Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau

In the paper

“The AD brain network proteome also features conserved upregulation of oligodendrocyte-enriched modules associated with myelination (Fig. 1).”

What the sources say

• Partly supported

  The Results section on protein co-expression identifies B-M2 as a myelin-related module with oligodendrocyte-specific hub proteins, and the Discussion reports preservation of some cell-type-enriched modules across networks. But the Results section on AD neuropathology identifies increases in inflammatory and other modules, not B-M2; our copy does not establish conserved upregulation of the oligodendrocyte/myelination module in AD. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  cites [62] 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. sourceExperimental — accuracy not yet measured
• Partly supported

  The Integrative Analysis section identifies M2 and M4 as oligodendrocyte-linked modules in a myelination panel, and the expression-trends section reports that the glial panels were upregulated in the AD brain. Figure S2 reports preservation of many brain modules across datasets, but does not establish conserved upregulation specifically for the oligodendrocyte-enriched modules. Page numbers were unavailable in our copy. (LLM, conf=0.78)

  cites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. sourceExperimental — accuracy not yet measured
• Disputed

  In Results, “Identification of Robust Disease-Relevant Protein Co-expression Signature” (page unavailable), the paper identifies C5 as its oligodendrocyte module but lists only C3, C4, C8, and C10 as upregulated in AD. The “Comparison of the AD Proteome and Transcriptome” Results section identifies the upregulated glial modules as astrocyte-enriched C8 and microglia/endothelial-enriched C10, not an oligodendrocyte-enriched myelination module. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites [64] Swarup V, Chang TS, Duong DM, Dammer EB, Dai J, Lah JJ, et al. Identification of conserved proteomic networks in neurodegenerative dementia. Cell Rep. 2020;31:107807. sourceExperimental — accuracy not yet measured
• Disputed

  In Results (‘AD genetic risk factors cluster in glial modules’; page unavailable), the oligodendrocyte- and neuron-associated module M33 correlates negatively, not positively, with amyloid plaques and tau tangles. The Discussion notes an increase in oligodendrocytes in asymptomatic AD, but does not describe conserved upregulation of myelination-associated oligodendrocyte modules. (LLM, conf=0.82)

  Checked by a reasoning model — may be wrong.

  cites [74] Johnson ECB, Dammer EB, Duong DM, Yin L, Thambisetty M, Troncoso JC, et al. Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease. Mol Neurodegener. 2018;13:52. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section, “Construction and Validation of a Consensus AD Protein Co-Expression Network” (page unavailable), identifies an M2 myelin module enriched in oligodendrocyte markers and reports changes in M2 in AD. The Results also report preservation of the network modules across cohorts and brain regions. However, the passages do not specify that M2 is upregulated in AD, so they do not establish conserved upregulation. (LLM, conf=0.84)

  cites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. sourceExperimental — accuracy not yet measured

In the paper

“Clinical trials of methylene blue-derived tau inhibitors in AD have generally yielded disappointing results [47–49].”

What the sources say

• Supported

  The Discussion (page not provided) states that the trial’s primary analysis was negative and found no benefit of LMTM as an add-on treatment for mild to moderate Alzheimer’s disease. That supports citing this trial as an example of a disappointing result, although the paper also reports a possible benefit in a monotherapy subgroup. (LLM, conf=0.90)

  cites [47] Gauthier S, Feldman HH, Schneider LS, Wilcock GK, Frisoni GB, et al. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet. 2016;388:2873–84. source
• Not checked yetcites [48] Seripa D, Solfrizzi V, Imbimbo BP, Daniele A, Santamato A, Lozupone M, et al. Tau-directed approaches for the treatment of Alzheimer’s disease: focus on leuco-methylthioninium. Expert Rev Neurother. 2016;16:259–77. source
• Supported

  The Conclusions state that clinical data on methylene blue derivatives are “not very promising.” The Tau aggregation inhibitors section reports no significant benefit in two phase III LMTX trials in patients with AD, supporting the characterization of generally disappointing results. (LLM, conf=0.94)

  cites [49] Congdon EE, Sigurdsson EM. Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2018;14:399–415. source

In the paper

“suggesting it maintains a causal role in disease pathogenesis [62, 64, 74, 96].”

What the sources say

• Partly supported

  The Discussion (page unavailable) says that AD-risk-gene enrichment in microglia- and oligodendrocyte-enriched networks strongly implies those modules reflect causal pathogenic processes. The Results identify MSN as a marker in module B-M6, but do not make that causal inference specifically for an MSN module. The source supports the broader glial-network inference, not the module-specific claim. (LLM, conf=0.80)

  cites [62] 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. sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion identifies MSN as a hub gene in the C8 module, which is associated with early Alzheimer’s disease changes and enriched for genetic risk. The Results and Discussion treat that enrichment as consistent with a potential causal role, but the paper does not identify an “MSN module” or establish that MSN itself has a causal role in disease pathogenesis. Page numbers were not available in our copy. (LLM, conf=0.84)

  cites [64] Swarup V, Chang TS, Duong DM, Dammer EB, Dai J, Lah JJ, et al. Identification of conserved proteomic networks in neurodegenerative dementia. Cell Rep. 2020;31:107807. sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Results section on AD genetic risk factors reports enrichment and correlations for modules M4, M7, M27, and M33, but does not identify an MSN module or establish a causal role in pathogenesis. Searches for “MSN” and “causal role” found no passage addressing that specific claim. (LLM, conf=0.72)

  cites [74] Johnson ECB, Dammer EB, Duong DM, Yin L, Thambisetty M, Troncoso JC, et al. Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease. Mol Neurodegener. 2018;13:52. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results and Discussion (page unavailable) suggest a potential causative role for the M4 astrocyte/microglial metabolism module in Alzheimer’s disease. The Discussion identifies MSN as a hub protein within M4, but does not identify an “MSN module” or assign that module a causal role. The claim appears to transfer the qualified finding about M4 to MSN. (LLM, conf=0.83)

  cites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. sourceExperimental — accuracy not yet measured

In the paper

“Modules enriched with RNA binding and splicing proteins are also consistently upregulated in the AD network proteome (Fig. 1).”

What the sources say

• Partly supported

  The Results section on neuropathology and cognitive status reports that RNA-metabolism module B-M8 was elevated in AsymAD and AD. But the Results section comparing RNA and protein networks says E-M6, a module enriched with DNA/RNA-associated proteins including splicing factors, was decreased. The paper therefore does not support the claim that such modules were consistently upregulated (page numbers unavailable in our copy). (LLM, conf=0.86)

  cites [62] 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. sourceExperimental — accuracy not yet measured
• Partly supported

  The figure text in the Brain2 module-preservation section identifies M16 and M21 with the ontology “Transcription / RNA Splicing.” The Systems-Based Analysis section reports increased abundance for glial-enriched modules, but does not establish that the RNA-splicing modules—or modules enriched with RNA-binding proteins—are consistently upregulated in AD. No page number is available in our copy. (LLM, conf=0.78)

  cites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Identification of Late Changes in the AD Proteome; page unavailable) identify an upregulated C4 module enriched for mRNA splicing, with similar trends in other cohorts. The copy does not establish that multiple RNA-binding-and-splicing-enriched modules were consistently upregulated: it identifies C4 as the splicing module, and the Results (Identification of Robust Disease-Relevant Protein Co-expression Signature; page unavailable) say C4 was significantly associated with AD in at least three of five datasets, not all five. (LLM, conf=0.82)

  cites [64] Swarup V, Chang TS, Duong DM, Dammer EB, Dai J, Lah JJ, et al. Identification of conserved proteomic networks in neurodegenerative dementia. Cell Rep. 2020;31:107807. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section on RNA-binding protein enrichment identifies several AD network modules enriched in RNA-binding proteins, and the Results section on alternative splicing says these modules are generally positively correlated with AD pathology. But a positive correlation is not a finding that the modules are consistently upregulated in AD. The paper also reports little overlap between RNA-binding-protein-enriched modules and modules enriched for alternative-splicing peptides. (LLM, conf=0.85)

  cites [74] Johnson ECB, Dammer EB, Duong DM, Yin L, Thambisetty M, Troncoso JC, et al. Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease. Mol Neurodegener. 2018;13:52. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Construction and Validation of a Consensus AD Protein Co-Expression Network; page unavailable) identify M10 as an RNA binding/splicing module significantly correlated with AD-related measures. The paper also reports preservation of its network modules across cohorts, but the passages do not establish that M10 is consistently upregulated in AD; the case-status discussion specifies the strongest changes for other modules. (LLM, conf=0.83)

  cites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. sourceExperimental — accuracy not yet measured

In the paper

“While differential protein expression within these overlapping modules is reasonably concordant (R~0.5), we have repeatedly observed targets among these modules with highly discordant changes at the protein and RNA levels [62–64].”

What the sources say

• Not checked yetcites [62] 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. source
• Not checked yetcites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. source
• Not checked yetcites [64] Swarup V, Chang TS, Duong DM, Dammer EB, Dai J, Lah JJ, et al. Identification of conserved proteomic networks in neurodegenerative dementia. Cell Rep. 2020;31:107807. source

In the paper

“Furthermore, only half of the disease-related variance observed in the AD network proteome is reflected in gene expression at the transcriptome level, the remainder representing post-transcriptional and post-translational effects [64].”

What the sources say

• Not checked yetcites [64] Swarup V, Chang TS, Duong DM, Dammer EB, Dai J, Lah JJ, et al. Identification of conserved proteomic networks in neurodegenerative dementia. Cell Rep. 2020;31:107807. source

In the paper

“Three of the modules are consistently increased in the AD brain network proteome: inflammatory, myelination, and RNA binding/splicing, while the remaining three are consistently decreased: synaptic, mitochondrial, and cytoskeleton.”

In the paper

“Using this framework, six core and highly conserved modules across AsymAD and AD cohorts with reproducible links to specific cell types, organelles, and biological functions have been identified.”

In the paper

“Johnson et al. demonstrated this advantage in one of the first TMT-MS network proteomes of the AD brain [74], which quantified 6533 proteins across 47 brain tissues compared to just 2736 proteins quantified by LFQ-MS when applied to the same samples.”

What the sources say

• Not checked yetcites [74] Johnson ECB, Dammer EB, Duong DM, Yin L, Thambisetty M, Troncoso JC, et al. Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease. Mol Neurodegener. 2018;13:52. source

In the paper

“Only 30–40% of modules in the AD brain network proteome overlap with those of the network transcriptome [62, 63].”

What the sources say

• Not checked yetcites [62] 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. source
• Not checked yetcites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. source

In the paper

“While differential protein expression within these overlapping modules is reasonably concordant (R~0.5), we have repeatedly observed targets among these modules with highly discordant changes at the protein and RNA levels [62–64].”

What the sources say

• Not checked yetcites [62] 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. source
• Not checked yetcites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. source
• Not checked yetcites [64] Swarup V, Chang TS, Duong DM, Dammer EB, Dai J, Lah JJ, et al. Identification of conserved proteomic networks in neurodegenerative dementia. Cell Rep. 2020;31:107807. source

In the paper

“Among the resulting 44 modules, we resolved an ECM-associated module with highly significant endothelial enrichment and relatively weak glial co-expression.”

What the sources say

• Not checked yetcites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. source
• Not checked yetcites [75] Ping L, Duong DM, Yin L, Gearing M, Lah JJ, Levey AI, et al. Global quantitative analysis of the human brain proteome in Alzheimer’s and Parkinson’s disease. Sci Data. 2018;5:180036. source

In the paper

“Antemortem diagnosis also relies heavily on the presence of Aβ and tau, either as measured in the spinal fluid or imaged using positron emission tomography (PET) [7–10].”

What the sources say

• Not checked yetcites [7] Jack CR Jr, Wiste HJ, Schwarz CG, Lowe VJ, Senjem ML, Vemuri P, et al. Longitudinal tau PET in ageing and Alzheimer’s disease. Brain. 2018;141:1517–28. source
• Not checked yetcites [8] Lowe VJ, Lundt ES, Albertson SM, Przybelski SA, Senjem ML, Parisi JE, et al. Neuroimaging correlates with neuropathologic schemes in neurodegenerative disease. Alzheimers Dement. 2019;15:927–39. source
• Not checked yetcites [9] Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR, et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol. 2006;59:512–9. source
• Not checked yetcites [10] Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007;64:343–9. source

In the paper

“Simultaneously, a growing number of genetic, cellular, and biochemical studies have linked AD pathogenesis to a more diverse array of biological mechanisms involving a variety of cell types.”

In the paper

“However, mounting evidence indicates that Aβ and tau represent only a fraction of the complex and heterogeneous biology of AD.”

In the paper

“Increasing evidence indicates that AD develops from an intricate web of biochemical and cellular processes that extend far beyond amyloid and tau accumulation.”

• Also stated in: § Expanding AD pathogenesis beyond amyloid and tau · hedged

  “Increasing evidence now suggests that AD features a diverse non-linear pathogenic landscape encompassing a variety of cellular mechanisms with equally prominent roles in disease progression [12].”

What the sources say

• Not checked yetcites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

In the paper

“In many instances, success in animal models has not translated into cognitive benefits in humans.”

In the paper

“These genetic findings are further supported by the common observation of aberrantly activated microglia in pathologically relevant AD brain regions, including within and surrounding Aβ plaques [59, 60].”

What the sources say

• Not checked yetcites [59] McGeer PL, Itagaki S, Tago H, McGeer EG. Occurrence of HLA-DR reactive microglia in Alzheimer’s disease. Ann N. Y Acad Sci. 1988;540:319–23. source
• Not checked yetcites [60] Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405. source

In the paper

“Together, these findings argue against tau accumulation as a linear consequence of Aβ deposition.”

In the paper

“Several genes encoding proteins intimately associated with the endothelium and Aβ clearance are highly validated AD risk factors, such as APOEε4, PICALM, and CLU [50, 51].”

What the sources say

• Not checked yetcites [50] Verghese PB, Castellano JM, Garai K, Wang Y, Jiang H, Shah A, et al. ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta association in physiological conditions. Proc Natl Acad Sci USA. 2013;110:E1807–16. source
• Not checked yetcites [51] Zhao Z, Sagare AP, Ma Q, Halliday MR, Kong P, Kisler K, et al. Central role for PICALM in amyloid-beta blood-brain barrier transcytosis and clearance. Nat Neurosci. 2015;18:978–87. source

In the paper

“Moreover, the growing recognition of overlapping pathologies (e.g., Lewy body inclusions, TDP-43 pathology, vascular lesions, etc.) among dementia patients indicates a wide range of biological heterogeneity within AD that necessitates a broader approach to scientific investigations of its pathophysiology [37–39].”

What the sources say

• Not checked yetcites [37] Armstrong RA, Lantos PL, Cairns NJ. Overlap between neurodegenerative disorders. Neuropathology. 2005;25:111–24. source
• Not checked yetcites [38] Attems J, Jellinger KA. The overlap between vascular disease and Alzheimer’s disease-lessons from pathology. BMC Med. 2014;12:206. source
• Not checked yetcites [39] Kapasi A, DeCarli C, Schneider JA. Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol. 2017;134:171–86. source

In the paper

“Subsequent genetic association studies of LOAD bolstered this framework, identifying risk factors such as APOE that modulate Aβ processing, trafficking, and clearance [19, 20, 30].”

What the sources say

• Not checked yetcites [19] Makin S. The amyloid hypothesis on trial. Nature. 2018;559:S4–7. source
• Not checked yetcites [20] Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL. Alzheimer’s disease. Nat Rev Dis Prim. 2015;1:15056. source
• Not checked yetcites [30] Penke B, Paragi G, Gera J, Berkecz R, Kovacs Z, Crul T, et al. The role of lipids and membranes in the pathogenesis of Alzheimer’s disease: a comprehensive view. Curr Alzheimer Res. 2018;15:1191–212. source

In the paper

“In this framework, AD begins with a “biochemical phase”, characterized by aberrant amyloid precursor protein (APP) processing, Aβ accumulation, and tau hyperphosphorylation.”

What the sources say

• Not checked yetcites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

In the paper

“However, the efficacy of these tau-targeting strategies has yet to be demonstrated.”

In the paper

“Such observations date back to the pathological descriptions of Heiko and Eva Braak in 1991, who found that AD-related tau deposition followed a stereotypical pattern of progression regardless of variations in Aβ distribution [40].”

What the sources say

• Not checked yetcites [40] Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59. source

In the paper

“Yet, the repeated failures of these drugs have brought the amyloid hypothesis under fire [19, 31, 34].”

What the sources say

• Not checked yetcites [19] Makin S. The amyloid hypothesis on trial. Nature. 2018;559:S4–7. source
• Not checked yetcites [31] Benilova I, Karran E, De, Strooper B. The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci. 2012;15:349–57. source
• Not checked yetcites [34] Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8:595–608. source

In the paper

“Furthermore, aggregated hyperphosphorylated tau is a well-described pathological hallmark of several other non-AD disorders, such as frontotemporal lobar degeneration (FTLD) [45].”

What the sources say

• Not checked yetcites [45] Kovacs GG. Invited review: Neuropathology of tauopathies: principles and practice. Neuropathol Appl Neurobiol. 2015;41:3–23. source

In the paper

“In one notable case, even harboring an autosomal dominant PSEN1 mutation was insufficient to cause overt dementia [36].”

What the sources say

• Not checked yetcites [36] Arboleda-Velasquez JF, Lopera F, O’Hare M, Delgado-Tirado S, Marino C, Chmielewska N, et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019;25:1680–83. source

In the paper

“More recently, Crary et al. coined the term “primary age-related tauopathy” (PART) after observing that the postmortem brains of many elderly individuals harbor NFTs indistinguishable from those of AD but in the absence of Aβ plaques or cognitive decline [44].”

What the sources say

• Not checked yetcites [44] Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I, et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 2014;128:755–66. source

In the paper

“Initially, this “cellular phase” maintains homeostasis amidst the growing proteopathic disruption.”

What the sources say

• Not checked yetcites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

In the paper

“There is strong evidence to support the causative role of cell-mediated dysfunction in the pathogenesis of AD.”

In the paper

“In addition, two groups of investigators independently identified variants of the microglial TREM2 gene that increase susceptibility to LOAD with an odds ratio similar to that of APOEε4 [56–58].”

What the sources say

• Not checked yetcites [56] Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, et al. TREM2 variants in Alzheimer’s disease. N. Engl J Med. 2013;368:117–27. source
• Not checked yetcites [57] Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl J Med. 2013;368:107–16. source
• Not checked yetcites [58] Hickman SE, El Khoury J. TREM2 and the neuroimmunology of Alzheimer’s disease. Biochem Pharm. 2014;88:495–8. source

In the paper

“These biochemical changes exert proteopathic or “aggregate” stress on surrounding tissues, sparking a cell-mediated phase of disease.”

What the sources say

• Not checked yetcites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

In the paper

“Its tendency to accumulate for years without causing symptomatic disease (i.e., asymptomatic AD or AsymAD) supports this conclusion [35, 36].”

What the sources say

• Not checked yetcites [35] Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71:362–81. source
• Not checked yetcites [36] Arboleda-Velasquez JF, Lopera F, O’Hare M, Delgado-Tirado S, Marino C, Chmielewska N, et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019;25:1680–83. source

In the paper

“However, as the diseased individual ages, these compensatory cellular mechanisms evolve into increasingly dysfunctional and detrimental processes.”

What the sources say

• Not checked yetcites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

In the paper

“Defective Aβ clearance, mediated by the brain’s perivascular circulation and glymphatic system, is considered one of the first events in this biochemical to cellular transition [12].”

What the sources say

• Not checked yetcites [12] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164:603–15. source

In the paper

“Select tau immunotherapies currently employed in AD trials have previously failed to demonstrate any effect on disease progression in the primary tauopathy progressive supranuclear palsy (PSP), fueling reservations about their utility in other neurodegenerative disorders [49].”

What the sources say

• Not checked yetcites [49] Congdon EE, Sigurdsson EM. Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2018;14:399–415. source

In the paper

“However, despite these achievements in quantification, TMT-MS may still yield missing values across multiplexed batches when analyzing large numbers of samples [80].”

What the sources say

• Not checked yetcites [80] Brenes A, Hukelmann J, Bensaddek D, Lamond AI. Multibatch TMT reveals false positives, batch effects and missing values. Mol Cell Proteom. 2019;18:1967–80. source

In the paper

“Similarly, data examining the effects of microglia and inflammatory mediators on Aβ deposition in APP transgenic mice are mixed, with some studies demonstrating reduced and others exacerbated Aβ accumulation [120–122].”

What the sources say

• Not checked yetcites [120] Chakrabarty P, Li A, Ceballos-Diaz C, Eddy JA, Funk CC, Moore B, et al. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron. 2015;85:519–33. source
• Not checked yetcites [121] Guillot-Sestier MV, Doty KR, Gate D, Rodriguez J Jr, Leung BP, Rezai-Zadeh K, et al. Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron. 2015;85:534–48. source
• Not checked yetcites [122] Grathwohl SA, Kalin RE, Bolmont T, Prokop S, Winkelmann G, Kaeser SA, et al. Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia. Nat Neurosci. 2009;12:1361–3. source

In the paper

“Of note, these consensus observations have been largely regressed for age, sex, and postmortem interval (PMI).”

What the sources say

• Not checked yetcites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source

In the paper

“single-cell RNA sequencing, which enables the profiling of individual microglial cells with high-throughput datasets, has revealed significant functional heterogeneity among microglial subtypes and their inflammatory profiles in the neurodegenerative setting [109, 119].”

What the sources say

• Not checked yetcites [109] Masuda T, Sankowski R, Staszewski O, Prinz M. Microglia heterogeneity in the single-cell era. Cell Rep. 2020;30:1271–81. source
• Not checked yetcites [119] Gerrits E, Heng Y, Boddeke E, Eggen BJL. Transcriptional profiling of microglia; current state of the art and future perspectives. Glia. 2020;68:740–55. source

In the paper

“emerging evidence suggests that APOE, a potent immune modulator and strongest of genetic risk factors for LOAD [113–115], may regulate neurodegeneration in a TREM2-mediated fashion [116, 117].”

What the sources say

• Not checked yetcites [116] Shi Y, Manis M, Long J, Wang K, Sullivan PM, Remolina Serrano J, et al. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med. 2019;216:2546–61. source
• Not checked yetcites [117] Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity. 2017;47:566–81. source

In the paper

“Due to differences in neurodegenerative vulnerability, one cortical region rich in disease pathology may not reflect the protein pathophysiology of a relatively spared distant region.”

In the paper

“To obtain module-level reproducibility, 20 independent samples are typically considered adequate; however, systematic consistency at the more granular hub and module membership levels may require hundreds of samples [61, 93, 94].”

What the sources say

• Not checked yetcites [61] Parikshak NN, Gandal MJ, Geschwind DH. Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders. Nat Rev Genet. 2015;16:441–58. source
• Not checked yetcites [93] Ballouz S, Verleyen W, Gillis J. Guidance for RNA-seq co-expression network construction and analysis: safety in numbers. Bioinformatics. 2015;31:2123–30. source
• Not checked yetcites [94] Marbach D, Costello JC, Kuffner R, et al. Wisdom of crowds for robust gene network inference. Nat Methods. 2012;9:796–804. source

In the paper

“In addition, reference data for cell type-specificity, derived from healthy brain tissues, may not fully reflect disease-related shifts in cellular protein expression.”

In the paper

“To obtain module-level reproducibility, 20 independent samples are typically considered adequate; however, systematic consistency at the more granular hub and module membership levels may require hundreds of samples [61, 93, 94].”

What the sources say

• Not checked yetcites [61] Parikshak NN, Gandal MJ, Geschwind DH. Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders. Nat Rev Genet. 2015;16:441–58. source
• Not checked yetcites [93] Ballouz S, Verleyen W, Gillis J. Guidance for RNA-seq co-expression network construction and analysis: safety in numbers. Bioinformatics. 2015;31:2123–30. source
• Not checked yetcites [94] Marbach D, Costello JC, Kuffner R, et al. Wisdom of crowds for robust gene network inference. Nat Methods. 2012;9:796–804. source

In the paper

“Nearly a dozen informative network-based analyses of the AD proteome have been performed in the human brain [62–64, 74, 78, 96, 104–108], including the dorsolateral prefrontal cortex (DLPFC), temporal cortex, and other cortical regions heavily affected in AD.”

What the sources say

• Not checked yetcites [62] 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. source
• Not checked yetcites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. source
• Not checked yetcites [64] Swarup V, Chang TS, Duong DM, Dammer EB, Dai J, Lah JJ, et al. Identification of conserved proteomic networks in neurodegenerative dementia. Cell Rep. 2020;31:107807. source
• Not checked yetcites [74] Johnson ECB, Dammer EB, Duong DM, Yin L, Thambisetty M, Troncoso JC, et al. Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease. Mol Neurodegener. 2018;13:52. source
• Not checked yetcites [78] Bai B, Wang X, Li Y, Chen PC, Yu K, Dey KK, et al. Deep multilayer brain proteomics identifies molecular networks in Alzheimer’s disease progression. Neuron 2020;105:975–91. source
• Not checked yetcites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source
• Not checked yetcites [104] Dai J, Johnson ECB, Dammer EB, Duong DM, Gearing M, Lah JJ, et al. Effects of APOE genotype on brain proteomic network and cell type changes in Alzheimer’s disease. Front Mol Neurosci. 2018;11:454. source
• Not checked yetcites [105] Higginbotham L, Dammer EB, Duong DM, Modeste E, Montine TJ, Lah JJ, et al. Network analysis of a membrane-enriched brain proteome across stages of Alzheimer’s disease. Proteomes. 2019;7:30. source
• Not checked yetcites [106] Wingo AP, Dammer EB, Breen MS, Logsdon BA, Duong DM, Troncosco JC, et al. Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age. Nat Commun. 2019;10:1619. source
• Not checked yetcites [107] Wingo AP, Fan W, Duong DM, Gerasimov ES, Dammer EB, Liu Y, et al. Shared proteomic effects of cerebral atherosclerosis and Alzheimer’s disease on the human brain. Nat Neurosci. 2020;23:696–700. source

In the paper

“Yet, protein-level analyses have demonstrated disease-related alterations not readily measured in transcriptomic networks.”

In the paper

“Intra-regional tissue heterogeneity in cell type densities or pathological burden may also yield poorly representative results.”

In the paper

“Bulk tissue analysis averages these variations in microenvironment and their contributions to protein levels.”

In the paper

“Finally, one major limitation of discovery-driven bulk tissue proteomics is its inability to directly probe disease mechanisms.”

In the paper

“the AMP-AD consortium recently performed a large-scale analysis of sex influences on proteomic data and found no statistically significant contribution of sex to protein module alterations [96]”

What the sources say

• Not checked yetcites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source

In the paper

“This association with genetic risk and early disease indicates that myelin dysfunction may be an inciting event in the pathogenesis of disease.”

In the paper

“Multiple network proteomes have resolved a large module enriched with microglial and astrocytic proteins that demonstrates progressively increasing abundance levels throughout AsymAD and AD.”

What the sources say

• Not checked yetcites [62] 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. source
• Not checked yetcites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. source
• Not checked yetcites [64] Swarup V, Chang TS, Duong DM, Dammer EB, Dai J, Lah JJ, et al. Identification of conserved proteomic networks in neurodegenerative dementia. Cell Rep. 2020;31:107807. source
• Not checked yetcites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source

In the paper

“this study and others have noted that the MSN module is enriched with AD genetic risk factors”

What the sources say

• Not checked yetcites [62] 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. source
• Not checked yetcites [64] Swarup V, Chang TS, Duong DM, Dammer EB, Dai J, Lah JJ, et al. Identification of conserved proteomic networks in neurodegenerative dementia. Cell Rep. 2020;31:107807. source
• Not checked yetcites [74] Johnson ECB, Dammer EB, Duong DM, Yin L, Thambisetty M, Troncoso JC, et al. Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease. Mol Neurodegener. 2018;13:52. source
• Not checked yetcites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source

In the paper

“a growing body of evidence suggests that myelin dysfunction is an early and essential component of AD pathogenesis.”

In the paper

“the authors also found several of these module proteins are decreased in rapidly progressive AD compared to sporadic disease”

What the sources say

• Not checked yetcites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source
• Not checked yetcites [126] Drummond E, Nayak S, Faustin A, Pires G, Hickman RA, Askenazi M, et al. Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer’s disease. Acta Neuropathol. 2017;133:933–54. source

In the paper

“Johnson et al. demonstrated enrichment of anti-inflammatory, neuroprotective markers throughout the MSN module [96].”

What the sources say

• Not checked yetcites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source

In the paper

“magnetic resonance imaging (MRI) data indicate that individuals with the risk allele APOEε4 have accentuated myelin breakdown in AD [128, 129].”

What the sources say

• Not checked yetcites [128] Bartzokis G. Alzheimer’s disease as homeostatic responses to age-related myelin breakdown. Neurobiol Aging. 2011;32:1341–71. source
• Not checked yetcites [129] Scheltens P, Barkhof F, Valk J, Algra PR, van der Hoop RG, Nauta J, et al. White matter lesions on magnetic resonance imaging in clinically diagnosed Alzheimer’s disease. Evidence for heterogeneity. Brain. 1992;115:735–48. source

In the paper

“Its activation in association with proteins ezrin and radixin has been implicated in the neuroprotective non-amyloidogenic processing of APP [123, 124].”

What the sources say

• Not checked yetcites [123] Darmellah A, Rayah A, Auger R, Cuif MH, Prigent M, Arpin M, et al. Ezrin/radixin/moesin are required for the purinergic P2X7 receptor (P2X7R)-dependent processing of the amyloid precursor protein. J Biol Chem. 2012;287:34583–95. source
• Not checked yetcites [124] Ahmed ME, Selvakumar GP, Kempuraj D, Raikwar SP, Thangavel R, Bazley K, et al. Neuroinflammation mediated by GMF exacerbates neuronal injury in an in vitro model of traumatic brain injury. J Neurotrauma. 2020;37:1645–55. source

In the paper

“This highly conserved module features hub proteins implicated in neuroprotection, such as the membrane receptor-cytoskeleton cross-linking protein moesin (MSN) [62–64, 96].”

What the sources say

• Not checked yetcites [62] 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. source
• Not checked yetcites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. source
• Not checked yetcites [64] Swarup V, Chang TS, Duong DM, Dammer EB, Dai J, Lah JJ, et al. Identification of conserved proteomic networks in neurodegenerative dementia. Cell Rep. 2020;31:107807. source
• Not checked yetcites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source

In the paper

“suggesting that a failure to activate this module may lead to more aggressive cognitive decline [96, 126].”

What the sources say

• Not checked yetcites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source
• Not checked yetcites [126] Drummond E, Nayak S, Faustin A, Pires G, Hickman RA, Askenazi M, et al. Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer’s disease. Acta Neuropathol. 2017;133:933–54. source

In the paper

“Indeed, it is becoming increasingly clear that glial-mediated inflammation is likely a complex process featuring a variety of disease-associated anti-inflammatory and pro-inflammatory components.”

In the paper

“white matter lesions attributable to aberrant myelin breakdown have been widely reported in the brains of individuals with mild cognitive impairment (MCI) [127].”

What the sources say

• Not checked yetcites [127] Tosto G, Zimmerman ME, Hamilton JL, Carmichael OT, Brickman AM. Alzheimer’s Disease Neuroimaging I. The effect of white matter hyperintensities on neurodegeneration in mild cognitive impairment. Alzheimers Dement. 2015;11:1510–9. source

In the paper

“In addition to this early neuroprotective module, the AD network proteome features a second inflammatory module co-enriched with microglia, astrocytes, and endothelial cell type markers that is consistently elevated later in disease.”

In the paper

“Network proteomics has provided insight into the complexity surrounding AD inflammation, supporting a predominantly protective, anti-inflammatory glial response in the earliest stages of disease.”

In the paper

“the authors found at least 50% overlap between oligodendrocyte modules of the two datasets.”

What the sources say

• Not checked yetcites [130] McKenzie AT, Moyon S, Wang M, Katsyv I, Song WM, Zhou X, et al. Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer’s disease. Mol Neurodegener. 2017;12:82. source

In the paper

“these aggregated U1 snRNPs have been observed in asymptomatic AD brains [135]”

What the sources say

• Not checked yetcites [135] Hales CM, Dammer EB, Deng Q, Duong DM, Gearing M, Troncoso JC, et al. Changes in the detergent-insoluble brain proteome linked to amyloid and tau in Alzheimer’s disease progression. Proteomics. 2016;16:3042–53. source

In the paper

“suggesting a causal role for oligodendrocyte processes in disease [62, 96].”

What the sources say

• Not checked yetcites [62] 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. source
• Not checked yetcites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source

In the paper

“In contrast to the inflammatory and myelination modules, these RNA-binding/splicing modules are not enriched with glial or other cell type-specific markers.”

In the paper

“This observation suggests that global protein-level analyses will maintain a uniquely valuable role in unraveling the proteopathic biochemical phase of AD.”

In the paper

“The disease-associated alterations in these protein modules were independent of cell type, persisting even after the dataset was regressed for cell type-specific effects [74].”

What the sources say

• Not checked yetcites [74] Johnson ECB, Dammer EB, Duong DM, Yin L, Thambisetty M, Troncoso JC, et al. Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease. Mol Neurodegener. 2018;13:52. source

In the paper

“The oligodendrocyte-enriched myelin module was one of only two protein communities in the co-expression network associated with both cerebral atherosclerosis and AD dementia, independent of Aβ, tau tangles, infarct burden, and a variety of other pathologies.”

What the sources say

• Not checked yetcites [107] Wingo AP, Fan W, Duong DM, Gerasimov ES, Dammer EB, Liu Y, et al. Shared proteomic effects of cerebral atherosclerosis and Alzheimer’s disease on the human brain. Nat Neurosci. 2020;23:696–700. source

In the paper

“a handful of studies have found that like the MSN module, this myelin module features over-representation of AD GWAS candidates”

What the sources say

• Not checked yetcites [62] 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. source
• Not checked yetcites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source

In the paper

“Johnson et al. identified several AD-associated RNA-binding/splicing modules notably increased in asymptomatic and symptomatic AD.”

What the sources say

• Not checked yetcites [74] Johnson ECB, Dammer EB, Duong DM, Yin L, Thambisetty M, Troncoso JC, et al. Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease. Mol Neurodegener. 2018;13:52. source

In the paper

“It is well-known that synaptic loss is one of the strongest correlates of cognitive decline in AD, even more so than Aβ plaques and tau tangles [139].”

What the sources say

• Not checked yetcites [139] Colom-Cadena M, Spires-Jones T, Zetterberg H, Blennow K, Caggiano A, DeKosky ST, et al. The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease. Alzheimers Res Ther. 2020;12:21. source

In the paper

“Overall, these findings suggest that cerebral atherosclerosis, a common occurrence among the elderly, contributes to AD through oligodendrocyte dysfunction and injury to the myelin sheath, regardless of hallmark proteinopathy, gross ischemic disease, or cerebrovascular risk factors.”

What the sources say

• Not checked yetcites [107] Wingo AP, Fan W, Duong DM, Gerasimov ES, Dammer EB, Liu Y, et al. Shared proteomic effects of cerebral atherosclerosis and Alzheimer’s disease on the human brain. Nat Neurosci. 2020;23:696–700. source

In the paper

“previous analyses of the AD brain detergent-insoluble proteome, which have repeatedly demonstrated the association of U1 small nuclear ribonucleoproteins (U1 snRNPs) and other RNA-binding proteins with tau tangles [133–137].”

What the sources say

• Not checked yetcites [133] Diner I, Hales CM, Bishof I, Rabenold L, Duong DM, Yi H, et al. Aggregation properties of the small nuclear ribonucleoprotein U1-70K in Alzheimer disease. J Biol Chem. 2014;289:35296–313. source
• Not checked yetcites [134] Bai B, Hales CM, Chen PC, Gozal Y, Dammer EB, Fritz JJ, et al. U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease. Proc Natl Acad Sci USA. 2013;110:16562–7. source
• Not checked yetcites [135] Hales CM, Dammer EB, Deng Q, Duong DM, Gearing M, Troncoso JC, et al. Changes in the detergent-insoluble brain proteome linked to amyloid and tau in Alzheimer’s disease progression. Proteomics. 2016;16:3042–53. source
• Not checked yetcites [136] Hales CM, Seyfried NT, Dammer EB, Duong D, Yi H, Gearing M, et al. U1 small nuclear ribonucleoproteins (snRNPs) aggregate in Alzheimer’s disease due to autosomal dominant genetic mutations and trisomy 21. Mol Neurodegener. 2014;9:15. source
• Not checked yetcites [137] Maziuk BF, Apicco DJ, Cruz AL, Jiang L, Ash PEA, da Rocha EL, et al. RNA binding proteins co-localize with small tau inclusions in tauopathy. Acta Neuropathol Commun. 2018;6:71. source

In the paper

“proteomic network analyses of the AD brain have demonstrated modest upregulation of a highly conserved oligodendrocyte-enriched myelination module in both asymptomatic and symptomatic disease [62–64, 74, 96].”

What the sources say

• Not checked yetcites [62] 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. source
• Not checked yetcites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. source
• Not checked yetcites [64] Swarup V, Chang TS, Duong DM, Dammer EB, Dai J, Lah JJ, et al. Identification of conserved proteomic networks in neurodegenerative dementia. Cell Rep. 2020;31:107807. source
• Not checked yetcites [74] Johnson ECB, Dammer EB, Duong DM, Yin L, Thambisetty M, Troncoso JC, et al. Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease. Mol Neurodegener. 2018;13:52. source
• Not checked yetcites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source

In the paper

“this aggregation of U1 snRNPs with tau appears to be unique to the AD brain and absent among other primary tauopathies, such as FTLD [134, 138].”

What the sources say

• Not checked yetcites [134] Bai B, Hales CM, Chen PC, Gozal Y, Dammer EB, Fritz JJ, et al. U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease. Proc Natl Acad Sci USA. 2013;110:16562–7. source
• Not checked yetcites [138] Bishof I, Dammer EB, Duong DM, Kundinger SR, Gearing M, Lah JJ, et al. RNA-binding proteins with basic-acidic dipeptide (BAD) domains self-assemble and aggregate in Alzheimer’s disease. J Biol Chem. 2018;293:11047–66. source

In the paper

“In contrast to cell type-enriched modules, RNA-binding/splicing modules demonstrate limited overlap with the transcriptomic network of the AD brain.”

In the paper

“Dai et al. also observed this APOEε2 effect on oligodendrocyte and other cell type markers in a separate network proteome of the AD brain [104].”

What the sources say

• Not checked yetcites [104] Dai J, Johnson ECB, Dammer EB, Duong DM, Gearing M, Lah JJ, et al. Effects of APOE genotype on brain proteomic network and cell type changes in Alzheimer’s disease. Front Mol Neurosci. 2018;11:454. source

In the paper

“A growing body of evidence in mouse models indicates alterations in synaptic networks, prior to the onset of gross neuronal loss in the cerebral cortex [140, 141].”

What the sources say

• Not checked yetcites [140] Palop JJ, Mucke L. Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci. 2010;13:812–8. source
• Not checked yetcites [141] Menkes-Caspi N, Yamin HG, Kellner V, Spires-Jones TL, Cohen D, Stern EA. Pathological tau disrupts ongoing network activity. Neuron. 2015;85:959–66. source

In the paper

“Wingo et al. found that cerebral atherosclerosis may be the missing link between oligodendrocytes and AD dementia [107].”

What the sources say

• Not checked yetcites [107] Wingo AP, Fan W, Duong DM, Gerasimov ES, Dammer EB, Liu Y, et al. Shared proteomic effects of cerebral atherosclerosis and Alzheimer’s disease on the human brain. Nat Neurosci. 2020;23:696–700. source

In the paper

“These associations also persisted after adjustment for hypertension, diabetes, and other cerebrovascular risk factors.”

What the sources say

• Not checked yetcites [107] Wingo AP, Fan W, Duong DM, Gerasimov ES, Dammer EB, Liu Y, et al. Shared proteomic effects of cerebral atherosclerosis and Alzheimer’s disease on the human brain. Nat Neurosci. 2020;23:696–700. source

In the paper

“Johnson et al. found that the most significant effect was exerted by the APOEε2 allele on the oligodendrocyte module, suppressing its disease-related changes in those with AD [96].”

What the sources say

• Not checked yetcites [96] Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–80. source

In the paper

“the authors observed no similar statistical correlations between cerebral atherosclerosis and Aβ accumulation or tau burden.”

What the sources say

• Not checked yetcites [107] Wingo AP, Fan W, Duong DM, Gerasimov ES, Dammer EB, Liu Y, et al. Shared proteomic effects of cerebral atherosclerosis and Alzheimer’s disease on the human brain. Nat Neurosci. 2020;23:696–700. source

In the paper

“a recent large-scale transcriptomic network analysis in the human AD brain (DLPFC, visual cortex, cerebellum), which demonstrated significant enrichment of AD GWAS candidates in conserved disease-associated oligodendrocyte-enriched modules, including BIN1, PICALM, and several others [130].”

What the sources say

• Not checked yetcites [130] McKenzie AT, Moyon S, Wang M, Katsyv I, Song WM, Zhou X, et al. Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer’s disease. Mol Neurodegener. 2017;12:82. source

In the paper

“These two modules, both linked to RNA splicing ontologies, were enriched in proteins with structural and aggregation properties similar to those of U1-70K that could serve as additional AD biomarkers, such as pre-mRNA splicing factor LUC7L3.”

What the sources say

• Not checked yetcites [138] Bishof I, Dammer EB, Duong DM, Kundinger SR, Gearing M, Lah JJ, et al. RNA-binding proteins with basic-acidic dipeptide (BAD) domains self-assemble and aggregate in Alzheimer’s disease. J Biol Chem. 2018;293:11047–66. source

In the paper

“One key strength of the MACS is the ability to rapidly isolate cells of interest with relatively high purity without dependence on cell sorters”

What the sources say

• Not checked yetcites [147] Rayaprolu S, Gao T, Xiao H, Ramesha S, Weinstock LD, Shah J, et al. Flow-cytometric microglial sorting coupled with quantitative proteomics identifies moesin as a highly-abundant microglial protein with relevance to Alzheimer’s disease. Mol Neurodegener. 2020;15:28. source

In the paper

“this study also found heightened levels of mitochondrial proteins among cases with preserved cognition”

What the sources say

• Not checked yetcites [106] Wingo AP, Dammer EB, Breen MS, Logsdon BA, Duong DM, Troncosco JC, et al. Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age. Nat Commun. 2019;10:1619. source

In the paper

“emerging cerebrospinal fluid (CSF) proteomic data has revealed alterations in a number of synapse-associated proteins in preclinical disease [63].”

What the sources say

• Not checked yetcites [63] Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. bioRxiv. 2019, https://doi.org/10.1101/806752. source

In the paper

“Several key proteins (e.g., APP, Grm5) linked to neurodevelopmental or neurodegenerative disorders were also identified [158].”

What the sources say

• Not checked yetcites [158] Alvarez-Castelao B, Schanzenbacher CT, Hanus C, Glock C, Tom Dieck S, Dorrbaum AR, et al. Cell-type-specific metabolic labeling of nascent proteomes in vivo. Nat Biotechnol. 2017;35:1196–201. source

In the paper

“This mechanism would also explain, at least in part, the glial protein elevations observed in the early AD brain, providing a mechanistic framework for a variety of proteomic network changes during the cellular phase of disease.”

In the paper

“deep and comprehensive proteomic study of isolated mouse microglia revealed shared neuroinflammatory disease mechanisms between mouse models of AD pathology and human AD, emphasizing the value of state-of-the-art proteomics methods for resolving cell type-specific contributions to disease [146].”

What the sources say

• Not checked yetcites [146] Rangaraju S, Dammer EB, Raza SA, Gao T, Xiao H, Betarbet R, et al. Quantitative proteomics of acutely-isolated mouse microglia identifies novel immune Alzheimer’s disease-related proteins. Mol Neurodegeneration. 2018;13:34.

In the paper

“Yu et al. paralleled these network results, identifying associations between cognitive resilience and cortical proteins involved in synaptic, metabolic, and neurogenic functions [142].”

What the sources say

• Not checked yetcites [142] Yu L, Tasaki S, Schneider JA, Arfanakis K, Duong DM, Wingo AP, et al. Cortical proteins associated with cognitive resilience in community-dwelling older persons. JAMA Psychiatry. 2020:e201807. source

In the paper

“Wingo et al. used co-expression network analysis to demonstrate the increased abundance of synaptic proteins in the postmortem brain tissues (DLPFC) of individuals with antemortem stable cognitive trajectories, regardless of the burden of Aβ plaques or tau tangles [106].”

What the sources say

• Not checked yetcites [106] Wingo AP, Dammer EB, Breen MS, Logsdon BA, Duong DM, Troncosco JC, et al. Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age. Nat Commun. 2019;10:1619. source

In the paper

“The prolonged handling of live cells for FACS and the shear stress imposed on them by the sorter can spuriously activate sensitive cells such as microglia.”

What the sources say

• Not checked yetcites Table 2

In the paper

“This suggests that the downregulation of synaptic proteins in AsymAD may ultimately prove detrimental to cognitive stability, promoting conversion to symptomatic disease.”

In the paper

“The MACS approach has been successfully applied to enrich four brain cell types (neuronal progenitors, microglia, astrocytes, and oligodendrocytes) from adult mice for high-resolution MS-based proteomics [97].”

What the sources say

• Not checked yetcites [97] Sharma K, Schmitt S, Bergner CG, Tyanova S, Kannaiyan N, Manrique-Hoyos N, et al. Cell type- and brain region-resolved mouse brain proteome. Nat Neurosci. 2015;18:1819–31. source

In the paper

“Comparative analysis of NeuN-positive and NeuN-negative nuclear proteomes revealed a number of transcription and splicing factors not previously known to be expressed in a cell type-specific manner in human brain [154].”

What the sources say

• Not checked yetcites [154] Dammer EB, Duong DM, Diner I, Gearing M, Feng Y, Lah JJ, et al. Neuron enriched nuclear proteome isolated from human brain. J Proteome Res. 2013;12:3193–206. source