{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T17:48:37Z","timestamp":1785779317855,"version":"3.56.0"},"reference-count":93,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T00:00:00Z","timestamp":1766534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000156","name":"FRQS","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000156","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000143","name":"Alzheimer Society of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000143","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["189919"],"award-info":[{"award-number":["189919"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT191687"],"award-info":[{"award-number":["PJT191687"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT183817"],"award-info":[{"award-number":["PJT183817"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["AD6192920"],"award-info":[{"award-number":["AD6192920"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT183817"],"award-info":[{"award-number":["PJT183817"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020951","name":"Fonds de Recherche du Qu\u00e9bec","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020951","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000406","name":"MND association","doi-asserted-by":"publisher","award":["McLaughlin\/Apr21\/879-791"],"award-info":[{"award-number":["McLaughlin\/Apr21\/879-791"]}],"id":[{"id":"10.13039\/501100000406","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000406","name":"MND association","doi-asserted-by":"publisher","award":["Byrne\/Oct22\/979-799"],"award-info":[{"award-number":["Byrne\/Oct22\/979-799"]}],"id":[{"id":"10.13039\/501100000406","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100025294","name":"Research Ireland","doi-asserted-by":"publisher","award":["21\/RC\/10294_P2"],"award-info":[{"award-number":["21\/RC\/10294_P2"]}],"id":[{"id":"10.13039\/501100025294","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30AG066515"],"award-info":[{"award-number":["P30AG066515"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001804","name":"Canada Research Chairs Program","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001804","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Sex differences, in terms of prevalence, symptoms and disease progression, are established in the aetiology of complex neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson\u2019s disease and Alzheimer\u2019s disease, but the underlying biology driving these differences remains poorly understood. There is emerging evidence from genetic and functional analyses affirming the role of the immune system in such diseases, but a thorough assessment of sex differences in the link between the immune system and neurodegenerative diseases remains lacking.<\/jats:p>\n                  <jats:p>Here, we applied a robust causal inference approach, two-sample Mendelian randomization, to evaluate the causal effect of immune-related protein levels on three neurodegenerative diseases with large-scale sex-stratified genome-wide association data available: amyotrophic lateral sclerosis (females = 10 895 cases, 57 062 controls; males = 15 547 cases, 50 145 controls); Parkinson\u2019s disease (females = 7947 cases, 90 662 controls; males = 13 020 cases, 89 660 controls); and Alzheimer\u2019s disease (females = 18 822 cases, 281 415 controls; males = 17 293 cases, 213 339 controls). As exposures, we focused on 932 immune system-related proteins with significant protein cis-quantitative trait loci (false discovery rate cut-off &amp;lt; 0.01) from a large sex-combined plasma protein dataset (n = 33 477), for which corresponding genes were included in the Immunology Database and Analysis Portal gene list. We tested for a causal relationship between genetically predicted levels of each of these proteins and each neurodegenerative disease in sex-stratified and sex-combined data, followed by colocalization and estimation of sex-differential effects. We additionally performed exploratory analyses using sex-combined CSF protein cis-quantitative trait loci (n = 971) as exposures.<\/jats:p>\n                  <jats:p>We observed evidence for a sex-differential causal relationship between FCGR2A and Parkinson\u2019s disease and between CD2AP, MAMDC2, PCDH17 or CSF3 and Alzheimer\u2019s disease. We validated significant results using two independent protein cis-quantitative trait loci datasets for those plasma proteins available. After performing sensitivity analyses, we validated the potential causal relationships of OMG on Parkinson\u2019s disease and of GRN, SERPINF2 and TREM2 on Alzheimer\u2019s disease. Mendelian randomization with CSF protein cis-quantitative trait loci showed a potential causal effect of ADGRE2, GPNMB and COLEC11 on Parkinson\u2019s disease and of CD33 on Alzheimer\u2019s disease, without evidence of sex-differential effects. Finally, we substantiated our findings of protein-disease pairs using triangulation, specifically reporting independent supporting evidence from the literature and drug-related databases.<\/jats:p>\n                  <jats:p>Overall, our results point to potential causal effects of genetically predicted levels of immune system-related plasma and CSF proteins in Alzheimer\u2019s disease and Parkinson\u2019s disease, some of which may be considered as potential candidates for drug development.<\/jats:p>","DOI":"10.1093\/brain\/awaf474","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T12:48:09Z","timestamp":1766494089000},"page":"2716-2730","source":"Crossref","is-referenced-by-count":5,"title":["Sex-aware causal inference assessment of the immune system in complex neurodegenerative diseases"],"prefix":"10.1093","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2585-5710","authenticated-orcid":false,"given":"Frida","family":"Lona-Durazo","sequence":"first","affiliation":[{"name":"Montr\u00e9al Heart Institute , Montr\u00e9al, QC H1T 1C8 ,","place":["Canada"]},{"name":"Faculty of Medicine, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, QC H3C 3J7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross P","family":"Byrne","sequence":"additional","affiliation":[{"name":"Smurfit Institute of Genetics, Trinity College Dublin , Dublin, D02 DK07, Republic of Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc-Olivier","family":"Pilon","sequence":"additional","affiliation":[{"name":"Montr\u00e9al Heart Institute , Montr\u00e9al, QC H1T 1C8 ,","place":["Canada"]},{"name":"Universit\u00e9 de Montr\u00e9al Beaulieu-Saucier Pharmacogenomics Centre , Montr\u00e9al, QC H1T 1C8 ,","place":["Canada"]},{"name":"Faculty of Pharmacy, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, QC H3T 1J4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D","family":"Greicius","sequence":"additional","affiliation":[{"name":"Neurology and Neurological Sciences, Standford University , Stanford, CA 94305 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Pierre","family":"Dub\u00e9","sequence":"additional","affiliation":[{"name":"Montr\u00e9al Heart Institute , Montr\u00e9al, QC H1T 1C8 ,","place":["Canada"]},{"name":"Universit\u00e9 de Montr\u00e9al Beaulieu-Saucier Pharmacogenomics Centre , Montr\u00e9al, QC H1T 1C8 ,","place":["Canada"]},{"name":"Department of Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, QC H3C 3J7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E","family":"Belloy","sequence":"additional","affiliation":[{"name":"NeuroGenomics and Informatics Center, Washington University School of Medicine , St.Louis, MO 63108 ,","place":["USA"]},{"name":"Department of Neurology, Washington University School of Medicine , St.Louis, MO 63110 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3915-2135","authenticated-orcid":false,"given":"Russell L","family":"McLaughlin","sequence":"additional","affiliation":[{"name":"Smurfit Institute of Genetics, Trinity College Dublin , Dublin, D02 DK07, Republic of Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1306-1868","authenticated-orcid":false,"given":"Sarah A","family":"Gagliano Taliun","sequence":"additional","affiliation":[{"name":"Montr\u00e9al Heart Institute , Montr\u00e9al, QC H1T 1C8 ,","place":["Canada"]},{"name":"Department of Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, QC H3C 3J7 ,","place":["Canada"]},{"name":"Department of Neurosciences, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, QC H3C 3J7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,12,24]]},"reference":[{"key":"2026080312473374200_awaf474-B1","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/j.genm.2010.11.010","article-title":"Effects of gender in amyotrophic lateral sclerosis","volume":"7","author":"McCombe","year":"2010","journal-title":"Gend Med"},{"key":"2026080312473374200_awaf474-B2","doi-asserted-by":"crossref","first-page":"501","DOI":"10.3233\/JPD-191683","article-title":"Parkinson\u2019s disease in women and men: What\u2019s the difference?","volume":"9","author":"Cerri","year":"2019","journal-title":"J Parkinsons 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