American Journal for Young Scientists · ISSN 3068-9015
Linking ER–Mitochondria Calcium Flux to Oxidative Stress and Protein Clearance Deficits in Alzheimer’s Disease
Authors: Swetha Dammalapati, Anusha Natraj
Published: November 24, 2025
Category: Computational Neuroscience
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by mitochondrial dysfunction, impaired protein clearance, and accumulation of pathological aggregates. In this study, we analyzed a multidimensional dataset comprising control, mild cognitive impairment (MCI), early AD, and late AD human brain samples. We investigated mitochondrial reactive oxygen species (ROS), autophagic flux, lipid peroxidation (4-HNE), mitochondrial dynamics (Mitofusin 2), lysosomal abundance, and amyloid peptide ratios (Aβ42/Aβ40), along with gene expression profiles for predictive modeling. Our results reveal a strong positive correlation between AD progression and both mitochondrial ROS and Aβ42/Aβ40 ratios, highlighting increased oxidative stress and amyloidogenic burden with disease severity. Conversely, autophagic flux showed a robust decline, while 4-HNE levels rose significantly in late AD, indicating impaired clearance mechanisms and elevated oxidative damage. Lysosome abundance increased in late-stage AD, potentially reflecting compensatory or dysfunctional remodeling. Mitofusin 2 expression exhibited moderate upregulation with progression, consistent with altered mitochondrial–ER tethering. Finally, machine learning models based on gene expression achieved modest classification accuracy (~40%), suggesting that transcriptional changes alone are insufficient for robust stage discrimination. Collectively, these findings provide an integrated view of mitochondrial stress, protein aggregation, and clearance pathway dysfunction across AD stages, and highlight the need for multimodal approaches to improve disease staging and mechanistic understanding.