{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T11:54:42Z","timestamp":1791633282729,"version":"4.3.4"},"reference-count":50,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["A&amp;amp;D Transl Res &amp;amp; Clin Interv"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>There are currently no US Food and Drug Administration\u2010approved treatments for vascular dementia (VaD). Genome\u2010wide approaches have successfully identified druggable targets and treatments for various disorders. In this study, we performed druggable genome\u2010wide two\u2010sample Mendelian randomization (2SMR) analysis to identify possible treatment targets for VaD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      2SMR analyses were used to estimate the causal effects of druggable gene expression on VaD risk. The exposure variables were significant cis\u2010expression quantitative trait loci (eQTLs) and cis\u2010protein quantitative trait loci (pQTLs) in the cerebrospinal fluid (CSF), brain, and plasma. The main outcome variable was genetic VaD risk, based on the Mega Vascular Cognitive Impairment and Dementia Consortium genome\u2010wide association study. 2SMR analysis examined the causal relationship between eQTLs\/pQTLs and imaging markers of VaD. A phenome\u2010wide 2SMR analysis explored the relationships between significant druggable genes and phenotype summary statistics derived from the UK Biobank. False discovery rate (FDR)\n                      <jats:italic>P<\/jats:italic>\n                      value corrections were applied to all analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      A total of 12,224 druggable genes were identified from the Drug\u2010Gene Interaction Database (DGIdb) and associated papers. Of these, the 2SMR analysis identified four FDR\u2010significant genes in the pQTL analysis, with none identified among the eQTLs. In the CSF,\n                      <jats:italic>TOMM40<\/jats:italic>\n                      had a significant (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a03.67E\u201036) effect on VaD outcomes as well as cerebral small vessel disease (cSVD), white matter hyperintensities (WMH;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.0001) and fractional anisotropy (FA;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.0028). In the brain, apolipoprotein E (\n                      <jats:italic>APOE<\/jats:italic>\n                      ;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a01.90E\u201054) was associated with VaD and three cSVD markers: WMH (\n                      <jats:italic>P<\/jats:italic>\n                      =\u00a01.61E\u201006), FA (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.0018), and mean diffusivity (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.0244).\n                      <jats:italic>ERAP1<\/jats:italic>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.0163), and\n                      <jats:italic>SAA1\u20104<\/jats:italic>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.0163) showed weaker associations with VaD, did not show colocalization, and were not associated with cSVD imaging markers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      This study identified four potential drug targets for VaD, using a 2SMR analysis approach. Two genes,\n                      <jats:italic>APOE<\/jats:italic>\n                      and\n                      <jats:italic>TOMM40<\/jats:italic>\n                      , are well understood to be associated with both Alzheimer's disease and VaD, whereas the other two,\n                      <jats:italic>ERAP1<\/jats:italic>\n                      and\n                      <jats:italic>SAA1\u20104<\/jats:italic>\n                      , are novel targets involved in immune system regulation and inflammation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.70258","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T03:44:11Z","timestamp":1776915851000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Druggable genome\u2010wide Mendelian randomization analysis identifies potential treatment targets in vascular dementia"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7097-3666","authenticated-orcid":false,"given":"Matthew J.","family":"Lennon","sequence":"first","affiliation":[{"name":"Centre for Healthy Brain Aging (CHeBA) Discipline of Psychiatry and Mental Health Faculty of Medicine and Health University of New South Wales  Sydney New South Wales Australia"},{"name":"Royal North Shore Hospital North Shore Local Health District  Sydney New South Wales Australia"},{"name":"Neuropsychiatric Institute The Prince of Wales Hospital  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Xu","sequence":"additional","affiliation":[{"name":"Centre for Healthy Brain Aging (CHeBA) Discipline of Psychiatry and Mental Health Faculty of Medicine and Health University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anbupalam","family":"Thalamuthu","sequence":"additional","affiliation":[{"name":"Centre for Healthy Brain Aging (CHeBA) Discipline of Psychiatry and Mental Health Faculty of Medicine and Health University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Mather","sequence":"additional","affiliation":[{"name":"Centre for Healthy Brain Aging (CHeBA) Discipline of Psychiatry and Mental Health Faculty of Medicine and Health University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perminder S.","family":"Sachdev","sequence":"additional","affiliation":[{"name":"Centre for Healthy Brain Aging (CHeBA) Discipline of Psychiatry and Mental Health Faculty of Medicine and Health University of New South Wales  Sydney New South Wales Australia"},{"name":"Neuropsychiatric 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