Multi-tissue proteomic signatures of Alzheimer’s disease: a systematic investigation in brain, CSF, blood and an exploratory study in tears

Proteomic studies have the potential to identify etiological biomarker and interventional targets for Alzheimer’s disease (AD). However, limited studies have systematically investigated and compared the proteomic profiling related to AD across multiple tissues. First, we systematically reviewed 112 proteomic studies of AD (comprising 107 case-control studies of 16,997 individuals and 5 prospective cohort studies of 60,782 individuals) and synthesized a map of 902 brain bulk, 315 cerebrospinal fluid (CSF), and 9 blood markers that were consistently altered in AD individuals across at least 5 studies. In particular, a total of 55 common proteins altered in the same direction in brain bulk and CSF, whereas 33 proteins altered in the opposite direction. Next, we applied proteome-wide Mendelian randomization and identified 28 brain, 32 CSF, and 59 plasma genetically predicted proteomic markers associated with AD (all FDR < 0.05). The comparison across multiple tissues uncovered a panel of 20 AD-related proteins altered in at least two human tissues. Overall, a pool of 1,219 multi-tissue high confidence proteins were identified in the two-phase investigation. In the exploratory analysis utilizing a matched case-control study among 79 community-dwelling older adults, we detected a total of 845 high confidence protein markers in tears, of which 312 markers altered in a severity-dependent manner across normal cognition controls, mild cognitive impairment (MCI) and dementia stages. Among these, levels of STXBP1, UBE2V1, PALM, PYGB, ST13, and GPD1 were significantly different in dementia or MCI individuals compared to controls (all P < 0.05). Overall, our study provides a comprehensive roadmap of multi-tissue proteomic biomarkers associated with AD to help enhance the exploration of underlying mechanisms, facilitate the development of minimally invasive screening methods, and identify potential targets for novel interventions.