Alzheimer's disease (AD) is a cognitive disorder with a number of complex neuropathologies, including, but not limited to, neurofibrillary tangles, neuritic plaques, neuronal shrinkage, hypomyelination, neuroinflammation and cholinergic dysfunction. The role of underlying pathological processes in the evolution of the cholinergic deficit responsible for cognitive decline has not been elucidated.Furthermore, generation of testable hypotheses for defining points of pharmacological intervention in AD are complicated by the large scale occurrence of older individuals dying with no cognitive impairment despite having a high burden of AD pathology (plaques and tangles). To further complicate these research challenges, there is no animal model that reproduces the combined hallmark neuropathologies of AD. These research limitations have stimulated the application of 'omics' technologies in AD research with the goals of defining biologic markers of disease and disease progression and uncovering potential points of pharmacological intervention for the design of AD therapeutics. In the case of sporadic AD, the dominant form of dementia, genomics has revealed that the ε4 allele of apolipoprotein E, a lipid transport/chaperone protein, is a susceptibility factor. This seminal observation points to the importance of lipid dynamics as an area of investigation in AD. In this regard, lipidomics studies have demonstrated that there are major deficits in brain structural glycerophospholipids and sphingolipids, as well as alterations in metabolites of these complex structural lipids, which act as signaling molecules. Peroxisomal dysfunction appears to be a key component of the changes in glycerophospholipid deficits. In this review, lipid alterations and their potential roles in the pathophysiology of AD are discussed.

Objective: We undertook a non-targeted lipidomics analysis of post-mortem cerebrospinal fluid (CSF), frontal cortex grey matter, and subjacent white matter to define potential biomarkers that distinguish cognitively intact subjects from those with incipient or established dementia. Our objective was to increase our understanding of the role of brain lipids in pathophysiology of aging and age-related cognitive impairment.Methods: Levels of 650 individual lipids, across 26 lipid subclasses, were measured utilising a high-resolution mass spectrometric analysis platform.Results: Monoacylglycerols (MAG), diacylglycerols (DAG), and the very-long-chain fatty acid 26:0 were elevated in the grey matter of the mild cognitive impairment (MCI) and old dementia (OD) cohorts. Ethanolamine plasmalogens (PlsEtn) were decreased in the grey matter of the young dementia (YD) and OD cohorts while and phosphatidylethanolamines (PtdEth) were lower in the MCI, YD and OD cohorts. In the white matter, decrements in sulphatide levels were detected in the YD group, DAG levels were elevated in the MCI group, and MAG levels were increased in the YD and OD groups.Conclusion: The parallel changes in grey matter MAGs and DAGs in the MCI and OD groups suggest that these two cohorts may have a similar underlying pathophysiology; consistent with this, MCI subjects were more similar in age to OD than to YD subjects. While PlsEtn and phosphatidylethanolamine were decreased in the YD and OD groups they were unaltered in the MCI group indicating that alterations in plasmalogen synthesis are unlikely to represent an initiating event in the transition from MCI to dementia.

Previous studies have demonstrated augmented levels of diacylglycerols (DAG) in the frontal cortex and plasma of Alzheimer’s disease (AD) patients. We extended these findings from non-targeted lipidomics studies to design a lipidomics platform to int

Research from our laboratory, and that of other investigators, has demonstrated augmented levels of diacylglycerols (DAG) in the frontal cortex and plasma of subjects with Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI). We have extended these observations to investigate the frontal cortex of subjects with Parkinson’s disease (PD) and Lewy Body Disease (LBD), with and without coexisting pathologic features of AD. Utilizing a high-resolution mass spectrometry analytical platform, we clearly demonstrate that DAG levels are significantly increased in the frontal cortex of subjects with PD, LBD with intermediate neocortical AD neuropathology, and in LBD with established neocortical AD neuropathology. In the case of the PD cohort, increases in cortical DAG levels were detected in cases with no neocortical pathology but were greater in subjects with neocortical pathology. These data suggest that DAG changes occur early in the disease processes and are amplified as cortical dysfunction becomes more established. These findings suggest that altered DAG synthesis/metabolism is a common feature of neurodegenerative diseases, characterized by proteinopathy, that ultimately result in cognitive deficits. With regard to the mechanism responsible for these biochemical alterations, selective decrements in cortical levels of phosphatidylcholines in LBD and PD suggest that augmented degradation and/or decreased synthesis of these structural glycerophospholipids may contribute to increases in the pool size of free DAGs. The observed augmentation of DAG levels may be phospholipase-driven since neuroinflammation is a consistent feature of all disease cohorts. If this conclusion can be validated it would support utilizing DAG levels as a biomarker of the early disease process and the investigation of early intervention with anti-inflammatory agents.

Diverse research approaches support the concept that a clinical diagnosis of Late-Onset Alzheimer's Disease (LOAD) does not distinguish between subpopulations with differing neuropathologies, including dementia patients with amyloid deposition and dementia patients without amyloid deposition but with cortical thinning. Mild cognitive impairment (MCI) is generally considered the prodromal phase for LOAD, however, while a number of studies have attempted to define plasma biomarkers for the conversion of MCI to LOAD, these studies have not taken into account the heterogeneity of patient cohorts within a clinical phenotype. Studies of MCI and LOAD in several laboratories have demonstrated decrements in ethanolamine plasmalogen levels in plasma and brain and increased levels of diacylglycerols in plasma and brain. To further extend these studies and to address the issue of heterogeneity in MCI and LOAD patient groups we investigated the levels of diacylglycerols and ethanolamine plasmalogens in larger cohorts of patients utilizing, high-resolution (0.2 to 2 ppm mass error) mass spectrometry. For the first time, our lipidomics data clearly stratify both MCI and LOAD subjects into 3 different patient cohorts within each clinical diagnosis. These include i) patients with lower circulating ethanolamine plasmalogen levels; ii) patients with augmented plasma diacylglycerol levels; and iii) patients with neither of these lipid alterations. These represent the first serum biochemical data to stratify MCI and LOAD patients, advancing efforts to biochemically define patient heterogeneity in cognitive disorders. Lipidomics offers a new approach for identifying biomarkers and biological targets in cognitive disorders.