Post-translational modifications in the brain are critical contributors to Alzheimer's disease neuropathology and cognitive decline.

Post-translational modifications (PTMs) in APP and MAPT contribute to plaques and tangles in Alzheimer's disease (AD). Yet broader proteome-wide PTMs in the AD brain are relatively unexplored. Therefore, this study highlights associations between PTMs, quantified by mass spectrometry in prefrontal cortex tissue, and Alzheimer's disease neuropathology and cognition. Leveraging PTMs quantified from prefrontal cortices in 101 Rush Memory and Aging Project participants. We assessed associations with post-mortem amyloid-β and tau burden, global cognition, and cognitive decline. First, APP and MAPT PTM associations were assessed on these outcomes given their known relevance in AD, followed by assessment of protein-wide effects of PTMs. Then, kinase enrichment analysis was performed on each outcome to assess which kinases might contribute to the results. We observed a novel association of APP-K687 acetylation, a known mutation hotspot driving pathology, with amyloid-β load (β=0.44, P=3.9e-8), while confirming known MAPT PTMs with tangle burden. Further, we identified 20+ novel PTMs' associations with AD neuropathology, including ENO2-K256 ubiquitination (β=0.353, P=1.13e-6), PSMD13-K31 ubiquitination (β=0.568, P=1.34e-6), and PLXND1-K1826 ubiquitination (β=0.577, P=7.08e-8) for tangle burden and SYP-K23 ubiquitination (β=1.50, P=4.7e-8), TMEFF2-C80 cysteine oxidation (β=1.64, P=1.1e-8), and STX1B-T121 phosphorylation (β=0.898, P=3.3e-7) for amyloid-β load. Further, kinase enrichment analyses highlight the complexity of disease-related proteome changes with some kinases like CDK5 showing expected over-enrichment (amyloid z=3.44, P=3.0e-4; tau z=4.98, P=3.3e-7) but others like PKC family kinases showing divergent enrichment between amyloid (z=8.98-11.55, P<1.0e-18) and tau (z=-2.83--3.88, P<0.006). This study provides an atlas of brain PTMs within crucial proteins like MAPT and APP and at the proteome-wide level, that impact AD neuropathology and clinical presentation. Further, we explored what kinases might be driving phosphorylation results, emphasizing the complex proteome changes which impact AD. In sum, these results highlight robust post-translational alterations in the AD brain and provide novel targets for future mechanistic studies.