{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:17:15Z","timestamp":1791908235602,"version":"4.3.4"},"reference-count":59,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Identifying modifiable factors influencing amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) risk is important for prevention. Blood biomarkers, particularly cholesterol, have been associated with neurodegenerative risk, but findings in ALS are inconsistent, and data on FTD are limited.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a population\u2010based cohort study using UK primary care records from QResearch linked with Hospital Episode Statistics. Adults with biomarker data recorded between 1998 and 2023 were included. We examined associations of low\u2010 and high\u2010density lipoprotein cholesterol (LDL\u2010C and HDL\u2010C), total cholesterol, triglycerides, creatinine, creatine kinase, and HbA1c with ALS and FTD risk. Cox proportional hazards models were used to estimate associations. Two\u2010sample Mendelian randomization (MR) was applied to explore genetically predicted associations of selected biomarkers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      There were up to 2,695 ALS and 781 FTD diagnoses, with a median follow\u2010up duration of 9.4 and 10.5\u2009years, respectively. Higher LDL\u2010C (hazard ratio [HR]\n                      <jats:sub>per 1\u2010SD<\/jats:sub>\n                      \u2009=\u20091.07, 95% confidence interval [CI]\u2009=\u20091.02\u20131.11) and total cholesterol levels (HR\n                      <jats:sub>per 1\u2010SD<\/jats:sub>\n                      \u2009=\u20091.06, 95% CI\u2009=\u20091.02\u20131.10) were linearly associated with higher ALS risk. Age\u2010stratified analysis showed a stronger association for total cholesterol in those \u2265\u200960\u2009years (HR\n                      <jats:sub>per 1\u2010SD<\/jats:sub>\n                      \u2009=\u20091.08, 95% CI\u2009=\u20091.04\u20131.13, P\n                      <jats:sub>interaction<\/jats:sub>\n                      \u2009=\u20090.003). Higher creatinine was inversely associated with FTD risk (HR\n                      <jats:sub>per 1\u2010SD<\/jats:sub>\n                      \u2009=\u20090.90, 95% CI\u2009=\u20090.83\u20130.97), supported by MR (odds ratio [OR] inverse variance weighted (\n                      <jats:sub>IVW<\/jats:sub>\n                      )\n                      <jats:sub>, per 1\u2010SD<\/jats:sub>\n                      \u2009=\u20090.73, 95% CI\u2009=\u20090.56\u20130.96). HbA1c showed a U\u2010shaped association with FTD (P\n                      <jats:sub>non\u2010linearity<\/jats:sub>\n                      \u2009=\u20090.006).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>LDL and total cholesterol may provide insights into early disease changes or the etiology of ALS, whereas creatinine and HbA1c may be relevant for FTD. Research in monogenic ALS and FTD is needed to determine whether these biomarkers inform targeted prevention or intervention strategies. ANN NEUROL 2026;99:844\u2013856<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78082","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T11:01:12Z","timestamp":1761822072000},"page":"844-856","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Have Distinct Prediagnostic Blood Biochemical Profiles"],"prefix":"10.1002","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0836-9385","authenticated-orcid":false,"given":"Christos V.","family":"Chalitsios","sequence":"first","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Gao","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol A.C.","family":"Coupland","sequence":"additional","affiliation":[{"name":"School of Medicine University of Nottingham  Nottingham UK"},{"name":"Wolfson Institute of Population Health Queen Mary University  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia Hippisley","family":"Cox","sequence":"additional","affiliation":[{"name":"Wolfson Institute of Population Health Queen Mary University  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0267-3180","authenticated-orcid":false,"given":"Martin R.","family":"Turner","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1063-3277","authenticated-orcid":false,"given":"Alexander G.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)01272-7"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)00461-4"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-021-05188-0"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1134108"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2017-315995"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.09.011"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00042"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01271-2"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.15855"},{"key":"e_1_2_10_11_1","first-page":"181","article-title":"Risk factors for amyotrophic lateral sclerosis","volume":"7","author":"Ingre C","year":"2015","journal-title":"Clin Epidemiol"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24936"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2021-327133"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2021.103397"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcad211"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-024-12665-x"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.672954"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0047279400020341"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a009034"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.4067"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1080\/21678421.2023.2295455"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2018.03.022"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy384"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1080\/21678421.2020.1822411"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.15810"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(13)70090-5"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16638"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201439225"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1515\/BC.2009.035"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-80378-y"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10312"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae074"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.13061"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab255"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-010-5735-9"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.3109\/17482968.2011.619197"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.3109\/21678421.2014.908311"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-014-1807-4"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1080\/21678421.2018.1550516"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2022.940375"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2014.1129"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.51299"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1134\/S1819712422010093"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcad347"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu328"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.3034"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2023.0697"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14066"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa033"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae230"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20112812"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.12995"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.24.5.477"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2016.01.005"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0172639"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-1331.2009.02586.x"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.3109\/21678421.2014.988161"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25276"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1080\/21678421.2023.2285428"},{"key":"e_1_2_10_60_1","first-page":"e1466","article-title":"Prediagnostic Neurofilament light chain levels in amyotrophic lateral sclerosis","volume":"97","author":"Bjornevik K","year":"2021","journal-title":"Neurology [Internet]"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.78082","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ana.78082","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.78082","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T14:15:09Z","timestamp":1787840109000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.78082"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,30]]},"references-count":59,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1002\/ana.78082"],"URL":"https:\/\/doi.org\/10.1002\/ana.78082","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,30]]},"assertion":[{"value":"2025-07-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}