Genomic stability is a commitment of regulation and establishment of cell lines in organisms. The instability of genomes greatly affects maintenance of genetic profile and is directly or indirectly associated with many disorders. With the exception of cancer, genomic instability is widely associated with neurodegenerative disorders. The conflicts among the molecular mechanisms, such as replication, transcription, and translation are majorly responsible for the genomic instability, among which, transcription-replication conflict is well understood. Despite immense research on DNA damage and repair systems, Reactive oxygen species and impaired disorders; neurodegenerative disorders are one of the prime causes for the high-level mortality. This article focuses on the replication-transcription conflicts, genetic basis of neurodegenerative disorders and possible medical applications and may help in understanding the molecular mechanisms and finding new biomarkers and therapeutic developments.