Involvement of Lipids in Alzheimer's Disease Pathology and Potential Therapies.
Authors:
Journal: Frontiers in physiology
Publication Type: Journal Article
Date: 2020
DOI: PMC7296164
ID: 32581851
Abstract
Lipids constitute the bulk of the dry mass of the brain and have been associated with healthy function as well as the most common pathological conditions of the brain. Demographic factors, genetics, and lifestyles are the major factors that influence lipid metabolism and are also the key components of lipid disruption in Alzheimer's disease (AD). Additionally, the most common genetic risk factor of AD, APOE ϵ4 genotype, is involved in lipid transport and metabolism. We propose that lipids are at the center of Alzheimer's disease pathology based on their involvement in the blood-brain barrier function, amyloid precursor protein (APP) processing, myelination, membrane remodeling, receptor signaling, inflammation, oxidation, and energy balance. Under healthy conditions, lipid homeostasis bestows a balanced cellular environment that enables the proper functioning of brain cells. However, under pathological conditions, dyshomeostasis of brain lipid composition can result in disturbed BBB, abnormal processing of APP, dysfunction in endocytosis/exocytosis/autophagocytosis, altered myelination, disturbed signaling, unbalanced energy metabolism, and enhanced inflammation. These lipid disturbances may contribute to abnormalities in brain function that are the hallmark of AD. The wide variance of lipid disturbances associated with brain function suggest that AD pathology may present as a complex interaction between several metabolic pathways that are augmented by risk factors such as age, genetics, and lifestyles. Herewith, we examine factors that influence brain lipid composition, review the association of lipids with all known facets of AD pathology, and offer pointers for potential therapies that target lipid pathways.
Reference List
- Abbott N. J. (2000). Inflammatory mediators and modulation of blood-brain barrier permeability. Cell. Mol. Neurobiol. 20 131–147.|||Abbott N. J., Patabendige A. A., Dolman D. E., Yusof S. R., Begley D. J. (2010). Structure and function of the blood-brain barrier. Neurobiol. Dis. 37 13–25.|||Agrawal M., Ajazuddin, Tripathi D. K., Saraf S., Saraf S., Antimisiaris S. G., et al. (2017). Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer’s disease. J. Control. Release 260 61–77. 10.1016/j.jconrel.2017.05.019|||Alaupovic P. (1996). Significance of apolipoproteins for structure, function, and classification of plasma lipoproteins. Methods Enzymol. 263 32–60. 10.1016/s0076-6879(96)63004-3|||Alexander G. E. (2017). An Emerging role for imaging white matter in the preclinical risk for Alzheimer disease: linking beta-amyloid to myelin. JAMA Neurol. 74 17–19.|||Almeida R. G., Lyons D. A. (2014). On the resemblance of synapse formation and CNS myelination. Neuroscience 276 98–108. 10.1016/j.neuroscience.2013.08.062|||Almeida R. G., Lyons D. A. (2017). On myelinated axon plasticity and neuronal circuit formation and function. J. Neurosci. 37 10023–10034. 10.1523/jneurosci.3185-16.2017|||Amadoro G., Corsetti V., Florenzano F., Atlante A., Ciotti M. T., Mongiardi M. P., et al. (2014). AD-linked, toxic NH2 human tau affects the quality control of mitochondria in neurons. Neurobiol. Dis. 62 489–507. 10.1016/j.nbd.2013.10.018|||Anceline M.-L., Ripoche E., Dupuy A.-M., Samieri C., Rouaud O., Berr C., et al. (2014). Gender-specific associations between lipids and cognitive decline in the elderly. Eur. Neuropsychopharmacol. 24 1056–1066. 10.1016/j.euroneuro.2014.02.003|||Anderson G. (2018). Linking the biological underpinnings of depression: role of mitochondria interactions with melatonin, inflammation, sirtuins, tryptophan catabolites, DNA repair and oxidative and nitrosative stress, with consequences for classification and cognition. Prog. Neuropsychopharmacol. Biol. Psychiatry 80 255–266. 10.1016/j.pnpbp.2017.04.022|||Ando S., Tanaka Y., Toyoda Y., Kon K. (2003). Turnover of myelin lipids in aging brain. Neurochem. Res. 28 5–13.|||Andreone B. J., Chow B. W., Tata A., Lacoste B., Ben-Zvi A., Bullock K., et al. (2017). Blood-brain barrier permeability is regulated by lipid transport-dependent suppression of caveolae-mediated transcytosis. Neuron 94 581.e5–594.e5. 10.1016/j.neuron.2017.03.043|||Andrew R. J., Kellett K. A., Thinakaran G., Hooper N. M. (2016). A greek tragedy: the growing complexity of alzheimer amyloid precursor protein proteolysis. J. Biol. Chem. 291 19235–19244. 10.1074/jbc.r116.746032|||Aoki C., Fujisawa S., Mahadomrongkul V., Shah P. J., Nader K., Erisir A. (2003). NMDA receptor blockade in intact adult cortex increases trafficking of NR2A subunits into spines, postsynaptic densities, and axon terminals. Brain Res. 963 139–149. 10.1016/s0006-8993(02)03962-8|||Apak R., Ozyurek M., Guclu K., Capanoglu E. (2016). Antioxidant activity/capacity measurement. 3. reactive oxygen and nitrogen species (ROS/RNS) scavenging assays, oxidative stress biomarkers, and chromatographic/chemometric assays. J. Agric. Food Chem. 64 1046–1070. 10.1021/acs.jafc.5b04744|||Arnoldussen I. A., Zerbi V., Wiesmann M., Noordman R. H., Bolijn S., Mutsaers M. P., et al. (2016). Early intake of long-chain polyunsaturated fatty acids preserves brain structure and function in diet-induced obesity. J. Nutr. Biochem. 30 177–188. 10.1016/j.jnutbio.2015.12.011|||Asada T., Kariya T., Yamagata Z., Kinoshita T., Asaka A. (1996). ApoE epsilon 4 allele and cognitive decline in patients with Alzheimer’s disease. Neurology 47:603. 10.1212/wnl.47.2.603|||Audagnotto M., Kengo Lorkowski A., Dal Peraro M. (2018). Recruitment of the amyloid precursor protein by gamma-secretase at the synaptic plasma membrane. Biochem. Biophys. Res. Commun. 498 334–341. 10.1016/j.bbrc.2017.10.164|||Ayloo S., Gu C. (2019). Transcytosis at the blood-brain barrier. Curr. Opin. Neurobiol. 57 32–38. 10.1016/0006-8993(87)90236-8|||Bacchetti T., Vignini A., Giulietti A., Nanetti L., Provinciali L., Luzzi S., et al. (2015). Higher levels of oxidized low density lipoproteins in Alzheimer’s disease patients: roles for platelet activating factor acetyl hydrolase and paraoxonase-1. J. Alzheimers Dis. 46 179–186. 10.3233/JAD-143096|||Balazs Z., Panzenboeck U., Hammer A., Sovic A., Quehenberger O., Malle E., et al. (2004). Uptake and transport of high-density lipoprotein (HDL) and HDL-associated alpha-tocopherol by an in vitro blood-brain barrier model. J. Neurochem. 89 939–950. 10.1111/j.1471-4159.2004.02373.x|||Baldo G., Giugliani R., Matte U. (2014). Lysosomal enzymes may cross the blood-brain-barrier by pinocytosis: implications for enzyme replacement therapy. Med. Hypotheses 82 478–480. 10.1016/j.mehy.2014.01.029|||Banks W. A. (1999). Physiology and pathology of the blood-brain barrier: implications for microbial pathogenesis, drug delivery and neurodegenerative disorders. J. Neurovirol. 5 538–555. 10.3109/13550289909021284|||Banks W. A., Farr S., Salameh T. S., Niehoff M. L., Rhea E. M., Morley J. E., et al. (2018). Triglycerides cross the blood–brain barrier and induce central leptin and insulin receptor resistance. Int. J. Obes. 42 391–397. 10.1038/ijo.2017.231|||Barbagallo C. M., Levine G. A., Blanche P. J., Ishida B. Y., Krauss R. M. (1998). Influence of apoE content on receptor binding of large, bouyant LDL in subjects with different LDL subclass phenotypes. Arterioscler. Thromb. Vasc. Biol. 18 466–472. 10.1161/01.atv.18.3.466|||Bartzokis G. (2011). Alzheimer’s disease as homeostatic responses to age-related myelin breakdown. Neurobiol. Aging 32 1341–1371. 10.1016/j.neurobiolaging.2009.08.007|||Bartzokis G., Lu P. H., Geschwind D. H., Edwards N., Mintz J., Cummings J. L. (2006). Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia. Arch. Gen. Psychiatry 63 63–72.|||Bassett C. N., Montine T. J. (2003). Lipoproteins and lipid peroxidation in Alzheimer’s disease. J. Nutr. Health Aging 7 24–29.|||Bassett C. N., Neely M. D., Sidell K. R., Markesbery W. R., Swift L. L., Montine T. J. (1999). Cerebrospinal fluid lipoproteins are more vulnerable to oxidation in Alzheimer’s disease and are neurotoxic when oxidized ex vivo. Lipids 34 1273–1280. 10.1007/s11745-999-0478-1|||Baum L., Chen L., Masliah E., Chan Y. S., Ng H. K., Pang C. P. (1999). Lipoprotein lipase mutations and Alzheimer’s disease. Am. J. Med. Genet. 88 136–139. 10.1002/(sici)1096-8628(19990416)88:2<136::aid-ajmg8>3.0.co;2-d|||Bazan N. G. (2005). Synaptic signaling by lipids in the life and death of neurons. Mol. Neurobiol. 31 219–230. 10.1385/mn:31:1-3:219|||Bedse G., Romano A., Lavecchia A. M., Cassano T., Gaetani S. (2015). The role of endocannabinoid signaling in the molecular mechanisms of neurodegeneration in Alzheimer’s disease. J. Alzheimers Dis. 43 1115–1136. 10.3233/jad-141635|||Belayev L., Hong S. H., Menghani H., Marcell S. J., Obenaus A., Freitas R. S., et al. (2018). Docosanoids promote neurogenesis and angiogenesis, blood-brain barrier integrity, penumbra protection, and neurobehavioral recovery after experimental ischemic stroke. Mol. Neurobiol. 55 7090–7106. 10.1007/s12035-018-1136-3|||Belkouch M., Hachem M., Elgot A., Lo Van A., Picq M., Guichardant M., et al. (2016). The pleiotropic effects of Omega-3 docosahexaenoic acid on the hallmarks of Alzheimer’s disease. J. Nutr. Biochem. 38 1–11. 10.1016/j.jnutbio.2016.03.002|||Bellet M. M., Masri S., Astarita G., Sassone-Corsi P., Della Fazia M. A., Servillo G. (2016). Histone deacetylase SIRT1 controls proliferation, circadian rhythm, and lipid metabolism during liver regeneration in mice. J. Biol. Chem. 291 23318–23329. 10.1074/jbc.m116.737114|||Benton D. (2001). The impact of the supply of glucose to the brain on mood and memory. Nutr. Rev. 59 S20–S21.|||Benton D., Parker P. Y., Donohoe R. T. (1996). The supply of glucose to the brain and cognitive functioning. J. Biosoc. Sci. 28 463–479. 10.1017/s0021932000022537|||Berg C. N., Sinha N., Gluck M. A. (2019). The effects of APOE and ABCA7 on cognitive function and Alzheimer’s disease risk in african americans: a focused mini review. Front. Hum. Neurosci. 13:387. 10.3389/fnhum.2019.00387|||Bernath M. M., Bhattacharyya S., Nho K., Barupal D. K., Fiehn O., Baillie R., et al. (2019). Serum triglycerides in Alzheimer’s disease: relation to neuroimaging and CSF biomarkers. bioRxiv [Preprint]. 10.1101/441394|||Betsholtz C. (2014). Physiology: double function at the blood-brain barrier. Nature 509 432–433. 10.1038/nature13339|||Bhattacharyya R., Barren C., Kovacs D. M. (2013). Palmitoylation of amyloid precursor protein regulates amyloidogenic processing in lipid rafts. J. Neurosci. 33 11169–11183. 10.1523/jneurosci.4704-12.2013|||Biondi E. (2007). Statin-like drugs for the treatment of brain cholesterol loss in Alzheimer’s disease. Curr. Drug. Saf. 2 173–176. 10.2174/157488607781668927|||Birben E., Sahiner U. M., Sackesen C., Erzurum S., Kalayci O. (2012). Oxidative stress and antioxidant defense. World Allergy Organ. J. 5 9–19. 10.1097/WOX.0b013e3182439613|||Biringer R. G. (2019). The role of eicosanoids in Alzheimer’s disease. Int. J. Environ. Res. Public Health 16:2560. 10.3390/ijerph16142560|||Black J. B., Premont R. T., Daaka Y. (2016). Feedback regulation of G protein-coupled receptor signaling by GRKs and arrestins. Semin. Cell Dev. Biol. 50 95–104. 10.1016/j.semcdb.2015.12.015|||Blain J. F., Poirier J. (2004). Cholesterol homeostasis and the pathophysiology of Alzheimer’s disease. Expert. Rev. Neurother. 4 823–829. 10.1586/14737175.4.5.823|||Blain J. F., Aumont N., Theroux L., Dea D., Poirier J. (2006). A polymorphism in lipoprotein lipase affects the severity of Alzheimer’s disease pathophysiology. Eur. J. Neurosci. 24 1245–1251. 10.1111/j.1460-9568.2006.05007.x|||Block J. (2019). Alzheimer’s disease might depend on enabling pathogens which do not necessarily cross the blood-brain barrier. Med. Hypotheses. 125 129–136. 10.1016/j.mehy.2019.02.044|||Bolanos-Garcia V. M., Miguel R. N. (2003). On the structure and function of apolipoproteins: more than a family of lipid-binding proteins. Prog. Biophys. Mol. Biol. 83 47–68. 10.1016/s0079-6107(03)00028-2|||Bos D. J., van Montfort S. J., Oranje B., Durston S., Smeets P. A. (2016). Effects of Omega-3 polyunsaturated fatty acids on human brain morphology and function: what is the evidence? Eur. Neuropsychopharmacol. 26 546–561. 10.1016/j.euroneuro.2015.12.031|||Bourre J. M. (1991). [Vitamin E: protection of membrane polyunsaturated fatty acids against radical peroxidation in the course of cerebral aging, particularly in cerebral capillaries and microvessels]. Bull. Acad. Natl. Med. 175 1305–1317.|||Bradbury M. W. (1984). The structure and function of the blood-brain barrier. Fed. Proc. 43 186–190.|||Bradley W. A., Gianturco S. H. (1986). ApoE is necessary and sufficient for the binding of large triglyceride-rich lipoproteins to the LDL receptor; apoB is unnecessary. J. Lipid. Res. 27 40–48.|||Braun V., Hantke K. (2019). Lipoproteins: structure, function, biosynthesis. Subcell. Biochem. 92 39–77. 10.1007/978-3-030-18768-2_3|||Brewer G. J., Herrera R. A., Philipp S., Sosna J., Reyes-Ruiz J. M., Glabe C. G. (2020). Age-related intraneuronal aggregation of amyloid-beta in endosomes, mitochondria, autophagosomes, and lysosomes. J. Alzheimers Dis. 73 229–246. 10.3233/jad-190835|||Brown J., III, Theisler C., Silberman S., Magnuson D., Gottardi-Littell N., Lee J. M., et al. (2004). Differential expression of cholesterol hydroxylases in Alzheimer’s disease. J. Biol. Chem. 279 34674–34681. 10.1074/jbc.m402324200|||Brown R. C., Davis T. P. (2002). Calcium modulation of adherens and tight junction function: a potential mechanism for blood-brain barrier disruption after stroke. Stroke 33 1706–1711. 10.1161/01.str.0000016405.06729.83|||Burgess B. L., McIsaac S., Naus K. E., Chan J. Y., Tansley G. H., Yang J., et al. (2006). Elevated plasma triglyceride levels precede amyloid deposition in Alzheimer’s disease mouse models with abundant A beta in plasma. Neurobiol. Dis. 24 114–127. 10.1016/j.nbd.2006.06.007|||Burgisser P., Matthieu J. M., Jeserich G., Waehneldt T. V. (1986). Myelin lipids: a phylogenetic study. Neurochem. Res. 11 1261–1272. 10.1007/bf00966121|||Butler R. N. (1994). ApoE: new risk factor for Alzheimer’s. Geriatrics 49 10–11.|||Butterfield D. A., Castegna A., Lauderback C. M., Drake J. (2002). Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal death. Neurobiol. Aging 23 655–664. 10.1016/s0197-4580(01)00340-2|||Button E. B., Gilmour M., Cheema H. K., Martin E. M., Agbay A., Robert J., et al. (2019). Vasoprotective functions of high-density lipoproteins relevant to Alzheimer’s disease are partially conserved in apolipoprotein B-depleted Plasma. Int. J. Mol. Sci. 20:462. 10.3390/ijms20030462|||Campbell S. D., Regina K. J., Kharasch E. D. (2014). Significance of lipid composition in a blood-brain barrier-mimetic PAMPA assay. J. Biomol. Screen 19 437–444. 10.1177/1087057113497981|||Cankurtaran M., Yesil Y., Kuyumcu M. E., Ozturk Z. A., Yavuz B. B., Halil M., et al. (2013). Altered levels of homocysteine and serum natural antioxidants links oxidative damage to Alzheimer’s disease. J. Alzheimers Dis. 33 1051–1058. 10.3233/jad-2012-121630|||Cantor R. S. (2018). Path to the desensitized state of ligand-gated ion channels: why are inhibitory and excitatory receptors different? J. Phys. Chem. B 122 5368–5374. 10.1021/acs.jpcb.7b10961|||Caporaso G. L., Takei K., Gandy S. E., Matteoli M., Mundigl O., Greengard P., et al. (1994). Morphologic and biochemical analysis of the intracellular trafficking of the Alzheimer beta/A4 amyloid precursor protein. J. Neurosci. 14 3122–3138. 10.1523/jneurosci.14-05-03122.1994|||Cardoso S. M., Santos S., Swerdlow R. H., Oliveira C. R. (2001). Functional mitochondria are required for amyloid beta-mediated neurotoxicity. FASEB J. 15 1439–1441. 10.1096/fj.00-0561fje|||Carvey P. M., Hendey B., Monahan A. J. (2009). The blood-brain barrier in neurodegenerative disease: a rhetorical perspective. J. Neurochem. 111 291–314. 10.1111/j.1471-4159.2009.06319.x|||Castro Dias M., Coisne C., Baden P., Enzmann G., Garrett L., Becker L., et al. (2019). Claudin-12 is not required for blood-brain barrier tight junction function. Fluids Barriers CNS 16:30. 10.1186/s12987-019-0150-9|||Chandrasekharan J. A., Sharma-Walia N. (2015). Lipoxins: nature’s way to resolve inflammation. J. Inflamm. Res. 8 181–192.|||Chang C. Y., Ke D. S., Chen J. Y. (2009). Essential fatty acids and human brain. Acta Neurol. Taiwan. 18 231–241.|||Chang Y. T., Hsu S. W., Huang S. H., Huang C. W., Chang W. N., Lien C. Y., et al. (2019). ABCA7 polymorphisms correlate with memory impairment and default mode network in patients with APOEepsilon4-associated Alzheimer’s disease. Alzheimers Res. Ther. 11:103. 10.1186/s13195-019-0563-3|||Chappus-McCendie H., Chevalier L., Roberge C., Plourde M. (2019). Omega-3 PUFA metabolism and brain modifications during aging. Prog. Neuropsychopharmacol. Biol. Psychiatry 94:109662. 10.1016/j.pnpbp.2019.109662|||Cheignon C., Jones M., Atrian-Blasco E., Kieffer I., Faller P., Collin F., et al. (2017). Identification of key structural features of the elusive Cu-Abeta complex that generates ROS in Alzheimer’s disease. Chem. Sci. 8 5107–5118. 10.1039/c7sc00809k|||Cheignon C., Tomas M., Bonnefont-Rousselot D., Faller P., Hureau C., Collin F. (2018). Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox. Biol. 14 450–464.|||Chen J., Wei Y., Chen X., Jiao J., Zhang Y. (2017). Polyunsaturated fatty acids ameliorate aging via redox-telomere-antioncogene axis. Oncotarget 8 7301–7314. 10.18632/oncotarget.14236|||Chen R., Zhang J., Wu Y., Wang D., Feng G., Tang Y. P., et al. (2012). Monoacylglycerol lipase is a therapeutic target for Alzheimer’s disease. Cell. Rep. 2 1329–1339. 10.1016/j.celrep.2012.09.030|||Chen X., Hui L., Geiger J. D. (2014). Role of LDL cholesterol and endolysosomes in amyloidogenesis and Alzheimer’s disease. J. Neurol. Neurophysiol. 5:236. 10.4172/2155-9562.1000236|||Cheng F., Cappai R., Lidfeldt J., Belting M., Fransson L. A., Mani K. (2014). Amyloid precursor protein (APP)/APP-like protein 2 (APLP2) expression is required to initiate endosome-nucleus-autophagosome trafficking of glypican-1-derived heparan sulfate. J. Biol. Chem. 289 20871–20878. 10.1074/jbc.m114.552810|||Cherubini A., Andres-Lacueva C., Martin A., Lauretani F., Iorio A. D., Bartali B., et al. (2007). Low plasma N-3 fatty acids and dementia in older persons: the InCHIANTI study. J. Gerontol. A Biol. Sci. Med. Sci. 62 1120–1126. 10.1093/gerona/62.10.1120|||Childs C. E., Romeu-Nadal M., Burdge G. C., Calder P. C. (2008). Gender differences in the n-3 fatty acid content of tissues. Proc. Nutr. Soc. 67 19–27. 10.1017/s0029665108005983|||Chiu C. C., Su K. P., Cheng T. C., Liu H. C., Chang C. J., Dewey M. E., et al. (2008). The effects of Omega-3 fatty acids monotherapy in Alzheimer’s disease and mild cognitive impairment: a preliminary randomized double-blind placebo-controlled study. Prog. Neuropsychopharmacol. Biol. Psychiatry 32 1538–1544. 10.1016/j.pnpbp.2008.05.015|||Chiurchiu V., Leuti A., Maccarrone M. (2018). Bioactive lipids and chronic inflammation: managing the fire within. Front. Immunol. 9:38. 10.3389/fimmu.2018.00038|||Chow V. W., Mattson M. P., Wong P. C., Gleichmann M. (2010). An overview of APP processing enzymes and products. Neuromol. Med. 12 1–12. 10.1007/s12017-009-8104-z|||Chrast R., Saher G., Nave K. A., Verheijen M. H. (2011). Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models. J. Lipid Res. 52 419–434. 10.1194/jlr.r009761|||Chu L. W., Li Y., Li Z., Tang A. Y., Cheung B. M., Leung R. Y., et al. (2007). A novel intronic polymorphism of ABCA1 gene reveals risk for sporadic Alzheimer’s disease in Chinese. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B 1007–1013. 10.1002/ajmg.b.30525|||Chun Y. S., Park Y., Oh H. G., Kim T. W., Yang H. O., Park M. K., et al. (2015). O-GlcNAcylation promotes non-amyloidogenic processing of amyloid-beta protein precursor via inhibition of endocytosis from the plasma membrane. J. Alzheimers. Dis. 44 261–275. 10.3233/jad-140096|||Chung S. J., Kim M. J., Kim Y. J., Kim J., You S., Jang E. H., et al. (2014). CR1, ABCA7, and APOE genes affect the features of cognitive impairment in Alzheimer’s disease. J. Neurol. Sci. 339 91–96. 10.1016/j.jns.2014.01.029|||Chung W. S., Verghese P. B., Chakraborty C., Joung J., Hyman B. T., Ulrich J. D., et al. (2016). Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc. Natl. Acad. Sci. U.S.A. 113 10186–10191. 10.1073/pnas.1609896113|||Clavey V., Lestavel-Delattre S., Copin C., Bard J. M., Fruchart J. C. (1995). Modulation of lipoprotein B binding to the LDL receptor by exogenous lipids and apolipoproteins CI, CII, CIII, and E. Arterioscler. Thromb. Vasc. Biol. 15 963–971. 10.1161/01.atv.15.7.963|||Csernansky J. G., Dong H., Fagan A. M., Wang L., Xiong C., Holtzman D. M., et al. (2006). Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia. Am. J. Psychiatry 163 2164–2169. 10.1176/ajp.2006.163.12.2164|||Cunnane S. C., Schneider J. A., Tangney C., Tremblay-Mercier J., Fortier M., Bennett D. A., et al. (2012). Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer’s disease. J. Alzheimers Dis. 29 691–697. 10.3233/jad-2012-110629|||Cutuli D. (2017). Functional and structural benefits induced by Omega-3 polyunsaturated fatty acids during aging. Curr. Neuropharmacol. 15 534–542. 10.2174/1570159x14666160614091311|||Daiello L. A., Gongvatana A., Dunsiger S., Cohen R. A., Ott B. R. (2015). Association of fish oil supplement use with preservation of brain volume and cognitive function. Alzheimers Dement. 11 226–235. 10.1016/j.jalz.2014.02.005|||Daneman R., Prat A. (2015). The blood-brain barrier. Cold Spring Harb. Perspect. Biol. 7:a020412.|||Dash P. K., Moore A. N. (1993). Inhibitors of endocytosis, endosome fusion, and lysosomal processing inhibit the intracellular proteolysis of the amyloid precursor protein. Neurosci. Lett. 164 183–186. 10.1016/0304-3940(93)90887-q|||Davison A. N. (1972). Metabolism of myelin lipids in the developing brain. Biochem. J. 128 68.|||de Chaves E. P., Narayanaswami V. (2008). Apolipoprotein E and cholesterol in aging and disease in the brain. Future Lipidol. 3 505–530. 10.2217/17460875.3.5.505|||de Vries H. E., Kooij G., Frenkel D., Georgopoulos S., Monsonego A., Janigro D. (2012). Inflammatory events at blood-brain barrier in neuroinflammatory and neurodegenerative disorders: implications for clinical disease. Epilepsia 53(Suppl. 6), 45–52. 10.1111/j.1528-1167.2012.03702.x|||de Wilde M. C., Vellas B., Girault E., Yavuz A. C., Sijben J. W. (2017). Lower brain and blood nutrient status in Alzheimer’s disease: results from meta-analyses. Alzheimers Dement. 3 416–431. 10.1016/j.trci.2017.06.002|||Decsi T., Kennedy K. (2011). Sex-specific differences in essential fatty acid metabolism. Am. J. Clin. Nutr. 94(6 Suppl), 1914S–1919S. 10.3945/ajcn.110.000893|||Dehouck B., Fenart L., Dehouck M. P., Pierce A., Torpier G., Cecchelli R. (1997). A new function for the LDL receptor: transcytosis of LDL across the blood-brain barrier. J. Cell Biol. 138 877–889. 10.1083/jcb.138.4.877|||Demeester N., Castro G., Desrumaux C., De Geitere C., Fruchart J. C., Santens P., et al. (2000). Characterization and functional studies of lipoproteins, lipid transfer proteins, and lecithin:cholesterol acyltransferase in CSF of normal individuals and patients with Alzheimer’s disease. J. Lipid. Res. 41 963–974.|||Denis I., Potier B., Heberden C., Vancassel S. (2015). Omega-3 polyunsaturated fatty acids and brain aging. Curr. Opin. Clin. Nutr. Metab. Care 18 139–146.|||Derby C. A., Crawford S., Pasternak R. C., Sowers M., Sternfeld B., Matthews K. A. (2009). Lipid changes during the menopause transition in relation to age and weight. Am. J. Epidemiol. 169 1352–1361. 10.1093/aje/kwp043|||Desai M. K., Mastrangelo M. A., Ryan D. A., Sudol K. L., Narrow W. C., Bowers W. J. (2010). Early oligodendrocyte/myelin pathology in Alzheimer’s disease mice constitutes a novel therapeutic target. Am. J. Pathol. 177 1422–1435. 10.2353/ajpath.2010.100087|||Devine M. J., Kittler J. T. (2018). Mitochondria at the neuronal presynapse in health and disease. Nat. Rev. Neurosci. 19 63–80. 10.1038/nrn.2017.170|||Dienel G. A., Cruz N. F., Adachi K., Sokoloff L., Holden J. E. (1997). Determination of local brain glucose level with [14C]methylglucose: effects of glucose supply and demand. Am. J. Physiol. 273 E839–E849.|||Dimas P., Montani L., Pereira J. A., Moreno D., Trotzmuller M., Gerber J., et al. (2019). CNS myelination and remyelination depend on fatty acid synthesis by oligodendrocytes. eLife 8:e44702. 10.7554/eLife.44702|||Ding R. B., Bao J., Deng C. X. (2017). Emerging roles of SIRT1 in fatty liver diseases. Int. J. Biol. Sci. 13 852–867. 10.7150/ijbs.19370|||do Couto F. S., de Mendonca A., Garcia C., Rocha L., Lechner M. C. (1998). Age of onset in patients with Alzheimer’s disease with different apoE genotypes. J. Neurol. Neurosurg. Psychiatry 64:817. 10.1136/jnnp.64.6.817|||Dodelet-Devillers A., Cayrol R., van Horssen J., Haqqani A. S., de Vries H. E., Engelhardt B., et al. (2009). Functions of lipid raft membrane microdomains at the blood-brain barrier. J. Mol. Med. 87 765–774. 10.1007/s00109-009-0488-6|||Doens D., Valiente P. A., Mfuh A. M., X T Vo A., Tristan A., Carreno L., et al. (2017). Identification of inhibitors of CD36-amyloid beta binding as potential agents for Alzheimer’s disease. ACS Chem. Neurosci. 8 1232–1241. 10.1021/acschemneuro.6b00386|||Duchen M. R. (2012). Mitochondria, calcium-dependent neuronal death and neurodegenerative disease. Pflugers. Arch. 464 111–121. 10.1007/s00424-012-1112-0|||Duka T., Tasker R., McGowan J. F. (2000). The effects of 3-week estrogen hormone replacement on cognition in elderly healthy females. Psychopharmacology 149 129–139. 10.1007/s002139900324|||Dunstan J. A., Simmer K., Dixon G., Prescott S. L. (2008). Cognitive assessment of children at age 2(1/2) years after maternal fish oil supplementation in pregnancy: a randomised controlled trial. Arch. Dis. Child. Fetal. Neonatal. Ed. 93 F45–F50.|||Dyall S. C. (2015). Long-chain Omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA. Front. Aging Neurosci. 7:52. 10.3389/fnagi.2015.00052|||Eckert A., Schulz K. L., Rhein V., Gotz J. (2010). Convergence of amyloid-beta and tau pathologies on mitochondria in vivo. Mol. Neurobiol. 41 107–114. 10.1007/s12035-010-8109-5|||Ehehalt R., Keller P., Haass C., Thiele C., Simons K. (2003). Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. J. Cell. Biol. 160 113–123. 10.1083/jcb.200207113|||El Haj M., Antoine P., Amouyel P., Lambert J. C., Pasquier F., Kapogiannis D. (2016). Apolipoprotein E (APOE) epsilon4 and episodic memory decline in Alzheimer’s disease: a review. Ageing Res. Rev. 27 15–22. 10.1016/j.arr.2016.02.002|||Elliott D. A., Weickert C. S., Garner B. (2010). Apolipoproteins in the brain: implications for neurological and psychiatric disorders. Clin. Lipidol. 51 555–573. 10.2217/clp.10.37|||Erk S., Meyer-Lindenberg A., Opitz von Boberfeld C., Esslinger C., Schnell K., Kirsch P., et al. (2011). Hippocampal function in healthy carriers of the CLU Alzheimer’s disease risk variant. J. Neurosci. 31 18180–18184. 10.1523/jneurosci.4960-11.2011|||Estus S., Golde T. E., Kunishita T., Blades D., Lowery D., Eisen M., et al. (1992). Potentially amyloidogenic, carboxyl-terminal derivatives of the amyloid protein precursor. Science 255 726–728. 10.1126/science.1738846|||Evans B. A., Evans J. E., Baker S. P., Kane K., Swearer J., Hinerfeld D., et al. (2009). Long-term statin therapy and CSF cholesterol levels: implications for Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 27 519–524. 10.1159/000221835|||Evin G., Li Q. X. (2012). Platelets and Alzheimer’s disease: potential of APP as a biomarker. World J. Psychiatry 2 102–113.|||Evin G., Zhu A., Holsinger R. M., Masters C. L., Li Q. X. (2003). Proteolytic processing of the Alzheimer’s disease amyloid precursor protein in brain and platelets. J. Neurosci. Res. 74 386–392.|||Eyster K. M. (2007). The membrane and lipids as integral participants in signal transduction: lipid signal transduction for the non-lipid biochemist. Adv. Physiol. Educ. 31 5–16. 10.1152/advan.00088.2006|||Farooqui A. A., Horrocks L. A. (1998). Plasmalogen-selective phospholipase A2 and its involvement in Alzheimer’s disease. Biochem. Soc. Trans. 26 243–246.|||Farooqui A. A., Liss L., Horrocks L. A. (1988). Stimulation of lipolytic enzymes in Alzheimer’s disease. Ann. Neurol. 23 306–308. 10.1002/ana.410230317|||Feingold K. R., Grunfeld C. (2000). “Introduction to lipids and lipoproteins,” in Endotext, eds Feingold K. R., Anawalt B., Boyce A., Chrousos G., Dungan K., Grossman A., et al. (South Dartmouth, MA: MDText.com, Inc; ).|||Ferreira L. (2019). What human blood-brain barrier models can tell us about BBB function and drug discovery? Expert. Opin. Drug. Discov. 14 1113–1123. 10.1080/17460441.2019.1646722|||Fester L., Zhou L., Butow A., Huber C., von Lossow R., Prange-Kiel J., et al. (2009). Cholesterol-promoted synaptogenesis requires the conversion of cholesterol to estradiol in the hippocampus. Hippocampus 19 692–705. 10.1002/hipo.20548|||Fidani L., Goulas A., Crook R., Petersen R. C., Tangalos E., Kotsis A., et al. (2004). An association study of the cholesteryl ester transfer protein TaqI B polymorphism with late onset Alzheimer’s disease. Neurosci. Lett. 357 152–154. 10.1016/j.neulet.2003.11.071|||Filippov V., Song M. A., Zhang K., Vinters H. V., Tung S., Kirsch W. M., et al. (2012). Increased ceramide in brains with Alzheimer’s and other neurodegenerative diseases. J. Alzheimers Dis. 29 537–547. 10.3233/jad-2011-111202|||Filou S., Lhomme M., Karavia E. A., Kalogeropoulou C., Theodoropoulos V., Zvintzou E., et al. (2016). Distinct roles of apolipoproteins A1 and E in the modulation of high-density lipoprotein composition and function. Biochemistry 55 3752–3762. 10.1021/acs.biochem.6b00389|||Finean J. B., Robertson J. D. (1958). Lipids and the structure of myelin. Br. Med. Bull. 14 267–273. 10.1093/oxfordjournals.bmb.a069695|||Fishman J. B., Rubin J. B., Handrahan J. V., Connor J. R., Fine R. E. (1987). Receptor-mediated transcytosis of transferrin across the blood-brain barrier. J. Neurosci. Res. 18 299–304. 10.1002/jnr.490180206|||Fonteh A. (2018). Reasons why Omega-3 polyunsaturated fatty acids produce mixed results in alzheimer’s disease. J. Glycom. Lipid. 7:1.|||Fonteh A. N., Chiang J., Cipolla M., Hale J., Diallo F., Chirino A., et al. (2013). Alterations in cerebrospinal fluid glycerophospholipids and phospholipase A2 activity in Alzheimer’s disease. J. Lipid. Res. 54 2884–2897. 10.1194/jlr.m037622|||Fonteh A. N., Cipolla M., Chiang A. J., Edminster S. P., Arakaki X., Harrington M. G. (2020). Polyunsaturated fatty acid composition of cerebrospinal fluid fractions shows their contribution to cognitive resilience of a pre-symptomatic Alzheimer’s disease cohort. Front. Physiol. 11:83. 10.3389/fphys.2020.00083|||Fonteh A. N., Cipolla M., Chiang J., Arakaki X., Harrington M. G. (2014). Human cerebrospinal fluid fatty acid levels differ between supernatant fluid and brain-derived nanoparticle fractions, and are altered in Alzheimer’s disease. PLoS One 9:e100519. 10.1371/journal.pone.0100519|||Fonteh A. N., Ormseth C., Chiang J., Cipolla M., Arakaki X., Harrington M. G. (2015). Sphingolipid metabolism correlates with cerebrospinal fluid Beta amyloid levels in Alzheimer’s disease. PLoS One 10:e0125597. 10.1371/journal.pone.0125597|||Foster E. M., Dangla-Valls A., Lovestone S., Ribe E. M., Buckley N. J. (2019). Clusterin in Alzheimer’s disease: mechanisms, genetics, and lessons from other pathologies. Front. Neurosci. 13:164. 10.3389/fnins.2019.00164|||Frank A. T., Zhao B., Jose P. O., Azar K. M., Fortmann S. P., Palaniappan L. P. (2014). Racial/ethnic differences in dyslipidemia patterns. Circulation 129 570–579. 10.1161/circulationaha.113.005757|||Frank B., Gupta S. (2005). A review of antioxidants and Alzheimer’s disease. Ann. Clin. Psychiatry 17 269–286.|||Frank M. G., Baratta M. V., Sprunger D. B., Watkins L. R., Maier S. F. (2007). Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav. Immun. 21 47–59. 10.1016/j.bbi.2006.03.005|||French H. M., Reid M., Mamontov P., Simmons R. A., Grinspan J. B. (2009). Oxidative stress disrupts oligodendrocyte maturation. J. Neurosci. Res. 87 3076–3087. 10.1002/jnr.22139|||Freund Levi Y., Vedin I., Cederholm T., Basun H., Faxen Irving G., Eriksdotter M., et al. (2014). Transfer of Omega-3 fatty acids across the blood-brain barrier after dietary supplementation with a docosahexaenoic acid-rich Omega-3 fatty acid preparation in patients with Alzheimer’s disease: the OmegAD study. J. Intern. Med. 275 428–436. 10.1111/joim.12166|||Freund-Levi Y., Basun H., Cederholm T., Faxen-Irving G., Garlind A., Grut M., et al. (2008). Omega-3 supplementation in mild to moderate Alzheimer’s disease: effects on neuropsychiatric symptoms. Int. J. Geriatr. Psychiatry 23 161–169. 10.1002/gps.1857|||Freund-Levi Y., Eriksdotter-Jonhagen M., Cederholm T., Basun H., Faxen-Irving G., Garlind A., et al. (2006). Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch. Neurol. 63 1402–1408.|||Frieden C., Wang H., Ho C. M. W. (2017). A mechanism for lipid binding to apoE and the role of intrinsically disordered regions coupled to domain-domain interactions. Proc. Natl. Acad. Sci. U.S.A. 114 6292–6297. 10.1073/pnas.1705080114|||Gazzola K., Reeskamp L., van den Born B. J. (2017). Ethnicity, lipids and cardiovascular disease. Curr. Opin. Lipidol. 28 225–230. 10.1097/mol.0000000000000412|||Ghosh M., Garcia-Castillo D., Aguirre V., Golshani R., Atkins C. M., Bramlett H. M., et al. (2012). Proinflammatory cytokine regulation of cyclic AMP-phosphodiesterase 4 signaling in microglia in vitro and following CNS injury. Glia 60 1839–1859. 10.1002/glia.22401|||Gilgun-Sherki Y., Melamed E., Offen D. (2001). Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier. Neuropharmacology 40 959–975. 10.1016/s0028-3908(01)00019-3|||Gilmore-Bykovskyi A. L., Jin Y., Gleason C., Flowers-Benton S., Block L. M., Dilworth-Anderson P., et al. (2019). Recruitment and retention of underrepresented populations in Alzheimer’s disease research: a systematic review. Alzheimers Dement. 19 751–770. 10.1016/j.trci.2019.09.018|||Giltay E. J., Gooren L., Toorians A. W., Katan M. B., Zock P. L. (2004). Docosahexaenoic acid concentrations are higher in women than in men because of estrogenic effects. Am. J. Clin. Nutr. 80 1167–1174. 10.1093/ajcn/80.5.1167|||Giulietti A., Vignini A., Nanetti L., Mazzanti L., Di Primio R., Salvolini E. (2016). Alzheimer’s disease risk and progression: the role of nutritional supplements and their effect on drug therapy outcome. Curr. Neuropharmacol. 14 177–190. 10.2174/1570159x13666150928155321|||Glorioso C. A., Pfenning A. R., Lee S. S., Bennett D. A., Sibille E. L., Kellis M., et al. (2019). Rate of brain aging and APOE epsilon4 are synergistic risk factors for Alzheimer’s disease. Life Sci. Alliance 2 e201900303. 10.26508/lsa.201900303|||Gold M., Dolga A. M., Koepke J., Mengel D., Culmsee C., Dodel R., et al. (2014). alpha1-antitrypsin modulates microglial-mediated neuroinflammation and protects microglial cells from amyloid-beta-induced toxicity. J. Neuroinflammation 11:165. 10.1186/s12974-014-0165-8|||Golde T. E., Estus S., Younkin L. H., Selkoe D. J., Younkin S. G. (1992). Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 255 728–730. 10.1126/science.1738847|||Gong C. X., Liu F., Grundke-Iqbal I., Iqbal K. (2006). Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation. J. Alzheimers Dis. 9 1–12. 10.3233/jad-2006-9101|||Goozee K., Chatterjee P., James I., Shen K., Sohrabi H. R., Asih P. R., et al. (2017). Alterations in erythrocyte fatty acid composition in preclinical Alzheimer’s disease. Sci. Rep. 7:676.|||Grabowska W., Sikora E., Bielak-Zmijewska A. (2017). Sirtuins, a promising target in slowing down the ageing process. Biogerontology 18 447–476. 10.1007/s10522-017-9685-9|||Grassi S., Giussani P., Mauri L., Prioni S., Sonnino S., Prinetti A. (2019). Lipid rafts and neurodegeneration: structural and functional roles in physiologic aging and neurodegenerative diseases. J. Lipid. Res. 61 636–654.|||Grimm M. O., Haupenthal V. J., Mett J., Stahlmann C. P., Blumel T., Mylonas N. T., et al. (2016). Oxidized docosahexaenoic acid species and lipid peroxidation products increase amyloidogenic amyloid precursor protein processing. Neurodegener. Dis. 16 44–54. 10.1159/000440839|||Grimm M. O., Rothhaar T. L., Grosgen S., Burg V. K., Hundsdorfer B., Haupenthal V. J., et al. (2012). Trans fatty acids enhance amyloidogenic processing of the Alzheimer amyloid precursor protein (APP). J. Nutr. Biochem. 23 1214–1223. 10.1016/j.jnutbio.2011.06.015|||Growdon J. H., Hyman B. T. (2014). APOE genotype and brain development. JAMA Neurol. 71 7–8.|||Guan Z., Wang Y., Cairns N. J., Lantos P. L., Dallner G., Sindelar P. J. (1999). Decrease and structural modifications of phosphatidylethanolamine plasmalogen in the brain with Alzheimer disease. J. Neuropathol. Exp. Neurol. 58 740–747. 10.1097/00005072-199907000-00008|||Guo X., Geng M., Du G. (2005). Glucose transporter 1, distribution in the brain and in neural disorders: its relationship with transport of neuroactive drugs through the blood-brain barrier. Biochem. Genet. 43 175–187. 10.1007/s10528-005-1510-5|||Hahn G., Ponce-Alvarez A., Deco G., Aertsen A., Kumar A. (2019). Portraits of communication in neuronal networks. Nat. Rev. Neurosci. 20 117–127. 10.1038/s41583-018-0094-0|||Halliday M. R., Rege S. V., Ma Q., Zhao Z., Miller C. A., Winkler E. A., et al. (2016). Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. J. Cereb. Blood Flow Metab. 36 216–227. 10.1038/jcbfm.2015.44|||Hameister R., Kaur C., Dheen S. T., Lohmann C. H., Singh G. (2020). Reactive oxygen/nitrogen species (ROS/RNS) and oxidative stress in arthroplasty. J. Biomed. Mater. Res. B Appl. Biomater. 108 2073–2087. 10.1002/jbm.b.34546|||Han X., M Holtzman D., McKeel D. W., Jr., Kelley J., Morris J. C. (2002). Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer’s disease: potential role in disease pathogenesis. J. Neurochem. 82 809–818. 10.1046/j.1471-4159.2002.00997.x|||Hansen D. V., Hanson J. E., Sheng M. (2018). Microglia in Alzheimer’s disease. J. Cell Biol. 217 459–472.|||Hansen S. B. (2015). Lipid agonism: the PIP2 paradigm of ligand-gated ion channels. Biochim. Biophys. Acta 1851 620–628. 10.1016/j.bbalip.2015.01.011|||Hao S., Wang R., Zhang Y., Zhan H. (2018). Prediction of Alzheimer’s disease-associated genes by integration of gwas summary data and expression data. Front. Genet. 9:653. 10.3389/fgene.2018.00653|||Harik S. I., Kalaria R. N. (1991). Blood-brain barrier abnormalities in Alzheimer’s disease. Ann. N. Y. Acad. Sci. 640 47–52.|||Harold D., Abraham R., Hollingworth P., Sims R., Gerrish A., Hamshere M. L., et al. (2009). Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat. Genet. 41 1088–1093.|||Harris J. J., Jolivet R., Attwell D. (2012). Synaptic energy use and supply. Neuron 75 762–777. 10.1016/j.neuron.2012.08.019|||Hartmann D. (2012). A brief history of APP secretases, their substrates and their functions. Curr. Alzheimer Res. 9 138–139. 10.2174/156720512799361628|||Hasadsri L., Wang B. H., Lee J. V., Erdman J. W., Llano D. A., Barbey A. K., et al. (2013). Omega-3 fatty acids as a putative treatment for traumatic brain injury. J. Neurotrauma. 30 897–906. 10.1089/neu.2012.2672|||Hascalovici J. R., Vaya J., Khatib S., Holcroft C. A., Zukor H., Song W., et al. (2009). Brain sterol dysregulation in sporadic AD and MCI: relationship to heme oxygenase-1. J. Neurochem. 110 1241–1253. 10.1111/j.1471-4159.2009.06213.x|||Hawkins R. A., Biebuyck J. F. (1979). Ketone bodies are selectively used by individual brain regions. Science 205 325–327. 10.1126/science.451608|||Hedqvist P., Raud J., Palmertz U., Kumlin M., Dahlen S. E. (1991). Eicosanoids as mediators and modulators of inflammation. Adv. Prostaglandin. Thromboxane. Leukot. Res. 21B 537–543.|||Helbecque N., Codron V., Cottel D., Amouyel P. (2008). An apolipoprotein A-I gene promoter polymorphism associated with cognitive decline, but not with Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 25 97–102. 10.1159/000112176|||Heppner F. L., Ransohoff R. M., Becher B. (2015). Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 16 358–372. 10.1038/nrn3880|||Hering H., Lin C. C., Sheng M. (2003). Lipid rafts in the maintenance of synapses, dendritic spines, and surface AMPA receptor stability. J. Neurosci. 23 3262–3271. 10.1523/jneurosci.23-08-03262.2003|||Herold C., Hooli B. V., Mullin K., Liu T., Roehr J. T., Mattheisen M., et al. (2016). Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer’s disease with OSBPL6, PTPRG, and PDCL3. Mol. Psychiatry 21 1608–1612. 10.1038/mp.2015.218|||Herskovits A. Z., Guarente L. (2014). SIRT1 in neurodevelopment and brain senescence. Neuron 81 471–483. 10.1016/j.neuron.2014.01.028|||Herz J. (2001). The LDL receptor gene family: (un)expected signal transducers in the brain. Neuron 29 571–581. 10.1016/s0896-6273(01)00234-3|||Heverin M., Bogdanovic N., Lutjohann D., Bayer T., Pikuleva I., Bretillon L., et al. (2004). Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer’s disease. J. Lipid Res. 45 186–193. 10.1194/jlr.m300320-jlr200|||Higgs G. A., Moncada S., Vane J. R. (1984). Eicosanoids in inflammation. Ann. Clin. Res. 16 287–299.|||Hirsch-Reinshagen V., Wellington C. L. (2007). Cholesterol metabolism, apolipoprotein E, adenosine triphosphate-binding cassette transporters, and Alzheimer’s disease. Curr. Opin. Lipidol. 18 325–332. 10.1097/mol.0b013e32813aeabf|||Hoglund K., Thelen K. M., Syversen S., Sjogren M., von Bergmann K., Wallin A., et al. (2005). The effect of simvastatin treatment on the amyloid precursor protein and brain cholesterol metabolism in patients with Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 19 256–265. 10.1159/000084550|||Hoofnagle A. N., Heinecke J. W. (2009). Lipoproteomics: using mass spectrometry-based proteomics to explore the assembly, structure, and function of lipoproteins. J. Lipid Res. 50 1967–1975. 10.1194/jlr.r900015-jlr200|||Hooper C., De Souto Barreto P., Pahor M., Weiner M., Vellas B. (2018). The relationship of Omega 3 polyunsaturated fatty acids in red blood cell membranes with cognitive function and brain structure: a review focussed on alzheimer’s disease. J. Prev. Alzheimers Dis. 5 78–84.|||Hosseini M., Poljak A., Braidy N., Crawford J., Sachdev P. (2020). Blood fatty acids in Alzheimer’s disease and mild cognitive impairment: a meta-analysis and systematic review. Ageing Res. Rev. 60 101043. 10.1016/j.arr.2020.101043|||Hottman D. A., Chernick D., Cheng S., Wang Z., Li L. (2014). HDL and cognition in neurodegenerative disorders. Neurobiol. Dis. 72(Pt.A), 22–36. 10.1016/j.nbd.2014.07.015|||Hu X., Xu B., Ge W. (2017). The role of lipid bodies in the microglial aging process and related diseases. Neurochem. Res. 42 3140–3148. 10.1007/s11064-017-2351-4|||Huang Y., Mahley R. W. (2014). Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiol. Dis. 72(Pt. A), 3–12. 10.1016/j.nbd.2014.08.025|||Hudry E., Van Dam D., Kulik W., De Deyn P. P., Stet F. S., Ahouansou O., et al. (2010). Adeno-associated virus gene therapy with cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse models of Alzheimer’s disease. Mol. Ther. 18 44–53. 10.1038/mt.2009.175|||Hulbert A. J., Faulks S. C., Harper J. M., Miller R. A., Buffenstein R. (2006). Extended longevity of wild-derived mice is associated with peroxidation-resistant membranes. Mech. Ageing Dev. 127 653–657. 10.1016/j.mad.2006.03.002|||Hussain G., Wang J., Rasul A., Anwar H., Imran A., Qasim M., et al. (2019). Role of cholesterol and sphingolipids in brain development and neurological diseases. Lipids Health Dis. 18:26. 10.1186/s12944-019-0965-z|||Hutchinson E. (2010). Blood-brain barrier: plugging the leak. Nat. Rev. Neurosci. 11:789.|||Igarashi M., Ma K., Gao F., Kim H. W., Rapoport S. I., Rao J. S. (2011). Disturbed choline plasmalogen and phospholipid fatty acid concentrations in Alzheimer’s disease prefrontal cortex. J. Alzheimers Dis. 24 507–517. 10.3233/jad-2011-101608|||Ihara M., Polvikoski T. M., Hall R., Slade J. Y., Perry R. H., Oakley A. E., et al. (2010). Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer’s disease, and dementia with Lewy bodies. Acta Neuropathol. 119 579–589. 10.1007/s00401-009-0635-8|||Ikeshima-Kataoka H., Yasui M. (2016). Correlation between astrocyte activity and recovery from blood-brain barrier breakdown caused by brain injury. Neuroreport 27 894–900. 10.1097/wnr.0000000000000619|||Irizarry M. C., Deng A., Lleo A., Berezovska O., Von Arnim C. A., Martin-Rehrmann M., et al. (2004). Apolipoprotein E modulates gamma-secretase cleavage of the amyloid precursor protein. J. Neurochem. 90 1132–1143.|||Ishiura S. (1991). Proteolytic cleavage of the Alzheimer’s disease amyloid A4 precursor protein. J. Neurochem. 56 363–369. 10.1111/j.1471-4159.1991.tb08160.x|||Ito J., Nagayasu Y., Lu R., Kheirollah A., Hayashi M., Yokoyama S. (2005). Astrocytes produce and secrete FGF-1, which promotes the production of apoE-HDL in a manner of autocrine action. J. Lipid Res. 46 679–686. 10.1194/jlr.m400313-jlr200|||Ito J., Nagayasu Y., Miura Y., Yokoyama S., Michikawa M. (2014). Astrocytes endogenous apoE generates HDL-like lipoproteins using previously synthesized cholesterol through interaction with ABCA1. Brain Res. 1570 1–12. 10.1016/j.brainres.2014.04.037|||Iwamoto N., Kobayashi K., Kosaka K. (1989). The formation of prostaglandins in the postmortem cerebral cortex of Alzheimer-type dementia patients. J. Neurol. 236 80–84. 10.1007/bf00314401|||Iwasaki A., Medzhitov R. (2015). Control of adaptive immunity by the innate immune system. Nat. Immunol. 16 343–353. 10.1038/ni.3123|||Iyu D., Juttner M., Glenn J. R., White A. E., Johnson A. J., Fox S. C., et al. (2011). PGE1 and PGE2 modify platelet function through different prostanoid receptors. Prostaglandins Other Lipid Mediat. 94 9–16. 10.1016/j.prostaglandins.2010.11.001|||Janciauskiene S., Wright H. T. (1998). Inflammation, antichymotrypsin, and lipid metabolism: autogenic etiology of Alzheimer’s disease. Bioessays 20 1039–1046. 10.1002/(sici)1521-1878(199812)20:12<1039::aid-bies10>3.0.co;2-z|||Janssen C. I., Kiliaan A. J. (2014). Long-chain polyunsaturated fatty acids (LCPUFA) from genesis to senescence: the influence of LCPUFA on neural development, aging, and neurodegeneration. Prog. Lipid Res. 53 1–17. 10.1016/j.plipres.2013.10.002|||Jean-Louis T., Rockwell P., Figueiredo-Pereira M. E. (2018). Prostaglandin J2 promotes O-GlcNAcylation raising APP processing by alpha- and beta-secretases: relevance to Alzheimer’s disease. Neurobiol. Aging 62 130–145. 10.1016/j.neurobiolaging.2017.10.009|||Joffre C., Nadjar A., Lebbadi M., Calon F., Laye S. (2014). n-3 LCPUFA improves cognition: the young, the old and the sick. Prostaglandins Leukot. Essent. Fatty Acids 91 1–20. 10.1016/j.plefa.2014.05.001|||Johnen A., Pawlowski M., Duning T. (2018). Distinguishing neurocognitive deficits in adult patients with NP-C from early onset Alzheimer’s dementia. Orphanet. J. Rare Dis. 13 91.|||Jones L., Holmans P. A., Hamshere M. L., Harold D., Moskvina V., Ivanov D., et al. (2010). Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease. PLoS One 5:e13950. 10.1371/journal.pone.0013950|||Jones N. S., Rebeck G. W. (2018). The synergistic effects of APOE genotype and obesity on Alzheimer’s disease risk. Int. J. Mol. Sci. 20:63. 10.3390/ijms20010063|||Kaether C., Haass C. (2004). A lipid boundary separates APP and secretases and limits amyloid beta-peptide generation. J. Cell Biol. 167 809–812. 10.1083/jcb.200410090|||Kagedal K., Kim W. S., Appelqvist H., Chan S., Cheng D., Agholme L., et al. (2010). Increased expression of the lysosomal cholesterol transporter NPC1 in Alzheimer’s disease. Biochim. Biophys. Acta 1801 831–838. 10.1016/j.bbalip.2010.05.005|||Kaiser H. J., Orlowski A., Rog T., Nyholm T. K., Chai W., Feizi T., et al. (2011). Lateral sorting in model membranes by cholesterol-mediated hydrophobic matching. Proc. Natl. Acad. Sci. U.S.A. 108 16628–16633. 10.1073/pnas.1103742108|||Kalaria R. N., Harik S. I. (1989). Abnormalities of the glucose transporter at the blood-brain barrier and in brain in Alzheimer’s disease. Prog. Clin. Biol. Res. 317 415–421.|||Kamboh M. I., Minster R. L., Demirci F. Y., Ganguli M., Dekosky S. T., Lopez O. L., et al. (2012). Association of CLU and PICALM variants with Alzheimer’s disease. Neurobiol. Aging 33 518–521. 10.1016/j.neurobiolaging.2010.04.015|||Kaminsky Y. G., Tikhonova L. A., Kosenko E. A. (2015). Critical analysis of Alzheimer’s amyloid-beta toxicity to mitochondria. Front Biosci 20:173–197. 10.2741/4304|||Kang J., Rivest S. (2012). Lipid metabolism and neuroinflammation in Alzheimer’s disease: a role for liver X receptors. Endocr. Rev. 33 715–746. 10.1210/er.2011-1049|||Kao Y. C., Ho P. C., Tu Y. K., Jou I. M., Tsai K. J. (2020). Lipids and Alzheimer’s Disease. Int. J. Mol. Sci. 21:1505 10.3390/ijms21041505|||Karamanos Y., Gosselet F., Dehouck M. P., Cecchelli R. (2014). Blood-brain barrier proteomics: towards the understanding of neurodegenerative diseases. Arch. Med. Res. 45 730–737. 10.1016/j.arcmed.2014.11.008|||Katt M. E., Mayo L. N., Ellis S. E., Mahairaki V., Rothstein J. D., Cheng L., et al. (2019). The role of mutations associated with familial neurodegenerative disorders on blood-brain barrier function in an iPSC model. Fluids Barriers CNS 16:20. 10.1186/s12987-019-0139-4|||Keaney J., Campbell M. (2015). The dynamic blood-brain barrier. FEBS J. 282 4067–4079.|||Kelsch W., Sim S., Lois C. (2010). Watching synaptogenesis in the adult brain. Annu. Rev. Neurosci. 33 131–149. 10.1146/annurev-neuro-060909-153252|||Kennedy M. B. (2013). Synaptic signaling in learning and memory. Cold Spring Harb. Perspect. Biol. 8:a016824. 10.1101/cshperspect.a016824|||Khalil A., Berrougui H., Pawelec G., Fulop T. (2012). Impairment of the ABCA1 and SR-BI-mediated cholesterol efflux pathways and HDL anti-inflammatory activity in Alzheimer’s disease. Mech. Ageing Dev. 133 20–29. 10.1016/j.mad.2011.11.008|||Kim M., Nevado-Holgado A., Whiley L., Snowden S. G., Soininen H., Kloszewska I., et al. (2017). Association between plasma ceramides and phosphatidylcholines and hippocampal brain volume in late onset Alzheimer’s disease. J. Alzheimers Dis. 60 809–817. 10.3233/jad-160645|||Kishimoto Y., Agranoff B. W., Radin N. S., Burton R. M. (1969). Comparison of the fatty acids of lipids of subcellular brain fractions. J. Neurochem. 16 397–404. 10.1111/j.1471-4159.1969.tb10380.x|||Kitazume S., Tachida Y., Oka R., Shirotani K., Saido T. C., Hashimoto Y. (2001). Alzheimer’s beta-secretase, beta-site amyloid precursor protein-cleaving enzyme, is responsible for cleavage secretion of a Golgi-resident sialyltransferase. Proc. Natl. Acad. Sci. U.S.A. 98 13554–13559. 10.1073/pnas.241509198|||Knebl J., DeFazio P., Clearfield M. B., Little L., McConathy W. J., McPherson R., et al. (1994). Plasma lipids and cholesterol esterification in Alzheimer’s disease. Mech. Ageing Dev. 73 69–77. 10.1016/0047-6374(94)90039-6|||Kniewallner K. M., Ehrlich D., Kiefer A., Marksteiner J., Humpel C. (2015). Platelets in the Alzheimer’s disease brain: do they play a role in cerebral amyloid angiopathy? Curr. Neurovasc. Res. 12 4–14. 10.2174/1567202612666150102124703|||Kohama S. G., Rosene D. L., Sherman L. S. (2012). Age-related changes in human and non-human primate white matter: from myelination disturbances to cognitive decline. Age 34 1093–1110. 10.1007/s11357-011-9357-7|||Koizumi K., Wang G., Park L. (2016). Endothelial dysfunction and amyloid-beta-induced neurovascular alterations. Cell Mol. Neurobiol. 36 155–165. 10.1007/s10571-015-0256-9|||Kojima S., Omori M. (1992). Two-way cleavage of beta-amyloid protein precursor by multicatalytic proteinase. FEBS Lett. 304 57–60. 10.1016/0014-5793(92)80588-8|||Kosicek M., Zetterberg H., Andreasen N., Peter-Katalinic J., Hecimovic S. (2012). Elevated cerebrospinal fluid sphingomyelin levels in prodromal Alzheimer’s disease. Neurosci. Lett. 516 302–305. 10.1016/j.neulet.2012.04.019|||Kotani S., Sakaguchi E., Warashina S., Matsukawa N., Ishikura Y., Kiso Y., et al. (2006). Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction. Neurosci. Res. 56 159–164. 10.1016/j.neures.2006.06.010|||Kramer S. D., Schutz Y. B., Wunderli-Allenspach H., Abbott N. J., Begley D. J. (2002). Lipids in blood-brain barrier models in vitro II: influence of glial cells on lipid classes and lipid fatty acids. In Vitro Cell. Dev. Biol. Anim. 38 566–571.|||Kumar A., Singh A. (2015). A review on mitochondrial restorative mechanism of antioxidants in Alzheimer’s disease and other neurological conditions. Front. Pharmacol. 6:206. 10.3389/fphar.2015.00206|||Kwon H. J., Cha M. Y., Kim D., Kim D. K., Soh M., Shin K., et al. (2016). Mitochondria-targeting ceria nanoparticles as antioxidants for Alzheimer’s disease. ACS Nano 10 2860–2870. 10.1021/acsnano.5b08045|||Lamsa R., Helisalmi S., Herukka S. K., Tapiola T., Pirttila T., Vepsalainen S., et al. (2007). Study on the association between SOAT1 polymorphisms, Alzheimer’s disease risk and the level of CSF biomarkers. Dement. Geriatr. Cogn. Disord. 24 146–150. 10.1159/000105164|||Laughlin S. B., Sejnowski T. J. (2003). Communication in neuronal networks. Science 301 1870–1874. 10.1126/science.1089662|||Leduc V., Jasmin-Belanger S., Poirier J. (2010). APOE and cholesterol homeostasis in Alzheimer’s disease. Trends Mol. Med. 16 469–477. 10.1016/j.molmed.2010.07.008|||Lee L. K., Shahar S., Chin A. V., Yusoff N. A. (2013). Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo-controlled trial. Psychopharmacology 225 605–612. 10.1007/s00213-012-2848-0|||Leonard A. E., Kelder B., Bobik E. G., Chuang L. T., Parker-Barnes J. M., Thurmond J. M., et al. (2000). cDNA cloning and characterization of human Delta5-desaturase involved in the biosynthesis of arachidonic acid. Biochem J. 347(Pt. 3), 719–724. 10.1042/bj3470719|||Lepara O., Valjevac A., Alajbegovic A., Zaciragic A., Nakas-Icindic E. (2009). Decreased serum lipids in patients with probable Alzheimer’s disease. Bosn. J. Basic Med. Sci. 9 215–220. 10.17305/bjbms.2009.2809|||Lepping R. J., Honea R. A., Martin L. E., Liao K., Choi I. Y., Lee P., et al. (2019). Long-chain polyunsaturated fatty acid supplementation in the first year of life affects brain function, structure, and metabolism at age nine years. Dev. Psychobiol. 61 5–16. 10.1002/dev.21780|||Leuti A., Maccarrone M., Chiurchiu V. (2019). Proresolving lipid mediators: endogenous modulators of oxidative stress. Oxid. Med. Cell. Longev. 2019:8107265. 10.1155/2019/8107265|||Levental I., Veatch S. (2016). The continuing mystery of lipid rafts. J. Mol. Biol. 428 4749–4764. 10.1016/j.jmb.2016.08.022|||Li M. Z., Zheng L. J., Shen J., Li X. Y., Zhang Q., Bai X., et al. (2018). SIRT1 facilitates amyloid beta peptide degradation by upregulating lysosome number in primary astrocytes. Neural Regen. Res. 13 2005–2013. 10.4103/1673-5374.239449|||Li X., Kan H. Y., Lavrentiadou S., Krieger M., Zannis V. (2002). Reconstituted discoidal ApoE-phospholipid particles are ligands for the scavenger receptor BI. The amino-terminal 1-165 domain of ApoE suffices for receptor binding. J. Biol. Chem. 277 21149–21157. 10.1074/jbc.m200658200|||Lim G. P., Yang F., Chu T., Chen P., Beech W., Teter B., et al. (2000). Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J. Neurosci. 20 5709–5714. 10.1523/jneurosci.20-15-05709.2000|||Lin Q., Cao Y., Gao J. (2015). Decreased expression of the APOA1-APOC3-APOA4 gene cluster is associated with risk of Alzheimer’s disease. Drug. Des. Devel. Ther. 9 5421–5431.|||Lingwood D., Simons K. (2010). Lipid rafts as a membrane-organizing principle. Science 327 46–50. 10.1126/science.1174621|||Lingwood D., Kaiser H. J., Levental I., Simons K. (2009). Lipid rafts as functional heterogeneity in cell membranes. Biochem. Soc. Trans. 37 955–960. 10.1042/bst0370955|||Liu K., Liu Y., Xu Y., Nandakumar K. S., Shen X., Lin J., et al. (2019). Regulatory role of Golgi brefeldin a resistance factor-1 in amyloid precursor protein trafficking, cleavage and Abeta formation. J. Cell Biochem. 120 15604–15615. 10.1002/jcb.28827|||Liu L., MacKenzie K. R., Putluri N., Maletic-Savatic M., Bellen H. J. (2017). The glia-neuron lactate shuttle and elevated ROS promote lipid synthesis in neurons and lipid droplet accumulation in glia via APOE/D. Cell Metab. 26 719–737e716.|||Loef M., Walach H. (2013). The Omega-6/Omega-3 ratio and dementia or cognitive decline: a systematic review on human studies and biological evidence. J. Nutr. Gerontol. Geriatr. 32 1–23. 10.1080/21551197.2012.752335|||Loera-Valencia R., Goikolea J., Parrado-Fernandez C., Merino-Serrais P., Maioli S. (2019). Alterations in cholesterol metabolism as a risk factor for developing Alzheimer’s disease: potential novel targets for treatment. J. Steroid. Biochem. Mol. Biol. 190 104–114. 10.1016/j.jsbmb.2019.03.003|||Lohner S., Fekete K., Marosvölgyi T., Decsi T. (2013). Gender differences in the long-chain polyunsaturated fatty acid status: systematic review of 51 publications. Ann. Nutr. Metabol. 62 98–112. 10.1159/000345599|||Lopez L. B., Kritz-Silverstein D., Barrett Connor E. (2011). High dietary and plasma levels of the omega-3 fatty acid docosahexaenoic acid are associated with decreased dementia risk: the rancho bernardo study. J. Nutr. Health Aging 15 25–31. 10.1007/s12603-011-0009-5|||Louveau A., Smirnov I., Keyes T. J., Eccles J. D., Rouhani S. J., Peske J. D., et al. (2015). Structural and functional features of central nervous system lymphatic vessels. Nature 523 337–341. 10.1038/nature14432|||Lovinger D. M. (2008). Communication networks in the brain: neurons, receptors, neurotransmitters, and alcohol. Alcohol. Res. Health 31 196–214.|||Lucatelli J. F., Barros A. C., Silva V. K., Machado Fda S., Constantin P. C., Dias A. A., et al. (2011). Genetic influences on Alzheimer’s disease: evidence of interactions between the genes APOE, APOC1 and ACE in a sample population from the South of Brazil. Neurochem. Res. 36 1533–1539. 10.1007/s11064-011-0481-7|||Luo C., Ren H., Yao X., Shi Z., Liang F., Kang J. X., et al. (2018). Enriched brain Omega-3 polyunsaturated fatty acids confer neuroprotection against microinfarction. EBioMedicine 32 50–61. 10.1016/j.ebiom.2018.05.028|||MacDonald-Wicks L., McEvoy M., Magennis E., Schofield P. W., Patterson A. J., Zacharia K. (2019). Dietary long-chain fatty acids and cognitive performance in older australian adults. Nutrients 11:711. 10.3390/nu11040711|||Mackic J. B., Stins M., McComb J. G., Calero M., Ghiso J., Kim K. S., et al. (1998). Human blood-brain barrier receptors for Alzheimer’s amyloid-beta 1- 40. asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer. J. Clin. Invest. 102 734–743. 10.1172/jci2029|||Maclean F. L., Horne M. K., Williams R. J., Nisbet D. R. (2018). Review: biomaterial systems to resolve brain inflammation after traumatic injury. APL Bioeng. 2:021502 10.1063/1.5023709|||Mahley R. W. (2016). Central nervous system lipoproteins: ApoE and regulation of cholesterol metabolism. Arterioscler. Thromb. Vasc. Biol. 36 1305–1315. 10.1161/atvbaha.116.307023|||Mancuso C., Bates T. E., Butterfield D. A., Calafato S., Cornelius C., De Lorenzo A., et al. (2007). Natural antioxidants in Alzheimer’s disease. Expert. Opin. Investig. Drugs 16 1921–1931.|||Marchi C., Adorni M. P., Caffarra P., Ronda N., Spallazzi M., Barocco F., et al. (2019). ABCA1- and ABCG1-mediated cholesterol efflux capacity of cerebrospinal fluid is impaired in Alzheimer’s disease. J. Lipid Res. 60 1449–1456. 10.1194/jlr.p091033|||Marquer C., Devauges V., Cossec J. C., Liot G., Lecart S., Saudou F., et al. (2011). Local cholesterol increase triggers amyloid precursor protein-Bace1 clustering in lipid rafts and rapid endocytosis. FASEB J. 25 1295–1305. 10.1096/fj.10-168633|||Martin R. E., Bazan N. G. (1992). Changing fatty acid content of growth cone lipids prior to synaptogenesis. J. Neurochem. 59 318–325. 10.1111/j.1471-4159.1992.tb08906.x|||Martin T. F. (2000). Racing lipid rafts for synaptic-vesicle formation. Nat. Cell. Biol. 2 E9–E11.|||Martinez-Frailes C., Di Lauro C., Bianchi C., de Diego-Garcia L., Sebastian-Serrano A., Bosca L., et al. (2019). Amyloid peptide induced neuroinflammation increases the p2x7 receptor expression in microglial cells, impacting on its functionality. Front. Cell Neurosci. 13:143. 10.3389/fncel.2019.00143|||Martins M. J., Constancia M., Neves D., Simm A. (2017). Biomarkers of aging: from cellular senescence to age-associated diseases. Oxid. Med. Cell Longev. 2017:7280690. 10.1155/2017/7280690|||Matthews K. A., Xu W., Gaglioti A. H., Holt J. B., Croft J. B., Mack D., et al. (2019). Racial and ethnic estimates of Alzheimer’s disease and related dementias in the United States (2015–2060) in adults aged =65 years. Alzheimers Dement. 15 17–24. 10.1016/j.jalz.2018.06.3063|||Mauch D. H., Nagler K., Schumacher S., Goritz C., Muller E. C., Otto A., et al. (2001). CNS synaptogenesis promoted by glia-derived cholesterol. Science 294 1354–1357. 10.1126/science.294.5545.1354|||Maulik M., Peake K., Chung J., Wang Y., Vance J. E., Kar S. (2015). APP overexpression in the absence of NPC1 exacerbates metabolism of amyloidogenic proteins of Alzheimer’s disease. Hum. Mol. Genet. 24 7132–7150.|||Mayer E. A. (1993). Neuronal communication. Biol Signals 2 57–76.|||Maysinger D., Ji J., Moquin A., Hossain S., Hancock M. A., Zhang I., et al. (2018). Dendritic polyglycerol sulfates in the prevention of synaptic loss and mechanism of action on glia. ACS Chem. Neurosci. 9 260–271. 10.1021/acschemneuro.7b00301|||McClean P. L., Jalewa J., Holscher C. (2015). Prophylactic liraglutide treatment prevents amyloid plaque deposition, chronic inflammation and memory impairment in APP/PS1 mice. Behav. Brain. Res. 293 96–106. 10.1016/j.bbr.2015.07.024|||McNamara R. K., Able J., Jandacek R., Rider T., Tso P., Eliassen J. C., et al. (2010). Docosahexaenoic acid supplementation increases prefrontal cortex activation during sustained attention in healthy boys: a placebo-controlled, dose-ranging, functional magnetic resonance imaging study. Am. J. Clin. Nutr. 91 1060–1067. 10.3945/ajcn.2009.28549|||McNamara R. K., Asch R. H., Lindquist D. M., Krikorian R. (2018). Role of polyunsaturated fatty acids in human brain structure and function across the lifespan: an update on neuroimaging findings. Prostaglandins Leukot. Essent. Fatty Acids 136 23–34. 10.1016/j.plefa.2017.05.001|||Mecca A. P., Barcelos N. M., Wang S., Bruck A., Nabulsi N., Planeta-Wilson B., et al. (2018). Cortical beta-amyloid burden, gray matter, and memory in adults at varying APOE epsilon4 risk for Alzheimer’s disease. Neurobiol. Aging 61 207–214. 10.1016/j.neurobiolaging.2017.09.027|||Melo R. C., D’Avila H., Wan H. C., Bozza P. T., Dvorak A. M., Weller P. F. (2011). Lipid bodies in inflammatory cells: structure, function, and current imaging techniques. J. Histochem. Cytochem. 59 540–556. 10.1369/0022155411404073|||Mergenthaler P., Lindauer U., Dienel G. A., Meisel A. (2013). Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci. 36 587–597. 10.1016/j.tins.2013.07.001|||Merino-Zamorano C., Fernandez-de Retana S., Montanola A., Batlle A., Saint-Pol J., Mysiorek C., et al. (2016). Modulation of amyloid-beta1-40 transport by ApoA1 and ApoJ across an in vitro model of the blood-brain barrier. J. Alzheimers Dis. 53 677–691. 10.3233/jad-150976|||Mesa-Herrera F., Taoro-Gonzalez L., Valdes-Baizabal C., Diaz M., Marin R. (2019). Lipid and lipid raft alteration in aging and neurodegenerative diseases: a window for the development of new biomarkers. Int. J. Mol. Sci. 20:3810. 10.3390/ijms20153810|||Mielke M. (2018). Sex and gender differences in alzheimer’s disease dementia. Psychiatric. Time 35 14–17.|||Mietelska-Porowska A., Wojda U. (2017). T lymphocytes and inflammatory mediators in the interplay between brain and blood in Alzheimer’s disease: potential pools of new biomarkers. J. Immunol. Res. 2017 4626540. 10.1155/2017/4626540|||Mills J., Reiner P. B. (1999). Regulation of amyloid precursor protein cleavage. J. Neurochem. 72 443–460. 10.1046/j.1471-4159.1999.0720443.x|||Mobraten K., Haug T. M., Kleiveland C. R., Lea T. (2013). Omega-3 and omega-6 PUFAs induce the same GPR120-mediated signalling events, but with different kinetics and intensity in Caco-2 cells. Lipids Health. Dis. 12:101. 10.1186/1476-511X-12-101|||Mochel F. (2018). Lipids and synaptic functions. J. Inherit. Metab. Dis. 41 1117–1122. 10.1007/s10545-018-0204-1|||Mohaibes R. J., Fiol-deRoque M. A., Torres M., Ordinas M., Lopez D. J., Castro J. A., et al. (2017). The hydroxy