Background and Objectives:To investigate the effects of enlarged perivascular space (EPVS) on amyloid burden and cognitive function in Alzheimer’s disease (AD) continuum.Methods:We retrospectively reviewed 208 patients with AD across the cognitive continuum (preclinical, prodromal, and AD dementia) who showed amyloid deposition on 18F-florbetaben positron emission tomography scans and 82 healthy controls. EPVSs were counted for each patient in the basal ganglia (BG), centrum semiovale (CSO), and hippocampus (HP) on axial T2-weighted images. Patients were then classified according to the number of EPVS into the EPVS+ (> 10 EPVSs) and EPVS– (0–10 EPVSs) groups for the BG and CSO, respectively. In terms of HP-EPVS, equal or more than seven EPVSs on bilateral hemisphere were regarded as the presence of HP-EPVS. After adjusting for markers of small vessel disease (SVD), multiple linear regression analyses were performed to determine the inter-group differences in global and regional amyloid deposition and cognitive function at the time of diagnosis of AD continuum. A linear mixed model was used to assess the effects of EPVSs on the longitudinal changes in the Mini-Mental State Examination (MMSE) scores.Results:Amyloid burden at the time of diagnosis of AD continuum was not associated with the degree of BG-, CSO-, or HP-EPVS. BG-EPVS affected language and frontal/executive function via SVD markers and HP-EPVS was associated with general cognition via SVD markers. However, CSO-EPVS was not associated with baseline cognition. A higher number of CSO-EPVS was significantly associated with a more rapid decline in MMSE scores (β = −0.58, SE = 0.23, p = 0.011) independent of the amyloid burden. In terms of BG and HP, there was no difference between the EPVS+ and EPVS– groups in the rate of longitudinal decreases in MMSE scores.Discussion:Our findings suggest that BG-, CSO-, and HP-EPVS are not associated with baseline β-amyloid burden or cognitive function independently of SVD at the diagnosis of AD continuum. However, CSO-EPVS appears to be associated with the progression of cognitive decline in an amyloid-independent manner. Further studies are needed to investigate whether CSO-EPVS is a potential therapeutic target in patients with AD continuum.