Circulating and Brain Lipidomics, Cognition and Dementia

Decline in cognition and the onset of Alzheimer’s disease (AD) and dementia impose a devastating personal and interpersonal burden with huge societal costs. To provide insights into new mechanisms and identify novel targets to prevent AD, dementia and cognition decline, we propose a comprehensive study of plasma and brain lipidomics species and incident AD, dementia and cognition. Lipids are thought to be involved in AD however most studies have examined overall fatty acid composition or total levels of a lipid class without regards to fatty acids. Precise identification of lipid species with their fatty acid chains is needed to discover pathways and new mechanisms involved in AD, potentially resolve prior inconsistent reports, and provide critical information on novel targets to prevent AD and cognition decline. We will leverage the novel Lipidyzer technology that can quantitate 1500 lipids with identification of their separate fatty acid chains to measure lipidomics species in 1) existing plasma specimens in a large prospective cohort, the Cardiovascular Health Study (CHS), and 2) postmortem brain samples from AD patients and controls from the Johns Hopkins University Brain Resource Center (BRC). We will examine the association of plasma lipidomic species with risks of incident AD, incident total dementia, and cognition decline in 3868 participants in CHS, a prospective cohort of older European and African ancestry men and women (Aim 1). In addition, we will examine the associations of the lipidomic species identified in Aim 1 with modifiable risk factors including dietary factors, physical activity, tobacco use, and medications to guide future interventions. Complementing the study of circulating lipids, we will measure lipidomics species using the same technology in postmortem brain samples from frontal and occipital neocortices from 570 patients, including 350 with AD dementia, 40 with mild cognitive impairment (MCI), 15 asymptomatic with β-amyloid (Aβ) deposits and tau/neuritic plaques (neurodegeneration), 45 asymptomatic with Aβ deposits only, and 120 controls without cognitive impairment and without Aβ deposits (Aim 2). We will identify lipids that differentiate the AD brains from the normal brains, carefully adjusting for the cell composition of the samples; and we will identify lipids that mark the transitions from normal brain to Aβ deposits, to tau/neuritic plaques in asymptomatic patients, to MCI and to overt AD. We will also examine whether the lipidomics signatures identified in Aim 2 are associated with cognitive decline and dementia risk in the CHS cohort and vice versa. With the combination of these two powerful approaches and a novel method to precisely measure lipids with their fatty acids, the study is poised to deliver new targets for the prevention of dementia, AD and cognitive decline.