Omega-3 fatty acids, lipids, and apoE lipidation in Alzheimer's disease: a rationale for multi-nutrient dementia prevention

Abstract

In the last decade, it has become obvious that Alzheimer's disease (AD) is closely linked to changes in lipids or lipid metabolism. One of the main pathological hallmarks of AD is amyloid-β (Aβ) deposition. Aβ is derived from sequential proteolytic processing of the amyloid precursor protein (APP). Interestingly, both, the APP and all APP secretases are transmembrane proteins that cleave APP close to and in the lipid bilayer. Moreover, apoE4 has been identified as the most prevalent genetic risk factor for AD. ApoE is the main lipoprotein in the brain, which has an abundant role in the transport of lipids and brain lipid metabolism. Several lipidomic approaches revealed changes in the lipid levels of cerebrospinal fluid or in post mortem AD brains. Here, we review the impact of apoE and lipids in AD, focusing on the major brain lipid classes, sphingomyelin, plasmalogens, gangliosides, sulfatides, DHA, and EPA, as well as on lipid signaling molecules, like ceramide and sphingosine-1-phosphate. As nutritional approaches showed limited beneficial effects in clinical studies, the opportunities of combining different supplements in multi-nutritional approaches are discussed and summarized.

Circulating ceramide ratios and risk of vascular brain aging and dementia

“…Individual ceramide species are believed to have different functions according to their length of fatty acyl chain. While very long‐chain fatty acyl ceramides are important for myelin function and have been suggested to protect against dementia, long‐chain ceramide species have been linked with deleterious proinflammatory and apoptotic effects . Abnormalities in the myelin sphingolipid pathway, including the synthesis of very long‐chain ceramides, have been shown to occur in preclinical and clinical stages of AD dementia.…”

“…While very long-chain fatty acyl ceramides are important for myelin function and have been suggested to protect against dementia, 18 long-chain ceramide species have been linked with deleterious proinflammatory and apoptotic effects. 11,18,30 Abnormalities in the myelin sphingolipid pathway, including the synthesis of very long-chain ceramides, have been shown to occur in preclinical and clinical stages of AD dementia. Reduced ceramide synthase-2 activity (the enzyme responsible for catalyzing the production of very long-chain ceramides), has been found in early Braak stages I/II in the temporal cortex and in stages III/IV in the frontal cortex and hippocampus of human brain tissue.…”

“…Recently, attention has focused on the role of circulating ratios of a very‐long‐chain to long‐chain ceramides as biomarkers for major vascular events and the possibility that these ratios may be of greater diagnostic and prognostic value for cardiovascular outcomes compared to total ceramide levels or concentrations of individual ceramide species. It has been contended, but is unproven, that the adverse cognitive effects of ceramides may be related to the relative proportions of circulating very long‐chain to long‐chain fatty acyl chains rather than simply due to elevated total ceramide levels . In the present investigation, we related circulating ratios of previously measured very long‐chain to long‐chain ceramides to MRI structural brain measures (cross‐sectionally) and amyloid burden on brain‐PET (longitudinally), and to the incidence of clinically confirmed dementia and AD dementia prospectively in a large, community‐based, sample of relatively healthy adults.…”

“…It has been contended, but is unproven, that the adverse cognitive effects of ceramides may be related to the relative proportions of circulating very long-chain to long-chain fatty acyl chains rather than simply due to elevated total ceramide levels. 18,19 In the present investigation, we related circulating ratios of previously measured very long-chain to long-chain ceramides 17 to MRI structural brain measures (cross-sectionally) and amyloid burden on brain-PET (longitudinally), and to the incidence of clinically confirmed dementia and AD dementia prospectively in a large, community-based, sample of relatively healthy adults.…”

The Cognitive Ageing, Nutrition and Neurogenesis (CANN) trial: Design and progress

“…The neural processes involved in cognitive decline are complex and multifactorial. Therefore, combination treatments with dietary compounds that target multiple physiological and molecular mechanisms are likely to have the most realistic chance of affecting cognition [11,12].…”