.

“These DN B cells have been associated with several inflammatory chronic disorders which suggest that they might be involved in the inflammatory component of AD [91].”

• cites [91] [91] [M.K.Y. Chung, L. Gong, D.L. Kwong, V.H. Lee, A.W. Lee, X.Y. Guan, N.W. Kam, W. Dai, Functions of double-negative B cells in autoimmune diseases, infections, and cancers, EMBO Mol. Med. 15 (2023) e17341.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0455) - sourceSupported

May combine two claims.

B cell deficiency reduced neuroinflammation and restored microglia function in 3xTgAD or APP/PS1 mice.

“B cell deficiency reduced neuroinflammation and restored microglia function [108].”

• cites [108] [108] [K. Kim, X. Wang, E. Ragonnaud, M. Bodogai, T. Illouz, M. DeLuca, R.A. McDevitt, F. Gusev, E. Okun, E. Rogaev, A. Biragyn, Therapeutic B-cell depletion reverses progression of Alzheimer ' s disease, Nat. Commun. 12 (2021) 2185.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0540) - sourceSupported

May combine two claims.

Naturally occurring anti-tau antibodies are detected in both AD patients and healthy controls without significant inter-group differences in their levels or correlation with cognitive decline.

“naturally occurring anti-tau antibodies are detected in both AD patients and healthy controls without significant inter-group differences in their levels or correlation with cognitive decline”

• cites [100] [100] [A. Bartos, L. Fialova, J. Svarcova, Lower serum antibodies against tau protein and heavy neurofilament in Alzheimer ' s disease, J. Alzheimer ' s Dis (2018) 751 -760.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0500) - sourceNot checked — no full text of the source
• cites [101] [101] [A.D. Magalhaes, M. Emmenegger, E. De Cecco, M. Carta, K. Frontzek, A. Chincisan, J. Guo, S. Hornemann, A. Aguzzi, Large-scale seroepidemiology uncovers nephro-urological pathologies in people with tau autoimmunity, PLoS Biol 23 (2025) e3003488.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0505) - sourcePartly supported

  The Introduction reports anti-tau antibodies in people with AD and in non-neurodegeneration controls. The Results section ‘Neurological disorders and anti-tau autoimmunity’ reports no significant difference in antibody reactivity between 47 AD patients and 68 similarly aged non-AD patients, but does not establish that those comparators were healthy or test a correlation between antibody levels and cognitive decline. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [102] [102] [H. Rosenmann, Z. Meiner, V. Geylis, O. Abramsky, M. Steinitz, Detection of circulating antibodies against tau protein in its unphosphorylated and in its neurofibrillary tangles-related phosphorylated state in Alzheimer ' s disease and healthy subjects, Neurosci. Lett. (2006) 90 -93.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0510) - sourceNot checked — no full text of the source
• cites [103] [103] [Z.Y. Yu, W.W. Li, H.M. Yang, N.B. Manucat-Tan, J. Wang, Y.R. Wang, B.L. Sun, Z. C. Hu, L.L. Zhang, L. Tan, J. Deng, Y.H. Liu, Naturally occurring antibodies to tau exists in human blood and are not changed in Alzheimer ' s disease, Neurotox. Res. (2020) 1029 -1035.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0515) - sourceNot checked — no full text of the source

May combine two claims.

B cell depletion can either worsen or improve pathology depending on the model, strongly suggesting that B cell involvement is not merely reactive but functionally consequential.

“the finding that B cell depletion can either worsen or improve pathology depending on the model strongly suggests that B cell involvement is not merely reactive but functionally conse­ quential.”

• cites [107] [107] [W. Feng, Y. Zhang, S. Ding, S. Chen, T. Wang, Z. Wang, Y. Zou, C. Sheng, Y. Chen, Y. Pang, C. Marshall, J. Shi, M. Nedergaard, Q. Li, M. Xiao, B lymphocytes ameliorate Alzheimer ' s disease-like neuropathology via interleukin-35, Brain Behav. Immun. 108 (2023) 16 -31.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0535) - sourceNot checked — no full text of the source
• cites [108] [108] [K. Kim, X. Wang, E. Ragonnaud, M. Bodogai, T. Illouz, M. DeLuca, R.A. McDevitt, F. Gusev, E. Okun, E. Rogaev, A. Biragyn, Therapeutic B-cell depletion reverses progression of Alzheimer ' s disease, Nat. Commun. 12 (2021) 2185.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0540) - sourcePartly supported

  The Discussion (page unavailable) reports that genetic loss or transient depletion of B cells improved symptoms in three AD mouse models, supporting a functional role. It attributes worsened pathology in Rag-deficient mice to the loss of both protective B cells and T cells, not to selective B-cell depletion in a different model. The claimed model-dependent worsening from B-cell depletion is therefore unsupported. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

• AssumptionRests on an assumption: Findings from experimental AD mouse models are informative about the role of B cells in human AD.

May combine two claims.

When 3xTgAD or APP/PS1 mice were crossed to JHT mice, these two AD models deficient in B cells developed disease with reduced amyloid pathology and a significant improvement in their cognitive capabilities as compared to their B cell-sufficient littermates.

“When 3xTgAD or APP/PS1 mice were crossed to JHT mice, these two AD models deficient in B cells developed disease with reduced amyloid pathology and a significant improvement in their cognitive capabilities as compared to their B cell-sufficient littermates [108].”

• cites [108] [108] [K. Kim, X. Wang, E. Ragonnaud, M. Bodogai, T. Illouz, M. DeLuca, R.A. McDevitt, F. Gusev, E. Okun, E. Rogaev, A. Biragyn, Therapeutic B-cell depletion reverses progression of Alzheimer ' s disease, Nat. Commun. 12 (2021) 2185.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0540) - sourceSupported

May combine two claims.

Rag2-/-Il2rγ-/-5xFAD mice had increased amyloid pathogenesis and exacerbated neuroinflammation.

“These Rag2 /-Il2r γ /-5xFAD mice had increased amyloid pathogenesis, and exacerbated neuroinflammation [109].”

• cites [109] [109] [S.E. Marsh, E.M. Abud, A. Lakatos, A. Karimzadeh, S.T. Yeung, H. Davtyan, G. M. Fote, L. Lau, J.G. Weinger, T.E. Lane, M.A. Inlay, W.W. Poon, M. BlurtonJones, The adaptive immune system restrains Alzheimer ' s disease pathogenesis by modulating microglial function, Proc. Natl. Acad. Sci. USA 113 (2016) E1316 -E1325.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0545) - sourceSupported

May combine two claims.

In another study using three different experimental models of AD pathology (3xTgAD, APP/PS1 and 5xFAD), B cells were found in the brain parenchyma of 8-11 months-old 5xFAD mice but their numbers were increased compared to age-matched WT controls.

“In another study using three different experi­ mental models of AD pathology (3xTgAD, APP/PS1 and 5xFAD), B cells were found in the brain parenchyma of 8 -11 months-old 5xFAD mice but in contrast to results from Feng et al., their numbers were increased compared to age-matched WT controls [107,108].”

• cites [107] [107] [W. Feng, Y. Zhang, S. Ding, S. Chen, T. Wang, Z. Wang, Y. Zou, C. Sheng, Y. Chen, Y. Pang, C. Marshall, J. Shi, M. Nedergaard, Q. Li, M. Xiao, B lymphocytes ameliorate Alzheimer ' s disease-like neuropathology via interleukin-35, Brain Behav. Immun. 108 (2023) 16 -31.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0535) - sourceNot checked — no full text of the source
• cites [108] [108] [K. Kim, X. Wang, E. Ragonnaud, M. Bodogai, T. Illouz, M. DeLuca, R.A. McDevitt, F. Gusev, E. Okun, E. Rogaev, A. Biragyn, Therapeutic B-cell depletion reverses progression of Alzheimer ' s disease, Nat. Commun. 12 (2021) 2185.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0540) - sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

These B cells populate the meninges, where they migrate via specialized vascular channels that circumvent systemic circulation.

“These B cells populate the meninges, a protective triple-layered membrane system surrounding the CNS where they migrate via specialized vascular channels that circum­ vent systemic circulation [105,106].”

• cites [105] [105] [S. Brioschi, W.L. Wang, V. Peng, M. Wang, I. Shchukina, Z.J. Greenberg, J. K. Bando, N. Jaeger, R.S. Czepielewski, A. Swain, D.A. Mogilenko, W.L. Beatty, P. Bayguinov, J.A.J. Fitzpatrick, L.G. Schuettpelz, C.C. Fronick, I. Smirnov, J. Kipnis, V.S. Shapiro, G.F. Wu, S. Gilfillan, M. Cella, M.N. Artyomov, S. H. Kleinstein, M. Colonna, Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders, Science 373 (2021).](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0525) - sourceSupported
• cites [106] [106] [F. Herisson, V. Frodermann, G. Courties, D. Rohde, Y. Sun, K. Vandoorne, G. R. Wojtkiewicz, G.S. Masson, C. Vinegoni, J. Kim, D.E. Kim, R. Weissleder, F. K. Swirski, M.A. Moskowitz, M. Nahrendorf, Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration, Nat. Neurosci. 21 (2018) 1209 -1217.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0530) - sourcePartly supported

  The Results section (‘Direct vascular channels connect skull marrow and the CNS surface’; page unavailable) reports neutrophils moving through skull channels toward the dura after stroke. The Discussion says this route challenges the assumption that recruited leukocytes must first enter systemic circulation. The paper does not establish that B cells populate the meninges or use these channels. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

The single cell RNA sequencing and BCR sequencing studies were limited in sample size and did not identify antigens driving B cell clonotype expansion.

“Although both studies were limited in their sample size and did not identify antigens driving B cell clonotype expansion”

• cites [84] [84] [L.L. Xiong, L.L. Xue, R.L. Du, R.Z. Niu, L. Chen, J. Chen, Q. Hu, Y.X. Tan, H. F. Shang, J. Liu, C.Y. Yu, T.H. Wang, Single-cell RNA sequencing reveals B cellrelated molecular biomarkers for Alzheimer ' s disease, Exp. Mol. Med. 53 (2021) 1888 -1901.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0420) - sourceSupported
• cites [94] [94] [H. Xu, J. Jia, Single-cell RNA sequencing of peripheral blood reveals immune cell signatures in Alzheimer ' s disease, Front. Immunol. 12 (2021) 645666.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0470) - sourceSupported

May combine two claims.

The frequency and number of B cells in the peripheral compartment, particularly B1a and B1b subsets, were significantly increased in the circulation and secondary lymphoid organs of 3xTgAD and APP/PS1 mice, whereas it remained unaffected in the 5xFAD model.

“the fre­ quency and number of B cells in the peripheral compartment, particu­ larly B1a and B1b subsets, were significantly increased in the circulation and secondary lymphoid organs of 3xTgAD and APP/PS1 mice, whereas it remained unaffected in the 5xFAD model.”

• cites [108] [108] [K. Kim, X. Wang, E. Ragonnaud, M. Bodogai, T. Illouz, M. DeLuca, R.A. McDevitt, F. Gusev, E. Okun, E. Rogaev, A. Biragyn, Therapeutic B-cell depletion reverses progression of Alzheimer ' s disease, Nat. Commun. 12 (2021) 2185.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0540) - sourceSupported

May combine two claims.

In APP/PS1 and 3xTgAD models, the dominant B cell population appears to be pro-inflammatory, consistent with elevated IFNγ, IL-6 production and B1a/B1b expansion, such that their depletion is beneficial.

“Conversely, in APP/PS1 and 3xTgAD models, the dominant B cell population appears to be proinflammatory, consistent with the elevated IFNγ , IL-6 production and B1a/B1b expansion observed in these models, such that their depletion is beneficial [108].”

• cites [108] [108] [K. Kim, X. Wang, E. Ragonnaud, M. Bodogai, T. Illouz, M. DeLuca, R.A. McDevitt, F. Gusev, E. Okun, E. Rogaev, A. Biragyn, Therapeutic B-cell depletion reverses progression of Alzheimer ' s disease, Nat. Commun. 12 (2021) 2185.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0540) - sourceSupported

May combine two claims.

B cell homeostasis is disrupted in ways that are independent of age and environmental factors, consistent with a disease-intrinsic mechanism.

“The observation that B cell homeostasis is disrupted in ways that are independent of age and environmental factors is consistent with a disease-intrinsic mechanism”

• cites [93] [93] [S. Humblet-Baron, Y. Feng, R. Veiga, J. Neumann, T. Prezzemolo, E. Pasciuto, R. Vandenberghe, L. Yshii, A. Liston, A systems immunology analysis of Alzheimer ' s disease reveals an age- and environmental exposure-independent disturbance in B cell maturation, Alzheimers Dement. 21 (11) (2025) e70952.](http://refhub.elsevier.com/S0008-8749(26)00095-X/h9005) - sourceSupported

May combine two claims.

In 3xTgAD x JHT/APP/PS1 x JHT mice, absence of all B cells reduced amyloid pathology, improved cognition, reduced neuroinflammation, and restored microglial function.

“Reduced amyloid pathology, improved cognition, reduced neuroinflammation, restored microglial function [108]”

• cites [108] [108] [K. Kim, X. Wang, E. Ragonnaud, M. Bodogai, T. Illouz, M. DeLuca, R.A. McDevitt, F. Gusev, E. Okun, E. Rogaev, A. Biragyn, Therapeutic B-cell depletion reverses progression of Alzheimer ' s disease, Nat. Commun. 12 (2021) 2185.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0540) - sourcePartly supported

  The Results (Figs. 2–3) report reduced amyloid plaques and improved cognitive performance in both B-cell-deficient 3×TgAD and APP/PS1 mice. The microglial findings are narrower: activation fell in 3×TgAD-BKO mice but remained elevated in APP/PS1-BKO mice, and IL1β expression was unchanged. Although some microglial markers normalized, the paper describes the disease-associated microglial phenotype as reversed only in part, rather than establishing fully restored microglial function. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

• AssumptionRests on an assumption: B cell manipulation in mouse models (e.g., μMT, anti-CD20) specifically affects B cells without confounding effects on other immune cells.

May combine two claims.

In 3xTgAD and APP/PS1 mice, B1a and B1b subsets are expanded in circulation and secondary lymphoid organs, with increased numbers and elevated IFN-γ, IL-6, IL-10, TGF-β production.

“| 3xTgAD and APP/PS1 peripheral B cells analysis | B1a and B1b subsets expanded in circulation and secondary lymphoid organs | Increased B1a/B1b numbers and elevated IFN- γ , IL-6, IL-10, TGF- β production [108] | B1 cell expansion and pro-inflammatory cytokine production implicate B cells in neuroinflammation |”

• cites [108] [108] [K. Kim, X. Wang, E. Ragonnaud, M. Bodogai, T. Illouz, M. DeLuca, R.A. McDevitt, F. Gusev, E. Okun, E. Rogaev, A. Biragyn, Therapeutic B-cell depletion reverses progression of Alzheimer ' s disease, Nat. Commun. 12 (2021) 2185.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0540) - sourcePartly supported

  The Results (Fig. 1; page not provided) report increased B1a and B1b cells in 3×TgAD mice and increased circulating B cells expressing IFNγ, IL6, IL10, and TGFβ, mostly among B1a cells. For APP/PS1 mice, the Results (Fig. 2; page not provided) specifically report increased B1a cells in circulation and cervical lymph nodes and increased IL10-expressing B cells. They do not establish expansion of both subsets across all stated sites or elevation of all four cytokines in APP/PS1 mice. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

• AssumptionRests on an assumption: B cell manipulation in mouse models (e.g., μMT, anti-CD20) specifically affects B cells without confounding effects on other immune cells.

May combine two claims.

In AD, accumulation of Aβ and NFT disrupts cerebral immune equilibrium, induces neuroinflammation, and prompts recruitment and activation of peripheral immune cells that infiltrate the CNS.

“In the context of AD, the accumulation of pathological aggregates of A β and NFT disrupts the finely tuned cerebral immune equilibrium, induces neuroinflammation, prompting the recruitment and activation of peripheral immune cells that infiltrate the CNS.”

May combine two claims.

Causal gene prioritization remains incomplete at many AD loci, and any contribution of B cell intrinsic mechanisms to AD susceptibility should currently be regarded as a biologically grounded hypothesis rather than an established causal pathway.

“However, causal gene prioritization remains incomplete at many of these loci, and any contribution of B cell intrinsic mechanisms to AD susceptibility should currently be regarded as a biologically grounded hypothesis rather than an established causal pathway.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

AD is characterized by senile plaques formed by extracellular Aβ aggregates and neurofibrillary tangles consisting of intra-neuronal hyperphosphorylated tau.

“AD is characterized by distinct neuropathological features: i) senile plaques formed by extracellular aggregates of amyloidβ (A β ) and ii) neurofibrillary tangles (NFT) consisting of intra-neuronal accumulation of hyperphosphorylated tau protein [4,5].”

• cites [4] [4] [M.T. Heneka, D.T. Golenbock, E. Latz, Innate immunity in Alzheimer ' s disease, Nat. Immunol. 16 (2015) 229 -236.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0020) - sourceNot checked — no full text of the source
• cites [5] [5] [P. Scheltens, K. Blennow, M.M. Breteler, B. de Strooper, G.B. Frisoni, S. Salloway, W.M. Van der Flier, Alzheimer's disease, Lancet 388 (2016) 505 -517.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0025) - sourceNot checked — no full text of the source

May combine two claims.

FAD-linked PSEN mutations may contribute to immune dysregulation in AD through mechanisms independent of Aβ production and remain largely unexplored.

“suggesting that FAD-linked PSEN mutations may contribute to immune dysregulation in AD through mechanisms that are independent of A β production and that remain largely unexplored.”

May combine two claims.

PU.1 is an important transcription factor for B cell development and CR1 is expressed by B cells, suggesting AD associated risk alleles may affect B cells in addition to microglia.

“Interestingly, PU.1 is an important tran­ scription factor for B cell development and CR1 is expressed by B cells, suggesting that AD associated risk alleles may affect B cells in addition to microglia [25].”

• cites [25] [25] [S.R. McKercher, B.E. Torbett, K.L. Anderson, G.W. Henkel, D.J. Vestal, H. Baribault, M. Klemsz, A.J. Feeney, G.E. Wu, C.J. Paige, R.A. Maki, Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities, EMBO J. 15 (1996) 5647 -5658.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0125) - sourceNot checked — no full text of the source

May combine two claims.

Genes relevant to B cell functions lie within or near several AD associated loci, suggesting B cell biology may be embedded within the genetic landscape of AD.

“Together, these findings suggest that genes relevant to B cell functions lie within or near several AD associated loci, suggesting that B cell biology may be embedded within the genetic landscape of AD.”

May combine two claims.

AD is a multifactorial disease unlikely to be cured by targeting amyloid alone.

“reflecting a growing recognition that AD is a multifactorial disease unlikely to be cured by targeting amyloid alone.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

B1 B cells are the primary producers of circulating IgM natural antibodies which provide immediate protection against pathogens and help clear apoptotic cells.

“B1 B cells are the primary producers of circulating IgM ' natural antibodies ' which provide immediate protection against pathogens and help clear apoptotic cells.”

• cites [46] [46] B. Duan, L. Morel, Role of B-1a cells in autoimmunity, Autoimmun. Rev. (2006) 403 -408. - sourceNot checked — no full text of the source

May combine two claims.

Other reports showed either no correlation or a positive association between peripheral B cell number and AD severity.

“while other reports showed either no correlation [86] or a positive association [90].”

• cites [86] [86] [E. Richartz-Salzburger, A. Batra, E. Stransky, C. Laske, N. Kohler, M. Bartels, G. Buchkremer, K. Schott, Altered lymphocyte distribution in Alzheimer ' s disease, J. Psychiatr. Res. 41 (2007) 174 -178.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0430) - sourceNot checked — no full text of the source
• cites [90] [90] [J.C. Park, J. Noh, S. Jang, K.H. Kim, H. Choi, D. Lee, J. Kim, J. Chung, D.Y. Lee, Y. Lee, H. Lee, D.K. Yoo, A.C. Lee, M.S. Byun, D. Yi, S.H. Han, S. Kwon, I. MookJung, Association of B cell profile and receptor repertoire with the progression of Alzheimer ' s disease, Cell Rep. 40 (2022) 111391.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0450) - sourceNot checked — no full text of the source

May combine two claims.

Although B lymphocytes were detected in AD brains, their number was limited, with significantly fewer B cells observed compared to T cells.

“Although B lymphocytes were detec­ ted in AD brains, their number was limited, with significantly fewer B cells observed compared to T cells [80].”

• cites [80] [80] [D.W. Dickson, J. Rogers, Neuroimmunology of Alzheimer ' s disease: a conference report, Neurobiol. Aging 13 (1992) 793 -798.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0400) - sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

In addition to ageing, ABCs expand prematurely in the context of chronic immune activation, including autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, and multiple sclerosis.

“In addition to ageing, ABCs expand prematurely in the context of chronic immune activation, including autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, Sj ¨ ogren's syndrome, and multiple sclerosis [76].”

• cites [76] [76] [M.P. Cancro, Age-associated B cells, Annu. Rev. Immunol. 38 (2020) 315 -340.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0380) - sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

ABCs are a heterogeneous subset of mature B lymphocytes that accumulate progressively with advancing age and can represent up to 30% of splenic mature B cells in very old mice.

“Age-associated B cells (ABCs) are an heterogeneous subset of mature B lymphocytes that accumulate progressively with advancing age and can represent up to 30% of splenic mature B cells in very old mice [69].”

• cites [69] [69] [Y. Hao, P. O'Neill, M.S. Naradikian, J.L. Scholz, M.P. Cancro, A B-cell subset uniquely responsive to innate stimuli accumulates in aged mice, Blood (2011) 1294 -1304.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0345) - sourceNot checked — no full text of the source

May combine two claims.

Analysis of the phenotype of circulating subpopulations of B cells in AD patients shows a decrease in naïve IgD+CD27- B cells and an increase in the percentage of double negative (DN) IgD-CD27- memory B cells.

“Analysis of the phenotype of circulating sub­ populations of B cells in AD patients shows a decrease in naïve IgD + CD27 B cells and an increase in the percentage of double negative (DN) IgD CD27 memory B cells [78].”

• cites [78] [78] [M. Bulati, S. Buffa, A. Martorana, F. Gervasi, C. Camarda, D.M. Azzarello, R. Monastero, C. Caruso, G. Colonna-Romano, Double negative (IgG + IgD-CD27-) B cells are increased in a cohort of moderate-severe Alzheimer ' s disease patients and show a pro-inflammatory trafficking receptor phenotype, J. Alzheimer ' s Dis 44 (2015) 1241 -1251.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0390) - sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

B1 B cells are innate-like immune cells that play a pivotal role in early immune defense.

“B1 B cells are a subset of innate-like immune cells that play a pivotal role in early immune defense.”

• cites [43] [43] [R.R. Hardy, B-1 B cell development, J. Immunol. (2006) 2749 -2754.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0215) - sourceNot checked — no full text of the source
• cites [44] [44] [N. Baumgarth, The double life of a B-1 cell: self-reactivity selects for protective effector functions, Nat. Rev. Immunol. (2011) 34 -46.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0220) - sourceNot checked — no full text of the source

May combine two claims.

Although the number of peripheral B cells decreases with age, a more pronounced decrease of B cells in AD was observed, suggesting that ongoing disease may exacerbate ageing effects.

“Although the number of peripheral B cells decreases with age, a more pronounced decrease of B cells in AD was observed, suggesting that ongoing disease may exacerbate ageing effects [88,89].”

• cites [88] [88] [R.P. Stephan, C.R. Reilly, P.L. Witte, Impaired ability of bone marrow stromal cells to support B-lymphopoiesis with age, Blood 91 (1998) 75 -88.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0440) - sourceNot checked — no full text of the source
• cites [89] [89] [W.W. Pang, E.A. Price, D. Sahoo, I. Beerman, W.J. Maloney, D.J. Rossi, S. L. Schrier, I.L. Weissman, Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age, Proc. Natl. Acad. Sci. USA 108 (2011) 20012 -20017.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0445) - sourceNot checked — no full text of the source

May combine two claims.

The existence of human B1 B cells remains unresolved, and caution is warranted when extrapolating findings from murine B1a and B1b cells to human disease contexts.

“The existence of human B1 B cells therefore remains unresolved, and in the absence of a universally accepted phenotypic definition, caution is warranted when extrapolating findings from mu­ rine B1a and B1b cells to human disease contexts.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Naive B cells, the largest splenic B cell population, are crucial for T cell-dependent responses.

“Naive B cells, the largest splenic B cell population, are crucial for T cell-dependent responses [52].”

• cites [52] [52] D. Allman, S. Pillai, Peripheral B cell subsets, Curr. Opin. Immunol. (2008) 149 -157. - sourceNot checked — no full text of the source

May combine two claims.

ABC differentiation is driven by a combination of BCR ligation, TLR7 and 9 engagement, cytokine exposure to IFNγ and IL-21, and can occur independently of germinal center reactions via a T-independent extrafollicular pathway.

“Their differentiation is driven by a combination of BCR ligation, toll-like re­ ceptor (TLR) 7 and 9 engagement, cytokine exposure to IFNγ and IL-21, and can occur independently of germinal center reactions via a T-in­ dependent extrafollicular pathway [76].”

• cites [76] [76] [M.P. Cancro, Age-associated B cells, Annu. Rev. Immunol. 38 (2020) 315 -340.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0380) - sourceNot checked — no full text of the source

May combine two claims.

Meningeal and parenchymal B cells are likely to be exposed to distinct antigenic and cytokine environments compared to peripheral B cells, and may therefore adopt different functional states.

“meningeal and parenchymal B cells are likely to be exposed to distinct antigenic and cytokine environments compared to peripheral B cells, and may therefore adopt different functional states.”

May combine two claims.

Longitudinal analysis of B cells during AD progression in 5xFAD mice revealed a significant increase in CD19+ B lymphocytes in the frontal cortex and meninges at 3 months of age, compared to age-matched WT controls, while no differences were detected in the spleen.

“Longitudinal analysis of B cells during AD progression in 5xFAD mice revealed a significant increase in CD19 + B lymphocytes in the frontal cortex and meninges at 3 months of age, compared to age-matched wildtype (WT) controls, while no differences were detected in the spleen [107].”

• cites [107] [107] [W. Feng, Y. Zhang, S. Ding, S. Chen, T. Wang, Z. Wang, Y. Zou, C. Sheng, Y. Chen, Y. Pang, C. Marshall, J. Shi, M. Nedergaard, Q. Li, M. Xiao, B lymphocytes ameliorate Alzheimer ' s disease-like neuropathology via interleukin-35, Brain Behav. Immun. 108 (2023) 16 -31.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0535) - sourceNot checked — no full text of the source

May combine two claims.

In JHT mice, functional B cells fail to develop due to deletion of the Ig JH locus, while μMT mice lack B cells as a result of inactivation of the Ig heavy chain of the class M gene.

“In JHT mice, functional B cells fail to develop due to deletion of the Ig JH locus, while μ MT mice lack B cells as a result of inactivation of the Ig heavy chain of the class M gene [112,113].”

• cites [112] [112] [H. Gu, Y.R. Zou, K. Rajewsky, Independent control of immunoglobulin switch recombination at individual switch regions evidenced through Cre-loxP-mediated gene targeting, Cell (1993) 1155 -1164.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0560) - sourceNot checked — no full text of the source
• cites [113] [113] [D. Kitamura, J. Roes, R. Kuhn, K. Rajewsky, A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene, Nature 350 (1991) 423 -426.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0565) sourceNot checked — no full text of the source

May combine two claims.

B cells are numerically and functionally altered in AD.

“converging lines of evidence indicate that B cells are numerically and functionally altered in AD”

• AssumptionRests on an assumption: Findings from experimental AD mouse models are informative about the role of B cells in human AD.

May combine two claims.

As disease progresses, the proportion of CD19+ B cells in the frontal cortex and meninges either normalizes or decreases relative to WT controls by 5 and 8 months of age, respectively.

“as the disease progresses, the proportion of CD19 + B cells in the frontal cortex and meninges either normalizes or decreases relative to WT controls by 5 and 8 months of age, respectively [107].”

• cites [107] [107] [W. Feng, Y. Zhang, S. Ding, S. Chen, T. Wang, Z. Wang, Y. Zou, C. Sheng, Y. Chen, Y. Pang, C. Marshall, J. Shi, M. Nedergaard, Q. Li, M. Xiao, B lymphocytes ameliorate Alzheimer ' s disease-like neuropathology via interleukin-35, Brain Behav. Immun. 108 (2023) 16 -31.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0535) - sourceNot checked — no full text of the source

May combine two claims.

5xFADμMT mice displayed increased Aβ plaque deposition, neuroinflammation, synaptic loss, and cognitive deficits.

“5xFADμ MT mice displayed increased A β plaque deposition, neuroinflammation, synaptic loss, and cognitive deficits [107].”

• cites [107] [107] [W. Feng, Y. Zhang, S. Ding, S. Chen, T. Wang, Z. Wang, Y. Zou, C. Sheng, Y. Chen, Y. Pang, C. Marshall, J. Shi, M. Nedergaard, Q. Li, M. Xiao, B lymphocytes ameliorate Alzheimer ' s disease-like neuropathology via interleukin-35, Brain Behav. Immun. 108 (2023) 16 -31.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0535) - sourceNot checked — no full text of the source

May combine two claims.

The finding that IL-35-producing B cells are specifically detected in the frontal cortex of 5xFAD mice and that their ablation worsens Aβ pathology suggests that parenchymal B cells in this compartment are preferentially skewed towards a regulatory, neuroprotective phenotype.

“The finding that IL35-producing B cells are specifically detected in the frontal cortex of 5xFAD mice and that their ablation worsens A β pathology suggests that parenchymal B cells in this compartment are preferentially skewed to­ wards a regulatory, neuroprotective phenotype [107].”

• cites [107] [107] [W. Feng, Y. Zhang, S. Ding, S. Chen, T. Wang, Z. Wang, Y. Zou, C. Sheng, Y. Chen, Y. Pang, C. Marshall, J. Shi, M. Nedergaard, Q. Li, M. Xiao, B lymphocytes ameliorate Alzheimer ' s disease-like neuropathology via interleukin-35, Brain Behav. Immun. 108 (2023) 16 -31.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0535) - sourceNot checked — no full text of the source

May combine two claims.

IL-35 reduced Aβ pathology and neuroinflammation, as neutralizing IL-35 (via anti-Ebi3 antibodies) worsened Aβ deposition and cognitive deficits.

“an anti-inflammatory cytokine that reduced A β pathology and neuroinflammation as neutralizing IL-35 (via antiEbi3 antibodies) worsened A β deposition and cognitive deficits [107].”

• cites [107] [107] [W. Feng, Y. Zhang, S. Ding, S. Chen, T. Wang, Z. Wang, Y. Zou, C. Sheng, Y. Chen, Y. Pang, C. Marshall, J. Shi, M. Nedergaard, Q. Li, M. Xiao, B lymphocytes ameliorate Alzheimer ' s disease-like neuropathology via interleukin-35, Brain Behav. Immun. 108 (2023) 16 -31.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0535) - sourceNot checked — no full text of the source

May combine two claims.

B cells are underappreciated yet multifaceted contributors to AD immunopathology, with both disease-modulating potential and translational relevance as immunotherapeutic targets.

“Collectively, these observations highlight B cells as underappreciated yet multifaceted contributors to AD immu­ nopathology, with both disease-modulating potential and translational relevance as immunotherapeutic targets.”

May combine two claims.

In 5xFAD x μMT mice, absence of mature B cells increased Aβ plaque deposition, neuroinflammation, synaptic loss, and cognitive deficits.

“Increased A β plaque deposition, neuroinflammation, synaptic loss, cognitive deficits [107]”

• cites [107] [107] [W. Feng, Y. Zhang, S. Ding, S. Chen, T. Wang, Z. Wang, Y. Zou, C. Sheng, Y. Chen, Y. Pang, C. Marshall, J. Shi, M. Nedergaard, Q. Li, M. Xiao, B lymphocytes ameliorate Alzheimer ' s disease-like neuropathology via interleukin-35, Brain Behav. Immun. 108 (2023) 16 -31.](http://refhub.elsevier.com/S0008-8749(26)00095-X/rf0535) - sourceNot checked — no full text of the source

• AssumptionRests on an assumption: B cell manipulation in mouse models (e.g., μMT, anti-CD20) specifically affects B cells without confounding effects on other immune cells.

May combine two claims.

Amyloid alone is an insufficient therapeutic target and neuroinflammation must be addressed in parallel.

“reinforces the view that amyloid alone is an insufficient therapeutic target and that neuroinflammation must be addressed in parallel.”

• AssumptionRests on an assumption: Anti-amyloid immunotherapies such as lecanemab and donanemab achieve robust amyloid clearance yet produce only modest clinical benefits.

Classified as probably not a substantial claim.

Final selection of articles was based on direct relevance to B cell biology in AD or ageing, methodological quality, and contribution to scientific questions.

“The final selection of articles was based on their direct relevance to B cell biology in the context of AD or ageing, methodological quality, and contribution to the scientific questions presented in this review.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Full texts of potentially relevant articles were retrieved and assessed for inclusion.

“Full texts of potentially relevant articles were retrieved and assessed for inclusion.”

Classified as probably not a substantial claim.

A systematic search of PubMed and Web of Science was conducted with no restriction on publication date using a specified search string.

“To identify relevant literature for this review, a systematic search of the PubMed and Web of Science databases was conducted, with no re­ striction on publication date. The following search string was applied:”

Probably not a substantial claim: may not pass S3 (load-bearing).

Preprint servers including bioRxiv were consulted for recent findings.

“preprint servers including bioRxiv were also consulted for recent findings of high rele­ vance.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Titles and abstracts of retrieved articles were independently screened by the authors for relevance.

“Titles and abstracts of retrieved articles were independently screened by the authors for relevance to the central focus of the review.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Reference lists of selected articles were analyzed to identify additional studies.

“Reference lists of all selected articles were additionally analyzed to identify studies not captured by the database search.”

May combine two claims.

Cortical B cells produce IL-35 that suppresses neuro-inflammation and limits Aβ pathology.

“Cortical B cells produce IL-35 that suppresses neuro-inflammation and limits A β pathology”

• AssumptionRests on an assumption: B cell manipulation in mouse models (e.g., μMT, anti-CD20) specifically affects B cells without confounding effects on other immune cells.