The public health burden of Alzheimer disease (AD), the most common neurodegenerative disease (Mayeux 2003
), threatens to explode in the middle of this century. The longevity of the US population and other developed countries is increasing and the prevalence of AD, comprising 60–70% of all dementia cases, doubles every decade after age 65 (Jorm and Jolley 1998
). Unless new discoveries are made in the prevention or treatment of AD, the number of cases in the US alone is estimated to increase threefold, to 13.2 million by the year 2050 (Hebert et al. 2003
). Since AD dementia is a lengthy and costly condition, this will create a large burden on the health care system in terms of both costs and services. Societal costs are estimated to be over $100 billion/year in the US alone (Fillit 2000
). These costs will continue to skyrocket as the prevalence of dementia increases. By 2040, an estimated 81 million people worldwide will have dementia (Ferri et al. 2005
Current FDA-approved AD treatments (e.g. cholinesterase inhibitors, NMDA-receptor agonists) do not provide a “cure”, but rather a transient alleviation of symptoms for some individuals. Other available therapies are few and of limited effectiveness. While the development of AD pathology in the brain is poorly understood, it is widely believed that it takes years, or even decades (Snowdon et al. 1996
), after its onset to develop the clinical symptoms of AD dementia. The current causal hypothesis, known as the amyloid hypothesis, postulates that the initial step in the disease is the misprocessing of amyloid precursor protein (APP) leading to production of neurotoxic oligo-meric amyloid species which, slowly over time, initiates a complex downstream cascade eventually leading to synaptic dysfunction, neuronal death, loss of neuronal systems, and symptoms in the prodromal phases (e.g., mild cognitive impairment or mild behavioral impairment), followed by the fully symptomatic stage of the disease, dementia (Lyketsos et al. 2008
By the time individuals develop dementia, the brain damage may be too extensive to be reversed by interventions targeted at early points of the cascade, such as the misprocessing of amyloid. The best example of this point is a randomized trial report showing that despite a greatly reduced amyloid-beta plaque load in actively immunized AD patients treated with AN1792 (Elan Pharmaceuticals), there was no evidence of improved survival or of an improvement in the time to severe dementia in the treated versus the placebo group (Holmes et al. 2008
). Since the vaccine appeared to remove the amyloid-plaques, one hypothesis is that a better outcome would have ensued if given at an earlier timepoint (i.e. Mild Cognitive Impairment (MCI) or earlier) to patients that had a high likelihood of progressing to AD dementia (Lyketsos et al. 2008
). This and other recent results from pharmaceutical trials have raised questions about the likely long-term value of anti-amyloid therapies, especially if delivered at the fully symptomatic phase of the disease (dementia). This has generated much interest in the pre-symptomatic phases of Alzheimer’s, and the development of biological markers to detect disease signatures at this stage. Additionally, interest has turned to non-amyloid aspects of the disease cascade since non-amyloid treatments may be necessary to reverse or slow disease progression.
Sphingolipid metabolism is a dynamic process that modulates the formation of a number of bioactive metabolites and second messengers critical in cellular signaling and apoptosis. In brain, the proper balance of sphingolipids is essential for normal neuronal function, as evidenced by a number of severe brain disorders that are the result of deficiencies in enzymes that control sphingolipid metabolism. For example, Niemann Pick disease (type I) involves a deficiency in sphingomyelinase (an enzyme that catalyzes the hydrolysis of sphingomyelin), and Tay-Sacks disease results from deficiency in hexosaminidase (involved in the hydrolysis of certain sphingolipids). While these severe disorders are the result of gross disruptions in sphingolipid metabolism, recent discoveries from a number of laboratories suggest that more subtle changes in sphingolipid balance may be intimately involved in neurodegenerative diseases including AD, Amyotrophic Lateral Sclerosis, Parkinson’s, and HIV-dementia (France-Lanord et al. 1997
; Cutler et al. 2002
; Haughey et al. 2004
Building on the laboratory and animal evidence demonstrating the importance of sphingolipid metabolism in AD (reviewed by Mattson in this issue), the aim of this review is to highlight the relevant translational research incorporating and expanding basic findings to humans. The role of glycosphingolipids and gangliosides in the pathogenesis of AD has recently been reviewed extensively (see Yanagisawa 2007
; Ariga et al. 2008
) and will not be discussed here. Instead we highlight sphingomyelins, ceramides, and sulfatides.