Multiomic analyses suggest a divergent aging trajectory in dementia

Abstract Background Aging is the main risk factor for neurodegenerative diseases such as Alzheimer’s disease (AD) and other forms of dementia. Both aging and dementia have been shown to leave a molecular signature in the plasma proteome. Understanding how the Dementia Plasma Proteome (DPP) diverges from the Aging Plasma Proteome may provide insights in pathological changes in the brains of dementia patients, or resilience mechanisms in the brain of cognitive healthy individuals. Here, we provide a more detailed overview on the aging trajectories of the DPP across ‘normal agers’ and dementia patients using a multiomic analysis approach. Method Using publicly available datasets such as the Human Protein Atlas, GTEx, and the Aging, Dementia and TBI study, we aim to link changes observed in the plasma to age‐associated changes in the brain and AD pathology. For this, we used publicly available databases. Using immunohistochemistry, we attempt to validate our findings in brain tissue. Result We show that differences in expression levels of proteins belonging to the DPP (Dementia Proteins) between non‐demented controls and demented cases are positively associated to previously identified aging associations. Furthermore, we show that Dementia Proteins are preferentially expressed in the brain and among multiple brain cell types, such as neurons, oligodendrocyte precursor cells and astrocytes. Expression trajectories during aging of brain‐expressed Dementia Proteins in the healthy brain appear largely similar as identified in the aging plasma proteome. However, we identified several proteins displaying differential aging trajectories in the brain of demented patients. Lastly, we present how these altered aging trajectories associate to several pathological measures, such as levels of Tau and Amyloid beta. Conclusion These results suggest differences in aging trajectories between non‐demented controls and dementia patients, which may be reflected in both the plasma and in brains of dementia patients. Together, these results may provide novel insights in proteins associated with dementia‐associated pathology and their contributions to the disease progression. Future studies are needed to further validate these findings and to discover the underlying mechanisms.