{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T02:28:01Z","timestamp":1793413681578,"version":"4.5.0"},"reference-count":65,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Wellcome Leap CARE program, Ann S. Bowers Women's Brain Health Initiative","id":[{"id":"https:\/\/ror.org\/03jzgvn02","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100007202","name":"Gouvernement du Canada | Instituts de Recherche en Sant\u00e9 du Canada | CIHR Skin Research Training Centre","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007202","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000143","name":"Alzheimer Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000143","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wellcome Leap CARE program, Ann S. Bowers Women\u2019s Brain Health Initiative","id":[{"id":"https:\/\/ror.org\/03jzgvn02","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Wellcome Leap CARE program","id":[{"id":"https:\/\/ror.org\/03jzgvn02","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Menopause is a hallmark process in biological aging that has been implicated in later neurodegenerative risk, but the pathways underlying this connection remain unclear. Here we used blood proteomics data from several cohorts to identify biological changes associated with menopause and its links to brain aging. In\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200980 rigorously staged (STRAW+10) pre-, peri- and postmenopausal women (aged 43\u201358\u2009years) with serum NULISAseq proteomics, we show that spontaneous menopause is characterized by dysregulation in inflammatory, synaptic, metabolic and Alzheimer\u2019s disease biologic processes, which tracked more strongly with hormones than with age. Validation analyses in age-matched pre-\/peri- and postmenopausal women (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20092,814) with plasma Olink proteomics replicated the observed proteomic shifts and revealed broader menopause-related upregulation of inflammatory and catabolic processes plus accelerated organ and cell aging, including brain aging. In four independent cohorts of older women (average age, 60.7\u201372.1\u2009years; total\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200911,925), higher menopause proteomic scores associated consistently with cognitive aging and dementia risk. The molecular signatures of menopause may inform the selection of biomarkers or therapeutic targets for brain health in midlife women.\n                  <\/jats:p>","DOI":"10.1038\/s41591-026-04648-4","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T09:03:29Z","timestamp":1790067809000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Blood proteomics of menopause map to brain aging and dementia risk"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4598-0201","authenticated-orcid":false,"given":"Madeline","family":"Wood Alexander","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4754-2221","authenticated-orcid":false,"given":"Jennifer S.","family":"Rabin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Caunca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allesandra","family":"Iadipaolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louisa","family":"Cornelis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ria","family":"Warrier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5989-9853","authenticated-orcid":false,"given":"Keenan A.","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Miolane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5060-1142","authenticated-orcid":false,"given":"Veronica Augustina","family":"Bot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan","family":"Wood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8192-7593","authenticated-orcid":false,"given":"Hamilton Se-Hwee","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5893-0831","authenticated-orcid":false,"given":"Tony","family":"Wyss-Coray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Pham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Borger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Diaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily W.","family":"Paolillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel","family":"Kramer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Pritschet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew S.","family":"Panizzon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramiro Eduardo","family":"Rea Reyes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa N.","family":"Denkinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Ashton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8501-545X","authenticated-orcid":false,"given":"Sterling C.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0001-5096","authenticated-orcid":false,"given":"Emily G.","family":"Jacobs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1351-6183","authenticated-orcid":false,"given":"Rowan","family":"Saloner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5000-7604","authenticated-orcid":false,"given":"Kaitlin B.","family":"Casaletto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"4648_CR1","doi-asserted-by":"publisher","first-page":"9327","DOI":"10.1073\/pnas.1604558113","volume":"113","author":"ME Levine","year":"2016","unstructured":"Levine, M. E. et al. Menopause accelerates biological aging. Proc. Natl Acad. Sci. USA 113, 9327\u20139332 https:\/\/doi.org\/10.1073\/pnas.1604558113 (2016).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"4648_CR2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-020-01998-9","volume":"17","author":"M McCarthy","year":"2020","unstructured":"McCarthy, M. & Raval, A. P. The peri-menopause in a woman\u2019s life: a systemic inflammatory phase that enables later neurodegenerative disease. J. Neuroinflammation 17, 317 https:\/\/doi.org\/10.1186\/s12974-020-01998-9 (2020).","journal-title":"J. Neuroinflammation"},{"key":"4648_CR3","doi-asserted-by":"publisher","first-page":"e506","DOI":"10.1161\/CIR.0000000000000912","volume":"142","author":"SR El Khoudary","year":"2020","unstructured":"El Khoudary, S. R. et al. Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association. Circulation 142, e506\u2013e532 https:\/\/doi.org\/10.1161\/CIR.0000000000000912 (2020).","journal-title":"Circulation"},{"key":"4648_CR4","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1152\/physrev.00036.2014","volume":"95","author":"Y Hara","year":"2015","unstructured":"Hara, Y., Waters, E. M., McEwen, B. S. & Morrison, J. H. Estrogen effects on cognitive and synaptic health over the lifecourse. Physiol. Rev. 95, 785\u2013807 https:\/\/doi.org\/10.1152\/physrev.00036.2014 (2015).","journal-title":"Physiol. Rev."},{"key":"4648_CR5","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adt0757","volume":"11","author":"M Wood Alexander","year":"2025","unstructured":"Wood Alexander, M. et al. The interplay between age at menopause and synaptic integrity on Alzheimer\u2019s disease risk in women. Sci. Adv. 11, eadt0757 https:\/\/doi.org\/10.1126\/sciadv.adt0757 (2025).","journal-title":"Sci. Adv."},{"key":"4648_CR6","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1001\/jamaneurol.2023.0455","volume":"80","author":"GT Coughlan","year":"2023","unstructured":"Coughlan, G. T. et al. Association of age at menopause and hormone therapy use with tau and \u03b2-amyloid positron emission tomography. JAMA Neurol. 80, 462\u2013473 https:\/\/doi.org\/10.1001\/jamaneurol.2023.0455 (2023).","journal-title":"JAMA Neurol."},{"key":"4648_CR7","doi-asserted-by":"publisher","first-page":"e1003955","DOI":"10.1371\/journal.pmed.1003955","volume":"19","author":"J Gong","year":"2022","unstructured":"Gong, J., Harris, K., Peters, S. A. E. & Woodward, M. Reproductive factors and the risk of incident dementia: a cohort study of UK Biobank participants. PLOS Med. 19, e1003955 https:\/\/doi.org\/10.1371\/journal.pmed.1003955 (2022).","journal-title":"PLOS Med."},{"key":"4648_CR8","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000209298","volume":"102","author":"M Wood Alexander","year":"2024","unstructured":"Wood Alexander, M. et al. Associations between age at menopause, vascular risk, and 3-year cognitive change in the Canadian longitudinal study on aging. Neurology 102, e209298 https:\/\/doi.org\/10.1212\/WNL.0000000000209298 (2024).","journal-title":"Neurology"},{"key":"4648_CR9","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1002\/ana.27308","volume":"98","author":"M Wood Alexander","year":"2025","unstructured":"Wood Alexander, M. et al. Sex differences in associations of Lewy body disease with Alzheimer\u2019s disease and cognitive decline. Ann. Neurol. 98, 1014\u20131026 https:\/\/doi.org\/10.1002\/ana.27308 (2025).","journal-title":"Ann. Neurol."},{"key":"4648_CR10","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1038\/s44159-025-00463-9","volume":"4","author":"RC Thurston","year":"2025","unstructured":"Thurston, R. C., Thomas, H. N., Castle, A. J. & Gibson, C. J. Menopause as a biological and psychological transition. Nat. Rev. Psychol. 4, 530\u2013543 https:\/\/doi.org\/10.1038\/s44159-025-00463-9 (2025).","journal-title":"Nat. Rev. Psychol."},{"key":"4648_CR11","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2020.562275","volume":"11","author":"PM Maki","year":"2020","unstructured":"Maki, P. M. & Thurston, R. C. Menopause and brain health: hormonal changes are only part of the story. Front. Neurol. 11, 562275 https:\/\/doi.org\/10.3389\/fneur.2020.562275 (2020).","journal-title":"Front. Neurol."},{"key":"4648_CR12","doi-asserted-by":"publisher","first-page":"e335","DOI":"10.1016\/S3050-5038(26)00043-9","volume":"2","author":"C Gurvich","year":"2026","unstructured":"Gurvich, C., Spector, A. & Hickey, M. Advances in understanding of cognitive symptoms during menopause. Lancet Obst. Gynaecol. Womens Health 2, e335\u2013e345 https:\/\/doi.org\/10.1016\/S3050-5038(26)00043-9 (2026).","journal-title":"Lancet Obst. Gynaecol. Womens Health"},{"key":"4648_CR13","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.mce.2008.11.012","volume":"299","author":"JL Downs","year":"2009","unstructured":"Downs, J. L. & Wise, P. M. The role of the brain in female reproductive aging. Mol. Cell Endocrinol. 299, 32\u201338 https:\/\/doi.org\/10.1016\/j.mce.2008.11.012 (2009).","journal-title":"Mol. Cell Endocrinol."},{"key":"4648_CR14","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.neurobiolaging.2018.09.029","volume":"74","author":"ER Bacon","year":"2019","unstructured":"Bacon, E. R. et al. Neuroendocrine aging precedes perimenopause and is regulated by DNA methylation. Neurobiol. Aging 74, 213\u2013224 https:\/\/doi.org\/10.1016\/j.neurobiolaging.2018.09.029 (2019).","journal-title":"Neurobiol. Aging"},{"key":"4648_CR15","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","volume":"14","author":"CR Jack Jr.","year":"2018","unstructured":"Jack, C. R. Jr. et al. NIA-AA research framework: toward a biological definition of Alzheimer\u2019s disease. Alzheimers Dement. 14, 535\u2013562 https:\/\/doi.org\/10.1016\/j.jalz.2018.02.018 (2018).","journal-title":"Alzheimers Dement."},{"key":"4648_CR16","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.jalz.2011.03.003","volume":"7","author":"RA Sperling","year":"2011","unstructured":"Sperling, R. A. et al. Toward defining the preclinical stages of Alzheimer\u2019s disease: recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease. Alzheimers Dement. 7, 280\u2013292 https:\/\/doi.org\/10.1016\/j.jalz.2011.03.003 (2011).","journal-title":"Alzheimers Dement."},{"key":"4648_CR17","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/j.ogc.2011.05.002","volume":"38","author":"EB Gold","year":"2011","unstructured":"Gold, E. B. The timing of the age at which natural menopause occurs. Obstet. Gynecol. Clin. North Am. 38, 425\u2013440 https:\/\/doi.org\/10.1016\/j.ogc.2011.05.002 (2011).","journal-title":"Obstet. Gynecol. Clin. North Am."},{"key":"4648_CR18","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1212\/WNL.0000000000000033","volume":"82","author":"R Bove","year":"2014","unstructured":"Bove, R. et al. Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology 82, 222\u2013229 https:\/\/doi.org\/10.1212\/WNL.0000000000000033 (2014).","journal-title":"Neurology"},{"key":"4648_CR19","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1097\/gme.0b013e31816d815e","volume":"15","author":"PM Maki","year":"2008","unstructured":"Maki, P. M. et al. Objective hot flashes are negatively related to verbal memory performance in midlife women. Menopause 15, 848\u2013856 https:\/\/doi.org\/10.1097\/gme.0b013e31816d815e (2008).","journal-title":"Menopause"},{"key":"4648_CR20","doi-asserted-by":"publisher","first-page":"e133","DOI":"10.1212\/WNL.0000000000201401","volume":"100","author":"RC Thurston","year":"2023","unstructured":"Thurston, R. C. et al. Menopausal vasomotor symptoms and white matter hyperintensities in midlife women. Neurology 100, e133\u2013e141 https:\/\/doi.org\/10.1212\/WNL.0000000000201401 (2023).","journal-title":"Neurology"},{"key":"4648_CR21","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1016\/j.ajog.2023.11.002","volume":"230","author":"RC THURSTON","year":"2024","unstructured":"THURSTON, R. C. et al. Menopausal vasomotor symptoms and plasma Alzheimer\u2019s disease biomarkers. Am. J. Obstet. Gynecol. 230, 342\u2013342 https:\/\/doi.org\/10.1016\/j.ajog.2023.11.002 (2024).","journal-title":"Am. J. Obstet. Gynecol."},{"key":"4648_CR22","doi-asserted-by":"publisher","first-page":"1150","DOI":"10.1097\/GME.0000000000002031","volume":"29","author":"D Appiah","year":"2022","unstructured":"Appiah, D. et al. Long-term changes in plasma proteomic profiles in premenopausal and postmenopausal Black and White women: the Atherosclerosis Risk in Communities study. Menopause 29, 1150\u20131160 https:\/\/doi.org\/10.1097\/GME.0000000000002031 (2022).","journal-title":"Menopause"},{"key":"4648_CR23","doi-asserted-by":"publisher","DOI":"10.1111\/acel.70249","volume":"24","author":"RPH De Maeyer","year":"2025","unstructured":"De Maeyer, R. P. H. et al. Age-associated inflammatory monocytes are increased in menopausal females and reversed by hormone replacement therapy. Aging Cell 24, e70249 https:\/\/doi.org\/10.1111\/acel.70249 (2025).","journal-title":"Aging Cell"},{"key":"4648_CR24","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1097\/gme.0b013e31824d8f40","volume":"19","author":"SD Harlow","year":"2012","unstructured":"Harlow, S. D. et al. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. Menopause 19, 387\u2013395 https:\/\/doi.org\/10.1097\/gme.0b013e31824d8f40 (2012).","journal-title":"Menopause"},{"key":"4648_CR25","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-024-00753-5","volume":"19","author":"X Zeng","year":"2024","unstructured":"Zeng, X. et al. Multi-analyte proteomic analysis identifies blood-based neuroinflammation, cerebrovascular and synaptic biomarkers in preclinical Alzheimer\u2019s disease. Mol. Neurodegeneration 19, 68 https:\/\/doi.org\/10.1186\/s13024-024-00753-5 (2024).","journal-title":"Mol. Neurodegeneration"},{"key":"4648_CR26","doi-asserted-by":"publisher","first-page":"R489","DOI":"10.1152\/ajpregu.00031.2026","volume":"330","author":"SF Salathe","year":"2026","unstructured":"Salathe, S. F. et al. Loss of ovarian function and estrogen therapy remodel the brain\u2019s synaptic and metabolic proteome. Am. J. Physiol. Regul. Integr. Comp. Physiol. 330, R489\u2013R500 https:\/\/doi.org\/10.1152\/ajpregu.00031.2026 (2026).","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"4648_CR27","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1007\/s13311-019-00766-9","volume":"16","author":"JK Russell","year":"2019","unstructured":"Russell, J. K., Jones, C. K. & Newhouse, P. A. The role of estrogen in brain and cognitive aging. Neurotherapeutics 16, 649\u2013665 https:\/\/doi.org\/10.1007\/s13311-019-00766-9 (2019).","journal-title":"Neurotherapeutics"},{"key":"4648_CR28","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1002\/ana.26382","volume":"92","author":"RF Buckley","year":"2022","unstructured":"Buckley, R. F. et al. Menopause status moderates sex differences in tau burden: a Framingham PET study. Ann. Neurol. 92, 11\u201322 https:\/\/doi.org\/10.1002\/ana.26382 (2022).","journal-title":"Ann. Neurol."},{"key":"4648_CR29","doi-asserted-by":"publisher","first-page":"e166","DOI":"10.1212\/WNL.0000000000009781","volume":"95","author":"A Rahman","year":"2020","unstructured":"Rahman, A. et al. Sex-driven modifiers of Alzheimer risk. Neurology 95, e166\u2013e178 https:\/\/doi.org\/10.1212\/WNL.0000000000009781 (2020).","journal-title":"Neurology"},{"key":"4648_CR30","doi-asserted-by":"publisher","first-page":"1382","DOI":"10.1212\/WNL.0000000000004425","volume":"89","author":"L Mosconi","year":"2017","unstructured":"Mosconi, L. et al. Sex differences in Alzheimer risk. Neurology 89, 1382\u20131390 https:\/\/doi.org\/10.1212\/WNL.0000000000004425 (2017).","journal-title":"Neurology"},{"key":"4648_CR31","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-025-04223-7","volume":"23","author":"Y Xiang","year":"2025","unstructured":"Xiang, Y. et al. Menopausal status, transition, and age at menopause with accelerated biological aging across multiple organ systems: findings from two cohort studies. BMC Med. 23, 461 https:\/\/doi.org\/10.1186\/s12916-025-04223-7 (2025).","journal-title":"BMC Med."},{"key":"4648_CR32","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-2-22","volume":"2","author":"SL Cole","year":"2007","unstructured":"Cole, S. L. & Vassar, R. The Alzheimer\u2019s disease Beta-secretase enzyme, BACE1. Mol. Neurodegeneration 2, 22 https:\/\/doi.org\/10.1186\/1750-1326-2-22 (2007).","journal-title":"Mol. Neurodegeneration"},{"key":"4648_CR33","doi-asserted-by":"publisher","first-page":"1961","DOI":"10.1016\/S0047-6374(01)00309-8","volume":"122","author":"VN Talesa","year":"2001","unstructured":"Talesa, V. N. Acetylcholinesterase in Alzheimer\u2019s disease. Mech. Ageing Dev. 122, 1961\u20131969 https:\/\/doi.org\/10.1016\/S0047-6374(01)00309-8 (2001).","journal-title":"Mech. Ageing Dev."},{"key":"4648_CR34","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1186\/s13195-018-0383-x","volume":"10","author":"M Chatterjee","year":"2018","unstructured":"Chatterjee, M. et al. Contactin-2, a synaptic and axonal protein, is reduced in cerebrospinal fluid and brain tissue in Alzheimer\u2019s disease. Alzheimers Res. Ther. 10, 52 https:\/\/doi.org\/10.1186\/s13195-018-0383-x (2018).","journal-title":"Alzheimers Res. Ther."},{"key":"4648_CR35","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1038\/s41586-022-04463-0","volume":"603","author":"J Xiong","year":"2022","unstructured":"Xiong, J. et al. FSH blockade improves cognition in mice with Alzheimer\u2019s disease. Nature 603, 470\u2013476 https:\/\/doi.org\/10.1038\/s41586-022-04463-0 (2022).","journal-title":"Nature"},{"key":"4648_CR36","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1210\/er.2007-0001","volume":"28","author":"RH Straub","year":"2007","unstructured":"Straub, R. H. The complex role of estrogens in inflammation. Endocr. Rev. 28, 521\u2013574 https:\/\/doi.org\/10.1210\/er.2007-0001 (2007).","journal-title":"Endocr. Rev."},{"key":"4648_CR37","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1097\/gme.0b013e31821f5d39","volume":"18","author":"RC Thurston","year":"2011","unstructured":"Thurston, R. C. et al. Are vasomotor symptoms associated with alterations in hemostatic and inflammatory markers? Findings from the Study of Women\u2019s Health Across the Nation. Menopause 18, 1044\u20131051 https:\/\/doi.org\/10.1097\/gme.0b013e31821f5d39 (2011).","journal-title":"Menopause"},{"key":"4648_CR38","doi-asserted-by":"publisher","first-page":"E760","DOI":"10.1210\/jc.2011-3151","volume":"97","author":"A Bechlioulis","year":"2012","unstructured":"Bechlioulis, A. et al. Increased vascular inflammation in early menopausal women is associated with hot flush severity. J. Clin. Endocrinol. Metabol. 97, E760\u2013E764 https:\/\/doi.org\/10.1210\/jc.2011-3151 (2012).","journal-title":"J. Clin. Endocrinol. Metabol."},{"key":"4648_CR39","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1016\/j.fertnstert.2013.05.005","volume":"100","author":"RC Thurston","year":"2013","unstructured":"Thurston, R. C., Chang, Y., Mancuso, P. & Matthews, K. A. Adipokines, adiposity, and vasomotor symptoms during the menopause transition: findings from the Study of Women\u2019s Health Across the Nation. Fertil. Steril. 100, 793\u2013800 https:\/\/doi.org\/10.1016\/j.fertnstert.2013.05.005 (2013).","journal-title":"Fertil. Steril."},{"key":"4648_CR40","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1007\/s13760-022-01984-3","volume":"122","author":"D Nazarinia","year":"2022","unstructured":"Nazarinia, D., Behzadifard, M., Gholampour, J., Karimi, R. & Gholampour, M. Eotaxin-1 (CCL11) in neuroinflammatory disorders and possible role in COVID-19 neurologic complications. Acta Neurol. Belg. 122, 865\u2013869 https:\/\/doi.org\/10.1007\/s13760-022-01984-3 (2022).","journal-title":"Acta Neurol. Belg."},{"key":"4648_CR41","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.dadm.2016.05.004","volume":"3","author":"BM Bettcher","year":"2016","unstructured":"Bettcher, B. M. et al. MCP-1 and eotaxin-1 selectively and negatively associate with memory in MCI and Alzheimer\u2019s disease dementia phenotypes. Alzheimers Dement. (Amst.) 3, 91\u201397, https:\/\/doi.org\/10.1016\/j.dadm.2016.05.004 (2016).","journal-title":"Alzheimers Dement. (Amst.)"},{"key":"4648_CR42","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1158\/1055-9965.EPI-24-1644","volume":"34","author":"MC Orenduff","year":"2025","unstructured":"Orenduff, M. C. et al. Plasma insulin-like growth factor-binding protein-7 is positively associated with age, obesity, mortality, and cancer in postmenopausal women. Cancer Epidemiol. Biomarkers Prev. 34, 922\u2013932 https:\/\/doi.org\/10.1158\/1055-9965.EPI-24-1644 (2025).","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"4648_CR43","doi-asserted-by":"publisher","first-page":"18056","DOI":"10.1038\/s41598-026-46409-w","volume":"16","author":"MF Farinas","year":"2026","unstructured":"Farinas, M. F. et al. Evaluation of serum as an alternative matrix to plasma for NULISA\u2011based proteomic blood biomarker measurements. Sci. Rep. 16, 18056 https:\/\/doi.org\/10.1038\/s41598-026-46409-w (2026).","journal-title":"Sci. Rep."},{"key":"4648_CR44","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1097\/GME.0000000000002730","volume":"33","author":"MS Hedges","year":"2026","unstructured":"Hedges, M. S. et al. Global perspectives on perimenopause: a digital survey of knowledge and symptoms using the Flo application. Menopause 33, 789\u2013798 https:\/\/doi.org\/10.1097\/GME.0000000000002730 (2026).","journal-title":"Menopause"},{"key":"4648_CR45","doi-asserted-by":"publisher","DOI":"10.1186\/s12889-024-19280-5","volume":"24","author":"Y Fang","year":"2024","unstructured":"Fang, Y. et al. Mapping global prevalence of menopausal symptoms among middle-aged women: a systematic review and meta-analysis. BMC Public Health 24, 1767 https:\/\/doi.org\/10.1186\/s12889-024-19280-5 (2024).","journal-title":"BMC Public Health"},{"key":"4648_CR46","doi-asserted-by":"publisher","first-page":"e70166","DOI":"10.1002\/alz.70166","volume":"21","author":"RE Rea Reyes","year":"2025","unstructured":"Rea Reyes, R. E. et al. Targeted proteomic biomarker profiling using NULISA in a cohort enriched with risk for Alzheimer\u2019s disease and related dementias. Alzheimers Dement. 21, e70166 https:\/\/doi.org\/10.1002\/alz.70166 (2025).","journal-title":"Alzheimers Dement."},{"key":"4648_CR47","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42834-x","volume":"14","author":"W Feng","year":"2023","unstructured":"Feng, W. et al. NULISA: a proteomic liquid biopsy platform with attomolar sensitivity and high multiplexing. Nat. Commun. 14, 7238 https:\/\/doi.org\/10.1038\/s41467-023-42834-x (2023).","journal-title":"Nat. Commun."},{"key":"4648_CR48","doi-asserted-by":"publisher","unstructured":"Higginbotham L, et al. Multiplex proteomics of Lewy body dementia reveals cerebrospinal fluid biomarkers of disease pathology and progression. Preprint at bioRxiv https:\/\/doi.org\/10.1101\/2025.06.10.658994 (2025).","DOI":"10.1101\/2025.06.10.658994"},{"key":"4648_CR49","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/s41586-023-06592-6","volume":"622","author":"BB Sun","year":"2023","unstructured":"Sun, B. B. et al. Plasma proteomic associations with genetics and health in the UK Biobank. Nature. 622, 329\u2013338 https:\/\/doi.org\/10.1038\/s41586-023-06592-6 (2023).","journal-title":"Nature."},{"key":"4648_CR50","doi-asserted-by":"publisher","first-page":"2703","DOI":"10.1038\/s41591-025-03798-1","volume":"31","author":"HSH Oh","year":"2025","unstructured":"Oh, H. S. H. et al. Plasma proteomics links brain and immune system aging with healthspan and longevity. Nat. Med. 31, 2703\u20132711 https:\/\/doi.org\/10.1038\/s41591-025-03798-1 (2025).","journal-title":"Nat. Med."},{"key":"4648_CR51","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1212\/WNL.0b013e3181cb3e25","volume":"74","author":"RC Petersen","year":"2010","unstructured":"Petersen, R. C. et al. Alzheimer\u2019s disease neuroimaging initiative (ADNI). Neurology 74, 201\u2013209 https:\/\/doi.org\/10.1212\/WNL.0b013e3181cb3e25 (2010).","journal-title":"Neurology"},{"key":"4648_CR52","doi-asserted-by":"publisher","first-page":"2305","DOI":"10.1001\/jama.2017.6669","volume":"317","author":"MC Donohue","year":"2017","unstructured":"Donohue, M. C. et al. Association between elevated brain amyloid and subsequent cognitive decline among cognitively normal persons. JAMA 317, 2305 https:\/\/doi.org\/10.1001\/jama.2017.6669 (2017).","journal-title":"JAMA"},{"key":"4648_CR53","doi-asserted-by":"publisher","first-page":"7340","DOI":"10.1002\/alz.14165","volume":"20","author":"WJ Jagust","year":"2024","unstructured":"Jagust, W. J. et al. The ADNI PET core at 20. Alzheimers Dement. 20, 7340\u20137349 https:\/\/doi.org\/10.1002\/alz.14165 (2024).","journal-title":"Alzheimers Dement."},{"key":"4648_CR54","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1186\/s13195-021-00836-1","volume":"13","author":"SK Royse","year":"2021","unstructured":"Royse, S. K. et al. Alzheimer\u2019s Disease Neuroimaging Initiative Validation of amyloid PET positivity thresholds in centiloids: a multisite PET study approach. Alz. Res. Therapy 13, 99 https:\/\/doi.org\/10.1186\/s13195-021-00836-1 (2021).","journal-title":"Alz. Res. Therapy"},{"key":"4648_CR55","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1017\/S1355617720001009","volume":"27","author":"CA Lindbergh","year":"2021","unstructured":"Lindbergh, C. A. et al. Worth the wait: delayed recall after 1 week predicts cognitive and medial temporal lobe trajectories in older adults. J. Int. Neuropsychol. Soc. 27, 382\u2013388 https:\/\/doi.org\/10.1017\/S1355617720001009 (2021).","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"4648_CR56","doi-asserted-by":"publisher","first-page":"e198","DOI":"10.1016\/j.lanogw.2025.100024","volume":"1","author":"Y Wang","year":"2025","unstructured":"Wang, Y., Islam, R. M., Bond, M., Skiba, M. A. & Davis, S. R. Sexual dysfunction in women at midlife: a cross-sectional study of data from the Australian Women\u2019s Midlife Years study. Lancet Obst. Gynaecol. Womens Health 1, e198\u2013e208 https:\/\/doi.org\/10.1016\/j.lanogw.2025.100024 (2025).","journal-title":"Lancet Obst. Gynaecol. Womens Health"},{"key":"4648_CR57","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1080\/10532528.2003.10559811","volume":"14","author":"L Dennerstein","year":"2003","unstructured":"Dennerstein, L., Alexander, J. L. & Kotz, K. The menopause and sexual functioning: a review of the population-based studies. Annu. Rev. Sex Res. 14, 64\u201382 (2003).","journal-title":"Annu. Rev. Sex Res."},{"key":"4648_CR58","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1097\/GME.0000000000002386","volume":"31","author":"PM Maki","year":"2024","unstructured":"Maki, P. M., Panay, N. & Simon, J. A. Sleep disturbance associated with the menopause. Menopause 31, 724\u2013733 https:\/\/doi.org\/10.1097\/GME.0000000000002386 (2024).","journal-title":"Menopause"},{"key":"4648_CR59","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.jad.2024.04.041","volume":"357","author":"Y Badawy","year":"2024","unstructured":"Badawy, Y., Spector, A., Li, Z. & Desai, R. The risk of depression in the menopausal stages: a systematic review and meta-analysis. J. Affect. Disord. 357, 126\u2013133 https:\/\/doi.org\/10.1016\/j.jad.2024.04.041 (2024).","journal-title":"J. Affect. Disord."},{"key":"4648_CR60","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1089\/jwh.2018.27099.mensocrec","volume":"28","author":"PM Maki","year":"2019","unstructured":"Maki, P. M. et al. Guidelines for the evaluation and treatment of perimenopausal depression: summary and recommendations. J. Womens Health (Larchmt) 28, 117\u2013134 https:\/\/doi.org\/10.1089\/jwh.2018.27099.mensocrec (2019).","journal-title":"J. Womens Health (Larchmt)"},{"key":"4648_CR61","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1016\/j.ogc.2011.05.011","volume":"38","author":"JT Bromberger","year":"2011","unstructured":"Bromberger, J. T. & Kravitz, H. M. Mood and menopause: findings from the Study of Women\u2019s Health Across the Nation (SWAN) over 10 years. Obstet. Gynecol. Clin. North Am. 38, 609\u2013625 https:\/\/doi.org\/10.1016\/j.ogc.2011.05.011 (2011).","journal-title":"Obstet. Gynecol. Clin. North Am."},{"key":"4648_CR62","doi-asserted-by":"publisher","first-page":"2036","DOI":"10.1038\/s41591-025-03622-w","volume":"31","author":"S Palmqvist","year":"2025","unstructured":"Palmqvist, S. et al. Plasma phospho-tau217 for Alzheimer\u2019s disease diagnosis in primary and secondary care using a fully automated platform. Nat. Med. 31, 2036\u20132043 https:\/\/doi.org\/10.1038\/s41591-025-03622-w (2025).","journal-title":"Nat. Med."},{"key":"4648_CR63","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1038\/s41596-018-0103-9","volume":"14","author":"J Reimand","year":"2019","unstructured":"Reimand, J. et al. Pathway enrichment analysis and visualization of omics data using g:Profiler, GSEA, Cytoscape and EnrichmentMap. Nat. Protoc. 14, 482\u2013517 https:\/\/doi.org\/10.1038\/s41596-018-0103-9 (2019).","journal-title":"Nat. Protoc."},{"key":"4648_CR64","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-026-04446-y","author":"DY Ding","year":"2026","unstructured":"Ding, D. Y. et al. Plasma proteomic signatures of cellular aging predict human disease. Nat. Med. https:\/\/doi.org\/10.1038\/s41591-026-04446-y (2026).","journal-title":"Nat. Med."},{"key":"4648_CR65","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1002\/pro.3307","volume":"27","author":"PJ Thul","year":"2018","unstructured":"Thul, P. J. & Lindskog, C. The human protein atlas: a spatial map of the human proteome. Protein Sci. 27, 233\u2013244 https:\/\/doi.org\/10.1002\/pro.3307 (2018).","journal-title":"Protein Sci."}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04648-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04648-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04648-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T09:03:31Z","timestamp":1790067811000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04648-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,22]]},"references-count":65,"alternative-id":["4648"],"URL":"https:\/\/doi.org\/10.1038\/s41591-026-04648-4","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-8752767\/v1","asserted-by":"object"}]},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,22]]},"assertion":[{"value":"31 January 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 September 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"K.A.W. is an Associate Editor for\n                      Alzheimer\u2019s & Dementia: The Journal of the Alzheimer\u2019s Association\n                      ,\n                      Alzheimer\u2019s & Dementia: Translational Research and Clinical Interventions\n                      and on the Editorial Board of\n                      Annals of Clinical and Translational Neurology\n                      ; is on the Board of Directors of the National Academy of Neuropsychology; has given unpaid presentations and seminars on behalf of SomaLogic; and is the founder of Centia Bio. The work presented in this manuscript was conducted independently of Centia Bio and without financial support from the company. All efforts were performed in the government research settings. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}