Lipid–protein interactions are central to maintaining the structural and functional balance of biological membranes, influencing a wide array of cellular processes. These interactions, however, become pathological in neurodegenerative diseases (NDDs), such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. In these disorders, the misfolding and aggregation of proteins like amyloid-beta (Aβ), alphasynuclein (α-syn), and mutant huntingtin (mHTT) disrupt the lipid bilayer, compromising membrane integrity, fluidity, and signaling. In this review we explore the critical role of lipid–protein interactions in NDDs, emphasizing how protein misfolding leads to toxic aggregates that embed into membranes, triggering neurotoxic events. Advanced spectroscopic techniques have been instrumental in studying these molecular interactions. Photon-based methods, including Förster resonance energy transfer (FRET), circular dichroism (CD), and Raman spectroscopy, provide real-time insights into protein aggregation and lipid membrane dynamics. Neutron-based techniques, such as neutron reflectometry and small-angle neutron scattering (SANS), further enhance the resolution of lipid–protein interactions, particularly in the context of neurodegenerative aggregation.
Moreover, the review highlights the significance of lipid microdomains, particularly cholesterol-rich lipid rafts, which act as platforms for protein aggregation, influencing disease progression. Therapeutic strategies aimed at targeting these lipid–protein interfaces are also discussed, with a focus on how spectroscopic insights have driven the development of drugs that stabilize membrane integrity or prevent toxic aggregation. Finally, the integration of spectroscopy with computational models, such as molecular dynamics (MD) simulations, is proposed as a promising approach to further unravel the complex dynamics of lipid–protein interactions, providing a more complete picture of disease mechanisms.