Abnormally accumulated α-synuclein (α-syn) is a pathological hallmark of Lewy body-related disorders such as Parkinson's disease (PD) and dementia with Lewy body disease (DLB). However, it is not well understood whether and how abnormal accumulation of α-syn leads to cognitive impairment or dementia in PD and DLB. Furthermore, it is not known whether targeted removal of α-syn pathology can reverse cognitive decline. Here, we found that the distribution of α-syn pathology in an inducible α-syn transgenic mouse model recapitulates that in human DLB. Abnormal accumulation of α-syn in the limbic system, particularly in the hippocampus, correlated with memory impairment and led to structural synaptic deficits. Furthermore, when α-syn expression was suppressed, we observed partial clearing of pre-existing α-syn pathology and reversal of structural synaptic defects, resulting in an improvement in memory function.