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

05/08/2026

AI Summary

Lipid dysregulation centrally drives brain energy failure in AD by disrupting membrane composition, mitochondrial bioenergetics, synaptic function and membrane-associated signalling.
Altered lipid composition and turnover compromise membrane fluidity, impair mitochondrial dynamics, obstruct energy substrate transport and heighten oxidative stress and neuroinflammation.
Advances in lipidomics reveal AD-specific lipid signatures and highlight lipid metabolism as a therapeutic target neglected in integrative amyloid and tau-centred models.

AI Summary

In AD, modifications in lipid composition, distribution, and turnover compromise membrane fluidity, disturb mitochondrial dynamics, and obstruct lipid-mediated transport of energy substrates.

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.

Basic summary

Int Rev Neurobiol. 2026;188:363-396. doi: 10.1016/bs.irn.2026.02.004. Epub 2026 Mar 14.

ABSTRACT

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.

PMID:42552046 | DOI:10.1016/bs.irn.2026.02.004

Document this CPD