| Title: | Genetic evidence supports therapeutic modulation of progranulin levels in Alzheimer's Disease |
| Journal: | Molecular Neurodegeneration Advances |
| Published: | 19 Jan 2026 |
| DOI: | https://doi.org/10.1186/s44477-025-00011-y |
Publication 18622
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Abstract
BackgroundGenetic variants in GRN resulting in progranulin (PGRN) deficiency are causal or are associated with the risk of multiple neurodegenerative diseases. Elevation and/or restoration of PGRN is under development as a therapeutic strategy for frontotemporal dementia (FTD) and Alzheimer's disease (AD). Here, we integrate human genetics with proteomic and transcriptomic data to evaluate the causal human evidence for the therapeutic benefit of increasing progranulin.MethodsUsing summary statistics from genome-wide association studies (GWAS) of AD, we performed colocalization and Mendelian randomization (MR) analyses with plasma cis protein quantitative trait loci (pQTL) data from UK Biobank and cerebrospinal fluid (CSF) cis pQTL data from neurodegeneration-focused cohorts. To gain therapeutic insight into how efficacious PGRN elevation might be, we scaled our MR analyses to mimic the CSF progranulin increases observed in recent Phase 1 clinical trials of PGRN elevating antibodies that inhibit sortilin (SORT1). We also used UK Biobank whole genome sequencing data to examine the association of GRN rare variants with AD and dementia.ResultsWe observe consistent genetic evidence suggesting that increased PGRN levels are associated with reduced risk of AD and dementia through GWAS (rs5848, p = 1.6 × 10-13) with pQTL colocalization, and MR evidence, as well as rare variant association (p = 9.18 × 10-14). Given the interaction between sortilin and PGRN, we re-scaled our MR analyses to estimate the therapeutic effect of increasing PGRN with sortilin inhibitors. This analysis suggested a genetically predicted two-fold increase in CSF PGRN levels, as observed in Phase 1 clinical trials of sortilin inhibitors, may be associated with a ~ 35% lower odds of developing AD (OR = 0.65, p = 2.2 × 10-12).ConclusionsOur work demonstrates a consistent causal association of GRN on AD risk. Furthermore, it provides human genetic evidence to support potential therapeutic benefits on AD and dementia through the elevation of PGRN levels.</p>
10 Authors
- Chloe Robins
- John D. Eicher
- Jimmy Liu
- Yancy Lo
- Tom G. Richardson
- Daniel Western
- Jonathan Davitte
- Carlos Cruchaga
- Sanjay Kumar
- Chun-Fang Xu
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