Alzheimer's Disease (AD) is the most prevalent form of dementia and one of the leading causes of death in the United States, and despite our best efforts and recent advancements, a treatment that stops or substantially slows its progression has remained elusive. Small extracellular vesicles (sEVs), hold the potential to alleviate some of the common issues in the field by serving to better differentiate AD and non-AD individuals. These vesicles could provide insights into therapeutic targets, and potentially an avenue towards early detection. We compared the sEV cargo profiles of AD and non-AD brains (n = 6) and identified significant differences in both the micro RNA (miRNA) and Piwi-interacting RNA (piRNA) cargo through sEV isolation from temporal cortex tissue, followed by small RNA sequencing, and differential expression analysis. Differentially expressed miRNAs targeting systems relevant to AD included miR-206, miR-4516, miR-219a-5p, and miR-486-5p. Significant piRNAs included piR-6,565,525, piR-2,947,194, piR-7,181,973, and piR-7,326,987. These targets warrant further study for their potential role in the progression of AD pathology by dysregulating cellular activity; additionally, future large-scale studies of neuronal sEV miRNA profiles may facilitate the development of diagnostic tools which can aid in clinical trial design and recruitment. Longitudinal analysis of sEV data, perhaps accessible through plasma surveyance, will help determine at what point these miRNA and/or piRNA profiles begin to diverge between AD and non-AD individuals.