Amyloid β protein (Aβ) is a peptide processed from amyloid precursor protein cleavage by β- and γ-secretases. Many evidences suggest that Aβ plays a central role in the development of Alzheimer's disease pathology. Aβ accumulation leads to a high-diversity neurotoxic mechanism, but little is known about the underlying influence of the chromatin and genome. The human genome consists of interspersed repeats, sequences that evidence the long-standing activities and high preservative quality of mobile DNAs. Long interspersed element-1 (LINE-1 or L1), a highly active autonomous retrotransposon (RTP), is the most abundant endogenous retroelement in humans, and accounts for approximately 17% of the human genome, approximately 10% of which comprises "hot L1" copies, primed for "jumping" within the genome. This study aimed to identify the mechanism by which Aβ induces L1-RTP. We found that Aβ peptides, Aβ1-40 and Aβ1-43, induced L1-RTP, but not Aβ1-42 wild type. Our results revealed that the Aβ peptides Aβ1-40 and Aβ1-43 induce L1-RTP in neuronal cell lines. This effect was found to be reverse transcriptase-dependent, but not accompanied by the induction of double-strand breaks. We studied this using an inhibitor (VO-OHpic) and siRNA against PTEN (phosphatase and tensin homolog deleted on chromosome 10), and analyzed it as the target factor of Aβ. Interestingly, biochemical analysis revealed that Aβ induced L1-RTP in a PTEN-dependent manner. Moreover, Aβ activated MAPK by phosphorylating p44/42 MAPK. Further, PD98059 as a MAPK inhibitor inhibited the Aβ-induced L1-RTP. Our investigations evaluated the dynamics of genome instability mediated by Aβ-induced L1-RTP from early-stage Alzheimer's disease to the advanced phases of the disease.