Altered lipid metabolic homeostasis in the pathogenesis of Alzheimer’s disease

Abstract Alzheimer’s disease (AD) is rapidly becoming one of the major global causes of death and disability, as populations age and the management of other chronic diseases continues to improve. There is no disease-modifying treatment for AD, and large clinical trials targeting toxic amyloid β (Aβ) aggregates as a likely disease driver have all failed to date. While the dominant risk factor for developing AD is advanced age, the major determinants of genetic risk are single-nucleotide polymorphisms in genes involved in lipid transport and metabolism, endosomal trafficking, and inflammation. The central involvement of altered lipid metabolism in the pathogenesis of AD is a topic of growing interest as the research community looks beyond Aβ-based therapeutics for tractable treatment targets. This chapter will describe the current knowledge on altered lipid metabolism in AD, and how this relates to genetic risk, myelin deterioration, impaired endosomal–lysosomal flux, and the neuropathological hallmarks of the disease.