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Abstract Autophagy-related gene (ATG) 5 regulates blood lipids, chronic inflammation, CD4+ T-cell differentiation, and neuronal death and is involved in post-stroke cognitive impairment. This study aimed to explore the correlation of serum ATG5 with CD4+ T cells and cognition impairment in stroke patients. Peripheral blood was collected from 180 stroke patients for serum ATG5 and T helper (Th) 1, Th2, Th17, and regulatory T (Treg) cell detection via enzyme-linked immunosorbent assays and flow cytometry. The Mini-Mental State Examination (MMSE) scale was completed at enrollment, year (Y)1, Y2, and Y3 in stroke patients. Serum ATG5 was also measured in 50 healthy controls (HCs). Serum ATG5 was elevated in stroke patients compared to HCs (P<0.001) and was positively correlated to Th2 cells (P=0.022), Th17 cells (P<0.001), and Th17/Treg ratio (P<0.001) in stroke patients but not correlated with Th1 cells, Th1/Th2 ratio, or Treg cells (all P>0.050). Serum ATG5 (P=0.037), Th1 cells (P=0.022), Th17 cells (P=0.002), and Th17/Treg ratio (P=0.018) were elevated in stroke patients with MMSE score-identified cognition impairment vs those without cognition impairment, whereas Th2 cells, Th1/Th2 ratio, and Treg cells were not different between them (all P>0.050). Importantly, serum ATG5 was negatively linked with MMSE score at enrollment (P=0.004), Y1 (P=0.002), Y2 (P=0.014), and Y3 (P=0.001); moreover, it was positively related to 2-year (P=0.024) and 3-year (P=0.012) MMSE score decline in stroke patients. Serum ATG5 was positively correlated with Th2 and Th17 cells and estimated cognitive function decline in stroke patients. Autophagyrelated Autophagy ATG (ATG lipids inflammation CD4 CD Tcell differentiation poststroke post 18 Th (Th 1 (Treg enzymelinked enzyme cytometry MiniMental Mini Mental (MMSE Y1, Y (Y)1 HCs. . (HCs) P<0.001 P0001 P 0 001 (P<0.001 P=0.022, P0022 P=0.022 , 022 (P=0.022) P<0.001, Th17Treg ThTreg Th1Th2 ThTh Th1/Th all P>0.050. P0050 P>0.050 050 P>0.050) P=0.037, P0037 P=0.037 037 (P=0.037) P=0.002, P0002 P=0.002 002 (P=0.002) P=0.018 P0018 018 (P=0.018 scoreidentified identified Importantly P=0.004, P0004 P=0.004 004 (P=0.004) P=0.014, P0014 P=0.014 014 (P=0.014) P=0.001 (P=0.001) moreover 2year 2 P=0.024 P0024 024 (P=0.024 3year 3 P=0.012 P0012 012 (P=0.012 (Y) (HCs P<0.00 P000 00 (P<0.00 P002 P=0.02 02 (P=0.022 Th1Th P005 P>0.05 05 P003 P=0.03 03 (P=0.037 P=0.00 (P=0.002 P=0.01 P001 01 (P=0.01 (P=0.004 (P=0.014 (P=0.001 (P=0.02 (Y P<0.0 P00 (P<0.0 P=0.0 P>0.0 (P=0.03 (P=0.00 (P=0.0 P<0. P0 (P<0. P=0. P>0. (P=0. P<0 (P<0 P=0 P>0 (P=0 P< (P< P= P> (P= (P