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This disruption contributes to cognitive decline and neuropsychiatric symptoms, highlighting the need to better understand its complex effects. This study investigated the associations among cerebrospinal fluid (CSF) A\u03b242 levels, cerebral glucose metabolism (assessed via FDG-PET), neuropsychiatric symptoms (evaluated using the NPI), and cognitive performance (measured by ADAS-Cog13 and MoCA) in individuals with AD, mild cognitive impairment (MCI), and cognitively normal (CN) participants. After adjusting for age, gender, education, and ApoE \u025b4 status, a significant positive relationship between CSF A\u03b242 levels and cerebral glucose metabolism was observed in the MCI and AD groups, but not in the CN group. In the MCI group, higher cerebral glucose metabolism was associated with reductions in both neuropsychiatric and depressive symptoms, suggesting that higher glucose metabolism reflect higher activation state of investigated brain regions. In contrast, in the CN group, elevated CSF A\u03b242 levels were directly linked to increased depressive symptoms, indicating that higher CSF A\u03b242 may contribute to depression even in the absence of cognitive decline. Further analysis revealed that CSF A\u03b242 levels were indirectly associated with reduced neuropsychiatric and depressive symptoms through enhanced cerebral glucose metabolism as mediator solely in the MCI group. Regarding cognitive performance, cerebral glucose metabolism showed a strong relationship with cognition in both the MCI and AD groups. Furthermore, higher CSF A\u03b242 levels were positively associated with better cognitive performance in the MCI and AD groups, with cerebral glucose metabolism potentially mediating this relationship, while no effect was seen in the CN group. In short, CSF A\u03b242 positively influenced cerebral glucose metabolism, which was linked to reduced neuropsychiatric and depressive symptoms as well as improved cognitive performance in MCI and AD groups.<\/jats:p>","DOI":"10.1186\/s13041-025-01229-3","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T13:31:55Z","timestamp":1751376715000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["CSF Amyloid-\u03b242 associates with neuropsychiatric and cognitive outcomes via cerebral glucose metabolism"],"prefix":"10.1186","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6997-9419","authenticated-orcid":false,"given":"Ali","family":"Azargoonjahromi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2853-2298","authenticated-orcid":false,"given":"Hamide","family":"Nasiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative#","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"issue":"1","key":"1229_CR1","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/s13041-024-01118-1","volume":"17","author":"A Azargoonjahromi","year":"2024","unstructured":"Azargoonjahromi A. 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