Identification of Druggable Targets for Alzheimer's Disease by Analyzing Circulating Inflammatory Proteins With
Hongliang An1, Jianhong Gu2, Taiping Li3
1Department of Pharmacy, Nanjing Meishan Hospital, Nanjing, China.
Objective:
To identify potential druggable targets for Alzheimer's disease (AD) by analyzing circulating inflammatory proteins using Mendelian randomization (MR).
Methods:
Two-sample MR analysis was employed to investigate the causal relationships between 91 circulating inflammatory proteins and AD. The primary MR method utilized was the inverse variance weighted (IVW) model, while the weighted median (WM) and MR-Egger models were applied for sensitivity analysis. To assess the heterogeneity of instrumental variables (IVs), Cochran's Q-test and I2 statistics were utilized. Additionally, ChEMBL and DGIdb databases with Bayesian colocalization analysis were consulted to identify potential druggable proteins.
Results:
MR analysis identified eight inflammatory proteins significantly associated with AD risk. Among these proteins, TNFB [odds ratio (OR): 1.06, 95% Confidence Interval (CI): 1.02-1.11, p = 8.77×10- 3], TSLP (OR: 1.10, 95% CI: 1.01-1.19, p = 0.028), S100A12 (OR: 1.09, 95% CI: 1.01-1.18, p = 0.03), CD244 (OR: 1.07, 95% CI: 1.00-1.13, p = 0.036), and IL33 (OR: 1.08, 95% CI: 1.00 -1.17, p = 0.048) were identified as proteins associated with elevated AD risk. Conversely, three inflammatory proteins exhibited a protective effect against AD, including NRTN (OR: 0.91, 95% CI: 0.85-0.99; p = 0.019), CCL4 (OR: 0.95, 95% CI: 0.91-1.00, p = 0.029), and MMP1 (OR: 0.93, 95% CI: 0.87-1.00, p = 0.049). Notably, according to the gene-drug analysis, TSLP, S100A12, CD244, CCL4, and MMP1 were identified as druggable. Additionally, MMP1 (PP4 = 0.92) and CCL4 (PP4 = 0.87) in the prefrontal cortex had the strongest colocalization evidence (PP4 > 0.85), suggesting they could potentially serve as novel therapeutic targets for AD.
Conclusions:
Integrative genetic analyses indicate that genetically determined circulating levels of TSLP, S100A12, CD244, CCL4, and MMP1 exert causal effects on AD risk. These findings nominate all five proteins as potential therapeutic targets, with MMP1 and CCL4 representing priority candidates warranting further mechanistic investigation and clinical validation.
Insights
This study used Mendelian randomization to find that five inflammatory proteins—TSLP, S100A12, CD244, CCL4, and MMP1—are potential druggable targets for Alzheimer's disease (AD). MMP1 and CCL4 show the most promise for future Alzheimer's therapies.
Area of Science:
- Genetics
- Neuroscience
- Pharmacology
Background:
- Alzheimer's disease (AD) poses a significant global health challenge.
- Identifying novel therapeutic targets is crucial for effective AD treatment.
- Circulating inflammatory proteins are increasingly recognized for their role in AD pathogenesis.
Purpose of the Study:
- To identify druggable targets for Alzheimer's disease (AD) by analyzing circulating inflammatory proteins.
- To investigate the causal relationships between inflammatory proteins and AD risk using Mendelian randomization (MR).
Main Methods:
- A two-sample MR analysis was conducted on 91 circulating inflammatory proteins and AD.
- Inverse variance weighted (IVW) model was the primary method, with weighted median (WM) and MR-Egger for sensitivity analyses.
- Bayesian colocalization and gene-drug interaction analyses were performed using ChEMBL and DGIdb databases.
Main Results:
- Eight inflammatory proteins were significantly associated with AD risk.
- Five proteins—TSLP, S100A12, CD244, CCL4, and MMP1—were identified as druggable targets.
- MMP1 and CCL4 demonstrated the strongest colocalization evidence in the prefrontal cortex, suggesting a causal role in AD.
Conclusions:
- Genetically determined circulating levels of TSLP, S100A12, CD244, CCL4, and MMP1 causally influence AD risk.
- These five proteins are nominated as potential therapeutic targets for AD.
- MMP1 and CCL4 are priority candidates for further mechanistic studies and clinical validation.
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