Transfer RNA-derived fragments (tRFs) are known to contribute to multiple illnesses, including cancers, viral infections, and age-related neurodegeneration. In this study, we used senescence-accelerated mouse prone 8 (SAMP8) as a model of neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease, and a control, the senescence-accelerated mouse resistant 1 (SAMR1) model, to comprehensively explore differences in tRF expression between them. We discovered 570 tRF transcripts among which eight were differentially expressed. We then obtained 110 potential target genes in a miRNA-like pattern. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation suggest that these target genes participate in a variety of brain functions; e.g., synapse formation (GO: 0045202) and the synaptic vesicle cycle pathway. We further assessed in detail those tRFs whose miRNA-like pattern was most likely to promote the progression of either Alzheimer’s or Parkinson’s disease, such as AS-tDR-011775 acting on Mobp and Park2. Our findings suggest the eight dysregulated tRFs we uncovered here may be beneficially exploited as potential diagnostic biomarkers and/or therapeutic targets to treat age-related brain diseases.