The 5xFAD mouse model was used to study the influence of amyloid pathology on the cerebrospinal fluid (CSF) proteome. Therefore, CSF of 7-months old 5xFAD and WT control mice was sampled with an improved collection protocol. Using a minute amount of 5 µL CSF, we applied data dependent and data independent acquisition of the same samples on a Q-Exactive HF mass spectrometer. Comparison of DDA and DIA demonstrate a higher data completeness for DIA. The results show a strong effect on microglia activation exemplified by strongly increased abundances of Trem2 and Cst7. Furthermore, neurodegenerative markers such as neurofilaments and tau (Mapt) were strongly increased for 5xFAD mice.