Objective To investigate the protective mechanism of donepezil against Alzheimer's disease （AD） based on tau protein phosphorylation in plasma.Methods From January 2019 to July 2022， the samples of two groups of participants were collected from Department of Neurology， The First Hospital of Qiqihar. The first group of samples were collected from 58 patients with mild to severe AD and 20 healthy elderly controls， while the other group of samples were collected from 37 patients with mild to moderate AD， among whom 18 patients received donepezil treatment for 24 weeks and 19 patients received placebo treatment for 24 weeks. Extracellular vesicles （EVs） derived from neurons were extracted from the blood samples of the patients， and ELISA kits were used to measure the levels of β-amyloid 42 （Aβ₄₂）， P-T181-tau， P-S396-tau， t-tau， and NRGN.Results Compared with the control group， the patients with AD had significant increases in the levels of Aβ₄₂， t-tau， P-T181-tau， and P-S396-tau （P<0.05） and a significant reduction in the level of NRGN in EVs （P<0.05）. In the patients with AD， the levels of t-tau， NRGN， and REST in EVs were negatively correlated with the scores of Mini-Mental State Examination and Alzheimer's Disease Cooperative Study-Activity of Daily Living （P<0.05） and was positively correlated with the score of Alzheimer's Disease Assessment Scale-cognitive subscale （P<0.05）. During the 24-week treatment， compared with the placebo group， the donepezil group showed significant reductions in the levels of Aβ₄₂， t-tau， P-T181-tau， and P-S396-tau in EVs from baseline to week 24 （P<0.05）.Conclusions There are increases in the levels of Aβ₄₂， t-tau， P-T181-tau， and P-S393-tau in plasma EVs of patients with mild to moderate AD， and the increases in the levels of t-tau， NRGN， and REST may be associated with the decline in cognitive function and activities of daily living. Donepezil treatment can reduce the expression levels of t-tau， P-T181-tau， and P-S396-tau in patients with mild to moderate AD. ［Journal of International Neurology and Neurosurgery, 2024, 51(4): 23-27］