Abstract Background In Alzheimer’s disease (AD), intraneuronal tau protein accumulation into neurofibrillary tangles correlates with clinical signs and neurodegeneration 1 . Besides neurotoxic protein aggregation, dysregulation of lipid metabolism is emerging as a common disease mechanism 2 . The main regulators of lipid metabolism in the brain are astrocytes and astrocyte‐neuron communication is key to provide metabolic support to neuron 3 . While tau has been suggested to bind to lipids 4 , little is known about the potential tau‐lipid interactions in the brain, it’s role in neuron‐astrocyte crosstalk and how this relates to AD pathology. Methods We employ a multiscale approach harnessing human 2D and 3D multicellular models combined with advanced imaging techniques, spanning from single molecule insights to ultrastructural features and functional imaging. We aim to unravel the structural and functional complexity of emerging protein‐lipid landscapes in AD and to elucidate how their misregulation triggers early lipid dyshomeostasis. Results Tau propagates in brain organoids in highly dynamic intracellular droplet‐like structures rich in lipids. Strikingly, the molecular identity of tau droplets is cell‐type specific; tau interact with lipids in neurons but not in astrocytes (fig.1‐2). The dynamics of neuronal tau‐lipid accumulations are driven by microtubule interactions and show liquid‐like behavior. Furthermore, highly dynamic tau‐lipid droplets transition to stillness overtime giving rise to a heterogenous spectrum of conformational ensembles of tau (fig.3). Conclusion Tau‐lipid interactions in vivo are neuron‐specific. Lipid colocalization correlates with dramatic changes in the structural properties of tau. In neurons, tau and lipids coalesce in highly dynamic intracellular liquid‐like droplets that undergo time‐dependent transition to potential pathological states. Our results highlight intriguing functional implications of cell‐type specific tau‐lipid interactions impacting on neuron‐astrocyte communication and overall brain lipid metabolism. Targeting tau‐lipid interactions in neurons promise exciting new avenues in AD therapeutic strategies. 1. Busche, et al. Synergy between amyloid‐β and tau in Alzheimer’s disease. Nat. Neurosci . (2020). 2. Yin. Lipid metabolism and Alzheimer’s disease: clinical evidence, mechanistic link and therapeutic promise. FEBS J . (2022). 3. Yang, et al. Lipid metabolism and storage in neuroglia: role in brain development and neurodegenerative diseases. Cell Biosci . (2022). 4. Sallaberry, et al. Tau and Membranes: Interactions That Promote Folding and Condensation. Front. Cell Dev. Biol . (2021).