Brain lipid dysregulation as a driver of energy metabolism failure in Alzheimer's disease.

Alzheimer's Disease (AD) is becoming more widely recognized as a condition of brain energy metabolism, wherein lipid dysregulation plays a crucial, although unrecognized, role. In addition to functioning as structural elements of neuronal membranes, lipids such as phospholipids, sphingolipids, and cholesterol play a crucial role in regulating mitochondrial bioenergetics, synaptic activity, and membrane-associated signaling pathways. In AD, modifications in lipid composition, distribution, and turnover compromise membrane fluidity, disturb mitochondrial dynamics, and obstruct lipid-mediated transport of energy substrates. These alterations intensify oxidative stress, impair glucose and ketone utilization, and stimulate neuroinflammatory pathways that further diminish metabolic capacity. Progress in lipidomics has uncovered disease-specific lipid signatures, providing a fresh understanding of the relationship between lipid homeostasis and neuronal energy loss. Despite extensive focus on amyloid and tau, lipid-mediated bioenergetic failure remains underrepresented in integrative AD models; this chapter addresses this gap and consolidates existing information connecting lipid modifications to metabolic dysfunction in AD, emphasizing molecular pathways and prospective treatment strategies aimed at lipid metabolism to re-establish bioenergetic equilibrium.