Proteome-wide association study identifies novel Alzheimer's disease- associated proteins

Background Alzheimer's disease (AD) is a progressive neurodegenerative disease, with a critical shortage of effective prevention and treatment options. Here, we aimed to identify proteins whose genetically regulated plasma levels were associated with AD and its related phenotypes. Methods An integrative proteome-wide search using Olink-based plasma proteomes (N = 45,540) from the UK Biobank Pharma Proteomics Project (UKB-PPP) and a large-scale genome-wide association study (GWAS) for AD (N case = 111,326, N control = 677,663) was employed to identify AD-associated proteins. Cohort studies for AD or mild cognitive disorder (MCD) with average follow-ups of 13.7 years, alongside cross-sectional studies for the volume of whole hippocampus (WH) and white matter hyperintensities (WMH) were performed to provide additional supports. Results We identified 30 AD-associated proteins through a genetic-informed proteome-wide association study (PWAS). Among these, 14 proteins (including TREM2 and GRN) have been previously reported to be associated with AD. No clear evidence has linked the remaining 16 proteins (including PILRB, FES, and HDGF) with AD. PILRB and FES were further supported by cohort studies for AD and/or MCD. A higher plasma abundance of HDGF was found to be associated with a lower volume of whole-hippocampus and an increased risk of AD, consistent with a previous study which showed a potentially risk role of HDGF for AD in both brain tissues and cerebrospinal fluid. The protein-protein interaction analysis linked PILRB with ABCA7, an AD-related protein involved in the immune system. Conclusions The integrative genetic-informed proteome-wide scan provides promising AD-associated proteins for further mechanistic studies.