Alzheimer’s disease (AD) is the most common form of dementia. The deposition of β-amyloid (Aβ) plaques in the brain was considered one of the main neuropathological hallmarks of AD. As the loss of synapses always occurs during AD progression, AD has been gradually regarded as a “synaptopathy.” The activity-regulated cytoskeleton-associated protein (Arc) was recently identified as a key factor for AD due to its active roles in synaptic plasticity, learning, memory, and Aβ generation. However, there is little evidence to support the association of the Arc gene with AD. In this study, a two-stage case-control study of 1471 Han Chinese was conducted to investigate the genetic association between the Arc gene and AD. Variant rs10097505 in the 3′UTR region was significantly associated with AD. The whole exons of the Arc gene were also screened in 99 AD patients with a high heritability (familial and/or onset age A, p.T7I) was identified in two AD patients but was absent in the controls from the general populations. Both rs10097505 and c.20G>A were predicted to be potentially pathogenic. Further luciferase assay, data mining, and integrative analyses revealed that the AD-risk genotype AA of rs10097505 was associated with an increased Arc mRNA expression and an elevated Aβ level. Our results indicated that the Arc gene would confer susceptibility to AD in Han Chinese, probably through changing the protein structure or affecting the Arc expression in brain tissues, which would finally contribute to the pathogenesis and development of AD.