Identification of potential therapeutic targets for Alzheimer's disease from the proteomes of plasma and cerebrospinal fluid in a multicenter Mendelian randomization study.

Background: Certain peripheral proteins are believed to be involved in the development of Alzheimer's disease (AD), but the roles of other new protein biomarkers are still unclear. Current treatments aim to manage symptoms, but they are not effective in stopping the progression of the disease. New drug targets are needed to prevent Alzheimer's disease.

Methods: We used Mendelian randomization (MR) to study drug targets for Alzheimer's disease. We analyzed data from the European Alzheimer's and Dementia Biobank consortium and replicated our findings in GWAS data from IGAP and FinnGen cohorts. We identified genetic instruments for plasma and cerebrospinal fluid (CSF) proteins and conducted sensitivity analyses using various methods. Additionally, a comparison and analysis of protein-protein interactions (PPI) were conducted to identify potential causal proteins. The implications of these findings were further explored through an examination of existing AD drugs and their respective targets.

Results: Through MR analysis, 10 protein AD pairs were identified as statistically significant at the Bonferroni level (P < 6.35 × 10). The specific findings indicate that elevated levels of plasma cathepsin H (CTSH) (OR = 1.06, 95%CI: 1.03-1.08, p = 6.12 × 10), plasma signal regulatory protein alpha (SIRPA) (OR = 1.03, 95%CI: 1.02-1.05, p = 1.37 × 10), plasma TMEM106B (OR = 1.16, 95%CI: 1.09-1.23, p = 1.92 × 10), and CSF bone sialoprotein (BSP) (OR = 1.33, 95%CI: 1.17-1.51, p = 9.34 × 10), CSF Interleukin-34 (IL-34) (OR = 2.13, 95%CI: 1.51-3.01, p = 1.85 × 10), CSF immunoglobulin-like transcript 2 (ILT-2) (OR = 1.33, 95%CI: 1.17-1.51, p = 9.34 × 10) are associated with an increased risk of AD, while increased levels of plasma progranulin gene (GRN) (OR = 0.79, 95%CI: 0.74-0.84, p = 2.19 × 10), plasma triggering receptor expressed on myeloid cells 2 (TREM2) (OR = 0.67, 95%CI: 0.58-0.78, p = 6.95 × 10), plasma sialic acid-bind immunoglobulin-like lectins (SIGLEC)-9 (OR = 0.67, 95%CI: 0.58-0.78, p = 6.95 × 10), and CSF SIGLEC7 (OR = 0.42, 95%CI: 0.28-0.64, p = 4.30 × 10) are associated with a decreased risk of AD. Bayesian colocalization found that the above protein-related genes shared the same mutation as AD.

Conclusion: Increased levels of plasma CTSH, SIRPA, TMEM106B, CSF BSP, CSF IL-34, and CSF ILT-2 have been found to be correlated with an elevated risk of AD, whereas elevated levels of plasma GRN, TREM2, SIGLEC9, and CSF SIGLEC7 are associated with a decreased risk of developing AD. Further investigation through clinical trials is needed.