Alzheimer’s disease (AD) is the most common type of dementia. Numerous reports have revealed that peripheral immune systems are linked to neuropathology; however, little is known about the contribution of B lymphocytes in AD. For this longitudinal study, one hundred-thirty-three participants were included in both baseline and follow-up 2nd year. Next, we performed next-generation sequencing (NGS)-based B cell receptor (BCR) repertoire profiling followed by pair-wise overlap analysis. The longitudinal change in the B lymphocytes population was associated with increased cerebral amyloid deposition. Furthermore, patients with AD shared highly similar class-switched BCR sequences with identical isotypes despite the high somatic hypermutation rate of BCR sequences. These commonalities of BCR repertoires of the patients with AD show the possibility of immunological stimuli by amyloid precursor protein (APP). Thus, we provide evidence for both quantitative and qualitative changes in B lymphocytes during AD pathogenesis. The genetic information of patients from the NGS-based BCR repertoire profiling can lead to the development of immune-based therapeutics and treatments for AD.