Organelle abnormalities in Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia, pathologically characterized by extracellular amyloid plaques and intracellular neurofibrillary tangles. While these pathological hallmarks remain central to our understanding of AD, they do not fully explain the complex cellular failures observed throughout the disease course. Neurons are highly specialized and polarized cells that depend on an integrated and dynamic network of specialized subcellular compartments named organelles to maintain structure, metabolism, and communication. Given these critical roles, organelle dysfunction is increasingly recognized as a key contributor to AD pathogenesis. Structural and functional impairments in conventional organelles, including mitochondria, endoplasmic reticulum (ER), lysosomes, Golgi apparatus, and peroxisomes, are consistently observed in AD brains and experimental models. These impairments are believed to cause energy failure, disrupted proteostasis, intracellular trafficking defects, and elevated oxidative and ER stress. In parallel, abnormalities in membraneless organelles (MLOs) further compromise RNA regulation, protein synthesis, and cellular stress responses. Additionally, perturbed communication between organelles, such as at mitochondria-associated ER membranes (MAMs), lipid droplets, and primary cilia, further exacerbates signaling imbalances and neuronal vulnerability. In this review, we not only provide a comprehensive overview of abnormalities in both membrane-bound and membraneless organelles in AD, emphasizing how their dysfunction contributes to cellular stress, impaired homeostasis, and neurodegeneration, but also discuss how disruptions in organelles intersect with amyloid, tau, and other AD-associated pathologies to intensify disease progression. A deeper understanding of organelle dysfunction in AD may provide new mechanism insights and advance the development of effective disease modifying interventions.