{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T11:02:50Z","timestamp":1790334170654,"version":"4.1.0"},"reference-count":65,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"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":["Alzheimer's &amp; Dementia"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Lysosomal dysfunction contributes to Alzheimer's disease (AD) by impairing protein clearance and promoting neuroinflammation. Cathepsin H (CTSH), a lysosomal protease, recently emerged as a protective AD locus. We investigated how CTSH is regulated and how it influences early AD pathophysiology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We analyzed genomic, transcriptomic, and proteomic data from cerebrospinal fluid (CSF) and brain tissue across three independent clinical and\n                      <jats:italic>post mortem<\/jats:italic>\n                      cohorts to assess CTSH regulation, expression, and disease associations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>The coding variant rs2289702 acts as a cis\u2010regulatory variant, altering CTSH mRNA and protein levels. The T allele associates with better cognition and reduced amyloid plaque burden. CSF CTSH correlates with total tau, phosphorylated tau181, neuronal markers, and multiple glial and complement\u2010related inflammatory proteins.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>CTSH tracks early neurodegenerative, synaptic, and inflammatory changes, and co\u2010expression analyses link it to broader immune\u2013metabolic pathways. The findings position CTSH as a genetically regulated contributor to AD pathophysiology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71833","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:26:53Z","timestamp":1789468013000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic and molecular evidence linking CTSH to Alzheimer's disease pathophysiology"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1107-6839","authenticated-orcid":false,"given":"Cynthia","family":"Picard","sequence":"first","affiliation":[{"name":"Douglas Mental Health University Institute  Montr\u00e9al Qu\u00e9bec Canada"},{"name":"Centre for the Studies on Prevention of Alzheimer's Disease  Montr\u00e9al Qu\u00e9bec 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