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The<jats:italic>GSN<\/jats:italic>genotype\u2013phenotype heterogeneity and the role of<jats:italic>GSN<\/jats:italic>frameshift mutations in patients with AD are unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>In total, 1192 patients with AD and 1403 controls were screened through whole genome sequencing, and 884 patients with AD were enrolled for validation. Effects of<jats:italic>GSN<\/jats:italic>mutations were evaluated in vitro. GSN, A\u03b242, A\u03b240 and A\u03b242\/40 were detected in both plasma and cerebrospinal fluid (CSF).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Six patients with AD with<jats:italic>GSN<\/jats:italic>P3fs and K346fs mutations (0.50%, 6\/1192) were identified, who were diagnosed with AD but not FAF. In addition, 13 patients with AD with<jats:italic>GSN<\/jats:italic>frameshift mutations were found in the validation cohort (1.47%, 13\/884). Further in vitro experiments showed that both K346fs and P3fs mutations led to the<jats:italic>GSN<\/jats:italic>loss of function in inhibiting A\u03b2-induced toxicity. Moreover, a higher level of plasma (p=0.001) and CSF (p=0.005) GSN was observed in AD cases than controls, and a positive correlation was found between the CSF GSN and CSF A\u03b242 (r=0.289, p=0.009). Besides, the GSN level was initially increasing and then decreasing with the disease course and cognitive decline.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:italic>GSN<\/jats:italic>frameshift mutations may be associated with AD. An increase in plasma GSN is probably a compensatory reaction in AD, which is a potential biomarker for early AD.<\/jats:p><\/jats:sec>","DOI":"10.1136\/jnnp-2022-330465","type":"journal-article","created":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T09:28:25Z","timestamp":1674034105000},"page":"436-447","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["<i>GSN<\/i>gene frameshift mutations in Alzheimer\u2019s 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