Abbreviations AD: Alzheimer’s disease; AHRQ: Agency for Healthcare Research and Quality; ApoE: apolipoprotein E; BMI: body mass index; CAIDE: Cardiovascular selleck chem inhibitor Risk Factors: Aging and Incidence of Dementia; EDPI: European Dementia Prevention Initiative; FINGER: Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability; HRT: hormone replacement therapy; MAPT: Multidomain Alzheimer Preventive Trial; NIH: National Institutes of Health; NSAID: non-steroidal anti-inflammatory drug; PreDIVA: Prevention of Dementia by Intensive Vascular Care; PUFA: polyunsaturated fatty acid; RCT: randomized controlled trial; VaD: vascular dementia. Competing interests The authors declare that they have no competing interests.

Acknowledgements This study was supported by Karolinska Institutet (Sweden), the Swedish Research Council for Medical Research, the Academy of Finland, the La Carita Foundation of Finland, the Alzheimer’s Association (USA), and the Swedish Foundations of Ragnhild och Einar Lundstr?ms-Minne-Lindh??s, Stohnes-Stiftelse, and Gamla-Tj?narinnor. The funding sources did not play any role in the design or conduct of the study or in the collection, management, analysis, or interpretation of data or in the preparation, review, or approval of the manuscript. Editor Kimberly Kane revised the language in the manuscript.
Early reports [4] of decreased phospholipid content in AD white matter were soon followed by reports of decreased levels of the phospholipid precursor ethanolamine in AD brain [5,6], cerebrospinal fluid (CSF) [7] and plasma [7] and increased brain levels of the degradation product glycerophosphoethanolamine [6].

The first descriptions of decrements in ethanolamine plasmalogens (PlsEtns), relative to phosphatidylethanolamines in AD brain, were published in 1995 [8]. Plasmalogens are a subclass of glycerophospholipids that possess a vinyl ether fatty alcohol substituent at sn-1 of the glycerol backbone (Figure ?(Figure1).1). The ether linkage at sn-1 is achieved by addition of a fatty alcohol to the glycerol backbone and is conducted solely in peroxisomes (Figure ?(Figure2).2). Subsequent desaturation to form the vinyl ether linkage takes place in the endoplasmic reticulum (Figure ?(Figure2).2).

Decrements in PlsEtns were shown to be disease specific since they were not measured in Huntington’s Anacetrapib caudate nucleus or Parkinson’s substantia nigra and demonstrated anatomic specificity, being marked in the mid- temporal cortex but not the cerebellum [8,9]. These deficiencies in a major structural phospholipid pool were rapidly validated by other research groups and quantification of individual PlsEtns by tandem mass spectrometry demonstrated that white matter PlsEtns (that is, oleic or linoleic acid at sn-2; Figure ?Figure1)1) were decreased by up to 40% early in the disease Imatinib Mesylate purchase process [9,10].