For the reproducible analysis of peptides by mass spectrometry-based proteomics, data-independent acquisition (DIA) and parallel/multiple reaction monitoring (PRM/MRM) deliver unrivalled performance with respect to sensitivity and reproducibility. Both approaches, however, come with distinct advantages and shortcomings. While DIA enables unbiased whole proteome analysis, it shows limitations with respect to dynamic range and the quantification of low-abundant proteins. PRM, on the other hand, is ideally suited to reproducibly quantify selected proteins even if they are low-abundant, but no knowledge of the remaining sample is obtained. Here, we combine both methods into a mixed DIA-PRM acquisition approach, merging their benefits while operating at reduced machine run times and needed sample amounts. We demonstrate the feasibility of DIA-PRM by merging a scheduled PRM assay for 103 peptides, representing 59 low-abundant lysosomal hydrolases, with a DIA data acquisition scheme. After benchmarking DIA-PRM with mouse embryonic fibroblast (MEF) whole cell lysates, we use the approach to investigate age-related proteomic changes in brain tissues of a mouse model of metachromatic leukodystrophy (MLD). This revealed an MLD-related progressive increase in distinct classes of lysosomal hydrolases as well as alterations of proteins related to myelin and cellular metabolism. All data are available via ProteomeXchange with PXD052313.