{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T16:24:49Z","timestamp":1789143889926,"version":"build-2803163510"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T00:00:00Z","timestamp":1624320000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T00:00:00Z","timestamp":1624320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Institute of Information & Communication Technology Planning & Evaluation","award":["No.2020-0-01373, Artificial Intelligence Graduate School Programing [Hanyang University]"],"award-info":[{"award-number":["No.2020-0-01373, Artificial Intelligence Graduate School Programing [Hanyang University]"]}]},{"name":"Korea Health Technology R&D Project and Ministry of Health & Welfare","award":["#HI18C1254"],"award-info":[{"award-number":["#HI18C1254"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Microglial activation is a central player in the pathophysiology of Alzheimer\u2019s disease (AD). The soluble fragment of triggering receptor expressed on myeloid cells 2 (sTREM2) can serve as a marker for microglial activation and has been shown to be overexpressed in AD. However, the relationship of sTREM2 with other AD biomarkers has not been extensively studied. We investigated the relationship between cerebrospinal fluid (CSF) sTREM2 and other AD biomarkers and examined the correlation of plasma sTREM2 with CSF sTREM2 in a cohort of individuals with AD and without AD. Participants were consecutively recruited from Asan Medical Center from 2018 to 2020. Subjects were stratified by their amyloid positivity and clinical status. Along with other AD biomarkers, sTREM2 level was measured in the plasma as well as CSF. In 101 patients with either amyloid-positive or negative status, CSF sTREM2 was closely associated with CSF T-tau and P-tau and not with Abeta42. CSF sTREM2 levels were found to be strongly correlated with CSF neurofilament light chain. The comparison of CSF and plasma sTREM2 levels tended to have an inverse correlation. Plasma sTREM2 and P-tau levels were oppositely influenced by age. Our results suggest that neuroinflammation may be closely associated with tau-induced neurodegeneration.<\/jats:p>","DOI":"10.1038\/s41598-021-92101-6","type":"journal-article","created":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T10:02:49Z","timestamp":1624356169000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["The relationship of soluble TREM2 to other biomarkers of sporadic Alzheimer\u2019s disease"],"prefix":"10.1038","volume":"11","author":[{"given":"So-Hee","family":"Park","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Hye","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyung-Ji","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sungyang","family":"Jo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunju","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang Won","family":"Seo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun-Hee","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong-Ho","family":"Koh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Hong","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,22]]},"reference":[{"key":"92101_CR1","doi-asserted-by":"publisher","first-page":"272","DOI":"10.3389\/fnagi.2020.00272","volume":"12","author":"C Bjorkli","year":"2020","unstructured":"Bjorkli, C., Sandvig, A. & Sandvig, I. Bridging the gap between fluid biomarkers for Alzheimer\u2019s disease, model systems, and patients. Front. Aging Neurosci. 12, 272 (2020).","journal-title":"Front. Aging Neurosci."},{"key":"92101_CR2","doi-asserted-by":"publisher","first-page":"227","DOI":"10.3109\/00207454.2013.831852","volume":"124","author":"M Obulesu","year":"2014","unstructured":"Obulesu, M. & Jhansilakshmi, M. Neuroinflammation in Alzheimer\u2019s disease: An understanding of physiology and pathology. Int. J. Neurosci. 124, 227\u2013235 (2014).","journal-title":"Int. J. Neurosci."},{"key":"92101_CR3","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","volume":"14","author":"MT Heneka","year":"2015","unstructured":"Heneka, M. T. et al. Neuroinflammation in Alzheimer\u2019s disease. Lancet Neurol. 14, 388\u2013405 (2015).","journal-title":"Lancet Neurol."},{"key":"92101_CR4","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1016\/j.jalz.2016.02.010","volume":"12","author":"V Calsolaro","year":"2016","unstructured":"Calsolaro, V. & Edison, P. Neuroinflammation in Alzheimer\u2019s disease: Current evidence and future directions. Alzheimers Dement. 12, 719\u2013732 (2016).","journal-title":"Alzheimers Dement."},{"key":"92101_CR5","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1016\/j.cell.2017.05.018","volume":"169","author":"H Keren-Shaul","year":"2017","unstructured":"Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer\u2019s disease. Cell 169, 1276\u20131290 (2017).","journal-title":"Cell"},{"key":"92101_CR6","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1083\/jcb.201709069","volume":"217","author":"DV Hansen","year":"2018","unstructured":"Hansen, D. V., Hanson, J. E. & Sheng, M. Microglia in Alzheimer\u2019s disease. J. Cell Biol. 217, 459\u2013472 (2018).","journal-title":"J. Cell Biol."},{"key":"92101_CR7","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/j.molmed.2017.03.008","volume":"23","author":"FL Yeh","year":"2017","unstructured":"Yeh, F. L., Hansen, D. V. & Sheng, M. TREM2, microglia, and neurodegenerative diseases. Trends Mol. Med. 23, 512\u2013533 (2017).","journal-title":"Trends Mol. Med."},{"key":"92101_CR8","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.neuron.2017.02.042","volume":"94","author":"JD Ulrich","year":"2017","unstructured":"Ulrich, J. D., Ulland, T. K., Colonna, M. & Holtzman, D. M. Elucidating the role of TREM2 in Alzheimer\u2019s disease. Neuron 94, 237\u2013248 (2017).","journal-title":"Neuron"},{"key":"92101_CR9","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1126\/scitranslmed.aag1767","volume":"8","author":"M Suarez-Calvet","year":"2016","unstructured":"Suarez-Calvet, M. et al. Early changes in CSF sTREM2 in dominantly inherited Alzheimer\u2019s disease occur after amyloid deposition and neuronal injury. Sci. Transl. Med. 8, 178\u2013369 (2016).","journal-title":"Sci. Transl. Med."},{"key":"92101_CR10","doi-asserted-by":"publisher","first-page":"466","DOI":"10.15252\/emmm.201506123","volume":"8","author":"M Suarez-Calvet","year":"2016","unstructured":"Suarez-Calvet, M. et al. sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer\u2019s disease and associate with neuronal injury markers. EMBO Mol. Med. 8, 466\u2013476 (2016).","journal-title":"EMBO Mol. Med."},{"key":"92101_CR11","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.neulet.2018.08.038","volume":"686","author":"D Liu","year":"2018","unstructured":"Liu, D. et al. Soluble TREM2 changes during the clinical course of Alzheimer\u2019s disease: A meta-analysis. Neurosci. Lett. 686, 10\u201316 (2018).","journal-title":"Neurosci. Lett."},{"key":"92101_CR12","doi-asserted-by":"publisher","first-page":"e12308","DOI":"10.15252\/emmm.202012308","volume":"12","author":"M Ewers","year":"2020","unstructured":"Ewers, M. et al. Higher CSF sTREM2 and microglia activation are associated with slower rates of beta-amyloid accumulation. EMBO Mol. Med. 12, e12308 (2020).","journal-title":"EMBO Mol. Med."},{"key":"92101_CR13","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.jneuroim.2018.03.003","volume":"319","author":"LM Bekris","year":"2018","unstructured":"Bekris, L. M. et al. Soluble TREM2 and biomarkers of central and peripheral inflammation in neurodegenerative disease. J. Neuroimmunol. 319, 19\u201327 (2018).","journal-title":"J. Neuroimmunol."},{"key":"92101_CR14","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1002\/ana.25385","volume":"85","author":"T Ohara","year":"2019","unstructured":"Ohara, T. et al. Serum soluble triggering receptor expressed on myeloid cells 2 as a biomarker for incident dementia: The Hisayama study. Ann. Neurol. 85, 47\u201358 (2019).","journal-title":"Ann. Neurol."},{"key":"92101_CR15","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1084\/jem.20160844","volume":"214","author":"L Zhong","year":"2017","unstructured":"Zhong, L. et al. Soluble TREM2 induces inflammatory responses and enhances microglial survival. J. Exp. Med. 214, 597\u2013607 (2017).","journal-title":"J. Exp. Med."},{"key":"92101_CR16","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s13024-016-0071-x","volume":"11","author":"A Heslegrave","year":"2016","unstructured":"Heslegrave, A. et al. Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer\u2019s disease. Mol. Neurodegener. 11, 3 (2016).","journal-title":"Mol. Neurodegener."},{"key":"92101_CR17","doi-asserted-by":"publisher","first-page":"6221","DOI":"10.1126\/scitranslmed.aav6221","volume":"11","author":"M Ewers","year":"2019","unstructured":"Ewers, M. et al. Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer\u2019s disease. Sci. Transl. Med. 11, 6221 (2019).","journal-title":"Sci. Transl. Med."},{"key":"92101_CR18","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1186\/s12974-020-01878-2","volume":"17","author":"J Yang","year":"2020","unstructured":"Yang, J. et al. TREM2 ectodomain and its soluble form in Alzheimer\u2019s disease. J. Neuroinflammation 17, 204 (2020).","journal-title":"J. Neuroinflammation"},{"key":"92101_CR19","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1016\/j.neuron.2020.02.008","volume":"105","author":"EC Damisah","year":"2020","unstructured":"Damisah, E. C., Rai, A. & Grutzendler, J. TREM2: Modulator of lipid metabolism in microglia. Neuron 105, 759\u2013761 (2020).","journal-title":"Neuron"},{"key":"92101_CR20","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.2174\/1567205016666190903102822","volume":"16","author":"AK Singh","year":"2019","unstructured":"Singh, A. K. et al. Role of TREM2 in Alzheimer\u2019s disease and its consequences on \u03b2-amyloid, tau and neurofibrillary tangles. Curr. Alzheimer Res. 16, 1216\u20131229 (2019).","journal-title":"Curr. Alzheimer Res."},{"key":"92101_CR21","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1016\/j.cell.2020.05.003","volume":"181","author":"A Deczkowska","year":"2020","unstructured":"Deczkowska, A., Weiner, A. & Amit, I. The physiology, pathology, and potential therapeutic applications of the TREM2 signaling pathway. Cell 181, 1207\u20131217 (2020).","journal-title":"Cell"},{"key":"92101_CR22","doi-asserted-by":"publisher","first-page":"2295","DOI":"10.1093\/cercor\/bhz240","volume":"30","author":"NB Halaas","year":"2020","unstructured":"Halaas, N. B. et al. CSF sTREM2 and tau work together in predicting increased temporal lobe atrophy in older adults. Cereb. Cortex 30, 2295\u20132306 (2020).","journal-title":"Cereb. Cortex"},{"key":"92101_CR23","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1016\/j.cell.2015.01.049","volume":"160","author":"Y Wang","year":"2015","unstructured":"Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer\u2019s disease model. Cell 160, 1061\u20131071 (2015).","journal-title":"Cell"},{"key":"92101_CR24","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1016\/j.neuron.2019.06.010","volume":"103","author":"A Griciuc","year":"2019","unstructured":"Griciuc, A. et al. TREM2 acts downstream of CD33 in modulating microglial pathology in Alzheimer\u2019s disease. Neuron 103, 820\u2013835 (2019).","journal-title":"Neuron"},{"key":"92101_CR25","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1016\/j.neuron.2016.05.003","volume":"90","author":"P Yuan","year":"2016","unstructured":"Yuan, P. et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90, 724\u2013739 (2016).","journal-title":"Neuron"},{"key":"92101_CR26","doi-asserted-by":"publisher","first-page":"1956","DOI":"10.1523\/JNEUROSCI.1871-19.2019","volume":"40","author":"WJ Meilandt","year":"2020","unstructured":"Meilandt, W. J. et al. Trem2 deletion reduces late-stage amyloid plaque accumulation, elevates the A\u03b242:A\u03b240 ratio, and exacerbates axonal dystrophy and dendritic spine loss in the PS2APP Alzheimer\u2019s mouse model. J. Neurosci. 40, 1956\u20131974 (2020).","journal-title":"J. Neurosci."},{"key":"92101_CR27","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.biopsych.2017.10.007","volume":"83","author":"C Condello","year":"2018","unstructured":"Condello, C., Yuan, P. & Grutzendler, J. Microglia-mediated neuroprotection, TREM2, and Alzheimer\u2019s disease: Evidence from optical imaging. Biol. Psychiatry 83, 377\u2013387 (2018).","journal-title":"Biol. Psychiatry"},{"key":"92101_CR28","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s13024-020-00374-8","volume":"15","author":"LZ Ma","year":"2020","unstructured":"Ma, L. Z. et al. Dynamic changes of CSF sTREM2 in preclinical Alzheimer\u2019s disease: The CABLE study. Mol. Neurodegener. 15, 25 (2020).","journal-title":"Mol. Neurodegener."},{"key":"92101_CR29","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1007\/s00401-014-1371-2","volume":"129","author":"RM Nisbet","year":"2015","unstructured":"Nisbet, R. M., Polanco, J. C., Ittner, L. M. & G\u00f6tz, J. Tau aggregation and its interplay with amyloid-\u03b2. Acta Neuropathol. 129, 207\u2013220 (2015).","journal-title":"Acta Neuropathol."},{"key":"92101_CR30","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1007\/s12640-018-9895-1","volume":"34","author":"SH Xin","year":"2018","unstructured":"Xin, S. H., Tan, L., Cao, X., Yu, J. T. & Tan, L. Clearance of amyloid beta and tau in Alzheimer\u2019s disease: From mechanisms to therapy. Neurotox. Res. 34, 733\u2013748 (2018).","journal-title":"Neurotox. Res."},{"key":"92101_CR31","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1007\/s10753-018-0735-5","volume":"41","author":"T Jiang","year":"2018","unstructured":"Jiang, T. et al. TREM2 ameliorates neuronal tau pathology through suppression of microglial inflammatory response. Inflammation 41, 811\u2013823 (2018).","journal-title":"Inflammation"},{"key":"92101_CR32","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1038\/s41593-019-0433-0","volume":"22","author":"CEG Leyns","year":"2019","unstructured":"Leyns, C. E. G. et al. TREM2 function impedes tau seeding in neuritic plaques. Nat. Neurosci. 22, 1217\u20131222 (2019).","journal-title":"Nat. Neurosci."},{"key":"92101_CR33","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1186\/s13195-019-0545-5","volume":"11","author":"NJ Ashton","year":"2019","unstructured":"Ashton, N. J. et al. Plasma levels of soluble TREM2 and neurofilament light chain in TREM2 rare variant carriers. Alzheimers Res. Ther. 11, 94 (2019).","journal-title":"Alzheimers Res. Ther."},{"key":"92101_CR34","doi-asserted-by":"publisher","first-page":"e1007","DOI":"10.1212\/WNL.0000000000007032","volume":"92","author":"J Kuhle","year":"2019","unstructured":"Kuhle, J. et al. Blood neurofilament light chain as a biomarker of MS disease activity and treatment response. Neurology 92, e1007\u2013e1015 (2019).","journal-title":"Neurology"},{"key":"92101_CR35","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1002\/ana.24954","volume":"81","author":"G Disanto","year":"2017","unstructured":"Disanto, G. et al. Serum neurofilament light: A biomarker of neuronal damage in multiple sclerosis. Ann. Neurol. 81, 857\u2013870 (2017).","journal-title":"Ann. Neurol."},{"key":"92101_CR36","doi-asserted-by":"publisher","first-page":"497","DOI":"10.3233\/JAD-130854","volume":"38","author":"N Hu","year":"2014","unstructured":"Hu, N. et al. Increased expression of TREM2 in peripheral blood of Alzheimer\u2019s disease patients. J. Alzheimers Dis. 38, 497\u2013501 (2014).","journal-title":"J. Alzheimers Dis."},{"key":"92101_CR37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13024-018-0301-5","volume":"14","author":"M Su\u00e1rez-Calvet","year":"2019","unstructured":"Su\u00e1rez-Calvet, M. et al. Early increase of CSF sTREM2 in Alzheimer\u2019s disease is associated with tau related-neurodegeneration but not with amyloid-\u03b2 pathology. Mol. Neurodegener. 14, 1 (2019).","journal-title":"Mol. Neurodegener."},{"key":"92101_CR38","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1111\/ene.13583","volume":"25","author":"M Casati","year":"2018","unstructured":"Casati, M. et al. Increased expression of TREM2 in peripheral cells from mild cognitive impairment patients who progress into Alzheimer\u2019s disease. Eur J Neurol 25, 805\u2013810 (2018).","journal-title":"Eur J Neurol"},{"key":"92101_CR39","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1007\/s00401-016-1533-5","volume":"131","author":"L Piccio","year":"2016","unstructured":"Piccio, L. et al. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 131, 925\u2013933 (2016).","journal-title":"Acta Neuropathol."},{"key":"92101_CR40","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.4049\/jimmunol.1901166","volume":"204","author":"GE Weber","year":"2020","unstructured":"Weber, G. E. et al. An altered relationship between soluble trem2 and inflammatory markers in young adults with down syndrome: A preliminary report. J. Immunol. 204, 1111\u20131118 (2020).","journal-title":"J. Immunol."},{"key":"92101_CR41","doi-asserted-by":"publisher","first-page":"1656","DOI":"10.1016\/j.neurobiolaging.2014.01.139","volume":"35","author":"F Yue","year":"2014","unstructured":"Yue, F., Lu, C., Ai, Y., Chan, P. & Zhang, Z. Age-associated changes of cerebrospinal fluid amyloid-\u03b2 and tau in cynomolgus monkeys. Neurobiol. Aging 35, 1656\u20131659 (2014).","journal-title":"Neurobiol. Aging"},{"key":"92101_CR42","doi-asserted-by":"publisher","first-page":"1837","DOI":"10.1212\/01.wnl.0000219668.47116.e6","volume":"66","author":"DA Bennett","year":"2006","unstructured":"Bennett, D. A. et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 66, 1837\u20131844 (2006).","journal-title":"Neurology"},{"key":"92101_CR43","doi-asserted-by":"publisher","first-page":"7561","DOI":"10.1523\/JNEUROSCI.1388-17.2017","volume":"37","author":"ET Reas","year":"2017","unstructured":"Reas, E. T. Amyloid and tau pathology in normal cognitive aging. J. Neurosci. 37, 7561\u20137563 (2017).","journal-title":"J. Neurosci."},{"key":"92101_CR44","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s13195-016-0182-1","volume":"8","author":"K Henjum","year":"2016","unstructured":"Henjum, K. et al. Cerebrospinal fluid soluble TREM2 in aging and Alzheimer\u2019s disease. Alzheimers Res. Ther. 8, 17 (2016).","journal-title":"Alzheimers Res. Ther."},{"key":"92101_CR45","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1016\/j.neuron.2020.02.034","volume":"106","author":"N Zhao","year":"2020","unstructured":"Zhao, N. et al. Alzheimer\u2019s risk factors age, APOE genotype, and sex drive distinct molecular pathways. Neuron 106, 727\u2013742 (2020).","journal-title":"Neuron"},{"key":"92101_CR46","doi-asserted-by":"publisher","first-page":"1776","DOI":"10.1093\/clinchem\/47.10.1776","volume":"47","author":"M Sj\u00f6gren","year":"2001","unstructured":"Sj\u00f6gren, M. et al. Tau and A\u03b242 in cerebrospinal fluid from healthy adults 21\u201393 years of age: Establishment of reference values. Clin. Chem. 47, 1776\u20131781 (2001).","journal-title":"Clin. Chem."},{"key":"92101_CR47","doi-asserted-by":"publisher","first-page":"1401","DOI":"10.3233\/JAD-2010-1337","volume":"19","author":"EL Koedam","year":"2010","unstructured":"Koedam, E. L. et al. Early-versus late-onset Alzheimer\u2019s disease: More than age alone. J. Alzheimers Dis. 19, 1401\u20131408 (2010).","journal-title":"J. Alzheimers Dis."},{"key":"92101_CR48","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1177\/0891988706297086","volume":"20","author":"GA Marshall","year":"2007","unstructured":"Marshall, G. A., Fairbanks, L. A., Tekin, S., Vinters, H. V. & Cummings, J. L. Early-onset Alzheimer\u2019s disease is associated with greater pathologic burden. J. Geriatr. Psychiatry Neurol. 20, 29\u201333 (2007).","journal-title":"J. Geriatr. Psychiatry Neurol."},{"key":"92101_CR49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/alzrt155","volume":"5","author":"B Lam","year":"2013","unstructured":"Lam, B., Masellis, M., Freedman, M., Stuss, D. T. & Black, S. E. Clinical, imaging, and pathological heterogeneity of the Alzheimer\u2019s disease syndrome. Alzheimer\u2019s Res. Ther. 5, 1 (2013).","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"92101_CR50","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1046\/j.1440-1789.2003.00514.x","volume":"23","author":"Y Mizuno","year":"2003","unstructured":"Mizuno, Y., Ikeda, K., Tsuchiya, K., Ishihara, R. & Shibayama, H. Two distinct subgroups of senile dementia of Alzheimer type: Quantitative study of neurofibrillary tangles. Neuropathology 23, 282\u2013289 (2003).","journal-title":"Neuropathology"},{"key":"92101_CR51","doi-asserted-by":"publisher","first-page":"1825","DOI":"10.1097\/00001756-200210070-00028","volume":"13","author":"GJ Ho","year":"2002","unstructured":"Ho, G. J. et al. Age at onset is associated with disease severity in Lewy body variant and Alzheimer\u2019s disease. NeuroReport 13, 1825\u20131828 (2002).","journal-title":"NeuroReport"},{"key":"92101_CR52","doi-asserted-by":"publisher","first-page":"34873","DOI":"10.1074\/jbc.M405131200","volume":"279","author":"C AlonsoAdel","year":"2004","unstructured":"AlonsoAdel, C., Mederlyova, A., Novak, M., Grundke-Iqbal, I. & Iqbal, K. Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J. Biol. Chem. 279, 34873\u201334881 (2004).","journal-title":"J. Biol. Chem."},{"key":"92101_CR53","doi-asserted-by":"publisher","first-page":"4418","DOI":"10.1073\/pnas.1916895117","volume":"117","author":"T Sen","year":"2020","unstructured":"Sen, T., Saha, P., Jiang, T. & Sen, N. Sulfhydration of AKT triggers Tau-phosphorylation by activating glycogen synthase kinase 3\u03b2 in Alzheimer\u2019s disease. Proc. Natl. Acad. Sci. USA. 117, 4418\u20134427 (2020).","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"92101_CR54","doi-asserted-by":"publisher","first-page":"26043","DOI":"10.1074\/jbc.M115.679043","volume":"290","author":"Y Atagi","year":"2015","unstructured":"Atagi, Y. et al. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J. Biol. Chem. 290, 26043\u201326050 (2015).","journal-title":"J. Biol. Chem."},{"key":"92101_CR55","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/s13024-020-00394-4","volume":"15","author":"NF Fitz","year":"2020","unstructured":"Fitz, N. F. et al. Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice. Mol. Neurodegener. 15, 41 (2020).","journal-title":"Mol. Neurodegener."},{"key":"92101_CR56","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1007\/s40263-015-0258-7","volume":"29","author":"YY Syed","year":"2015","unstructured":"Syed, Y. Y. & Deeks, E. [18F]Florbetaben: a review in \u03b2-amyloid PET imaging in cognitive impairment. CNS Drugs 29, 605\u2013613 (2015).","journal-title":"CNS Drugs"},{"key":"92101_CR57","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1038\/nprot0415-644b","volume":"10","author":"RY Nong","year":"2015","unstructured":"Nong, R. Y. et al. Corrigendum: Solid-phase proximity ligation assays for individual or parallel protein analyses with readout via real-time PCR or sequencing. Nat. Protoc. 10, 643 (2015).","journal-title":"Nat. Protoc."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-92101-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-92101-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-92101-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T10:24:14Z","timestamp":1670063054000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-92101-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,22]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["92101"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-92101-6","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,22]]},"assertion":[{"value":"26 February 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 May 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 June 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"13050"}}