A Multi-Scale View of Alzheimer’s Disease: Linking Cellular Dysfunction to Brain Activity

A Multi-Scale View of Alzheimer’s Disease: Linking Cellular Dysfunction to Brain Activity | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Multi-Scale View of Alzheimer’s Disease: Linking Cellular Dysfunction to Brain Activity Sahaana Vasudevan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9458287/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Alzheimer’s disease is a progressive neurodegenerative disorder characterized by cognitive decline and widespread cellular dysfunction. While individual pathological features such as mitochondrial impair-ment, lysosomal dysfunction, and altered brain activity have been studied extensively, how these changes relate to one another across disease progression remains less clear. In this work, we integrate cellular-and neural-level data to examine how Alzheimer’s disease evolves across multiple biological scales. Using literature-derived measurements of mitochondrial function, lysosomal properties, organelle interactions, and oxidative stress, together with publicly available electroencephalography (EEG) data, we analyze trends across control, mild cognitive impairment, early Alzheimer’s disease, and late Alzheimer’s disease stages. We observe a progressive decline in mitochondrial ATP production, increased oxidative stress, and disrupted calcium regulation, accompanied by impaired lysosomal acidification and increased lyso-some number. Altered interactions between mitochondria and the endoplasmic reticulum emerge as a key feature of disease progression, linking metabolic stress to cellular dysfunction. Age- and sex-dependent analyses reveal distinct trajectories of mitochondrial dysfunction, with males exhibiting stronger age-related increases in oxidative stress and altered organelle coupling. At the neural level, individuals with Alzheimer’s disease show reduced alpha-band EEG power compared to controls, reflecting disrupted brain network activity. These results provide a unified, multi-scale view of Alzheimer’s disease progression, connecting intracellular pathology to large-scale neural dysfunction. This framework highlights poten-tial early markers of disease and suggests that targeting mitochondrial health, lysosomal function, and organelle communication may be important for future therapeutic strategies. Alzheimer’s disease neurodegeneration multi-scale analysis mitochondrial dysfunction lysosomal dysfunction oxidative stress EEG electroencephalography systems biology metabolic stress cognitive decline secondary data analysis Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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While individual pathological features such as mitochondrial impair-ment, lysosomal dysfunction, and altered brain activity have been studied extensively, how these changes relate to one another across disease progression remains less clear. In this work, we integrate cellular-and neural-level data to examine how Alzheimer\u0026rsquo;s disease evolves across multiple biological scales. Using literature-derived measurements of mitochondrial function, lysosomal properties, organelle interactions, and oxidative stress, together with publicly available electroencephalography (EEG) data, we analyze trends across control, mild cognitive impairment, early Alzheimer\u0026rsquo;s disease, and late Alzheimer\u0026rsquo;s disease stages. We observe a progressive decline in mitochondrial ATP production, increased oxidative stress, and disrupted calcium regulation, accompanied by impaired lysosomal acidification and increased lyso-some number. Altered interactions between mitochondria and the endoplasmic reticulum emerge as a key feature of disease progression, linking metabolic stress to cellular dysfunction. Age- and sex-dependent analyses reveal distinct trajectories of mitochondrial dysfunction, with males exhibiting stronger age-related increases in oxidative stress and altered organelle coupling. At the neural level, individuals with Alzheimer\u0026rsquo;s disease show reduced alpha-band EEG power compared to controls, reflecting disrupted brain network activity. These results provide a unified, multi-scale view of Alzheimer\u0026rsquo;s disease progression, connecting intracellular pathology to large-scale neural dysfunction. 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