{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T11:41:58Z","timestamp":1794051718426,"version":"4.8.0"},"reference-count":117,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Aging"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia with no specific treatment, of which molecular mechanisms remain poorly understood. To identify potential biomarkers and therapeutic targets, we applied Mendelian randomization to examine over 2,500 proteins measured in plasma and, uniquely, cerebrospinal fluid, in relation to magnetic resonance imaging (MRI) markers of cSVD in more than 40,000 individuals. Here we show that 49 proteins are associated with MRI markers of cSVD, most prominently in cerebrospinal fluid. We highlight associations that are consistent across platforms and ancestries, and supported by complementary observational analyses, and we explore differences between fluids. The proteins are enriched in pathways related to the extracellular matrix, immune response and microglial activity. Many also associate with stroke and dementia, and several correspond to existing drug targets. Together, these findings reveal a robust biological fingerprint of cSVD and highlight opportunities for biomarker and drug discovery and repositioning.<\/jats:p>","DOI":"10.1038\/s43587-025-01006-w","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T10:01:53Z","timestamp":1763632913000},"page":"2514-2531","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease"],"prefix":"10.1038","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3075-4682","authenticated-orcid":false,"given":"Ilana","family":"Caro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3725-9553","authenticated-orcid":false,"given":"Daniel","family":"Western","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7486-3146","authenticated-orcid":false,"given":"Shinichi","family":"Namba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4045-6518","authenticated-orcid":false,"given":"Shuji","family":"Kawaguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8581-7826","authenticated-orcid":false,"given":"Yunye","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Fujita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gennady","family":"Roshchupkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"D\u2019Aoust","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Gabrielle","family":"Duperron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1684-3750","authenticated-orcid":false,"given":"Muralidharan","family":"Sargurupremraj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ami","family":"Tsuchida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0348-0666","authenticated-orcid":false,"given":"Masaru","family":"Koido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marziehsadat","family":"Ahmadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4577-5590","authenticated-orcid":false,"given":"Chengran","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4794-9187","authenticated-orcid":false,"given":"Jigyasha","family":"Timsina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Ibanez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Matsuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4852-1879","authenticated-orcid":false,"given":"Yutaka","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiya","family":"Oda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akinori","family":"Kanai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pouria","family":"Jandaghi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Munter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9486-1105","authenticated-orcid":false,"given":"Daniel","family":"Auld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iana","family":"Astafeva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1191-5893","authenticated-orcid":false,"given":"Raquel","family":"Puerta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7191-1723","authenticated-orcid":false,"given":"Jerome I.","family":"Rotter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7278-2190","authenticated-orcid":false,"given":"Bruce M.","family":"Psaty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3409-1110","authenticated-orcid":false,"given":"Joshua C.","family":"Bis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"WT","family":"Longstreth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Couffinhal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0125-5403","authenticated-orcid":false,"given":"Pablo","family":"Garc\u00eda-Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanesa","family":"Pytel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0660-0950","authenticated-orcid":false,"given":"Marta","family":"Marqui\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Cano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2617-3009","authenticated-orcid":false,"given":"Merc\u00e8","family":"Boada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7792-308X","authenticated-orcid":false,"given":"Marc","family":"Joliot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Lathrop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9299-0747","authenticated-orcid":false,"given":"Quentin","family":"Le Grand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3238-7612","authenticated-orcid":false,"given":"Lenore J.","family":"Launer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9812-6642","authenticated-orcid":false,"given":"Joanna M.","family":"Wardlaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Heiman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2633-2495","authenticated-orcid":false,"given":"Agustin","family":"Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Matthews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6135-2622","authenticated-orcid":false,"given":"Sudha","family":"Seshadri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0677-8158","authenticated-orcid":false,"given":"Myriam","family":"Fornage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hieab","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aniket","family":"Mishra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9084-7800","authenticated-orcid":false,"given":"David-Alexandre","family":"Tr\u00e9gou\u00ebt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0311-8472","authenticated-orcid":false,"given":"Yukinori","family":"Okada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7113-9630","authenticated-orcid":false,"given":"Manolis","family":"Kellis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8057-2505","authenticated-orcid":false,"given":"Philip L.","family":"De Jager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6517-2984","authenticated-orcid":false,"given":"Christophe","family":"Tzourio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8748-5597","authenticated-orcid":false,"given":"Yoichiro","family":"Kamatani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumihiko","family":"Matsuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0276-2899","authenticated-orcid":false,"given":"Carlos","family":"Cruchaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8675-7968","authenticated-orcid":false,"given":"St\u00e9phanie","family":"Debette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"key":"1006_CR1","doi-asserted-by":"crossref","first-page":"CXI","DOI":"10.1177\/23969873211012132","volume":"6","author":"JM Wardlaw","year":"2021","unstructured":"Wardlaw, J. M. et al. ESO Guideline on covert cerebral small vessel disease. Eur. Stroke J. 6, CXI\u2013CLXII (2021).","journal-title":"Eur. Stroke J."},{"key":"1006_CR2","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/S1474-4422(23)00131-X","volume":"22","author":"M Duering","year":"2023","unstructured":"Duering, M. et al. Neuroimaging standards for research into small vessel disease-advances since 2013. Lancet Neurol. 22, 602\u2013618 (2023).","journal-title":"Lancet Neurol."},{"key":"1006_CR3","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1212\/WNL.0000000000000312","volume":"82","author":"JM Wardlaw","year":"2014","unstructured":"Wardlaw, J. M. et al. Vascular risk factors, large-artery atheroma, and brain white matter hyperintensities. Neurology 82, 1331\u20131338 (2014).","journal-title":"Neurology"},{"key":"1006_CR4","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/d41573-023-00158-x","volume":"22","author":"PV Rusina","year":"2023","unstructured":"Rusina, P. V. et al. Genetic support for FDA-approved drugs over the past decade. Nat. Rev. Drug Discov. 22, 864 (2023).","journal-title":"Nat. Rev. Drug Discov."},{"key":"1006_CR5","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1038\/s41591-023-02268-w","volume":"29","author":"M-G Duperron","year":"2023","unstructured":"Duperron, M.-G. et al. Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease. Nat. Med. 29, 950\u2013962 (2023).","journal-title":"Nat. Med."},{"key":"1006_CR6","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/s41582-021-00592-8","volume":"18","author":"C Bordes","year":"2022","unstructured":"Bordes, C., Sargurupremraj, M., Mishra, A. & Debette, S. Genetics of common cerebral small vessel disease. Nat. Rev. Neurol. 18, 84\u2013101 (2022).","journal-title":"Nat. Rev. Neurol."},{"key":"1006_CR7","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/s41582-020-0350-6","volume":"16","author":"J Montaner","year":"2020","unstructured":"Montaner, J. et al. Multilevel omics for the discovery of biomarkers and therapeutic targets for stroke. Nat. Rev. Neurol. 16, 247\u2013264 (2020).","journal-title":"Nat. Rev. Neurol."},{"key":"1006_CR8","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/s43587-021-00064-0","volume":"1","author":"KA Walker","year":"2021","unstructured":"Walker, K. A. et al. Large-scale plasma proteomic analysis identifies proteins and pathways associated with dementia risk. Nat. Aging 1, 473\u2013489 (2021).","journal-title":"Nat. Aging"},{"key":"1006_CR9","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.adf5681","volume":"15","author":"KA Walker","year":"2023","unstructured":"Walker, K. A. et al. Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life. Sci. Transl. Med. 15, eadf5681 (2023).","journal-title":"Sci. Transl. Med."},{"key":"1006_CR10","volume":"13","author":"L Chen","year":"2022","unstructured":"Chen, L. et al. Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke. Nat. Commun. 13, 6143 (2022).","journal-title":"Nat. Commun."},{"key":"1006_CR11","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1186\/s13195-022-01113-5","volume":"14","author":"EB Dammer","year":"2022","unstructured":"Dammer, E. B. et al. Multi-platform proteomic analysis of Alzheimer\u2019s disease cerebrospinal fluid and plasma reveals network biomarkers associated with proteostasis and the matrisome. Alzheimers Res. Ther. 14, 174 (2022).","journal-title":"Alzheimers Res. Ther."},{"key":"1006_CR12","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.1038\/s41588-024-01972-8","volume":"56","author":"D Western","year":"2024","unstructured":"Western, D. et al. Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer's disease. Nat. Genet. 56, 2672\u20132684 (2024).","journal-title":"Nat. Genet."},{"key":"1006_CR13","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1038\/s41593-021-00886-6","volume":"24","author":"C Yang","year":"2021","unstructured":"Yang, C. et al. Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders. Nat. Neurosci. 24, 1302\u20131312 (2021).","journal-title":"Nat. Neurosci."},{"key":"1006_CR14","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1177\/0271678X221077339","volume":"42","author":"S Kuipers","year":"2022","unstructured":"Kuipers, S. et al. A cluster of blood-based protein biomarkers reflecting coagulation relates to the burden of cerebral small vessel disease. J. Cereb. Blood Flow. 42, 1282\u20131293 (2022).","journal-title":"J. Cereb. Blood Flow."},{"key":"1006_CR15","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1111\/cns.14047","volume":"29","author":"S Wan","year":"2023","unstructured":"Wan, S. et al. Plasma inflammatory biomarkers in cerebral small vessel disease: a review. CNS Neurosci. Ther. 29, 498\u2013515 (2023).","journal-title":"CNS Neurosci. Ther."},{"key":"1006_CR16","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.1161\/STROKEAHA.107.508135","volume":"39","author":"M Fornage","year":"2008","unstructured":"Fornage, M. et al. Biomarkers of inflammation and MRI-defined small vessel disease of the brain: the cardiovascular health study. Stroke 39, 1952\u20131959 (2008).","journal-title":"Stroke"},{"key":"1006_CR17","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1212\/WNL.0b013e318248e50f","volume":"78","author":"CL Satizabal","year":"2012","unstructured":"Satizabal, C. L., Zhu, Y. C., Mazoyer, B., Dufouil, C. & Tzourio, C. Circulating IL-6 and CRP are associated with MRI findings in the elderly: the 3C-Dijon Study. Neurology 78, 720\u2013727 (2012).","journal-title":"Neurology"},{"key":"1006_CR18","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-021-93498-w","volume":"11","author":"J Jim\u00e9nez-Balado","year":"2021","unstructured":"Jim\u00e9nez-Balado, J. et al. New candidate blood biomarkers potentially associated with white matter hyperintensities progression. Sci. Rep. 11, 14324 (2021).","journal-title":"Sci. Rep."},{"key":"1006_CR19","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1038\/s41588-021-00978-w","volume":"53","author":"E Ferkingstad","year":"2021","unstructured":"Ferkingstad, E. et al. Large-scale integration of the plasma proteome with genetics and disease. Nat. Genet. 53, 1712\u20131721 (2021).","journal-title":"Nat. Genet."},{"key":"1006_CR20","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-020-19111-2","volume":"11","author":"M Sargurupremraj","year":"2020","unstructured":"Sargurupremraj, M. et al. Cerebral small vessel disease genomics and its implications across the lifespan. Nat. Commun. 11, 6285 (2020).","journal-title":"Nat. Commun."},{"key":"1006_CR21","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/bpa.12218","volume":"25","author":"RO Weller","year":"2015","unstructured":"Weller, R. O., Hawkes, C. A., Kalaria, R. N., Werring, D. J. & Carare, R. O. White matter changes in dementia: role of impaired drainage of interstitial fluid. Brain Pathol. 25, 63\u201378 (2015).","journal-title":"Brain Pathol."},{"key":"1006_CR22","first-page":"1512","volume":"26","author":"TF Patankar","year":"2005","unstructured":"Patankar, T. F. et al. Dilatation of the Virchow-Robin space is a sensitive indicator of cerebral microvascular disease: study in elderly patients with dementia. AJNR Am. J. Neuroradiol. 26, 1512\u20131520 (2005).","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"1006_CR23","doi-asserted-by":"crossref","first-page":"e193","DOI":"10.1212\/WNL.0000000000011046","volume":"96","author":"EC Gertje","year":"2021","unstructured":"Gertje, E. C., van Westen, D., Panizo, C., Mattsson-Carlgren, N. & Hansson, O. Association of enlarged perivascular spaces and measures of small vessel and Alzheimer disease. Neurology 96, e193\u2013e202 (2021).","journal-title":"Neurology"},{"key":"1006_CR24","volume":"15","author":"P Pan","year":"2025","unstructured":"Pan, P. et al. The enlarged perivascular spaces in the hippocampus is associated with memory function in patients with type 2 diabetes mellitus. Sci. Rep. 15, 3644 (2025).","journal-title":"Sci. Rep."},{"key":"1006_CR25","doi-asserted-by":"crossref","first-page":"149","DOI":"10.2337\/diabetes.52.1.149","volume":"52","author":"SC Ferguson","year":"2003","unstructured":"Ferguson, S. C. et al. Cognitive ability and brain structure in type 1 diabetes: relation to microangiopathy and preceding severe hypoglycemia. Diabetes 52, 149\u2013156 (2003).","journal-title":"Diabetes"},{"key":"1006_CR26","doi-asserted-by":"crossref","first-page":"e107","DOI":"10.1212\/WNL.0000000000201349","volume":"100","author":"TE Evans","year":"2023","unstructured":"Evans, T. E. et al. Determinants of perivascular spaces in the general population: a pooled cohort analysis of individual participant data. Neurology 100, e107\u2013e122 (2023).","journal-title":"Neurology"},{"key":"1006_CR27","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1161\/STROKEAHA.117.019309","volume":"49","author":"M-G Duperron","year":"2018","unstructured":"Duperron, M.-G. et al. Burden of dilated perivascular spaces, an emerging marker of cerebral small vessel disease, is highly heritable. Stroke 49, 282\u2013287 (2018).","journal-title":"Stroke"},{"key":"1006_CR28","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1001\/jamaneurol.2022.3832","volume":"79","author":"BPH Cho","year":"2022","unstructured":"Cho, B. P. H. et al. Association of vascular risk factors and genetic factors with penetrance of variants causing monogenic stroke. JAMA Neurol. 79, 1303\u20131311 (2022).","journal-title":"JAMA Neurol."},{"key":"1006_CR29","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1093\/brain\/awz024","volume":"142","author":"A Mishra","year":"2019","unstructured":"Mishra, A. et al. Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects. Brain J. Neurol. 142, 1009\u20131023 (2019).","journal-title":"Brain J. Neurol."},{"key":"1006_CR30","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s44161-024-00475-3","volume":"3","author":"R Malik","year":"2024","unstructured":"Malik, R. et al. Genetically proxied HTRA1 protease activity and circulating levels independently predict risk of ischemic stroke and coronary artery disease. Nat. Cardiovasc. Res. 3, 701\u2013713 (2024).","journal-title":"Nat. Cardiovasc. Res."},{"key":"1006_CR31","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1038\/ng.3406","volume":"47","author":"ReproGen Consortium","year":"2015","unstructured":"ReproGen Consortium et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236\u20131241 (2015).","journal-title":"Nat. Genet."},{"key":"1006_CR32","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/s41586-023-06563-x","volume":"622","author":"GH Eldjarn","year":"2023","unstructured":"Eldjarn, G. H. et al. Large-scale plasma proteomics comparisons through genetics and disease associations. Nature 622, 348\u2013358 (2023).","journal-title":"Nature"},{"key":"1006_CR33","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-020-15932-3","volume":"11","author":"E Persyn","year":"2020","unstructured":"Persyn, E. et al. Genome-wide association study of MRI markers of cerebral small vessel disease in 42,310 participants. Nat. Commun. 11, 2175 (2020).","journal-title":"Nat. Commun."},{"key":"1006_CR34","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.1093\/brain\/awab253","volume":"144","author":"R Malik","year":"2021","unstructured":"Malik, R. et al. Whole-exome sequencing reveals a role of HTRA1 and EGFL8 in brain white matter hyperintensities. Brain J. Neurol. 144, 2670\u20132682 (2021).","journal-title":"Brain J. Neurol."},{"key":"1006_CR35","doi-asserted-by":"crossref","first-page":"4386","DOI":"10.1016\/j.cell.2023.08.037","volume":"186","author":"N Sun","year":"2023","unstructured":"Sun, N. et al. Human microglial state dynamics in Alzheimer\u2019s disease progression. Cell 186, 4386\u20134403 (2023).","journal-title":"Cell"},{"key":"1006_CR36","doi-asserted-by":"crossref","first-page":"2423","DOI":"10.1177\/0271678X211004307","volume":"41","author":"A Pokhilko","year":"2021","unstructured":"Pokhilko, A. et al. Global proteomic analysis of extracellular matrix in mouse and human brain highlights relevance to cerebrovascular disease. J. Cereb. Blood Flow. Metab. 41, 2423\u20132438 (2021).","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"1006_CR37","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/jcbfm.2015.62","volume":"36","author":"A Joutel","year":"2016","unstructured":"Joutel, A., Haddad, I., Ratelade, J. & Nelson, M. T. Perturbations of the cerebrovascular matrisome: a convergent mechanism in small vessel disease of the brain?. J. Cereb. Blood Flow. 36, 143\u2013157 (2016).","journal-title":"J. Cereb. Blood Flow."},{"key":"1006_CR38","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.3389\/fnins.2019.01142","volume":"13","author":"C Haffner","year":"2019","unstructured":"Haffner, C. Proteostasis in cerebral small vessel disease. Front. Neurosci. 13, 1142 (2019).","journal-title":"Front. Neurosci."},{"key":"1006_CR39","doi-asserted-by":"crossref","first-page":"e1812","DOI":"10.1212\/WNL.0000000000207113","volume":"100","author":"EC Gertje","year":"2023","unstructured":"Gertje, E. C. et al. Associations between CSF markers of inflammation, white matter lesions, and cognitive decline in individuals without dementia. Neurology 100, e1812\u2013e1824 (2023).","journal-title":"Neurology"},{"key":"1006_CR40","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.tips.2020.09.011","volume":"41","author":"L Gaetani","year":"2020","unstructured":"Gaetani, L. et al. CSF and blood biomarkers in neuroinflammatory and neurodegenerative diseases: implications for treatment. Trends Pharmacol. Sci. 41, 1023\u20131037 (2020).","journal-title":"Trends Pharmacol. Sci."},{"key":"1006_CR41","doi-asserted-by":"crossref","first-page":"100062","DOI":"10.1016\/j.bionps.2023.100062","volume":"8","author":"M Luebke","year":"2023","unstructured":"Luebke, M., Parulekar, M. & Thomas, F. P. Fluid biomarkers for the diagnosis of neurodegenerative diseases. Biomark. Neuropsychiatry 8, 100062 (2023).","journal-title":"Biomark. Neuropsychiatry"},{"key":"1006_CR42","doi-asserted-by":"crossref","first-page":"FNL6","DOI":"10.2217\/fnl-2018-0029","volume":"14","author":"TT Robey","year":"2019","unstructured":"Robey, T. T. & Panegyres, P. K. Cerebrospinal fluid biomarkers in neurodegenerative disorders. Future Neurol. 14, FNL6 (2019).","journal-title":"Future Neurol."},{"key":"1006_CR43","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1038\/s41588-018-0205-x","volume":"50","author":"E Evangelou","year":"2018","unstructured":"Evangelou, E. et al. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat. Genet. 50, 1412\u20131425 (2018).","journal-title":"Nat. Genet."},{"key":"1006_CR44","volume":"6","author":"YH Park","year":"2020","unstructured":"Park, Y. H. et al. Association of blood-based transcriptional risk scores with biomarkers for Alzheimer disease. Neurol. Genet. 6, e517 (2020).","journal-title":"Neurol. Genet."},{"key":"1006_CR45","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.4049\/jimmunol.165.3.1197","volume":"165","author":"N Fournier","year":"2000","unstructured":"Fournier, N. et al. FDF03, a novel inhibitory receptor of the immunoglobulin superfamily, is expressed by human dendritic and myeloid cells. J. Immunol. 165, 1197\u20131209 (2000).","journal-title":"J. Immunol."},{"key":"1006_CR46","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/S1474-4422(22)00208-3","volume":"21","author":"A Charidimou","year":"2022","unstructured":"Charidimou, A. et al. The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI\u2013neuropathology diagnostic accuracy study. Lancet Neurol. 21, 714\u2013725 (2022).","journal-title":"Lancet Neurol."},{"key":"1006_CR47","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1007427","volume":"14","author":"N Rathore","year":"2018","unstructured":"Rathore, N. et al. Paired immunoglobulin-like type 2 receptor alpha G78R variant alters ligand binding and confers protection to Alzheimer\u2019s disease. PLoS Genet. 14, e1007427 (2018).","journal-title":"PLoS Genet."},{"key":"1006_CR48","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1124\/pharmrev.121.000527","volume":"74","author":"G Hook","year":"2022","unstructured":"Hook, G. et al. Cathepsin B gene knockout improves behavioral deficits and reduces pathology in models of neurologic disorders. Pharmacol. Rev. 74, 600\u2013629 (2022).","journal-title":"Pharmacol. Rev."},{"key":"1006_CR49","doi-asserted-by":"crossref","first-page":"33","DOI":"10.3233\/JAD-221005","volume":"93","author":"G Hook","year":"2023","unstructured":"Hook, G., Kindy, M. & Hook, V. Cathepsin B deficiency improves memory deficits and reduces amyloid-\u03b2 in hA\u03b2PP mouse models representing the major sporadic alzheimer\u2019s disease condition. J. Alzheimers Dis. 93, 33\u201346 (2023).","journal-title":"J. Alzheimers Dis."},{"key":"1006_CR50","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1212\/WNL.0000000000003251","volume":"87","author":"M Bugiani","year":"2016","unstructured":"Bugiani, M. et al. Cathepsin A\u2013related arteriopathy with strokes and leukoencephalopathy (CARASAL). Neurology 87, 1777\u20131786 (2016).","journal-title":"Neurology"},{"key":"1006_CR51","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1002\/glia.22604","volume":"62","author":"X Zhang","year":"2014","unstructured":"Zhang, X. et al. Arylsulfatase B modulates neurite outgrowth via astrocyte chondroitin-4-sulfate: dysregulation by ethanol. Glia 62, 259\u2013271 (2014).","journal-title":"Glia"},{"key":"1006_CR52","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/nature25739","volume":"554","author":"M Vanlandewijck","year":"2018","unstructured":"Vanlandewijck, M. et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature 554, 475\u2013480 (2018).","journal-title":"Nature"},{"key":"1006_CR53","volume":"5","author":"L He","year":"2018","unstructured":"He, L. et al. Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types. Sci. Data 5, 180160 (2018).","journal-title":"Sci. Data"},{"key":"1006_CR54","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1750-1172-5-5","volume":"5","author":"V Valayannopoulos","year":"2010","unstructured":"Valayannopoulos, V., Nicely, H., Harmatz, P. & Turbeville, S. Mucopolysaccharidosis VI. Orphanet J. Rare Dis. 5, 5 (2010).","journal-title":"Orphanet J. Rare Dis."},{"key":"1006_CR55","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1111\/ene.14183","volume":"27","author":"M Mancuso","year":"2020","unstructured":"Mancuso, M. et al. Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology. Eur. J. Neurol. 27, 909\u2013927 (2020).","journal-title":"Eur. J. Neurol."},{"key":"1006_CR56","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s40478-022-01497-3","volume":"11","author":"G Sol\u00e9-Guardia","year":"2023","unstructured":"Sol\u00e9-Guardia, G. et al. Association between hypertension and neurovascular inflammation in both normal-appearing white matter and white matter hyperintensities. Acta Neuropathol. Commun. 11, 2 (2023).","journal-title":"Acta Neuropathol. Commun."},{"key":"1006_CR57","doi-asserted-by":"crossref","first-page":"100916","DOI":"10.1016\/j.arr.2019.100916","volume":"53","author":"A Low","year":"2019","unstructured":"Low, A., Mak, E., Rowe, J. B., Markus, H. S. & O\u2019Brien, J. T. Inflammation and cerebral small vessel disease: a systematic review. Ageing Res. Rev. 53, 100916 (2019).","journal-title":"Ageing Res. Rev."},{"key":"1006_CR58","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1136\/jnnp-2020-323894","volume":"92","author":"A Low","year":"2021","unstructured":"Low, A. et al. In vivo neuroinflammation and cerebral small vessel disease in mild cognitive impairment and Alzheimer\u2019s disease. J. Neurol. Neurosurg. Psychiatry 92, 45\u201352 (2021).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"1006_CR59","first-page":"2575","volume":"117","author":"LE Evans","year":"2021","unstructured":"Evans, L. E. et al. Cardiovascular comorbidities, inflammation, and cerebral small vessel disease. Cardiovasc. Res. 117, 2575\u20132588 (2021).","journal-title":"Cardiovasc. Res."},{"key":"1006_CR60","doi-asserted-by":"crossref","first-page":"67","DOI":"10.3389\/fimmu.2018.00067","volume":"9","author":"Y Fu","year":"2018","unstructured":"Fu, Y. & Yan, Y. Emerging role of immunity in cerebral small vessel disease. Front. Immunol. 9, 67 (2018).","journal-title":"Front. Immunol."},{"key":"1006_CR61","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1093\/brain\/awac290","volume":"146","author":"Y Yang","year":"2023","unstructured":"Yang, Y. et al. Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI. Brain 146, 492\u2013506 (2023).","journal-title":"Brain"},{"key":"1006_CR62","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1038\/nature14252","volume":"518","author":"E Gjoneska","year":"2015","unstructured":"Gjoneska, E. et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer\u2019s disease. Nature 518, 365\u2013369 (2015).","journal-title":"Nature"},{"key":"1006_CR63","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1007\/s10534-018-0111-9","volume":"31","author":"ET Zakharova","year":"2018","unstructured":"Zakharova, E. T. et al. Erythropoietin and Nrf2: key factors in the neuroprotection provided by apo-lactoferrin. BioMetals 31, 425\u2013443 (2018).","journal-title":"BioMetals"},{"key":"1006_CR64","doi-asserted-by":"crossref","first-page":"3071","DOI":"10.1161\/STROKEAHA.112.663120","volume":"43","author":"Y Gan","year":"2012","unstructured":"Gan, Y. et al. Mutant erythropoietin without erythropoietic activity is neuroprotective against ischemic brain injury. Stroke 43, 3071\u20133077 (2012).","journal-title":"Stroke"},{"key":"1006_CR65","doi-asserted-by":"crossref","first-page":"2483","DOI":"10.1182\/blood-2016-10-743880","volume":"128","author":"P Ji","year":"2016","unstructured":"Ji, P. Pericytes: new EPO-producing cells in the brain. Blood 128, 2483\u20132485 (2016).","journal-title":"Blood"},{"key":"1006_CR66","doi-asserted-by":"crossref","first-page":"2550","DOI":"10.1182\/blood-2016-05-713545","volume":"128","author":"AA Urrutia","year":"2016","unstructured":"Urrutia, A. A. et al. Prolyl-4-hydroxylase 2 and 3 coregulate murine erythropoietin in brain pericytes. Blood 128, 2550\u20132560 (2016).","journal-title":"Blood"},{"key":"1006_CR67","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.3181\/0802-RM-53","volume":"233","author":"PA Spagnuolo","year":"2008","unstructured":"Spagnuolo, P. A. & Hoffman-Goetz, L. Dietary lactoferrin does not prevent dextran sulfate sodium induced murine intestinal lymphocyte death. Exp. Biol. Med. 233, 1099\u20131108 (2008).","journal-title":"Exp. Biol. Med."},{"key":"1006_CR68","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1002\/acn3.138","volume":"1","author":"Y Van De Looij","year":"2014","unstructured":"Van De Looij, Y. et al. Lactoferrin during lactation protects the immature hypoxic-ischemic rat brain. Ann. Clin. Transl. Neurol. 1, 955\u2013967 (2014).","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"1006_CR69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0048-9697(91)90096-W","volume":"101","author":"M Mercier","year":"1991","unstructured":"Mercier, M. International approach to the assessment of chemical risks. Sci. Total Environ. 101, 1\u20137 (1991).","journal-title":"Sci. Total Environ."},{"key":"1006_CR70","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1177\/0271678X20925667","volume":"41","author":"X Zhao","year":"2021","unstructured":"Zhao, X. et al. Optimized lactoferrin as a highly promising treatment for intracerebral hemorrhage: pre-clinical experience. J. Cereb. Blood Flow. Metab. 41, 53\u201366 (2021).","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"1006_CR71","doi-asserted-by":"crossref","first-page":"610","DOI":"10.3390\/ph16040610","volume":"16","author":"FS Kittur","year":"2023","unstructured":"Kittur, F. S., Hung, C.-Y., Li, P. A., Sane, D. C. & Xie, J. Asialo-rhuEPO as a potential neuroprotectant for ischemic stroke treatment. Pharmaceuticals 16, 610 (2023).","journal-title":"Pharmaceuticals"},{"key":"1006_CR72","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1161\/STROKEAHA.119.027759","volume":"51","author":"RP Giugliano","year":"2020","unstructured":"Giugliano, R. P. et al. Stroke prevention with the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab added to statin in high-risk patients with stable atherosclerosis. Stroke 51, 1546\u20131554 (2020).","journal-title":"Stroke"},{"key":"1006_CR73","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1007\/s00018-022-04237-x","volume":"79","author":"AD Mazura","year":"2022","unstructured":"Mazura, A. D. et al. PCSK9 acts as a key regulator of A\u03b2 clearance across the blood-brain barrier. Cell. Mol. Life Sci. 79, 212 (2022).","journal-title":"Cell. Mol. Life Sci."},{"key":"1006_CR74","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1042\/CS20160381","volume":"131","author":"H Mestre","year":"2017","unstructured":"Mestre, H., Kostrikov, S., Mehta, R. I. & Nedergaard, M. Perivascular spaces, glymphatic dysfunction, and small vessel disease. Clin. Sci. 131, 2257\u20132274 (2017).","journal-title":"Clin. Sci."},{"key":"1006_CR75","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/ijs.12270","volume":"9","author":"V Mok","year":"2014","unstructured":"Mok, V. et al. Race-ethnicity and cerebral small vessel disease\u2013comparison between Chinese and White populations. Int. J. Stroke 9, 36\u201342 (2014).","journal-title":"Int. J. Stroke"},{"key":"1006_CR76","volume":"16","author":"B Wang","year":"2025","unstructured":"Wang, B. et al. Comparative studies of 2168 plasma proteins measured by two affinity-based platforms in 4000 Chinese adults. Nat. Commun. 16, 1869 (2025).","journal-title":"Nat. Commun."},{"key":"1006_CR77","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41586-018-0175-2","volume":"558","author":"BB Sun","year":"2018","unstructured":"Sun, B. B. et al. Genomic atlas of the human plasma proteome. Nature 558, 73\u201379 (2018).","journal-title":"Nature"},{"key":"1006_CR78","doi-asserted-by":"crossref","DOI":"10.1186\/s13742-015-0047-8","volume":"4","author":"CC Chang","year":"2015","unstructured":"Chang, C. C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. GigaScience 4, 7 (2015).","journal-title":"GigaScience"},{"key":"1006_CR79","first-page":"e3331","volume":"95","author":"MJ Knol","year":"2020","unstructured":"Knol, M. J. et al. Association of common genetic variants with brain microbleeds: a genome-wide association study. Neurology 95, e3331\u2013e3343 (2020).","journal-title":"Neurology"},{"key":"1006_CR80","doi-asserted-by":"crossref","first-page":"e1007081","DOI":"10.1371\/journal.pgen.1007081","volume":"13","author":"G Hemani","year":"2017","unstructured":"Hemani, G., Tilling, K. & Davey Smith, G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet. 13, e1007081 (2017).","journal-title":"PLoS Genet."},{"key":"1006_CR81","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1002\/gepi.21758","volume":"37","author":"S Burgess","year":"2013","unstructured":"Burgess, S., Butterworth, A. & Thompson, S. G. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet. Epidemiol. 37, 658\u2013665 (2013).","journal-title":"Genet. Epidemiol."},{"key":"1006_CR82","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1007\/s10654-017-0255-x","volume":"32","author":"S Burgess","year":"2017","unstructured":"Burgess, S. & Thompson, S. G. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur. J. Epidemiol. 32, 377\u2013389 (2017).","journal-title":"Eur. J. Epidemiol."},{"key":"1006_CR83","doi-asserted-by":"crossref","first-page":"186","DOI":"10.12688\/wellcomeopenres.15555.1","volume":"4","author":"S Burgess","year":"2019","unstructured":"Burgess, S. et al. Guidelines for performing Mendelian randomization investigations. Wellcome Open Res. 4, 186 (2019).","journal-title":"Wellcome Open Res."},{"key":"1006_CR84","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","volume":"50","author":"M Verbanck","year":"2018","unstructured":"Verbanck, M., Chen, C.-Y., Neale, B. & Do, R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat. Genet. 50, 693\u2013698 (2018).","journal-title":"Nat. Genet."},{"key":"1006_CR85","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1093\/ije\/dyv080","volume":"44","author":"J Bowden","year":"2015","unstructured":"Bowden, J., Davey Smith, G. & Burgess, S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int. J. Epidemiol. 44, 512\u2013525 (2015).","journal-title":"Int. J. Epidemiol."},{"key":"1006_CR86","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1093\/ije\/dyy262","volume":"48","author":"E Sanderson","year":"2019","unstructured":"Sanderson, E., Davey Smith, G., Windmeijer, F. & Bowden, J. An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings. Int. J. Epidemiol. 48, 713\u2013727 (2019).","journal-title":"Int. J. Epidemiol."},{"key":"1006_CR87","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1093\/aje\/kwu283","volume":"181","author":"S Burgess","year":"2015","unstructured":"Burgess, S. & Thompson, S. G. Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects. Am. J. Epidemiol. 181, 251\u2013260 (2015).","journal-title":"Am. J. Epidemiol."},{"key":"1006_CR88","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1004383","volume":"10","author":"C Giambartolomei","year":"2014","unstructured":"Giambartolomei, C. et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014).","journal-title":"PLoS Genet."},{"key":"1006_CR89","doi-asserted-by":"crossref","DOI":"10.1186\/s12916-023-02867-x","volume":"21","author":"HT Cronj\u00e9","year":"2023","unstructured":"Cronj\u00e9, H. T. et al. Genetic evidence implicating natriuretic peptide receptor-3 in cardiovascular disease risk: a Mendelian randomization study. BMC Med. 21, 158 (2023).","journal-title":"BMC Med."},{"key":"1006_CR90","doi-asserted-by":"crossref","first-page":"e1010299","DOI":"10.1371\/journal.pgen.1010299","volume":"18","author":"Y Zou","year":"2022","unstructured":"Zou, Y., Carbonetto, P., Wang, G. & Stephens, M. Fine-mapping from summary data with the \u2018Sum of Single Effects\u2019 model. PLoS Genet. 18, e1010299 (2022).","journal-title":"PLoS Genet."},{"key":"1006_CR91","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/sj.hdy.6800717","volume":"95","author":"J Li","year":"2005","unstructured":"Li, J. & Ji, L. Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity 95, 221\u2013227 (2005).","journal-title":"Heredity"},{"key":"1006_CR92","doi-asserted-by":"crossref","first-page":"286","DOI":"10.3390\/ijms26010286","volume":"26","author":"R Puerta","year":"2024","unstructured":"Puerta, R. et al. Head-to-Head Comparison of Aptamer- and Antibody-Based Proteomic Platforms in Human Cerebrospinal Fluid Samples from a Real-World Memory Clinic Cohort. Int. J. Mol. Sci. 26, 286 (2024).","journal-title":"Int. J. Mol. Sci."},{"key":"1006_CR93","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.atherosclerosis.2015.07.023","volume":"242","author":"L Lind","year":"2015","unstructured":"Lind, L. et al. Use of a proximity extension assay proteomics chip to discover new biomarkers for human atherosclerosis. Atherosclerosis 242, 205\u2013210 (2015).","journal-title":"Atherosclerosis"},{"key":"1006_CR94","doi-asserted-by":"crossref","DOI":"10.3389\/fninf.2021.641600","volume":"15","author":"P Boutinaud","year":"2021","unstructured":"Boutinaud, P. et al. 3D Segmentation of perivascular spaces on T1-weighted 3 Tesla MR images with a convolutional autoencoder and a U-shaped neural network. Front. Neuroinform. 15, 641600 (2021).","journal-title":"Front. Neuroinform."},{"key":"1006_CR95","doi-asserted-by":"crossref","first-page":"709","DOI":"10.3174\/ajnr.A2366","volume":"32","author":"Y-C Zhu","year":"2011","unstructured":"Zhu, Y.-C. et al. Frequency and location of dilated Virchow-Robin spaces in elderly people: a population-based 3D MR imaging study. AJNR Am. J. Neuroradiol. 32, 709\u2013713 (2011).","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"1006_CR96","doi-asserted-by":"crossref","unstructured":"Viechtbauer, W. Conducting meta-analyses in R with the metafor Package. J. Stat. Softw. 36, 3 (2010).","DOI":"10.18637\/jss.v036.i03"},{"key":"1006_CR97","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1097\/JU.0000000000000683","volume":"203","author":"S Funada","year":"2020","unstructured":"Funada, S. et al. Longitudinal analysis of bidirectional relationships between nocturia and depressive symptoms: the Nagahama study. J. Urol. 203, 984\u2013990 (2020).","journal-title":"J. Urol."},{"key":"1006_CR98","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.neuroimage.2018.03.050","volume":"174","author":"J Jiang","year":"2018","unstructured":"Jiang, J. et al. UBO Detector \u2013 a cluster-based, fully automated pipeline for extracting white matter hyperintensities. NeuroImage 174, 539\u2013549 (2018).","journal-title":"NeuroImage"},{"key":"1006_CR99","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2015-009089","volume":"6","author":"I Montagni","year":"2016","unstructured":"Montagni, I., Guichard, E. & Kurth, T. Association of screen time with self-perceived attention problems and hyperactivity levels in French students: a cross-sectional study. BMJ Open 6, e009089 (2016).","journal-title":"BMJ Open"},{"key":"1006_CR100","doi-asserted-by":"crossref","first-page":"692152","DOI":"10.3389\/fnsys.2021.692152","volume":"15","author":"A Tsuchida","year":"2021","unstructured":"Tsuchida, A. et al. Age-related variations in regional white matter volumetry and microstructure during the post-adolescence period: a cross-sectional study of a cohort of 1,713 university students. Front. Syst. Neurosci. 15, 692152 (2021).","journal-title":"Front. Syst. Neurosci."},{"key":"1006_CR101","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1007\/s00429-021-02334-4","volume":"226","author":"A Tsuchida","year":"2021","unstructured":"Tsuchida, A. et al. The MRi-Share database: brain imaging in a cross-sectional cohort of 1870 university students. Brain Struct. Funct. 226, 2057\u20132085 (2021).","journal-title":"Brain Struct. Funct."},{"key":"1006_CR102","first-page":"616","volume":"7","author":"Q Le Grand","year":"2022","unstructured":"Le Grand, Q. et al. Genomic studies across the lifespan point to early mechanisms determining subcortical volumes. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 7, 616\u2013628 (2022).","journal-title":"Biol. Psychiatry Cogn. Neurosci. Neuroimaging"},{"key":"1006_CR103","doi-asserted-by":"crossref","first-page":"e26548","DOI":"10.1002\/hbm.26548","volume":"45","author":"A Tsuchida","year":"2024","unstructured":"Tsuchida, A. et al. Early detection of white matter hyperintensities using SHIVA-WMH detector. Hum. Brain Mapp. 45, e26548 (2024).","journal-title":"Hum. Brain Mapp."},{"key":"1006_CR104","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1038\/s41588-021-00870-7","volume":"53","author":"J Mbatchou","year":"2021","unstructured":"Mbatchou, J. et al. Computationally efficient whole-genome regression for quantitative and binary traits. Nat. Genet. 53, 1097\u20131103 (2021).","journal-title":"Nat. Genet."},{"key":"1006_CR105","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/s41586-022-05165-3","volume":"611","author":"A Mishra","year":"2022","unstructured":"Mishra, A. et al. Stroke genetics informs drug discovery and risk prediction across ancestries. Nature 611, 115\u2013123 (2022).","journal-title":"Nature"},{"key":"1006_CR106","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.ajhg.2014.02.012","volume":"94","author":"D Woo","year":"2014","unstructured":"Woo, D. et al. Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage. Am. J. Hum. Genet. 94, 511\u2013521 (2014).","journal-title":"Am. J. Hum. Genet."},{"key":"1006_CR107","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41588-018-0311-9","volume":"51","author":"IE Jansen","year":"2019","unstructured":"Jansen, I. E. et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer\u2019s disease risk. Nat. Genet. 51, 404\u2013413 (2019).","journal-title":"Nat. Genet."},{"key":"1006_CR108","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1016\/j.je.2016.12.005","volume":"27","author":"A Nagai","year":"2017","unstructured":"Nagai, A. et al. Overview of the BioBank Japan Project: study design and profile. J. Epidemiol. 27, S2\u2013S8 (2017).","journal-title":"J. Epidemiol."},{"key":"1006_CR109","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1038\/s41588-020-0705-3","volume":"52","author":"S Koyama","year":"2020","unstructured":"Koyama, S. et al. Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease. Nat. Genet. 52, 1169\u20131177 (2020).","journal-title":"Nat. Genet."},{"key":"1006_CR110","volume":"10","author":"X Liu","year":"2024","unstructured":"Liu, X. et al. Decoding triancestral origins, archaic introgression, and natural selection in the Japanese population by whole-genome sequencing. Sci. Adv. 10, eadi8419 (2024).","journal-title":"Sci. Adv."},{"key":"1006_CR111","doi-asserted-by":"crossref","first-page":"2190","DOI":"10.1093\/bioinformatics\/btq340","volume":"26","author":"CJ Willer","year":"2010","unstructured":"Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190\u20132191 (2010).","journal-title":"Bioinformatics"},{"key":"1006_CR112","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1038\/s41588-023-01569-7","volume":"55","author":"Y He","year":"2023","unstructured":"He, Y. et al. East Asian-specific and cross-ancestry genome-wide meta-analyses provide mechanistic insights into peptic ulcer disease. Nat. Genet. 55, 2129\u20132138 (2023).","journal-title":"Nat. Genet."},{"key":"1006_CR113","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1038\/s42003-024-07338-4","volume":"7","author":"J Flanagan","year":"2024","unstructured":"Flanagan, J. et al. Population-specific reference panel improves imputation quality for genome-wide association studies conducted on the Japanese population. Commun. Biol. 7, 1665 (2024).","journal-title":"Commun. Biol."},{"key":"1006_CR114","volume":"8","author":"K Watanabe","year":"2017","unstructured":"Watanabe, K., Taskesen, E., van Bochoven, A. & Posthuma, D. Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 8, 1826 (2017).","journal-title":"Nat. Commun."},{"key":"1006_CR115","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/s41588-024-01685-y","volume":"56","author":"M Fujita","year":"2024","unstructured":"Fujita, M. et al. Cell subtype-specific effects of genetic variation in the Alzheimer\u2019s disease brain. Nat. Genet. 56, 605\u2013614 (2024).","journal-title":"Nat. Genet."},{"key":"1006_CR116","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1038\/s41586-022-04521-7","volume":"603","author":"FJ Garcia","year":"2022","unstructured":"Garcia, F. J. et al. Single-cell dissection of the human brain vasculature. Nature 603, 893\u2013899 (2022).","journal-title":"Nature"},{"key":"1006_CR117","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1038\/s41593-023-01334-3","volume":"26","author":"N Sun","year":"2023","unstructured":"Sun, N. et al. Single-nucleus multiregion transcriptomic analysis of brain vasculature in Alzheimer\u2019s disease. Nat. Neurosci. 26, 970\u2013982 (2023).","journal-title":"Nat. Neurosci."}],"container-title":["Nature Aging"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s43587-025-01006-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43587-025-01006-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43587-025-01006-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T13:43:50Z","timestamp":1765806230000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s43587-025-01006-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,20]]},"references-count":117,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1006"],"URL":"https:\/\/doi.org\/10.1038\/s43587-025-01006-w","relation":{},"ISSN":["2662-8465"],"issn-type":[{"value":"2662-8465","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,20]]},"assertion":[{"value":"16 September 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"C.C. has received research support from GSK and EISAI and is a member of the advisory board of Circular Genomics and owns stocks in this company. C.C. is part of the scientific advisory board for ADmit. B.P. serves on the Steering Committee of the Yale Open Data Project funded by Johnson & Johnson. C.C. is a member of the scientific advisory board of Circular Genomics and owns stocks, and is on the scientific advisory board of ADmit and Alamar. C.C. consults for Sanofi, Novo Nordisk and Owkin. C.C. has received research support from GSK, Danaher and EISAI. P.M.M. has received an honorarium as Chair of the UKRI Medical Research Council Neuroscience and Mental Health Board until March 2024. P.M.M. acknowledges consultancy fees from Biogen, Sudo, Nimbus and GSK. P.M.M. has received speakers\u2019 honoraria from Sanofi and Redburn, and has received research or educational funds from Biogen, Merck, Bristol Myers Squibb and Nimbus. J.M.W. declares no commercial competing interests, is in receipt of various academic research grants and is chief investigator for LACunar Intervention Trials. The authors declare no competing interests with respect to research, authorship and\/or publication of this article. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}