The epigenetic remodeling of chromatin histone proteins by acetylation has been the subject of recent investigations searching for biomarkers indicative of late onset cognitive loss. Histone acetylations affect the regulation of gene transcription, and the loss of learning induced deacetylation at specific histone sites may represent biomarkers for memory loss and Alzheimer's disease (AD). Selected‐reaction‐monitoring (SRM) has recently been advanced to quantitate peptides and proteins in complex biological systems. In this paper, we provide evidence that SRM‐based targeted proteomics can reliably quantify specific histone acetylations in both AD and control brain by identifying the patterns of H3 K18/K23 acetylations Results of targeted proteomics assays have been validated by Western blot (WB) analysis. As compared with LC‐MS/MS‐TMT (tandem‐mass‐tagging) and WB methods, the targeted proteomics method has shown higher throughput, and therefore promised to be more suitable for clinical applications. With this methodology, we find that histone acetylation is significantly lower in AD temporal lobe than found in aged controls. Targeted proteomics warrants increased application for studying epigenetics of neurodegenerative diseases.