Background:Alzheimer’s Disease(AD), a serious neurodegenerative disease,is pathologicallycharacterized by synaptic loss and dysfunction.Synaptic vesicle protein 2A (SV2A) is an indispensable vesicular protein specifically expressed in synapses and can be used as a biomarker for synaptic density. Nevertheless, the involvement of SV2A in the pathogenesis and development of ADand its relation to other hallmarks of AD pathology, such as amyloid precursor protein (APP), β-amyloid (Aβ), and tau protein are not fully understood.Methods:We first examined and compared the mRNA levels of SV2A in the hippocampus of AD patients and non-AD subject in the Allen Brain database,thenwe constructed SV2A knockout mouse model.Using PET imagingwe compared the expression of Aβ in SV2A knockout mice and WT mice, analyze the relationship between SV2A and AD related proteins by quantitative real-time polymerase chain reaction (PCR), western blotting and ELISA.Results:Our results showed thatthe expression of SV2A was downregulated in the hippocampus of AD patients.In addition,SV2A colocalized with APPandwas downregulated at Aβ deposition. Moreover, we used APPswe293T cells lines to either silence or overexpress SV2A and found that SV2A deficiency leads to a simultaneous increase in Aβand Tau hyperphosphorylation,whileSV2A overexpression was associated with down-regulation of BACE1 and APOE. In addition, evidence gained in the study points PI3K signaling pathway as a possible mediator in SV2A regulation influencing the incidence and development of AD. Conclusions:Our research demonstrated that SV2A is an important regulator of AD, close interplay between SV2A and AD related proteins demonstrated in our studyprovide novel diagnostic and therapeutic opportunities of AD. This study provides guidelines and information regarding the mechanism of SV2A influence in the regulation of AD and possible future research of neurological diseases.