Genetic and molecular evidence linking CTSH to Alzheimer's disease pathophysiology
Alzheimer's & Dementia, 2026
Picard C., Aumont‐Rodrigue G., Sarty I., Loncke J., Savard M., Maligne‐Bruneau L., Poirier J.,
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Neurology | Pathophysiology | CSF |  Olink Explore HT |
Abstract
INTRODUCTION
Lysosomal dysfunction contributes to Alzheimer’s disease (AD) by impairing protein clearance and promoting neuroinflammation. Cathepsin H (CTSH), a lysosomal protease, recently emerged as a protective AD locus. We investigated how CTSH is regulated and how it influences early AD pathophysiology.
METHODS
We analyzed genomic, transcriptomic, and proteomic data from cerebrospinal fluid (CSF) and brain tissue across three independent clinical and post mortem cohorts to assess CTSH regulation, expression, and disease associations.
RESULTS
The coding variant rs2289702 acts as a cis‐regulatory variant, altering CTSH mRNA and protein levels. The T allele associates with better cognition and reduced amyloid plaque burden. CSF CTSH correlates with total tau, phosphorylated tau181, neuronal markers, and multiple glial and complement‐related inflammatory proteins.
DISCUSSION
CTSH tracks early neurodegenerative, synaptic, and inflammatory changes, and co‐expression analyses link it to broader immune–metabolic pathways. The findings position CTSH as a genetically regulated contributor to AD pathophysiology.