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LAL was lost with age in mice and humans with greater losses in AD and inverse associations with amyloid \u03b2 (A\u03b2). LAL loss preceded A\u03b2 pathology in AD mice, and neuronal LAL knockdown enhanced pathology and cognitive decline. In human AD brain, robust reductions in LAL protein were found with indications of a transcriptional mechanism. LAL gene therapy reduced pathology and improved cognition and affect in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>LAL loss is an age\u2010related contributor to AD pathology that can be targeted therapeutically.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>The loss of lysosomal acid lipase (LAL) contributes to Alzheimer's disease progression.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>LAL is lost is normal aging and Alzheimer's disease risk exposures.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>LAL loss is greater in human Alzheimer's brain and predicts the extent of pathology.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>LAL gene therapy blunts Alzheimer\u2019 pathology, improving cognition and mood with age.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70486","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T08:34:03Z","timestamp":1752827643000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Loss of lysosomal acid lipase contributes to Alzheimer's disease pathology and cognitive decline"],"prefix":"10.1002","volume":"21","author":[{"given":"Alexandra 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