Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review

May combine two claims.

Three studies, using CD36, HLA-DR or proteomics, reported no difference between AD and the high-pathology control group despite increases relative to the regular control group, whereas one reported more HLA-DR-positive microglia in the high pathology control group than in AD.

“In contrast, three studies, using CD36, HLA-DR or proteomics, reported no difference between AD and the high-pathology control group despite increases relative to the regular control group,45, 127, 177 whereas one reported more HLA-DR-positive microglia in the high pathology control group than in AD.24”

• cites [45] Vehmas AK, Kawas CH, Stewart WF, Troncoso JC . Immune reactive cells in senile plaques and cognitive decline in Alzheimer's disease. Neurobiol Aging 2003; 24: 321–331. sourceDisputed

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

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [127] Seyfried NT, Dammer EB, Swarup V, Nandakumar D, Duong DM, Yin L et al. A multi-network approach identifies protein-specific co-expression in asymptomatic and symptomatic Alzheimer's disease. Cell Syst 2017; 4: 60–72 e64. sourcePartly supported

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

  Experimental — accuracy not yet measured
• cites [177] Ricciarelli R, D'Abramo C, Zingg JM, Giliberto L, Markesbery W, Azzi A et al. CD36 overexpression in human brain correlates with beta-amyloid deposition but not with Alzheimer's disease. Free Radic Biol Med 2004; 36: 1018–1024. sourceNot checked — no full text of the source

May combine two claims.

Differences in plaque load between studies could influence the results, as microglial markers were found to correlate with plaque loads in several studies.

“Few studies reported on the amount of plaque in the brains included in their cohorts, but differences in plaque load between studies could also influence the results, as microglial markers were found to correlate with plaque loads in several studies.47, 48, 52, 56, 186”

• cites [47] Xiang Z, Haroutunian V, Ho L, Purohit D, Pasinetti GM . Microglia activation in the brain as inflammatory biomarker of Alzheimer's disease neuropathology and clinical dementia. Dis Markers 2006; 22: 95–102. sourceSupported
• cites [48] Egensperger R, Kosel S, von Eitzen U, Graeber MB . Microglial activation in Alzheimer disease: association with APOE genotype. Brain Pathol 1998; 8: 439–447. sourceDisputed

  The Abstract reports that the study measured microglial activation and diffuse and neuritic plaques, but in a multiple-regression analysis only APOE genotype had a significant effect on microglial activation. It therefore does not report the plaque-load association for which this citation is offered. This adjusted result does not rule out an unadjusted correlation, but our copy provides no such finding. (LLM, conf=0.75)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [52] Overmyer M, Helisalmi S, Soininen H, Laakso M, Riekkinen P Sr., Alafuzoff I . Reactive microglia in aging and dementia: an immunohistochemical study of postmortem human brain tissue. Acta Neuropathol 1999; 97: 383–392. sourceNot checked — no full text of the source

May combine two claims.

Ionized calcium-binding adaptor molecule 1 was not consistently elevated in Alzheimer's disease relative to controls; 10 of 20 studies identified increases.

“ionized calcium-binding adaptor molecule 1 (10/20 studies)”

• Also stated in: § Ionized calcium-binding adaptor molecule 1 · plain

  “Ten studies identified increases in Iba1 cell counts, staining intensity or expression in AD compared with control samples in at least one brain region”

• cites [20] Dal Bianco A, Bradl M, Frischer J, Kutzelnigg A, Jellinger K, Lassmann H . Multiple sclerosis and Alzheimer's disease. Ann Neurol 2008; 63: 174–183. sourceNot checked — no full text of the source
• cites [60] Walker DG, Lue LF . Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains. Alzheimers Res Ther 2015; 7: 56. sourceCould not verify

  The “Microglia in human brains” section discusses IBA-1 as a marker and reports no overall difference between control and Aβ-immunized Alzheimer’s cases. It does not report how often IBA-1 was elevated in Alzheimer’s disease versus controls across studies; searches for the 10-of-20 count and that comparison found no supporting passage. No page number was available in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [61] Lue LF, Schmitz CT, Serrano G, Sue LI, Beach TG, Walker DG . TREM2 protein expression changes correlate with Alzheimer's disease neurodegenerative pathologies in post-mortem temporal cortices. Brain Pathol 2015; 25: 469–480. sourcePartly supported

  The Results (‘Levels of TREM2 protein and AD degenerative markers in studied samples’) report significantly elevated IBA1 in AD cases compared with nondemented controls. This paper reports one study, not a comparison across 20 studies, so it does not support the ‘10 of 20 studies’ tally or the claim about consistency across studies. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Increased major histocompatibility complex II staining, counts or expression was noted in the entorhinal cortex, frontal and temporal gyri, hippocampus, and frontal, temporal and occipital cortices.

“Increased MHCII staining, counts or expression was noted in: the entorhinal cortex,7, 18, 20, 35, 43, 47 frontal and temporal gyri,7, 19, 24, 32, 33, 39, 45, 56 hippocampus20, 25, 27, 30, 32, 33, 34, 35, 36, 37, 38, 40, 42, 43, 44, 47 and frontal,18, 21, 25, 40, 41, 44, 46, 48, 49, 52 temporal16, 17, 18, 28, 30, 35, 43, 44, 48, 52 and occipital cortices.25, 35, 41, 43, 44”

• cites [7] Lue LF, Brachova L, Civin WH, Rogers J . Inflammation, A beta deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration. J Neuropathol Exp Neurol 1996; 55: 1083–1088. sourcePartly supported

  The Histochemistry and Immunohistochemistry section (p. 2) identifies the examined regions as the entorhinal cortex and superior frontal gyrus. The Inflammation section (p. 3) reports higher LN3-positive microglial staining in Alzheimer’s disease patients, with no significant difference between those two regions. This supports the claim for the examined regions, but not for the temporal gyri, hippocampus, or temporal and occipital cortices. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [18] Kellner A, Matschke J, Bernreuther C, Moch H, Ferrer I, Glatzel M . Autoantibodies against beta-amyloid are common in Alzheimer's disease and help control plaque burden. Ann Neurol 2009; 65: 24–31. sourceNot checked — no full text of the source
• cites [20] Dal Bianco A, Bradl M, Frischer J, Kutzelnigg A, Jellinger K, Lassmann H . Multiple sclerosis and Alzheimer's disease. Ann Neurol 2008; 63: 174–183. sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

The neuroinflammatory hypothesis of Alzheimer's disease suggests that aberrant activation of immune cells may drive neuronal death and dysfunction in Alzheimer's disease.

“This has contributed to the development of the neuroinflammatory hypothesis of AD that suggests that aberrant activation of immune cells may drive neuronal death and dysfunction in AD.8”

• cites [8] Griffin WS . Inflammation and neurodegenerative diseases. Am J Clin Nutr 2006; 83: 470S–474S. sourceSupported

May combine two claims.

In the hippocampus, six of eight studies identified higher CD68 in Alzheimer's disease and two identified no differences.

“CD68-positive cell counts, staining area or gene expression were measured in the hippocampus in eight studies: six identified higher levels in AD20, 69, 76, 78, 79, 86 and two identified no differences.69, 87”

• cites [20] Dal Bianco A, Bradl M, Frischer J, Kutzelnigg A, Jellinger K, Lassmann H . Multiple sclerosis and Alzheimer's disease. Ann Neurol 2008; 63: 174–183. sourceNot checked — no full text of the source
• cites [69] Bachstetter AD, Van Eldik LJ, Schmitt FA, Neltner JH, Ighodaro ET, Webster SJ et al. Disease-related microglia heterogeneity in the hippocampus of Alzheimer's disease, dementia with Lewy bodies, and hippocampal sclerosis of aging. Acta Neuropathol Commun 2015; 3: 32. sourcePartly supported

  The Results section (page unavailable) reports higher CD68 staining in AD than in controls when averaged across hippocampal subregions, supporting this paper’s inclusion among studies finding higher levels. It also reports no significant disease-status effect in some individual regions, but not an overall absence of difference; this paper alone does not establish the six-of-eight and two-of-eight study counts. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [76] Sanchez-Mejias E, Navarro V, Jimenez S, Sanchez-Mico M, Sanchez-Varo R, Nunez-Diaz C et al. Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration. Acta Neuropathol 2016; 132: 897–916. sourcePartly supported

  The Results section, “Weak activation and marked degeneration of microglial cells in the AD hippocampus” (page unavailable), reports significantly increased CD68 gene expression in Braak V–VI samples, supporting this study’s inclusion among those finding higher levels. It does not report a no-difference finding for CD68 or establish the citing sentence’s six-of-eight and two-of-eight study counts; its no-difference finding concerns other markers. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Iba1 was higher in Alzheimer's disease than control in the hippocampus in three studies, unchanged in five studies, and reduced in one study.

“Similarly, although Iba1 was higher in AD than control in the hippocampus in three studies,20, 62, 67 it was unchanged in five studies32, 69, 71, 73, 75 and reduced in one study.76”

• cites [20] Dal Bianco A, Bradl M, Frischer J, Kutzelnigg A, Jellinger K, Lassmann H . Multiple sclerosis and Alzheimer's disease. Ann Neurol 2008; 63: 174–183. sourceNot checked — no full text of the source
• cites [62] Nielsen HM, Ek D, Avdic U, Orbjorn C, Hansson O et alNetherlands Brain Bank. NG2 cells, a new trail for Alzheimer's disease mechanisms? Acta Neuropathol Commun 2013; 1: 7. sourceCould not verify

  Citation 76 is attached to the claim that hippocampal Iba1 was reduced in one study. The Results section reports reduced NG2 immunoreactivity and uses Iba-1 to identify microglia, but does not report a decrease in Iba1 in AD versus controls; searches for Iba-1 staining intensity and AD–control differences found no such comparison. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [67] Lastres-Becker I, Innamorato NG, Jaworski T, Rabano A, Kugler S, Van Leuven F et al. Fractalkine activates NRF2/NFE2L2 and heme oxygenase 1 to restrain tauopathy-induced microgliosis. Brain 2014; 137 (Pt 1): 78–91. sourceNot checked — no full text of the source

May combine two claims.

Higher Iba1 was noted in the Alzheimer's disease frontal cortex in four studies, was the same as control in three others, and was lower in the white matter of the frontal lobe in one study.

“Higher Iba1 was noted in the AD frontal cortex in four studies,20, 63, 64, 68 but was the same as control in three others32, 70, 74 and lower in the white matter of the frontal lobe in one study.32”

• cites [20] Dal Bianco A, Bradl M, Frischer J, Kutzelnigg A, Jellinger K, Lassmann H . Multiple sclerosis and Alzheimer's disease. Ann Neurol 2008; 63: 174–183. sourceNot checked — no full text of the source
• cites [63] Rangaraju S, Gearing M, Jin LW, Levey A . Potassium channel Kv1.3 is highly expressed by microglia in human Alzheimer's disease. J Alzheimers Dis 2015; 44: 797–808. sourceSupported
• cites [64] Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM . Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine. J Alzheimers Dis 2005; 8: 247–268. sourceNot checked — no full text of the source

May combine two claims.

CD68 labels the lysosome and is commonly considered a marker of activated phagocytic microglia.

“Although there is some CD68 expression on resting microglia,14 it labels the lysosome and is therefore commonly considered a marker of activated phagocytic microglia.60”

• cites [14] Lee YB, Nagai A, Kim SU . Cytokines, chemokines, and cytokine receptors in human microglia. J Neurosci Res 2002; 69: 94–103. sourceNot checked — no full text of the source
• cites [60] Walker DG, Lue LF . Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains. Alzheimers Res Ther 2015; 7: 56. sourceSupported

May combine two claims.

Iba1 was higher in the entorhinal cortex and inferior parietal cortex in Alzheimer's disease compared with control, but this is based on a limited number of studies.

“Iba1 was higher in the entorhinal cortex20, 62 and inferior parietal cortex65 in AD compared with control, but this is based on a limited number of studies.”

• cites [20] Dal Bianco A, Bradl M, Frischer J, Kutzelnigg A, Jellinger K, Lassmann H . Multiple sclerosis and Alzheimer's disease. Ann Neurol 2008; 63: 174–183. sourceNot checked — no full text of the source
• cites [62] Nielsen HM, Ek D, Avdic U, Orbjorn C, Hansson O et alNetherlands Brain Bank. NG2 cells, a new trail for Alzheimer's disease mechanisms? Acta Neuropathol Commun 2013; 1: 7. sourcePartly supported

  The Results section reports more microglial clustering and glial nests in individuals with high amyloid plaque load, and the Methods identify tissue taken from the hippocampus–entorhinal cortex region. But Iba-1 was used to identify microglia, not reported as higher in AD than controls. The inferior parietal cortex finding is attached to a different citation in the citing sentence. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [65] Tang SC, Lathia JD, Selvaraj PK, Jo DG, Mughal MR, Cheng A et al. Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal. Exp Neurol 2008; 213: 114–121. sourceNot checked — no full text of the source

May combine two claims.

HLA-DR reactivity increased in both Alzheimer's disease and control patients over 75 years of age in one study, but decreased in Alzheimer's disease patients over 80 years of age in another, making the effect of age on HLA-DR expression unclear.

“HLA-DR reactivity increased in both AD and control patients >75 of age in one study,52 but decreased in AD patients >80 of age in another,28 making the effect of age on HLA-DR expression unclear.”

• cites [52] Overmyer M, Helisalmi S, Soininen H, Laakso M, Riekkinen P Sr., Alafuzoff I . Reactive microglia in aging and dementia: an immunohistochemical study of postmortem human brain tissue. Acta Neuropathol 1999; 97: 383–392. sourceNot checked — no full text of the source
• cites [28] Hoozemans JJ, Rozemuller AJ, van Haastert ES, Eikelenboom P, van Gool WA . Neuroinflammation in Alzheimer's disease wanes with age. J Neuroinflamm 2011; 8: 171. 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.

CD68 was higher in Alzheimer's disease than control in the frontal cortex in three studies, though for white matter only in one of the studies.

“CD68 was higher in AD than control in the frontal cortex in three studies,18, 41, 82 though for white matter only in one of the studies.41”

• cites [18] Kellner A, Matschke J, Bernreuther C, Moch H, Ferrer I, Glatzel M . Autoantibodies against beta-amyloid are common in Alzheimer's disease and help control plaque burden. Ann Neurol 2009; 65: 24–31. sourceNot checked — no full text of the source
• cites [41] Rezaie P, Pontikis CC, Hudson L, Cairns NJ, Lantos PL . Expression of cellular prion protein in the frontal and occipital lobe in Alzheimer's disease, diffuse Lewy body disease, and in normal brain: an immunohistochemical study. J Histochem Cytochem 2005; 53: 929–940. sourceSupported
• cites [82] Hultman K, Strickland S, Norris EH . The APOE varepsilon4/varepsilon4 genotype potentiates vascular fibrin(ogen) deposition in amyloid-laden vessels in the brains of Alzheimer's disease patients. J Cereb Blood Flow Metab 2013; 33: 1251–1258. sourceNot checked — no full text of the source

May combine two claims.

CD68 immunoreactivity appears to increase with age in control subjects, but decreases with age in patients with Alzheimer's disease.

“CD68 immunoreactivity appears to increase with age in control subjects, but decreases with age in patients with AD.28”

• cites [28] Hoozemans JJ, Rozemuller AJ, van Haastert ES, Eikelenboom P, van Gool WA . Neuroinflammation in Alzheimer's disease wanes with age. J Neuroinflamm 2011; 8: 171. sourceSupported

May combine two claims.

Four studies reported higher CD45 in Alzheimer's disease in at least one brain region, two reported no difference relative to control, and one reported no difference in at least one region.

“Four studies reported higher CD45 in AD in at least one brain region,15, 76, 93, 94 whereas two reported no difference relative to control71, 95 and one reported no difference in at least one region.94”

• cites [15] Akiyama H, McGeer PL . Brain microglia constitutively express beta-2 integrins. J Neuroimmunol 1990; 30: 81–93. sourceNot checked — no full text of the source
• cites [76] Sanchez-Mejias E, Navarro V, Jimenez S, Sanchez-Mico M, Sanchez-Varo R, Nunez-Diaz C et al. Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration. Acta Neuropathol 2016; 132: 897–916. sourcePartly supported

  The Results section ('Weak activation and marked degeneration of microglial cells in the AD hippocampus'; page unavailable) reports significantly increased CD45 expression in Braak V–VI hippocampal samples, supporting this paper’s place among studies finding higher CD45. It does not report a CD45 comparison showing no difference in another brain region; the no-difference findings shown concern other markers or measures. The counts of four and two studies depend on the other cited papers, not this source. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [93] Licastro F, Mallory M, Hansen LA, Masliah E . Increased levels of alpha-1-antichymotrypsin in brains of patients with Alzheimer's disease correlate with activated astrocytes and are affected by APOE 4 genotype. J Neuroimmunol 1998; 88: 105–110. sourceNot checked — no full text of the source

May combine two claims.

Polymorphisms in the R47H allele of the TREM2 gene are a strong genetic risk factor for the development of Alzheimer's disease, though their impact on microglial function remains unclear.

“Polymorphisms in the R47H allele of the TREM2 gene have recently been identified as a strong genetic risk factor for the development of AD,13 though the actual impact of these polymorphisms on microglial function remain unclear.”

• cites [13] Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E et al. TREM2 variants in Alzheimer's disease. N Engl J Med 2013; 368: 117–127. sourceSupported

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

Iron is stored in the brain as heavy or light subunits; neurons and other cells primarily contain H ferritin, whereas glial cells contain the L subunit.

“Iron is stored in the brain as heavy (H) or light (L) subunits. Neurons and other cells primarily contain H ferritin, which is the less reactive form, whereas glial cells contain the L subunit, which can be used to generate free radicals as part of the inflammatory response.96, 97”

• cites [96] Kwiatek-Majkusiak J, Dickson DW, Tacik P, Aoki N, Tomasiuk R, Koziorowski D et al. Relationships between typical histopathological hallmarks and the ferritin in the hippocampus from patients with Alzheimer's disease. Acta Neurobiol Exp 2015; 75: 391–398. sourceSupported
• cites [97] Meadowcroft MD, Connor JR, Yang QX . Cortical iron regulation and inflammatory response in Alzheimer's disease and APPSWE/PS1DeltaE9 mice: a histological perspective. Front Neurosci 2015; 9: 255. sourcePartly supported

  The Results report neuronal H-ferritin staining and L-ferritin staining in microglia and oligodendrocytes; the Discussion describes H-ferritin as protective against iron-induced oxidative damage. The paper does not establish that neurons and other cells primarily contain H-ferritin. Nor does it say glial L-ferritin is used to generate free radicals: it describes microglial L-ferritin as storing iron following phagocytosis of cells undergoing oxidative stress. Page numbers were not available in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

Two polymorphisms in the CD33 gene modulate Alzheimer's disease risk, with the protective allele associated with reduced CD33 and increased phagocytosis.

“Two polymorphisms in the CD33 gene have recently been identified that modulate AD risk,102, 103 with the protective allele associated with reduced CD3312, 66, 70 and increased phagocytosis.12”

• cites [102] Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF et al. Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE. Am J Hum Genet 2008; 83: 623–632. sourceNot checked — no full text of the source
• cites [103] Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet 2011; 43: 429–435. sourceSupported
• cites [12] Bradshaw EM, Chibnik LB, Keenan BT, Ottoboni L, Raj T, Tang A et al. CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology. Nat Neurosci 2013; 16: 848–850. sourceSupported

May combine two claims.

In microglia, TREM2 seems to be important for microglial activation and phagocytosis of apoptotic neurons.

“In microglia, TREM2 seems to be important for microglial activation and phagocytosis of apoptotic neurons.105”

• cites [105] Takahashi K, Rochford CD, Neumann H . Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 2005; 201: 647–657. sourceSupported

May combine two claims.

Sanchez-Mejias et al. detected higher CD45 gene expression in the hippocampus and parahippocampal gyrus in Alzheimer's disease, whereas Magistri et al. identified no such increase in the hippocampus relative to controls.

“Sanchez-Mejias et al.76 detected higher CD45 gene expression in the hippocampus and parahippocampal gyrus in AD, whereas Magistri et al.71 identified no such increase in the hippocampus relative to controls.”

• cites [76] Sanchez-Mejias E, Navarro V, Jimenez S, Sanchez-Mico M, Sanchez-Varo R, Nunez-Diaz C et al. Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration. Acta Neuropathol 2016; 132: 897–916. sourcePartly supported

  The Results section, “Weak activation and marked degeneration of microglial cells in the AD hippocampus” (page unavailable), reports significantly increased CD45 expression by qPCR in Braak V–VI hippocampal samples. The paper discusses the parahippocampal gyrus, but the passages do not establish a separate increase in CD45 gene expression there. The statement about Magistri et al. is not attributed to this source. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [71] Magistri M, Velmeshev D, Makhmutova M, Faghihi MA . Transcriptomics profiling of Alzheimer's disease reveal neurovascular defects, altered amyloid-beta homeostasis, and deregulated expression of long noncoding RNAs. J Alzheimers Dis 2015; 48: 647–665. sourceSupported

May combine two claims.

Two papers identified an increase of TREM2 in Alzheimer's disease, one reported no difference relative to control, and one reported opposing results for qPCR and western analysis.

“Two identified an increase of TREM2 in AD,61, 106 whereas one reported no difference relative to control76 and one reported opposing results for qPCR and western analysis.107”

• cites [61] Lue LF, Schmitz CT, Serrano G, Sue LI, Beach TG, Walker DG . TREM2 protein expression changes correlate with Alzheimer's disease neurodegenerative pathologies in post-mortem temporal cortices. Brain Pathol 2015; 25: 469–480. sourceSupported
• cites [106] Steubl D, Roos M, Hettwer S, Angermann S, Wen M, Schmaderer C et al. Comparison of peritoneal low-molecular-weight-protein-removal in CCPD and CAPD patients based on C-terminal agrin fragment clearance. Kidney Blood Press Res 2016; 41: 175–185. sourceCould not verify

  The paper’s Discussion and results address peritoneal clearance of C-terminal agrin fragment in dialysis patients, not TREM2 in Alzheimer’s disease. Searches for TREM2, Alzheimer’s disease, and the claimed qPCR-versus-western-analysis result found no relevant passage in our copy. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [76] Sanchez-Mejias E, Navarro V, Jimenez S, Sanchez-Mico M, Sanchez-Varo R, Nunez-Diaz C et al. Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration. Acta Neuropathol 2016; 132: 897–916. sourceSupported

May combine two claims.

In microglia, CD33 seems to regulate phagocytosis of amyloid-β, with a reduction in CD33 associated with increased phagocytosis.

“In microglia, CD33 seems to regulate phagocytosis of amyloid-β, with a reduction in CD33 associated with increased phagocytosis.70”

• cites [70] Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K et al. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 2013; 78: 631–643. sourceSupported

May combine two claims.

Of two studies in the hippocampus, one identified an increase in CD11b gene expression, whereas the other identified no difference in expression between Alzheimer's disease and controls.

“Of two studies in the hippocampus, one identified an increase in CD11b gene expression,38 whereas the other identified no difference in expression between AD and controls.76”

• cites [38] McGeer PL, McGeer EG, Yasojima K . Alzheimer disease and neuroinflammation. J Neural Transm Suppl 2000; 59: 53–57.Not matched

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

• cites [76] Sanchez-Mejias E, Navarro V, Jimenez S, Sanchez-Mico M, Sanchez-Varo R, Nunez-Diaz C et al. Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration. Acta Neuropathol 2016; 132: 897–916. sourceSupported

May combine two claims.

Five of the nine studies comparing microglial markers between AD and high pathology control group reported higher levels of microglia markers in AD, three using HLA-DR, one using CD68, and one using both TREM2 and Iba1.

“Five of these studies reported higher levels of microglia markers in AD, three using HLA-DR,7, 33, 40 one using CD68,83 and one using both TREM2 and Iba1.61”

• cites [7] Lue LF, Brachova L, Civin WH, Rogers J . Inflammation, A beta deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration. J Neuropathol Exp Neurol 1996; 55: 1083–1088. sourceSupported
• cites [33] Lopes KO, Sparks DL, Streit WJ . Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivity. Glia 2008; 56: 1048–1060. sourceNot checked — no full text of the source
• cites [40] Parachikova A, Agadjanyan MG, Cribbs DH, Blurton-Jones M, Perreau V, Rogers J et al. Inflammatory changes parallel the early stages of Alzheimer disease. Neurobiol Aging 2007; 28: 1821–1833. sourceNot checked — no full text of the source

May combine two claims.

There is still controversy surrounding what markers are indicative of activation, as well as the type of activation they are associated with.

“However, there is still controversy surrounding what markers are indicative of activation, as well as the type of activation they are associated with,60”

• cites [60] Walker DG, Lue LF . Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains. Alzheimers Res Ther 2015; 7: 56. sourceSupported

May combine two claims.

Marutle et al. identified no difference in PK11195 binding in the hippocampus between control and Alzheimer's disease brains, though they reported higher levels in the frontal cortex.

“In contrast, Marutle et al.118 identified no difference in PK11195 binding in the hippocampus between control and AD brains, though they reported higher levels in the frontal cortex.”

• cites [118] Marutle A, Gillberg PG, Bergfors A, Yu W, Ni R, Nennesmo I et al. (3)H-deprenyl and (3)H-PIB autoradiography show different laminar distributions of astroglia and fibrillar beta-amyloid in Alzheimer brain. J Neuroinflamm 2013; 10: 90. sourcePartly supported

  The Results section (page unavailable) reports significantly higher [3H]-PK11195 binding in the frontal cortex of AD cases, but does not report a significant hippocampal difference. The Abstract’s Results section nevertheless describes increased binding in both regions, so the categorical claim of “no difference” in the hippocampus is not fully supported. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

May combine two claims.

Roussos et al. protein measurements indicated decreased TREM2 in Alzheimer's disease R47H carriers relative to controls with no difference between Alzheimer's disease noncarriers and control.

“Their protein measurements, however, indicated decreased TREM2 in AD R47H carriers relative to controls with no difference between AD noncarriers and control.”

• cites [107] Roussos P, Katsel P, Fam P, Tan W, Purohit DP, Haroutunian V . The triggering receptor expressed on myeloid cells 2 (TREM2) is associated with enhanced inflammation, neuropathological lesions and increased risk for Alzheimer's dementia. Alzheimers Dement 2015; 11: 1163–1170. sourcePartly supported

  Results §3.5 reports higher TREM2 protein in controls than in AD R47H carriers (P = 0.014), supporting the first comparison. It does not report a TREM2 comparison between AD noncarriers and controls, so the claimed absence of a difference is not established by our copy. Page numbers were not available. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

TREM2 expression is increased even when adjusting for Iba1, and hence it can be considered a marker of microglial function as opposed to number.

“As with CD33, TREM2 expression is increased even when adjusting for Iba1,106 and hence it can be considered a marker of microglial function as opposed to number.”

• cites [106] Steubl D, Roos M, Hettwer S, Angermann S, Wen M, Schmaderer C et al. Comparison of peritoneal low-molecular-weight-protein-removal in CCPD and CAPD patients based on C-terminal agrin fragment clearance. Kidney Blood Press Res 2016; 41: 175–185. sourceCould not verify

  The Introduction and peritoneal-clearance analysis describe tCAF removal in dialysis patients, not microglial markers. Searches for TREM2, Iba1, CD33, and microglial function found no passage addressing the claimed expression increase or its interpretation. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

May combine two claims.

Elevated IL-1α-positive microglia were reported in the parahippocampal cortex, hippocampus and frontal, occipital and temporal lobes.

“Elevated IL-1α-positive microglia were reported in the parahippocampal cortex,111 the hippocampus112 and the frontal,112 occipital112 and temporal lobes.112, 113”

• cites [111] Sheng JG, Jones RA, Zhou XQ, McGinness JM, Van Eldik LJ, Mrak RE et al. Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease: potential significance for tau protein phosphorylation. Neurochem Int 2001; 39: 341–348. sourceNot checked — no full text of the source
• cites [112] Sheng JG, Mrak RE, Griffin WS . Microglial interleukin-1 alpha expression in brain regions in Alzheimer's disease: correlation with neuritic plaque distribution. Neuropathol Appl Neurobiol 1995; 21: 290–301. sourceNot checked — no full text of the source
• cites [113] Sheng JG, Griffin WS, Royston MC, Mrak RE . Distribution of interleukin-1-immunoreactive microglia in cerebral cortical layers: implications for neuritic plaque formation in Alzheimer's disease. Neuropathol Appl Neurobiol 1998; 24: 278–283. sourceSupported

May combine two claims.

Kravitz et al. measured translocator protein mRNA and identified higher expression in the hippocampus in Alzheimer's disease relative to controls, but no difference in the striatum.

“Kravitz et al.117 also measured TSPO mRNA and identified higher expression in the hippocampus in AD relative to controls, but no difference in the striatum.”

• cites [117] Kravitz E, Gaisler-Salomon I, Biegon A . Hippocampal glutamate NMDA receptor loss tracks progression in Alzheimer's disease: quantitative autoradiography in postmortem human brain. PLoS ONE 2013; 8: e81244. sourceSupported

May combine two claims.

Iba1 is a pan-microglial marker whose expression increases with microglial activation.

“Iba1 is a pan-microglial marker whose expression increases with microglial activation,58, 77”

• cites [58] Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S . Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res Mol Brain Res 1998; 57: 1–9. sourceNot checked — no full text of the source
• cites [77] Streit WJ, Braak H, Xue QS, Bechmann I . Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer's disease. Acta Neuropathol 2009; 118: 475–485. sourcePartly supported

  The Results (Fig. 1; page unavailable) say anti-Iba1 labeled the entire microglial population, supporting its use as a pan-microglial marker. The Results and Discussion distinguish activated cells by hypertrophy and morphology, but do not say that Iba1 expression increases with activation. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Within the temporal cortex, layers III-VI were found to be enriched in IL-1α-expressing microglia in Alzheimer's disease, whereas layers I-II were no different from controls.

“Within the temporal cortex, layers III–VI were found to be enriched in IL-1α-expressing microglia in AD, whereas layers I–II were no different from controls.113”

• cites [113] Sheng JG, Griffin WS, Royston MC, Mrak RE . Distribution of interleukin-1-immunoreactive microglia in cerebral cortical layers: implications for neuritic plaque formation in Alzheimer's disease. Neuropathol Appl Neurobiol 1998; 24: 278–283. sourceSupported

May combine two claims.

Roussos et al. reported higher TREM2 gene expression in Alzheimer's disease R47H carriers relative to controls and no difference in TREM2 between Alzheimer's disease noncarriers and control.

“They also reported higher TREM2 gene expression in AD R47H carriers relative to controls and no difference in TREM2 between AD noncarriers and control.”

• cites [107] Roussos P, Katsel P, Fam P, Tan W, Purohit DP, Haroutunian V . The triggering receptor expressed on myeloid cells 2 (TREM2) is associated with enhanced inflammation, neuropathological lesions and increased risk for Alzheimer's dementia. Alzheimers Dement 2015; 11: 1163–1170. sourcePartly supported

  Results §3.4 reports significantly higher TREM2 gene expression in AD R47H carriers than in controls. It does not explicitly report no difference between AD noncarriers and controls; the Discussion (§4) instead describes noncarriers as showing intermediate changes in expression. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Microglial activation appears to be affected by APOE genotype, with carriers of the ε4 risk allele exhibiting greater activation in some but not all studies.

“Microglial activation appears to be affected by APOE genotype, with carriers of the ε4 risk allele exhibiting greater activation in some48, 56 but not all studies.82”

• cites [48] Egensperger R, Kosel S, von Eitzen U, Graeber MB . Microglial activation in Alzheimer disease: association with APOE genotype. Brain Pathol 1998; 8: 439–447. sourceSupported
• cites [56] Minett T, Classey J, Matthews FE, Fahrenhold M, Taga M, Brayne C et al. Microglial immunophenotype in dementia with Alzheimer's pathology. J Neuroinflamm 2016; 13 (1): 135. sourceSupported
• cites [82] Hultman K, Strickland S, Norris EH . The APOE varepsilon4/varepsilon4 genotype potentiates vascular fibrin(ogen) deposition in amyloid-laden vessels in the brains of Alzheimer's disease patients. J Cereb Blood Flow Metab 2013; 33: 1251–1258. sourceNot checked — no full text of the source

May combine two claims.

Nonsteroidal anti-inflammatory drug treatment reduces activated glial cells in a mouse model of AD, and the use of nonsteroidal anti-inflammatory drugs is associated with less microglial activation in the brains of elderly patients post-mortem.

“nonsteroidal anti-inflammatory drug treatment reduces activated glial cells in a mouse model of AD,181 and the use of nonsteroidal anti-inflammatory drugs is associated with less microglial activation in the brains of elderly patients post-mortem,182”

• cites [181] Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C et al. Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain 2005; 128 (Pt 6): 1442–1453. sourceSupported
• cites [182] Mackenzie IR, Munoz DG . Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging. Neurology 1998; 50: 986–990. sourceNot checked — no full text of the source

May combine two claims.

For controls, Braak stages less than III were most commonly used, but some studies included controls with Braak stages IV or higher.

“Similarly for controls, Braak stages less than III were most commonly used, but some studies included controls with Braak stages IV or higher.123, 127”

• cites [123] Cribbs DH, Berchtold NC, Perreau V, Coleman PD, Rogers J, Tenner AJ et al. Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. J Neuroinflamm 2012; 9: 179. sourceCould not verify

  The Materials and methods section describes controls by cognitive status and gives Braak stages II–VI for Alzheimer’s disease cases, but it does not give Braak stages for controls. Searches for control Braak staging and stage IV or higher found no passage establishing either the claimed common cutoff or an exception. (LLM, conf=0.70)

  Experimental — accuracy not yet measured
• cites [127] Seyfried NT, Dammer EB, Swarup V, Nandakumar D, Duong DM, Yin L et al. A multi-network approach identifies protein-specific co-expression in asymptomatic and symptomatic Alzheimer's disease. Cell Syst 2017; 4: 60–72 e64. sourceCould not verify

  The Results section (‘Proteomic analysis of human brain tissues,’ page unavailable) identifies control cases and says their Braak data are in Table S1. The STAR Methods (‘Experimental Model and Subject Details,’ page unavailable) confirms that Braak staging was used, but the passages found do not give control-stage distributions or identify controls at stage IV or higher. Searches for stages below III and stage IV did not resolve the claim. (LLM, conf=0.74)

  Experimental — accuracy not yet measured

May combine two claims.

Serrano-Pozo et al. reported that the absolute number of microglia was the same in AD and control samples when stereology was used, but higher in AD when nonstereology-based counting was applied because of an apparent concentration of cells caused by cortical atrophy.

“In our review, Serrano-Pozo et al.54 reported that the absolute number of microglia was the same in AD and control samples when stereology was used, but higher in AD when nonstereology-based counting was applied because of an apparent concentration of cells caused by cortical atrophy.”

• cites [54] Serrano-Pozo A, Gomez-Isla T, Growdon JH, Frosch MP, Hyman BT . A phenotypic change but not proliferation underlies glial responses in Alzheimer disease. Am J Pathol 2013; 182: 2332–2344. 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.

Most studies used AD cases with a Braak score of V-VI, but some used AD cases with scores as low as I and II.

“Most studies used AD cases with a Braak score of V–VI, but some used AD cases with scores as low as I and II.18, 45, 53, 64, 67, 123”

• cites [18] Kellner A, Matschke J, Bernreuther C, Moch H, Ferrer I, Glatzel M . Autoantibodies against beta-amyloid are common in Alzheimer's disease and help control plaque burden. Ann Neurol 2009; 65: 24–31. sourceNot checked — no full text of the source
• cites [45] Vehmas AK, Kawas CH, Stewart WF, Troncoso JC . Immune reactive cells in senile plaques and cognitive decline in Alzheimer's disease. Neurobiol Aging 2003; 24: 321–331. sourceSupported
• cites [53] Pugliese M, Rodriguez MJ, Gimeno-Bayon J, Pujadas L, Billett EE, Wells C et al. Alzheimer's disease modifies progenitor cell expression of monoamine oxidase B in the subventricular zone. J Neurosci Res 2010; 88: 2588–2597. sourceNot checked — no full text of the source

May combine two claims.

Bachstetter et al. counted CD68-positive microglia in the hippocampus CA1, CA2/3, CA4 and the dentate gyrus, and noted increases in the CA1 and dentate gyrus relative to controls, but no difference in CA2/3 or CA4.

“For example, Bachstetter et al.69 counted CD68-positive microglia in the hippocampus CA1, CA2/3, CA4 and the dentate gyrus, and noted increases in the CA1 and dentate gyrus relative to controls, but no difference in CA2/3 or CA4.”

• cites [69] Bachstetter AD, Van Eldik LJ, Schmitt FA, Neltner JH, Ighodaro ET, Webster SJ et al. Disease-related microglia heterogeneity in the hippocampus of Alzheimer's disease, dementia with Lewy bodies, and hippocampal sclerosis of aging. Acta Neuropathol Commun 2015; 3: 32. sourcePartly supported

  The Results section (page unavailable) reports more CD68-positive staining in CA1 for HS-aging, AD, and AD plus HS-aging than in normal controls, and more staining in the dentate gyrus for AD than in the other groups; it found no significant disease-status effect in CA2/3 or CA4. Those regional comparisons come from staining-positive pixel measurements. The paper also counted large round CD68-positive cells, but the claim conflates those cell counts with the staining results and omits which disease groups showed the increases. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

The three stereology studies that counted all microglia, identified by either Iba1 or morphology, reported no differences in total microglial counts in AD relative to control samples, whereas increases were noted in the number of cells positive for activation-associated markers MHCII, CD68 and CD33.

“Interestingly, the three stereology studies that counted all microglia, identified by either Iba1 or morphology, reported no differences in total microglial counts in AD relative to control samples,54, 122, 70 whereas increases were noted in the number of cells positive for activation-associated markers MHCII, CD68 and CD33.54, 70, 83, 84”

• cites [54] Serrano-Pozo A, Gomez-Isla T, Growdon JH, Frosch MP, Hyman BT . A phenotypic change but not proliferation underlies glial responses in Alzheimer disease. Am J Pathol 2013; 182: 2332–2344. sourcePartly supported

  Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable, 1 not checked. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [122] Pelvig DP, Pakkenberg H, Regeur L, Oster S, Pakkenberg B . Neocortical glial cell numbers in Alzheimer's disease. A stereological study. Dement Geriatr Cogn Disord 2003; 16: 212–219. sourceNot checked — no full text of the source
• cites [70] Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K et al. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 2013; 78: 631–643. sourceSupported

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

Fifty-three papers that made a nonquantitative comparison between Alzheimer's disease and control were not fully extracted.

“Fifty-three papers that made a nonquantitative comparison between AD and control, often as a qualitative assessment of the intensity of immunohistochemistry staining, were not fully extracted but are summarized under the ‘Non-quantitative comparisons’ heading.”

Classified as probably not a substantial claim.

A total of 113 relevant articles were identified.

“A total of 113 relevant articles were identified.”

• Also stated in: § Results · plain

  “A total of 113 papers that quantified microglia and compared the results statistically between control and AD groups were fully extracted and are presented in the tables below”

May combine two claims.

Cluster of differentiation 11b was not consistently elevated in Alzheimer's disease relative to controls; 2 of 5 studies reported increases.

“cluster of differentiation 11b (2/5 studies)”

• Also stated in: § Cluster of differentiation 11b · plain

  “Two papers reported an increase in CD11b,15, 38 whereas three reported no differences between AD and control.74, 76, 91”

• cites [15] Akiyama H, McGeer PL . Brain microglia constitutively express beta-2 integrins. J Neuroimmunol 1990; 30: 81–93. sourceNot checked — no full text of the source
• cites [38] McGeer PL, McGeer EG, Yasojima K . Alzheimer disease and neuroinflammation. J Neural Transm Suppl 2000; 59: 53–57.Not matched

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

May combine two claims.

A total of 22,229 articles were screened, of which 757 met inclusion for full text review for inflammatory markers, including 224 that examined microglia.

“A total of 22 229 articles were screened, of which 757 met inclusion for full text review for inflammatory markers, including 224 that examined microglia (Figure 1).”

May combine two claims.

Six of the 10 null studies used cell counting, 2 of which used stereology.

“In contrast, 6 of the 10 null studies used cell counting, 2 of which used stereology, the gold standard for quantifying cells without bias.”

May combine two claims.

Women had higher HLA-DR reactivity than men in Alzheimer's disease, whereas the reverse was true in controls.

“Overmyer et al.52 noted that women had higher HLA-DR reactivity than men in AD, whereas the reverse was true in the controls”

• cites [52] Overmyer M, Helisalmi S, Soininen H, Laakso M, Riekkinen P Sr., Alafuzoff I . Reactive microglia in aging and dementia: an immunohistochemical study of postmortem human brain tissue. Acta Neuropathol 1999; 97: 383–392. sourceNot checked — no full text of the source

May combine two claims.

Iba1-positive cell density and gene expression was the same in Alzheimer's disease and control in the temporal cortex in two studies, but greater by western blot or immunocytochemistry in three other studies.

“Iba1-positive cell density72 and gene expression74 was the same in AD and control in the temporal cortex in two studies, but greater by western blot or immunocytochemistry in three other studies.20, 61, 66”

• cites [72] Davies DS, Ma J, Jegathees T, Goldsbury C . Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer's disease. Brain Pathol 2016; 27: 795–808. sourceNot checked — no full text of the source
• cites [74] Lee C, Low CY, Francis PT, Attems J, Wong PT, Lai MK et al. An isoform-specific role of FynT tyrosine kinase in Alzheimer's disease. J Neurochem 2016; 136: 637–650. sourceNot checked — no full text of the source
• cites [20] Dal Bianco A, Bradl M, Frischer J, Kutzelnigg A, Jellinger K, Lassmann H . Multiple sclerosis and Alzheimer's disease. Ann Neurol 2008; 63: 174–183. sourceNot checked — no full text of the source

May combine two claims.

Two studies that identified increases in CD11b also measured major histocompatibility complex II, and both reported greater increases in major histocompatibility complex II than CD11b in the Alzheimer's disease brain.

“Interestingly, two of the studies that identified increases in CD11b also measured MHCII, and both reported greater increases in MHCII than CD11b in the AD brain.15, 38”

• cites [15] Akiyama H, McGeer PL . Brain microglia constitutively express beta-2 integrins. J Neuroimmunol 1990; 30: 81–93. sourceNot checked — no full text of the source
• cites [38] McGeer PL, McGeer EG, Yasojima K . Alzheimer disease and neuroinflammation. J Neural Transm Suppl 2000; 59: 53–57.Not matched

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

May combine two claims.

One study that combined counts from the hippocampus with the amygdala, superior frontal gyrus and the superior, middle and inferior temporal gyri found no significant difference relative to control, though a nonsignificant increase was noted.

“whereas one that combined counts from the hippocampus with the amygdala, superior frontal gyrus and the superior, middle and inferior temporal gyri found no significant difference relative to control, though a nonsignificant increase was noted.33”

• cites [33] Lopes KO, Sparks DL, Streit WJ . Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivity. Glia 2008; 56: 1048–1060. sourceNot checked — no full text of the source

May combine two claims.

Two papers found no difference in ferritin cell counts relative to control, and one identified no change in ferritin-associated plaques in one region and a decrease in another.

“whereas two found no difference in cell counts relative to control,33, 51 and one identified no change in ferritin-associated plaques in one region and a decrease in another.100”

• cites [33] Lopes KO, Sparks DL, Streit WJ . Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivity. Glia 2008; 56: 1048–1060. sourceNot checked — no full text of the source
• cites [51] Wojtera M, Sobow T, Kloszewska I, Liberski PP, Brown DR, Sikorska B . Expression of immunohistochemical markers on microglia in Creutzfeldt-Jakob disease and Alzheimer's disease: morphometric study and review of the literature. Folia Neuropathol 2012; 50: 74–84.Not checked — no full text of the source
• cites [100] Fukumoto H, Asami-Odaka A, Suzuki N, Iwatsubo T . Association of A beta 40-positive senile plaques with microglial cells in the brains of patients with Alzheimer's disease and in non-demented aged individuals. Neurodegeneration 1996; 5: 13–17. sourceNot checked — no full text of the source

May combine two claims.

Akiyama et al. reported an increase in CD11b-positive cells in the temporal lobe of Alzheimer's disease cases, whereas Lee et al. found no difference in gene expression relative to controls in the same region.

“Similarly, Akiyama et al. reported an increase in CD11b-positive cells in the temporal lobe of AD cases,15 whereas Lee et al.74 found no difference in gene expression relative to controls in the same region.”

• cites [15] Akiyama H, McGeer PL . Brain microglia constitutively express beta-2 integrins. J Neuroimmunol 1990; 30: 81–93. sourceNot checked — no full text of the source
• cites [74] Lee C, Low CY, Francis PT, Attems J, Wong PT, Lai MK et al. An isoform-specific role of FynT tyrosine kinase in Alzheimer's disease. J Neurochem 2016; 136: 637–650. sourceNot checked — no full text of the source

May combine two claims.

Four papers compared levels of CD33 in the brains of patients with Alzheimer's disease to controls, three of which reported elevations in Alzheimer's disease, whereas one reported no change.

“Four papers were identified that used qPCR, western blot or immunohistochemistry to compare levels of CD33 in the brains of patients with AD to controls, three of which reported elevations in AD, whereas one reported no change (Supplementary Materials Table 5).”

May combine two claims.

Two papers reported an increase in CD11b, whereas three reported no differences between Alzheimer's disease and control.

“Two papers reported an increase in CD11b,15, 38 whereas three reported no differences between AD and control.74, 76, 91”

• cites [15] Akiyama H, McGeer PL . Brain microglia constitutively express beta-2 integrins. J Neuroimmunol 1990; 30: 81–93. sourceNot checked — no full text of the source
• cites [38] McGeer PL, McGeer EG, Yasojima K . Alzheimer disease and neuroinflammation. J Neural Transm Suppl 2000; 59: 53–57.Not matched

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

• cites [74] Lee C, Low CY, Francis PT, Attems J, Wong PT, Lai MK et al. An isoform-specific role of FynT tyrosine kinase in Alzheimer's disease. J Neurochem 2016; 136: 637–650. sourceNot checked — no full text of the source

May combine two claims.

Findings with CD11b, which labels resting and activated microglia, also had mixed results, and studies using other activation markers, such as ferritin, IL-1α and CD33, were consistently increased in AD.

“This is supported by findings with CD11b that, like Iba1, labels resting and activated microglia, that also had mixed results, and by studies using other activation markers, such as ferritin, IL-1α and CD33, that were consistently increased in AD.”

• AssumptionRests on an assumption: CD11b labels resting and activated microglia.
• AssumptionRests on an assumption: Ferritin, IL-1α and CD33 are activation markers.

May combine two claims.

9/10 studies noting an increase in Iba1 in AD relative to controls used expression-based quantification methods (qPCR, western, fluorescence intensity) that indicate only the amount of Iba1 in the sample, whereas most that identified no difference used cell counting, including two studies that used stereological quantification.

“Importantly, 9/10 studies noting an increase in Iba1 in AD relative to controls used expression-based quantification methods (qPCR, western, fluorescence intensity) that indicate only the amount of Iba1 in the sample, whereas most that identified no difference used cell counting, including two studies that used stereological quantification.”

May combine two claims.

Four studies compared CD11c in Alzheimer's disease and control post-mortem brains, all of which used immunohistochemistry and reported higher staining scores or cell counts in Alzheimer's disease in at least one brain region.

“Four studies were identified that compared CD11c in AD and control post-mortem brains, all of which used immunohistochemistry and reported higher staining scores or cell counts in AD in at least one brain region15, 108, 109, 110”

• cites [15] Akiyama H, McGeer PL . Brain microglia constitutively express beta-2 integrins. J Neuroimmunol 1990; 30: 81–93. sourceNot checked — no full text of the source
• cites [108] Itoh Y, Yamada M, Suematsu N, Matsushita M, Otomo E . An immunohistochemical study of centenarian brains: a comparison. J Neurol Sci 1998; 157: 73–81. sourceNot checked — no full text of the source
• cites [109] Paulus W, Bancher C, Jellinger K . Microglial reaction in Pick's disease. Neurosci Lett 1993; 161: 89–92. sourceNot checked — no full text of the source

May combine two claims.

Shefer identified both a greater absolute number of glia and a greater number of microglia per volume in the subiculum of the archicortex in the hippocampal fissure.

“Shefer121 identified both a greater absolute number of glia and a greater number of microglia per volume in the subiculum of the archicortex in the hippocampal fissure.”

• cites [121] Shefer VF . Hippocampal pathology as a possible factor in the pathogenesis of senile dementias. Neurosci Behav Physiol 1977; 8: 236–239. sourceNot checked — no full text of the source

May combine two claims.

Studies measuring MHCII or CD68 consistently identified increases in AD relative to control in most brain regions studied, whereas 10 of the 20 studies that compared Iba1 identified no difference or a decrease relative to controls.

“Although studies measuring MHCII or CD68 consistently identified increases in AD relative to control in most brain regions studied, 10 of the 20 studies that compared Iba1 identified no difference or a decrease relative to controls.”

May combine two claims.

In vivo imaging studies of microglia in AD found that of five papers using the PK11195 ligand, three identified increases in AD relative to controls and two identified no differences, whereas for the second-generation radioligands, 5/6 reported increases in AD in various brain regions.

“imaging of microglia in AD in vivo found that of the five papers using the PK11195 ligand, three identified increases in AD relative to controls and two identified no differences, whereas for the second-generation radioligands, 5/6 reported increases in AD in various brain regions.119”

• cites [119] Knezevic D, Mizrahi R . Molecular imaging of neuroinflammation in Alzheimer's disease and mild cognitive impairment. Prog Neuropsychopharmacol Biol Psychiatry 2017. sourceNot checked — no full text of the source

May combine two claims.

Pelvig et al. identified microglia based on morphology and quantified them using stereology, but found no difference in the total number of cells in the neocortex.

“In contrast, Pelvig et al.122 also identified microglia based on morphology and quantified them using stereology, but found no difference in the total number of cells in the neocortex.”

• cites [122] Pelvig DP, Pakkenberg H, Regeur L, Oster S, Pakkenberg B . Neocortical glial cell numbers in Alzheimer's disease. A stereological study. Dement Geriatr Cogn Disord 2003; 16: 212–219. sourceNot checked — no full text of the source

May combine two claims.

Two papers used Ricinus communis agglutinin-1 immunohistochemistry to compare microglia counts; both reported significantly more RCA-1-labelled microglia in Alzheimer's disease in the inferomedial temporal lobe and the association cortex, periallocortex/allocortex and primary cortex.

“Both reported significantly more RCA-1-labelled microglia in AD in the inferomedial temporal lobe115 and the association cortex, periallocortex/allocortex and primary cortex, respectively.116”

• cites [115] Mackenzie IR, Hao C, Munoz DG . Role of microglia in senile plaque formation. Neurobiol Aging 1995; 16: 797–804. sourceNot checked — no full text of the source
• cites [116] Sheffield LG, Marquis JG, Berman NE . Regional distribution of cortical microglia parallels that of neurofibrillary tangles in Alzheimer's disease. Neurosci Lett 2000; 285: 165–168. sourceNot checked — no full text of the source

May combine two claims.

Three studies examined CD11c in the hippocampus; two reported higher levels of staining by semiquantitative scoring in Alzheimer's disease in the CA1 and subiculum, but Paulus et al. quantified CD11c by unbiased cell counts and identified no difference in CA1 or the granular layer of the dentate gyrus relative to control.

“Three studies examined CD11c in the hippocampus. Two reported higher levels of staining quantified by a semiquantitative scoring system in AD in the CA1 and subiculum;108, 110 however, Paulus et al.109 quantified CD11c by unbiased cell counts and identified no difference in CA1 or the granular layer of the dentate gyrus relative to control.”

• cites [108] Itoh Y, Yamada M, Suematsu N, Matsushita M, Otomo E . An immunohistochemical study of centenarian brains: a comparison. J Neurol Sci 1998; 157: 73–81. sourceNot checked — no full text of the source
• cites [110] Yamada M, Itoh Y, Sodeyama N, Suematsu N, Otomo E, Matsushita M et al. Senile dementia of the neurofibrillary tangle type: a comparison with Alzheimer's disease. Dement Geriatr Cogn Disord 2001; 12: 117–126. sourceNot checked — no full text of the source
• cites [109] Paulus W, Bancher C, Jellinger K . Microglial reaction in Pick's disease. Neurosci Lett 1993; 161: 89–92. sourceNot checked — no full text of the source

May combine two claims.

Three papers measuring IL-1α-positive microglia were included; all three were from the same research group and reported higher IL-1α-positive microglia in Alzheimer's disease in at least one of the measured brain areas, but two reported no difference relative to control in one region.

“All three papers are from the same research group and reported higher IL-1α-positive microglia in AD in at least one of the measured brain areas, but two reported no difference relative to control in one region.”

May combine two claims.

Post-mortem analyses from brains of AD patients administered amyloid-β vaccines demonstrate positive correlations between Iba1 and CD68 and markers of neuronal loss and degeneration that are attenuated following immunization and amyloid-β clearance, when the number of activated CD68-positive but not total Iba1-positive microglia are reduced.

“as post-mortem analyses from brains of AD patients administered amyloid-β vaccines demonstrate positive correlations between Iba1 and CD68 and markers of neuronal loss and degeneration that are attenuated following immunization and amyloid-β clearance,187 when the number of activated CD68-positive but not total Iba1-positive microglia are reduced.186”

• cites [187] Paquet C, Amin J, Mouton-Liger F, Nasser M, Love S, Gray F et al. Effect of active Abeta immunotherapy on neurons in human Alzheimer's disease. J Pathol 2015; 235: 721–730. sourceNot checked — no full text of the source
• cites [186] Zotova E, Bharambe V, Cheaveau M, Morgan W, Holmes C, Harris S et al. Inflammatory components in human Alzheimer's disease and after active amyloid-beta42 immunization. Brain 2013; 136 (Pt 9): 2677–2696. sourceNot checked — no full text of the source

May combine two claims.

Among those that reported genotype, there was variability, with some studies excluding those with the ε4 allele, and others including a majority of AD subjects carrying the risk allele.

“Among those that reported genotype, there was variability, with some studies excluding those with the ε4 allele,68, 172 and others including a majority of AD subjects carrying the risk allele.30, 62, 79”

• cites [68] Satoh J, Kino Y, Asahina N, Takitani M, Miyoshi J, Ishida T et al. TMEM119 marks a subset of microglia in the human brain. Neuropathology 2016; 36: 39–49. sourceNot checked — no full text of the source
• cites [172] Rozemuller AJ, Eikelenboom P, Theeuwes JW, Jansen Steur EN, de Vos RA . Activated microglial cells and complement factors are unrelated to cortical Lewy bodies. Acta Neuropathol 2000; 100: 701–708. sourceNot checked — no full text of the source
• cites [30] Itagaki S, McGeer PL, Akiyama H . Presence of T-cytotoxic suppressor and leucocyte common antigen positive cells in Alzheimer's disease brain tissue. Neurosci Lett 1988; 91: 259–264. sourceNot checked — no full text of the source

May combine two claims.

Half the studies examining microglia in the white matter showed either no difference between AD and control or higher levels in control.

“Similarly, half the studies examining microglia in the white matter showed either no difference between AD and control25, 44, 52, 69, 94, 109, 139 or higher levels in control.32”

• cites [25] Giulian D, Haverkamp LJ, Li J, Karshin WL, Yu J, Tom D et al. Senile plaques stimulate microglia to release a neurotoxin found in Alzheimer brain. Neurochem Int 1995; 27: 119–137. sourceNot checked — no full text of the source
• cites [44] Van Everbroeck B, Dobbeleir I, De Waele M, De Leenheir E, Lubke U, Martin JJ et al. Extracellular protein deposition correlates with glial activation and oxidative stress in Creutzfeldt-Jakob and Alzheimer's disease. Acta Neuropathol 2004; 108: 194–200. sourceNot checked — no full text of the source
• cites [52] Overmyer M, Helisalmi S, Soininen H, Laakso M, Riekkinen P Sr., Alafuzoff I . Reactive microglia in aging and dementia: an immunohistochemical study of postmortem human brain tissue. Acta Neuropathol 1999; 97: 383–392. sourceNot checked — no full text of the source

May combine two claims.

Masliah et al. quantified microglia in different layers of the hippocampus and reported higher levels relative to control in the molecular and pyramidal layer, but lower levels in the stratus polymorphous.

“Similarly, Masliah et al.94 quantified microglia in different layers of the hippocampus and reported higher levels relative to control in the molecular and pyramidal layer, but lower levels in the stratus polymorphous.”

• cites [94] Masliah E, Mallory M, Hansen L, Alford M, Albright T, Terry R et al. Immunoreactivity of CD45, a protein phosphotyrosine phosphatase, in Alzheimer's disease. Acta Neuropathol 1991; 83: 12–20. sourceNot checked — no full text of the source

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

Other infiltrating or perivascular immune cells may have contributed to the results.

“and hence it is possible that other infiltrating or perivascular immune cells may have contributed to the results.”

May combine two claims.

Within the brain, major histocompatibility complex II is primarily expressed on microglia, where it is generally considered a marker of activated cells, though it may have weaker expression in resting cells.

“Within the brain, MHCII is primarily expressed on microglia, where it is generally considered a marker of activated cells, though it may have weaker expression in resting cells.14”

• cites [14] Lee YB, Nagai A, Kim SU . Cytokines, chemokines, and cytokine receptors in human microglia. J Neurosci Res 2002; 69: 94–103. sourceNot checked — no full text of the source

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

Data from included studies were extracted by at least two independent reviewers, with a third reviewer employed in the case of a conflict.

“Data from included studies were extracted by at least two independent reviewers (KEH and DM, VG or MT), with a third reviewer employed in the case of a conflict.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Aberrant microglial activation is a causal factor in the development of Alzheimer's disease, as opposed to a consequence of Alzheimer's disease pathology.

“This suggests that aberrant microglial activation is a causal factor in the development of AD, as opposed to a consequence of AD pathology.”

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

The search protocol was developed based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses and World Health Organization Review Protocol Template Guidelines.

“The search protocol was developed based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and World Health Organization (WHO) Review Protocol Template Guidelines where applicable for a systematic review of descriptive (non-interventional) data”

May combine two claims.

CD68 is primarily localized to microglia within the brain parenchyma, and to perivascular macrophages in the cerebral blood vessels and occasionally parenchyma.

“CD68 is a common marker for macrophage lineage cells, primarily localized to microglia within the brain parenchyma, and perivascular macrophages in the cerebral blood vessels and, occasionally, parenchyma.78”

• cites [78] Fiala M, Liu QN, Sayre J, Pop V, Brahmandam V, Graves MC et al. Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer's disease brain and damage the blood-brain barrier. Eur J Clin Invest 2002; 32: 360–371. sourceNot checked — no full text of the source

May combine two claims.

Expression-based assays indicate the amount of Iba1 in a sample; an increase could reflect a change in cell numbers, cell size or function.

“Expression-based assays like qPCR, western blot, or intensity of immunohistochemistry staining indicate the amount of Iba1 in a sample. An increase could reflect a change in cell numbers, cell size or function, as Iba1 expression is thought to increase with microglial activation.”

May combine two claims.

Alzheimer's disease pathology may stimulate the activation of microglia and upregulation of major histocompatibility complex II.

“indicating that AD pathology may stimulate the activation of microglia and upregulation of MHCII.”

May combine two claims.

Iba1 is a cytoplasmic protein expressed in monocyte lineage cells and in the brain and is primarily restricted to microglia.

“Iba1 is a cytoplasmic protein expressed in monocyte lineage cells and in the brain and is primarily restricted to microglia.57”

• cites [57] Imai Y, Ibata I, Ito D, Ohsawa K, Kohsaka S . A novel gene iba1 in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage. Biochem Biophys Res Commun 1996; 224: 855–862. sourceNot checked — no full text of the source

May combine two claims.

The evidence suggests that there are more CD45-positive cells in the brains of patients with Alzheimer's disease, but that this is not necessarily accompanied by increased CD45 gene expression.

“The evidence suggests that there are more CD45-positive cells in the brains of patients with AD, but that this is not necessarily accompanied by increased CD45 gene expression.”

May combine two claims.

CD45 is expressed by both resting and activated microglia, but it does not appear to be inducible with activation in humans.

“CD45 is expressed by both resting and activated microglia, but it does not appear to be inducible with activation in humans.92”

• cites [92] Becher B, Antel JP . Comparison of phenotypic and functional properties of immediately ex vivo and cultured human adult microglia. Glia 1996; 18: 1–10. sourceNot checked — no full text of the source

May combine two claims.

On balance, CD68 appears to be increased in the brains of patients with Alzheimer's disease, though there is some variation between studies and brain regions.

“On balance, CD68 appears to be increased in the brains of patients with AD, though there is some variation between studies and brain regions.”

May combine two claims.

CD11b is expressed by both resting and activated microglia, though it is inducible with activation.

“Like Iba1, CD11b is expressed by both resting and activated microglia, though it too is inducible with activation.14”

• cites [14] Lee YB, Nagai A, Kim SU . Cytokines, chemokines, and cytokine receptors in human microglia. J Neurosci Res 2002; 69: 94–103. sourceNot checked — no full text of the source

May combine two claims.

CD33 is likely a marker of microglial function or activity, and not of the number of microglia.

“As CD33 increases when adjusting for Iba1 in most of studies, it is likely a marker of microglial function or activity, and not of the number of microglia.”

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

Increases in ferritin levels with inflammation are thought to be caused by increases in microglial number and activation.

“and increases in ferritin levels with inflammation are thought to be caused by increases in microglial number and activation.”

Classified as probably not a substantial claim. May combine two claims.

Translocator protein is a mitochondrial protein expressed on activated microglia in the brain.

“Translocator protein (TSPO), also known as the peripheral benzodiazepine receptor, is a mitochondrial protein expressed on activated microglia in the brain.”

May combine two claims.

These results indicate that there are increases in the expression of Iba1, but not the absolute number of microglia in AD.

“and hence these results indicate that there are increases in the expression of Iba1, but not the absolute number of microglia in AD.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

CD11c is a transmembrane protein expressed on the surface of various immune cells, including microglia, macrophages and neutrophils.

“CD11c is a transmembrane protein expressed on the surface of various immune cells, including microglia, macrophages and neutrophils.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

IL-1α is a proinflammatory cytokine that plays a central role in the induction of an immune response.

“IL-1α is a proinflammatory cytokine that plays a central role in the induction of an immune response.”

May combine two claims.

Based on the limited number of studies, CD11c appears to be increased in the brain of patients with Alzheimer's disease relative to controls, but this may be influenced by differences in methodology between the studies.

“Based on the limited number of studies, it appears that CD11c is increased in brain of patients with AD relative to controls, but this may be influenced by differences in methodology between the studies.”

May combine two claims.

PK11195 has a lower affinity for translocator protein and a lower signal-to-noise ratio than newer ligands, which may explain some of the discrepancy.

“PK11195 has a lower affinity for TSPO and a lower signal-to-noise ratio than newer ligands which may explain some of the discrepancy.”

May combine two claims.

Increased microglial activation is a contributor to AD development, and not merely a response to established AD pathology.

“supporting the notion that increased microglial activation is a contributor to AD development, and not merely a response to established AD pathology.”

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

Differences in the methods used for measuring gene expression or for quantifying protein by western blot or enzyme-linked immunosorbent assay could similarly contribute to variability in the results.

“Differences in the methods used for measuring gene expression or for quantifying protein by western blot or enzyme-linked immunosorbent assay could similarly contribute to variability in the results.”

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

The large number of papers returned in the initial search (>20 000) may have increased the risk of misidentifying a paper.

“The large number of papers returned in the initial search (>20 000) may have increased the risk of misidentifying a paper.”

May combine two claims.

Studies that did not examine microglia as a primary objective are more likely to have been omitted which may introduce some bias into the results of this review.

“Thus, studies that did not examine microglia as a primary objective are more likely to have been omitted which may introduce some bias into the results of this review.”

May combine two claims.

Several studies report higher levels of HLA-DR-expressing microglia in the white matter than the gray matter of nondemented cases, suggesting that microglia in this tissue may be constitutively activated.

“Several studies report higher levels of HLA-DR-expressing microglia in the white matter than the gray matter of nondemented cases, suggesting that microglia in this tissue may be constitutively activated.49, 52, 143”

• cites [49] Mattiace LA, Davies P, Dickson DW . Detection of HLA-DR on microglia in the human brain is a function of both clinical and technical factors. Am J Pathol 1990; 136: 1101–1114.Not checked — no full text of the source
• cites [52] Overmyer M, Helisalmi S, Soininen H, Laakso M, Riekkinen P Sr., Alafuzoff I . Reactive microglia in aging and dementia: an immunohistochemical study of postmortem human brain tissue. Acta Neuropathol 1999; 97: 383–392. sourceNot checked — no full text of the source
• cites [143] Styren SD, Civin WH, Rogers J . Molecular, cellular, and pathologic characterization of HLA-DR immunoreactivity in normal elderly and Alzheimer's disease brain. Exp Neurol 1990; 110: 93–104. sourceNot checked — no full text of the source

May combine two claims.

Studies that examined staining in the whole hippocampus could dilute potential differences between AD and control by examining multiple regions simultaneously, and this may help to explain why nearly a third of studies using hippocampal tissue reported no difference between AD and control.

“Thus, studies that examined staining in the whole hippocampus could dilute potential differences between AD and control by examining multiple regions simultaneously, and this may help to explain why nearly a third of studies using hippocampal tissue reported no difference between AD and control.”

May combine two claims.

This supports the suggestion that microglial activation is increased in AD without an absolute increase in the number of microglia.

“This supports the suggestion that microglial activation is increased in AD without an absolute increase in the number of microglia.”

May combine two claims.

The lack of consistent differences in the white matter between patients with AD and controls in the studies in our review could indicate that AD pathology does not stimulate further increases in microglial markers on top of their already activated state, whereas elevations in AD can be observed in the grey matter that does not demonstrate this constitutive elevation.

“The lack of consistent differences in the white matter between patients with AD and controls in the studies in our review could therefore indicate that AD pathology does not stimulate further increases in microglial markers on top of their already activated state, whereas elevations in AD can be observed in the grey matter that does not demonstrate this constitutive elevation.”