AUTOPHAGY-LYSOSOMAL PATHWAY PROTEINS IN DERMAL FIBROBLASTS AS POTENTIAL PERIPHERAL BIOMARKERS FOR ALZHEIMER'S DISEASE DIAGNOSIS

Accumulation of abnormal/unwanted intracellular substances is one of the main causes of the development of various neurodegenerative diseases including Alzheimer's disease (AD). While current AD diagnostic methods rely heavily on cerebrospinal fluid biomarkers and neuroimaging, there is an urgent need for minimally invasive and cost-effective diagnostic tools. Autophagy-lysosomal pathway (ALP) dysfunction is a key pathogenic mechanism in AD, and its alterations have been reported in various AD model systems and patient brains. Dermal fibroblasts, the most common cells of human connective tissue, could serve as critical peripheral biomarkers reflecting central nervous system pathology. Here, we investigated ALP-associated proteins in dermal fibroblasts from AD patients and age-matched controls. Through comprehensive analysis of AD- and ALP-associated protein expression profiles and autophagic activities, we identified several promising biomarkers including BACE1, which showed significantly reduced expression, and TAX1BP1, which was markedly elevated in AD fibroblasts. In this study with AD patients and age-matched controls, our integrated multivariable logistic regression model demonstrated promising diagnostic performance, with the BAG2 + OPTN combination achieving an AUC of 0.963 for distinguishing AD patients from controls. The combination of these protein markers with APOE4 status further enhanced diagnostic accuracy. Moreover, baseline autophagic flux and lysosomal function were preserved in AD fibroblasts, suggesting that ALP dysfunction in AD may be pathway-specific rather than systemic. These findings establish dermal fibroblast-derived ALP proteins as potential peripheral biomarkers for AD diagnosis, offering a minimally invasive approach for disease detection and monitoring.