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Current therapies primarily aim to slow disease progression or manage symptoms, leaving a critical gap in preventive strategies. Recent findings suggest that ultra-low-dose tetrahydrocannabinol (ULD-THC) may exert neuroprotective effects without the adverse consequences associated with chronic THC use. This study investigates whether preventive ULD-THC treatment can mitigate neuroinflammation and early cognitive decline in the 5xFAD mouse model of AD, with a specific focus on sex differences in treatment response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Male and female 5xFAD mice received monthly ULD-THC injections from 3 to 5 months of age, before significant pathology emerged. At 6 months, behavioral assessments were conducted, followed by molecular analyses of hippocampal and prefrontal cortex (PFC) tissue.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Results indicated that ULD-THC attuned AD-related cognitive decline in both males and females, with sex-specific neuroinflammatory responses. Males exhibited reduced hippocampal inflammation, whereas females showed reduced inflammation in the PFC, suggesting distinct neuroprotective mechanisms across sexes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings highlight ULD-THC\u2019s potential as a preventive strategy for AD, emphasizing the importance of sex-dependent therapeutic approaches. By attenuating neuroinflammatory processes before cognitive deficits fully manifest, ULD-THC offers a novel, biologically targeted approach to AD prevention. Future research should explore its long-term efficacy and translational potential in clinical settings.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13293-025-00815-3","type":"journal-article","created":{"date-parts":[[2026,1,4]],"date-time":"2026-01-04T02:11:02Z","timestamp":1767492662000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Sex-dependent effects of ultra-low-dose-THC preventive treatment on neuroinflammation and cognitive decline in 5xFAD mice"],"prefix":"10.1186","volume":"17","author":[{"given":"Keren","family":"Nitzan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziv","family":"Bentulila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noa","family":"Bregman-Yemini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niv","family":"Ayalon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dekel","family":"David","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Break","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yossi","family":"Sarne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravid","family":"Doron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,3]]},"reference":[{"key":"815_CR1","doi-asserted-by":"crossref","unstructured":"2024 Alzheimer\u2019s disease facts and figures. 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