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Updated: Sep 16, 2026

An Improved Method to Isolate Mitochondrial Contact Sites
Published on: June 16, 2023
Genetic and molecular evidence linking CTSH to Alzheimer's disease pathophysiology
Cynthia Picard1,2, Gabriel Aumont-Rodrigue1,2,3, Isabel Sarty1,2,3
1Douglas Mental Health University Institute, Montréal, Québec, Canada.
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.
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