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Nutritional metabolism and cerebral bioenergetics in Alzheimer's disease and related dementias.

Authors: Hussein N Yassine|||Wade Self|||Bilal E Kerman|||Giulia Santoni|||NandaKumar Navalpur Shanmugam|||Laila Abdullah|||Lesley R Golden|||Alfred N Fonteh|||Michael G Harrington|||Johannes Gräff|||Gary E Gibson|||Raj Kalaria|||Jose A Luchsinger|||Howard H Feldman|||Russell H Swerdlow|||Lance A Johnson|||Benedict C Albensi|||Berislav V Zlokovic|||Rudolph Tanzi|||Stephen Cunnane|||Cécilia Samieri|||Nikolaos Scarmeas|||Gene L Bowman

Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association

Publication Type: Journal Article

Date: 2023

DOI: NIHMS1934217

ID: 36479795

Affiliations:

Affiliations

    Department of Medicine, Keck School of Medicine, University of Southern, California, Los Angeles, California, USA.|||Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.|||Department of Medicine, Keck School of Medicine, University of Southern, California, Los Angeles, California, USA.|||Laboratory of Neuroepigenetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale Lausanne (EPFL), Lausanne, Switzerland.|||Department of Neurology, Genetics and Aging Research Unit, McCance Center for Brain Health, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|||Roskamp Institute, Sarasota, Florida, USA.|||Department of Physiology, University of Kentucky, Lexington, Kentucky, USA.|||Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.|||Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.|||Laboratory of Neuroepigenetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale Lausanne (EPFL), Lausanne, Switzerland.|||Brain and Mind Research Institute, Weill Cornell Medicine, Burke Neurological Institute, White Plains, New York, USA.|||Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.|||Department of Medicine and Epidemiology, Columbia University Irving Medical Center, New York City, New York, USA.|||Department of Neurosciences, University of California, San Diego, California, USA.|||Department of Neurology, University of Kansas School of Medicine, Kansas City, Kansas, USA.|||Department of Physiology, University of Kentucky, Lexington, Kentucky, USA.|||Nova Southeastern Univ. College of Pharmacy, Davie, Florida, USA.|||Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.|||Department of Neurology, Genetics and Aging Research Unit, McCance Center for Brain Health, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|||Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada.|||Univ. Bordeaux, INSERM, BPH, U1219, F-33000, Bordeaux, France.|||1st Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece.|||Department of Neurology, Genetics and Aging Research Unit, McCance Center for Brain Health, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Abstract

Disturbances in the brain's capacity to meet its energy demand increase the risk of synaptic loss, neurodegeneration, and cognitive decline. Nutritional and metabolic interventions that target metabolic pathways combined with diagnostics to identify deficits in cerebral bioenergetics may therefore offer novel therapeutic potential for Alzheimer's disease (AD) prevention and management. Many diet-derived natural bioactive components can govern cellular energy metabolism but their effects on brain aging are not clear. This review examines how nutritional metabolism can regulate brain bioenergetics and mitigate AD risk. We focus on leading mechanisms of cerebral bioenergetic breakdown in the aging brain at the cellular level, as well as the putative causes and consequences of disturbed bioenergetics, particularly at the blood-brain barrier with implications for nutrient brain delivery and nutritional interventions. Novel therapeutic nutrition approaches including diet patterns are provided, integrating studies of the gut microbiome, neuroimaging, and other biomarkers to guide future personalized nutritional interventions.


Reference List

    Mink JW, Blumenschine RJ, Adams DB. Ratio of central nervous system to body metabolism in vertebrates: its constancy and functional basis. Am J Physiol. 1981;241(3):R203–12. doi:10.1152/ajpregu.1981.241.3.R203|||Swerdlow RH. Mitochondria and cell bioenergetics: increasingly recognized components and a possible etiologic cause of Alzheimer’s disease. Antioxid Redox Signaling. 2012;16(12):1434–1455. doi:10.1089/ars.2011.4149|||Goyal MS, Hawrylycz M, Miller JA, Snyder AZ, Raichle ME. Aerobic glycolysis in the human brain is associated with development and neotenous gene expression. Cell Metab. 2014;19(1):49–57. doi:10.1016/j.cmet.2013.11.020|||Harris JJ, Jolivet R, Attwell D. Synaptic energy use and supply. Neuron. 2012;75(5):762–777. doi:10.1016/j.neuron.2012.08.019|||Magistretti PJ, Allaman I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci. 2018;19(4):235–249. doi:10.1038/nrn.2018.19|||Benarroch EE. Brain glucose transporters. Implications for neurologic disease. Neurology. 2014;82(15):1374–1379. doi:10.1212/wnl.0000000000000328|||Kapogiannis D, Avgerinos KI. Brain glucose and ketone utilization in brain aging and neurodegenerative diseases. Int Rev Neurobiol. 2020;154:79–110. doi:10.1016/bs.irn.2020.03.015|||Ames BN. Prolonging healthy aging: longevity vitamins and proteins. Proc Natl Acad Sci U S A. 2018;115(43):10836–10844. doi:10.1073/pnas.1809045115|||Ross C, Caballero B, Cousins R, Tucker K, Zeigler T. Modern Nutrition In Health and Disease. Wolters Kluwer Business, Lippincott Williams & Wilkins; 2014.|||Dong Y, Brewer GJ. Global metabolic shifts in age and Alzheimer’s disease mouse brains pivot at NAD+/NADH redox sites. J Alzheimers Dis. 2019;71(1):119–140. doi:10.3233/JAD-190408|||Yang Y, Tapias V, Acosta D, Xu H, Chen H, Bhawal R, et al. Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer’s disease. Nat Commun. 2022;13(1):159. doi:10.1038/s41467-021-27572-2|||Gerlach M, Ben-Shachar D, Riederer P, Youdim MB. Altered brain metabolism of iron as a cause of neurodegenerative diseases? J Neurochem. 1994;63(3):793–807. doi:10.1046/j.1471-4159.1994.63030793.x|||Schönfeld P, Reiser G. Why does brain metabolism not favor burning of fatty acids to provide energy? Reflections on disadvantages of the use of free fatty acids as fuel for brain. J Cereb Blood Flow Metab. 2013;33(10):1493–1499. doi:10.1038/jcbfm.2013.128|||Erecińska M, Silver IA. Tissue oxygen tension and brain sensitivity to hypoxia. Respir Physiol. 2001;128(3):263–276. doi:10.1016/s0034-5687(01)00306-1|||Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417(1):1–13. doi:10.1042/BJ20081386|||Brenna JT, Diau GY. The influence of dietary docosahexaenoic acid and arachidonic acid on central nervous system polyunsaturated fatty acid composition. Prostaglandins Leukot Essent Fatty Acids. 2007;77(5–6):247–250. doi:10.1016/j.plefa.2007.10.016|||Umhau JC, Zhou W, Carson RE, et al. Imaging incorporation of circulating docosahexaenoic acid into the human brain using positron emission tomography. J Lipid Res. 2009;50(7):1259–1268. doi:10.1194/jlr.M800530-JLR200|||Fox PT, Raichle ME, Mintun MA, Dence C. Nonoxidative glucose consumption during focal physiologic neural activity. Science. 1988;241(4864):462–464. doi:10.1126/science.3260686|||Sappey-Marinier D, Calabrese G, Fein G, Hugg JW, Biggins C, Weiner MW. Effect of photic stimulation on human visual cortex lactate and phosphates using 1H and 31P magnetic resonance spectroscopy. J Cereb Blood Flow Metab. 1992;12(4):584–592. doi:10.1038/jcbfm.1992.82|||Jernberg JN, Bowman CE, Wolfgang MJ, Scafidi S. Developmental regulation and localization of carnitine palmitoyltransferases (CPTs) in rat brain. J Neurochem. 2017;142(3):407–419. doi:10.1111/jnc.14072|||Pellerin L, Magistretti PJ. Neuroenergetics: calling upon astrocytes to satisfy hungry neurons. The neuroscientist: a review journal bringing neurobiology. Neurol Psychiatry. 2004;10(1):53–62. doi:10.1177/1073858403260159|||Pierre K, Pellerin L. Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem. 2005;94(1):1–14|||Pellerin L, Magistretti PJ. Food for thought: challenging the dogmas. J Cereb Blood Flow Metab. 2003;23(11):1282–1286. doi:10.1097/01.WCB.0000096064.12129.3D|||Beard E, Lengacher S, Dias S, Magistretti PJ, Finsterwald C. Astrocytes as key regulators of brain energy metabolism: new therapeutic perspectives. Front Physiol. 2021;12:825816. doi:10.3389/fphys.2021.825816|||Powell CL, Davidson AR, Brown AM. Universal glia to neurone lactate transfer in the nervous system: physiological functions and pathological consequences. Biosensors (Basel). 2020;10(11):183. doi:10.3390/bios10110183|||Guzman M, Blazquez C. Is there an astrocyte-neuron ketone body shuttle? Trends Endocrinol Metab. 2001;12(4):169–173|||Ettle B, Schlachetzki JCM, Winkler J. Oligodendroglia and myelin in neurodegenerative diseases: more than just bystanders? Mol Neurobiol. 2016;53(5):3046–3062. doi:10.1007/s12035-015-9205-3|||Nave KA. Myelination and the trophic support of long axons. Nat Rev Neurosci. 2010;11(4):275–283. doi:10.1038/nrn2797|||Mot AI, Depp C, Nave KA. An emerging role of dysfunctional axonoligodendrocyte coupling in neurodegenerative diseases. Dialogues Clin Neurosci. 2018;20(4):283–292|||Jha MK, Morrison BM. Glia-neuron energy metabolism in health and diseases: new insights into the role of nervous system metabolic transporters. Exp Neurol. 2018;309:23–31. doi:10.1016/j.expneurol.2018.07.009|||Lee Y, Morrison BM, Li Y, et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature. 2012;487(7408):443–448. doi:10.1038/nature11314|||Meyer N, Richter N, Fan Z, et al. Oligodendrocytes in the mouse corpus callosum maintain axonal function by delivery of glucose. Cell Rep. 2018;22(9):2383–2394. doi:10.1016/j.celrep.2018.02.022|||Philippot C, Griemsmann S, Jabs R, Seifert G, Kettenmann H, Steinhauser C. Astrocytes and oligodendrocytes in the thalamus jointly maintain synaptic activity by supplying metabolites. Cell Rep. 2021;34(3):108642. doi:10.1016/j.celrep.2020.108642|||Chamberlain KA, Huang N, Xie Y, et al. Oligodendrocytes enhance axonal energy metabolism by deacetylation of mitochondrial proteins through transcellular delivery of SIRT2. Neuron. 2021;109(21):3456–3472 e8. doi:10.1016/j.neuron.2021.08.011|||Ginhoux F, Greter M, Leboeuf M, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330(6005):841–845. doi:10.1126/science.1194637|||Sierra A, Encinas JM, Deudero JJ, et al. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell. 2010;7(4):483–495. doi:10.1016/j.stem.2010.08.014|||Paolicelli RC, Bolasco G, Pagani F, et al. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011;333(6048):1456–1458. doi:10.1126/science.1202529|||Parkhurst CN, Yang G, Ninan I, et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell. 2013;155(7):1596–1609. doi:10.1016/j.cell.2013.11.030|||Monsorno K, Buckinx A, Paolicelli RC. Microglial metabolic flexibility: emerging roles for lactate. Trends Endocrinol Metab. 2022;33(3):186–195. doi:10.1016/j.tem.2021.12.001|||Bernier L-P, York EM, Kamyabi A, Choi HB, Weilinger NL, MacVicar BA. Microglial metabolic flexibility supports immune surveillance of the brain parenchyma. Nat Commun. 2020;11(1):1559. doi:10.1038/s41467-020-15267-z|||Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14(3):133–150. doi:10.1038/nrneurol.2017.188. Epub 2018/01/30.|||Uchida Y, Zhang Z, Tachikawa M, Terasaki T. Quantitative targeted absolute proteomics of rat blood–cerebrospinal fluid barrier transporters: comparison with a human specimen. J Neurochem. 2015;134(6):1104–1115. doi:10.1111/jnc.13147|||Mak C, Waldvogel H, Dodd J, et al. Immunohistochemical localisation of the creatine transporter in the rat brain. Neuroscience. 2009;163(2):571–585.|||Kang YS, Lee KE, Lee NY, Terasaki T. Donepezil, tacrine and alpha-phenyl-n-tert-butyl nitrone (PBN) inhibit choline transport by conditionally immortalized rat brain capillary endothelial cell lines (TR-BBB). Arch Pharm Res. 2005;28(4):443–450. doi:10.1007/bf02977674|||Shawahna R, Uchida Y, Declèves X, et al. Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels. Mol Pharm. 2011;8(4):1332–1341. doi:10.1021/mp200129p|||Spector R, Johanson CE. Vitamin transport and homeostasis in mammalian brain: focus on Vitamins B and E. J Neurochem. 2007;103(2):425–438. doi:10.1111/j.1471-4159.2007.04773.x|||Montalbetti N, Simonin A, Kovacs G, Hediger MA. Mammalian iron transporters: families SLC11 and SLC40. Mol Aspects Med. 2013;34(2–3):270–287. doi:10.1016/j.mam.2013.01.002|||Oldendorf WH, Cornford ME, Brown WJ. The large apparent work capability of the blood-brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Ann Neurol. 1977;1(5):409–417.|||Campos-Bedolla P, Walter FR, Veszelka S, Deli MA. Role of the blood-brain barrier in the nutrition of the central nervous system. Arch Med Res. 2014;45(8):610–638. doi:10.1016/j.arcmed.2014.11.018|||Hall CN, Reynell C, Gesslein B, et al. Capillary pericytes regulate cerebral blood flow in health and disease. Nature. 2014;508(7494):55–60.|||Vlassenko AG, Vaishnavi SN, Couture L, et al. Spatial correlation between brain aerobic glycolysis and amyloid-beta (Abeta) deposition. Proc Natl Acad Sci U S A. 2010;107(41):17763–17767. 10.1073/pnas.1010461107|||Yin F, Sancheti H, Patil I, Cadenas E. Energy metabolism and inflammation in brain aging and Alzheimer’s disease. Free Radical Biol Med. 2016;100:108–122. doi:10.1016/j.freeradbiomed.2016.04.200|||Goyal MS, Vlassenko AG, Blazey TM, et al. Loss of brain aerobic glycolysis in normal human aging. Cell Metab. 2017;26(2):353–360.e3. doi:10.1016/j.cmet.2017.07.010|||Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6(8):734–746. doi:10.1016/s1474-4422(07)70178-3|||Kalaria RN, Harik SI. Reduced glucose transporter at the blood-brain barrier and in cerebral cortex in Alzheimer disease. J Neurochem. 1989;53(4):1083–1088. doi:10.1111/j.1471-4159.1989.tb07399.x|||Simpson IA, Davies P. Reduced glucose transporter concentrations in brains of patients with Alzheimer’s disease. Ann Neurol. 1994;36(5):800–801. doi:10.1002/ana.410360522|||Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Brain glucose transporters, O-GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer’s disease. J Neurochem. 2009;111(1):242–249. doi:10.1111/j.1471-4159.2009.06320.x|||Kim Y, Zheng X, Ansari Z, et al. Mitochondrial aging defects emerge in directly reprogrammed human neurons due to their metabolic profile. Cell Rep. 2018;23(9):2550–2558. doi:10.1016/j.celrep.2018.04.105|||Chao CC, Gutierrez-Vazquez C, Rothhammer V, et al. Metabolic control of astrocyte pathogenic activity via cPLA2-MAVS. Cell. 2019;179(7):1483–1498 e22. doi:10.1016/j.cell.2019.11.016|||Chuang DY, Simonyi A, Kotzbauer PT, Gu Z, Sun GY. Cytosolic phospholipase A 2 plays a crucial role in ROS/NO signaling during microglial activation through the lipoxygenase pathway. J Neuroinflammation. 2015;12(1):199.|||Ebright B, Assante I, Poblete RA, Wang S, Duro MV, Bennett DA, et al. Eicosanoid lipidome activation in post-mortem brain tissues of individuals with APOE4 and Alzheimer’s dementia. Alzheimer’s Research & Therapy. 2022;14:152.|||Duro MV, Ebright B, Yassine HN. Lipids and brain inflammation in APOE4-associated dementia. Curr Opin Lipidol. 2022;33(1):16–24.|||Blass JP, Sheu KF, Piacentini S, Sorbi S. Inherent abnormalities in oxidative metabolism in Alzheimer’s disease: interaction with vascular abnormalities. Ann N Y Acad Sci. 1997;826:382–385. doi:10.1111/j.1749-6632.1997.tb48488.x|||Sharma C, Kim S, Nam Y, Jung UJ, Kim SR. Mitochondrial dysfunction as a driver of cognitive impairment in Alzheimer’s disease. Int J Mol Sci. 2021;22(9):4850. doi:10.3390/ijms22094850|||Knottnerus SJG, Bleeker JC, Wust RCI, et al. Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle. Rev Endocr Metab Disord. 2018;19:93–106. doi:10.1007/s11154-018-9448-1|||Lehmann R, Zhao X, Weigert C, et al. Medium chain acylcarnitines dominate the metabolite pattern in humans under moderate intensity exercise and support lipid oxidation. PLoS One. 2010;5(7):e11519. doi:10.1371/journal.pone.0011519|||Morris AA. Cerebral ketone body metabolism. J Inherit Metab Dis. 2005;28(2):109–121. doi:10.1007/s10545-005-5518-0|||Cristofano A, Sapere N, La Marca G, et al. Serum levels of acylcarnitines along the continuum from normal to Alzheimer’s Dementia. PLOS ONE. 2016;11(5):e0155694. doi:10.1371/journal.pone.0155694|||Horgusluoglu E, Neff R, Song W-M, et al. Integrative metabolomics-genomics approach reveals key metabolic pathways and regulators of Alzheimer’s disease. Alzheimers Dement. 2022;18(6):1260–1278. doi:10.1002/alz.12468|||Huguenard CJC, Cseresznye A, Evans JE, et al. APOE ε4 and Alzheimer’s disease diagnosis associated differences in L-carnitine, GBB, TMAO and acylcarnitines in blood and brain. Curr Res Transl Med. 2022:103362. doi:10.1016/j.retram.2022.103362|||Sultana R, Perluigi M, Butterfield DA. Protein oxidation and lipid peroxidation in brain of subjects with Alzheimer’s disease: insights into mechanism of neurodegeneration from redox proteomics. Antioxid Redox Signaling. 2006;8(11–12):2021–2037. doi:10.1089/ars.2006.8.2021|||Gregersen N, Mortensen PB, Kolvraa S. On the biologic origin of C6-C10-dicarboxylic and C6-C10-omega-1-hydroxy monocarboxylic acids in human and rat with acyl-CoA dehydrogenation deficiencies: in vitro studies on the omega- and omega-1-oxidation of medium-chain (C6-C12) fatty acids in human and rat liver. Pediatr Res. 1983;17(10):828–834. doi:10.1203/00006450-198310000-00013|||Gregersen N, Ingerslev J. The excretion of C6-C10-dicarboxylic acids in the urine of newborn infants during starvation. Evidence for omega-oxidation of fatty acids in the newborn. Acta Paediatr Scand. 1979;68(5):677–681. doi:10.1111/j.1651-2227.1979.tb18437.x|||Johnson DC, Brunsvold RA, Ebert KA, Ray PD. Gluconeogenesis in rabbit liver. I. Pyruvate-derived dicarboxylic acids and phosphoenolpyruvate formation in rabbit liver. J Biol Chem. 1973;248(3):763–770|||Orrenius S Cytochrome P-450 in the omega-oxidation of fatty acids. Biochem J. 1969;115(5):25P–6P. doi:10.1042/bj1150025p|||Yang Y, Gibson GE. Succinylation links metabolism to protein functions. Neurochem Res. 2019;44(10):2346–2359. doi:10.1007/s11064-019-02780-x|||Sieber MA, Hegel JK. Azelaic acid: properties and mode of action. Skin Pharmacol Physiol. 2014;27(Suppl 1):9–17. doi:10.1159/000354888|||Bartzokis G Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer’s disease. Neurobiol Aging. 2004;25(1):5–18. doi:10.1016/j.neurobiolaging.2003.03.001|||Nasrabady SE, Rizvi B, Goldman JE, Brickman AM. White matter changes in Alzheimer’s disease: a focus on myelin and oligodendrocytes. Acta Neuropathol Commun. 2018;6(1):22. doi:10.1186/s40478-018-0515-3|||Rivera AD, Chacon-De-La-Rocha I, Pieropan F, Papanikolau M, Azim K, Butt AM. Keeping the ageing brain wired: a role for purine signalling in regulating cellular metabolism in oligodendrocyte progenitors. Pflugers Arch. 2021;473(5):775–783. doi:10.1007/s00424-021-02544-z|||Bartzokis G Alzheimer’s disease as homeostatic responses to age-related myelin breakdown. Neurobiol Aging. 2011;32(8):1341–1371. doi:10.1016/j.neurobiolaging.2009.08.007|||Teipel SJ, Bayer W, Alexander GE, et al. Progression of corpus callosum atrophy in Alzheimer disease. Arch Neurol. 2002;59(2):243–248. doi:10.1001/archneur.59.2.243|||Wu Y, Ma Y, Liu Z, Geng Q, Chen Z, Zhang Y. Alterations of myelin morphology and oligodendrocyte development in early stage of Alzheimer’s disease mouse model. Neurosci Lett. 2017;642:102–106. doi:10.1016/j.neulet.2017.02.007|||Vanzulli I, Papanikolaou M, De-La-Rocha IC, et al. Disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of Alzheimer’s disease. Neurobiol Aging. 2020;94:130–139. doi:10.1016/j.neurobiolaging.2020.05.016|||Butt AM, De La, Rocha IC, Rivera A. Oligodendroglial cells in Alzheimer’s disease. Adv Exp Med Biol. 2019;1175:325–333. doi:10.1007/978-981-13-9913-8_12|||Zhang X, Wang R, Hu D, et al. Oligodendroglial glycolytic stress triggers inflammasome activation and neuropathology in Alzheimer’s disease. Sci Adv. 2020;6(49):eabb8680. doi:10.1126/sciadv.abb8680|||Desai MK, Mastrangelo MA, Ryan DA, Sudol KL, Narrow WC, Bowers WJ. Early oligodendrocyte/myelin pathology in Alzheimer’s disease mice constitutes a novel therapeutic target. Am J Pathol. 2010;177(3):1422–1435. doi:10.2353/ajpath.2010.100087|||Acosta C, Anderson HD, Anderson CM. Astrocyte dysfunction in Alzheimer disease. J Neurosci Res. 2017;95(12):2430–2447. doi:10.1002/jnr.24075|||Baik SH, Kang S, Lee W, et al. A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer’s disease. Cell Metab. 2019;30(3):493–507.e6. doi:10.1016/j.cmet.2019.06.005|||Rubio-Araiz A, Finucane OM, Keogh S, Lynch MA. Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of β-amyloid. J Neuroinflammation. 2018;15(1):247. doi:10.1186/s12974-018-1281-7|||Pan R-Y, He L, Zhang J, et al. Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer’s disease. Cell Metab. 2022;34(4):634–648.e6. doi:10.1016/j.cmet.2022.02.013|||Liu Y, Zhang H, Wang S, et al. Reduced pericyte and tight junction coverage in old diabetic rats are associated with hyperglycemia-induced cerebrovascular pericyte dysfunction. Am J Physiol Heart Circ Physiol. 2021;320(2):H549–H62.|||Fisslthaler B, Fleming I. Activation and signaling by the AMP-activated protein kinase in endothelial cells. Circ Res. 2009;105(2):114–127.|||Nwadozi E, Rudnicki M, Haas TL. Metabolic coordination of pericyte phenotypes: therapeutic implications. Front Cell Dev Biol. 2020;8:77.|||Montagne A, Barnes SR, Sweeney MD, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015;85(2):296–302. doi:10.1016/j.neuron.2014.12.032|||Mooradian AD. Effect of aging on the blood-brain barrier. Neurobiol Aging. 1988;9(1):31–39. doi:10.1016/s0197-4580(88)80013-7|||Bowman GL, Dayon L, Kirkland R, et al. Blood-brain barrier breakdown, neuroinflammation, and cognitive decline in older adults. Alzheimers Dement. 2018;14(12):1640–1650. doi:10.1016/j.jalz.2018.06.2857|||Bowman GL, Kaye JA, Moore M, Waichunas D, Carlson NE, Quinn JF. Blood-brain barrier impairment in Alzheimer disease: stability and functional significance. Neurology. 2007;68(21):1809–1814. doi:10.1212/01.wnl.0000262031.18018.1a|||Bell RD, Winkler EA, Singh I, et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012;485(7399):512–516. doi:10.1038/nature11087|||Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood-brain barrier: from physiology to disease and back. Physiol Rev. 2019;99(1):21–78. doi:10.1152/physrev.00050.2017|||Montagne A, Nation DA, Sagare AP, et al. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature. 2020;581(7806):71–76. doi:10.1038/s41586-020-2247-3|||Van Dyken P, Lacoste B. Impact of metabolic syndrome on neuroinflammation and the blood-brain barrier. Front Neurosci. 2018;12:930. doi:10.3389/fnins.2018.00930|||Deane R, Sagare A, Hamm K, et al. apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest. 2008;118(12):4002–4013. doi:10.1172/jci36663|||Bowman GL, Dodge H, Frei B, et al. Ascorbic acid and rates of cognitive decline in Alzheimer’s disease. J Alzheimers Dis. 2009;16(1):93–98. doi:10.3233/JAD-2009-0923|||Dayon L, Guiraud SP, Corthesy J, et al. One-carbon metabolism, cognitive impairment and CSF measures of Alzheimer pathology: homocysteine and beyond. Alzheimers Res Ther. 2017;9(1):43. doi:10.1186/s13195-017-0270-x|||Stover PJ, Durga J, Field MS. Folate nutrition and blood-brain barrier dysfunction. Curr Opin Biotechnol. 2017;44:146–152. doi:10.1016/j.copbio.2017.01.006|||Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV. Establishment and dysfunction of the blood-brain barrier. Cell. 2015;163(5):1064–1078. doi:10.1016/j.cell.2015.10.067|||Arellanes IC, Choe N, Solomon V, et al. Brain delivery of supplemental docosahexaenoic acid (DHA): a randomized placebo-controlled clinical trial. EBioMedicine. 2020;59:102883. doi:10.1016/j.ebiom.2020.102883|||Nguyen LN, Ma D, Shui G, et al. Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature (London). 2014;509(7501):503–506. doi:10.1038/nature13241|||Yassine HN, Finch CE. APOE alleles and diet in brain aging and Alzheimer’s disease. Front Aging Neurosci. 2020;12(150):1–18. doi:10.3389/fnagi.2020.00150|||Brandon JA, Farmer BC, Williams HC, Johnson LA. APOE and Alzheimer’s disease: neuroimaging of metabolic and cerebrovascular dysfunction. Front Aging Neurosci. 2018;10:180. doi:10.3389/fnagi.2018.00180|||Farmer BC, Johnson LA, Hanson AJ. Effects of apolipoprotein E on nutritional metabolism in dementia. Curr Opin Lipidol. 2019;30(1):10–15. doi:10.1097/mol.0000000000000566|||Martínez-Martínez AB, Torres-Perez E, Devanney N, Del Moral R, Johnson LA, Arbones-Mainar JM. Beyond the CNS: the many peripheral roles of APOE. Neurobiol Dis. 2020;138:104809. doi:10.1016/j.nbd.2020.104809|||Fernandez CG, Hamby ME, McReynolds ML, Ray WJ. The role of APOE4 in disrupting the homeostatic functions of astrocytes and microglia in aging and Alzheimer’s disease. Front Aging Neurosci 2019;11:14. doi:10.3389/fnagi.2019.00014|||Wolf AB, Caselli RJ, Reiman EM, Valla J. APOE and neuroenergetics: an emerging paradigm in Alzheimer’s disease. Neurobiol Aging. 2013;34(4):1007–1017. doi:10.1016/j.neurobiolaging.2012.10.011|||Reiman EM, Chen K, Alexander GE, et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc Natl Acad Sci. 2004;101(1):284–289.|||Johnson ECB, Dammer EB, Duong DM, et al. Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26(5):769–780. doi:10.1038/s41591-020-0815-6|||Williams HC, Farmer BC, Piron MA, et al. APOE alters glucose flux through central carbon pathways in astrocytes. Neurobiol Dis. 2020;136:104742. doi:10.1016/j.nbd.2020.104742|||Farmer BC, Williams HC, Devanney NA, et al. APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis. Mol Neurodegener. 2021;16(1):62. doi:10.1186/s13024-021-00483-y|||Konttinen H, Cabral-da-Silva MEC, Ohtonen S, et al. PSEN1ΔE9, APPswe, and APOE4 confer disparate phenotypes in human iPSC-Derived Microglia. Stem Cell Reports. 2019;13(4):669–683. doi:10.1016/j.stemcr.2019.08.004|||Yassine HN, Croteau E, Rawat V, et al. DHA brain uptake and APOE4 status: a PET study with [1–11 C]-DHA. Alzheimers Res Ther. 2017;9(1):23.|||Farmer BC, Kluemper J, Johnson LA. Apolipoprotein E4 alters astrocyte fatty acid metabolism and lipid droplet formation. Cells. 2019;8(2):182. doi:10.3390/cells8020182|||Sienski G, Narayan P, Bonner JM, et al. APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia. Sci Transl Med. 2021;13(583):eaaz4564. doi:10.1126/scitranslmed.aaz4564|||Lin YT, Seo J, Gao F, et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron. 2018;98(6):1141–1154.e7. doi:10.1016/j.neuron.2018.05.008|||Qi G, Mi Y, Shi X, Gu H, Brinton RD, Yin F. ApoE4 impairs neuron-astrocyte coupling of fatty acid metabolism. Cell Rep. 2021;34(1):108572. doi:10.1016/j.celrep.2020.108572|||Rawat V, Wang S, Sima J, et al. ApoE4 alters ABCA1 membrane trafficking in astrocytes. J Neurosci. 2019;39(48):9611–9622. doi:10.1523/jneurosci.1400-19.2019|||Tomaszewski N, He X, Solomon V, et al. Effect of APOE genotype on plasma docosahexaenoic acid (DHA), eicosapentaenoic acid, arachidonic acid, and hippocampal volume in the Alzheimer’s disease cooperative study-sponsored DHA clinical trial. J Alzheimers Dis. 2020;74(3):975–990. doi:10.3233/JAD-191017|||Chouinard-Watkins R, Plourde M. Fatty acid metabolism in carriers of apolipoprotein E epsilon 4 allele: is it contributing to higher risk of cognitive decline and coronary heart disease? Nutrients. 2014;6(10):4452–4471. doi:10.3390/nu6104452|||Zilberter Y, Zilberter M. The vicious circle of hypometabolism in neurodegenerative diseases: ways and mechanisms of metabolic correction. J Neurosci Res. 2017;95(11):2217–2235. doi:10.1002/jnr.24064|||Zhao N, Ren Y, Yamazaki Y, et al. Alzheimer’s risk factors age, APOE genotype, and sex drive distinct molecular pathways. Neuron. 2020;106(5):727–742 e6. doi:10.1016/j.neuron.2020.02.034|||Ezra-Nevo G, Henriques SF, Ribeiro C. The diet-microbiome tango: how nutrients lead the gut brain axis. Curr Opin Neurobiol. 2020;62:122–132. doi:10.1016/j.conb.2020.02.005|||Lal S, Kirkup AJ, Brunsden AM, Thompson DG, Grundy D. Vagal afferent responses to fatty acids of different chain length in the rat. Am J Physiol Gastrointest Liver Physiol. 2001;281(4):G907–G915. doi:10.1152/ajpgi.2001.281.4.G907|||Baj A, Moro E, Bistoletti M, Orlandi V, Crema F, Giaroni C. Glutamatergic signaling along the microbiota-gut-brain axis. Int J Mol Sci. 2019;20(6):1482. doi:10.3390/ijms20061482|||Lyte M Probiotics function mechanistically as delivery vehicles for neuroactive compounds: microbial endocrinology in the design and use of probiotics. BioEssays. 2011;33(8):574–581. doi:10.1002/bies.201100024|||Sarkar A, Lehto SM, Harty S, Dinan TG, Cryan JF, Burnet PWJ. Psychobiotics and the manipulation of bacteria-gut-brain signals. Trends Neurosci. 2016;39(11):763–781. doi:10.1016/j.tins.2016.09.002|||Vogt NM, Romano KA, Darst BF, et al. The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease. Alzheimers Res Ther. 2018;10(1):124. doi:10.1186/s13195-018-0451-2|||Sharon G, Sampson TR, Geschwind DH, Mazmanian SK. The central nervous system and the gut microbiome. Cell. 2016;167(4):915–932. doi:10.1016/j.cell.2016.10.027|||Bonaz B, Bazin T, Pellissier S. The vagus nerve at the interface of the microbiota-gut-brain axis. Front Neurosci. 2018;12:49. doi:10.3389/fnins.2018.00049|||Nagpal R, Mainali R, Ahmadi S, et al. Gut microbiome and aging: physiological and mechanistic insights. Nutr Healthy Aging. 2018;4(4):267–285. doi:10.3233/NHA-170030|||Gevezova M, Sarafian V, Anderson G, Maes M. Inflammation and mitochondrial dysfunction in autism spectrum disorder. CNS Neurol Disord Drug Targets. 2020;19(5):320–333. doi:10.2174/1871527319666200628015039|||Wu SC, Cao ZS, Chang KM, Juang JL. Intestinal microbial dysbiosis aggravates the progression of Alzheimer’s disease in Drosophila. Nat Commun. 2017;8(1):24. doi:10.1038/s41467-017-00040-6|||Liu J, Wang F, Liu S, et al. Sodium butyrate exerts protective effect against Parkinson’s disease in mice via stimulation of glucagon like peptide-1. J Neurol Sci. 2017;381:176–181. doi:10.1016/j.jns.2017.08.3235|||Ho L, Ono K, Tsuji M, Mazzola P, Singh R, Pasinetti GM. Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer’s disease-type beta-amyloid neuropathological mechanisms. Expert Rev Neurother. 2018;18(1):83–90. doi:10.1080/14737175.2018.1400909|||Liu S, Li E, Sun Z, et al. Altered gut microbiota and short chain fatty acids in Chinese children with autism spectrum disorder. Sci Rep. 2019;9(1):287. doi:10.1038/s41598-018-36430-z|||Vogt NM, Kerby RL, Dill-McFarland KA, et al. Gut microbiome alterations in Alzheimer’s disease. Sci Rep. 2017;7(1):13537. doi:10.1038/s41598-017-13601-y|||Zeng Q, Shen J, Chen K, et al. The alteration of gut microbiome and metabolism in amyotrophic lateral sclerosis patients. Sci Rep. 2020;10(1):12998. doi:10.1038/s41598-020-69845-8|||Ramakrishna BS, Roediger WE. Bacterial short chain fatty acids: their role in gastrointestinal disease. Dig Dis. 1990;8(6):337–345. doi:10.1159/000171266|||Erny D, Dokalis N, Mezo C, et al. Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease. Cell Metab. 2021;33(11):2260–2276 e7. doi:10.1016/j.cmet.2021.10.010|||Fonteh AN, Cipolla M, Chiang J, Arakaki X, Harrington MG. Human cerebrospinal fluid fatty acid levels differ between supernatant fluid and brain-derived nanoparticle fractions, and are altered in Alzheimer’s disease. PLoS One. 2014;9(6):e100519. doi:10.1371/journal.pone.0100519|||Li D, Ke Y, Zhan R, et al. Trimethylamine-N-oxide promotes brain aging and cognitive impairment in mice. Aging Cell. 2018;17(4):e12768. doi:10.1111/acel.12768|||Del Rio D, Zimetti F, Caffarra P, et al. The gut microbial metabolite trimethylamine-N-oxide is present in human cerebrospinal fluid. Nutrients. 2017;9(10):1053. doi:10.3390/nu9101053|||Yassine HN, Samieri C, Livingston G, et al. Nutrition state of science and dementia prevention: recommendations of the nutrition for dementia prevention working group. Lancet Healthy Longev. 2022;3(7):e501–e12. doi:10.1016/s2666-7568(22)00120-9|||Samieri C, Yassine HN, Melo van Lent D, et al. Personalized nutrition for dementia prevention. Alzheimers Dement. 2021;18(7):1424–1437. doi:10.1002/alz.12486|||Cullen KM, Halliday GM. Neurof ibrillary tangles in chronic alcoholics. Neuropathol Appl Neurobiol. 1995;21(4):312–318. doi:10.1111/j.1365-2990.1995.tb01065.x|||Cullen KM, Halliday GM, Caine D, Kril JJ. The nucleus basalis (Ch4) in the alcoholic Wernicke-Korsakoff syndrome: reduced cell number in both amnesic and non-amnesic patients. J Neurol Neurosurg Psychiatr. 1997;63(3):315. doi:10.1136/jnnp.63.3.315|||Karuppagounder SS, Xu H, Shi Q, et al. Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer’s mouse model. Neurobiol Aging. 2009;30(10):1587–1600. doi:10.1016/j.neurobiolaging.2007.12.013|||Pan X, Gong N, Zhao J, et al. Powerful beneficial effects of benfotiamine on cognitive impairment and beta-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice. Brain. 2010;133(Pt 5):1342–1351|||Tapias V, Jainuddin S, Ahuja M, et al. Benfotiamine treatment activates the Nrf2/ARE pathway and is neuroprotective in a transgenic mouse model of tauopathy. Hum Mol Genet. 2018;27(16):2874–2892. doi:10.1093/hmg/ddy201|||Gibson GE, Luchsinger JA, Cirio R, et al. Benfotiamine and cognitive decline in Alzheimer’s disease: results of a randomized placebo-controlled phase IIa clinical trial. J Alzheimers Dis. 2020;78(3):989–1010.|||Li S, Guo Y, Men J, Fu H, Xu T. The preventive efficacy of vitamin B supplements on the cognitive decline of elderly adults: a systematic review and meta-analysis. BMC Geriatrics. 2021;21(1):367. doi:10.1186/s12877-021-02253-3|||Thomas A, Baillet M, Proust-Lima C, et al. Blood polyunsaturated omega-3 fatty acids, brain atrophy, cognitive decline, and dementia risk. Alzheimers Dement. 2020;17(3):407–416. doi:10.1002/alz.12195|||Wang S, Li B, Solomon V, et al. Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4. Mol Neurodegener. 2022;17(1):42. doi:10.1186/s13024-022-00549-5|||Bowman GL, Scarmeas N. Dietary patterns in early life pay dividends for midlife cognitive performance. Neurology. 2019;92(14):645–646. doi:10.1212/WNL.0000000000007229|||Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC. Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer’s disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutr Metab (Lond). 2009;6:31. doi:10.1186/1743-7075-6-31|||Juby AG, Blackburn TE, Mager DR. Use of medium chain triglyceride (MCT) oil in subjects with Alzheimer’s disease: a randomized, double-blind, placebo-controlled, crossover study, with an open-label extension. Alzheimers Dement (N Y). 2022;8(1):e12259–e. doi:10.1002/trc2.12259|||Fortier M, Castellano CA, Croteau E, et al. A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. Alzheimers Dement. 2019;15(5):625–634. doi:10.1016/j.jalz.2018.12.017|||Fortier M, Castellano CA, St-Pierre V, et al. A ketogenic drink improves cognition in mild cognitive impairment: results of a 6-month RCT. Alzheimers Dement. 2021;17(3):543–552. doi:10.1002/alz.12206|||Roy M, Fortier M, Rheault F, et al. A ketogenic supplement improves white matter energy supply and processing speed in mild cognitive impairment. medRxiv. 2021;7(1):e12217. doi:10.1101/2021.03.18.21253884|||Roy M, Edde M, Fortier M, et al. A ketogenic intervention improves dorsal attention network functional and structural connectivity in mild cognitive impairment. Neurobiol Aging. 2022;115:77–87. doi:10.1016/j.neurobiolaging.2022.04.005|||Xu Q, Zhang Y, Zhang X, et al. Medium-chain triglycerides improved cognition and lipid metabolomics in mild to moderate Alzheimer’s disease patients with APOE4(−/−): a double-blind, randomized, placebo-controlled crossover trial. Clin Nutr. 2020;39(7):2092–2105|||Grammatikopoulou MG, Goulis DG, Gkiouras K, et al. To keto or not to keto? A systematic review of randomized controlled trials assessing the effects of ketogenic therapy on Alzheimer Disease. Adv Nutr. 2020;11(6):1583–1602. doi:10.1093/advances/nmaa073|||Cunnane SC, Trushina E, Morland C, et al. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing. Nat Rev Drug Discovery. 2020;19(9):609–633. doi:10.1038/s41573-020-0072-x|||Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, Aggarwal NT. MIND diet associated with reduced incidence of Alzheimer’s disease. Alzheimers Dement. 2015;11(9):1007–1014. doi:10.1016/j.jalz.2014.11.009|||Neth BJ, Mintz A, Whitlow C, et al. Modified ketogenic diet is associated with improved cerebrospinal fluid biomarker profile, cerebral perfusion, and cerebral ketone body uptake in older adults at risk for Alzheimer’s disease: a pilot study. Neurobiol Aging. 2020;86:54–63. doi:10.1016/j.neurobiolaging.2019.09.015|||Jensen DEA, Leoni V, Klein-Flügge MC, Ebmeier KP, Suri S. Associations of dietary markers with brain volume and connectivity: a systematic review of MRI studies. Ageing Res Rev. 2021;70:101360. doi:10.1016/j.arr.2021.101360|||Berti V, Walters M, Sterling J, et al. Mediterranean diet and 3-year Alzheimer brain biomarker changes in middle-aged adults. Neurology. 2018;90(20):e1789–e98. doi:10.1212/wnl.0000000000005527|||Berti V, Murray J, Davies M, et al. Nutrient patterns and brain biomarkers of Alzheimer’s disease in cognitively normal individuals. J Nutr Health Aging. 2015;19(4):413–423. doi:10.1007/s12603-014-0534-0|||Small GW, Silverman DH, Siddarth P, et al. Effects of a 14-day healthy longevity lifestyle program on cognition and brain function. Am J Geriatr Psychiatry. 2006;14(6):538–545. doi:10.1097/01.JGP.0000219279.72210.ca|||Kim JW, Byun MS, Yi D, et al. Serum zinc levels and in vivo beta-amyloid deposition in the human brain. Alzheimers Res Ther. 2021;13(1):190. doi:10.1186/s13195-021-00931-3|||Nugent S, Croteau E, Pifferi F, et al. Brain and systemic glucose metabolism in the healthy elderly following fish oil supplementation. Prostaglandins Leukot Essent Fatty Acids. 2011;85(5):287–291. doi:10.1016/j.plefa.2011.04.008|||Scheltens NME, Briels CT, Yaqub M, et al. Exploring effects of Souvenaid on cerebral glucose metabolism in Alzheimer’s disease. Alzheimers Dement (N Y). 2019;5:492–500. doi:10.1016/j.trci.2019.08.002|||Manzano Palomo MS, Anaya Caravaca B, Balsa Bretón MA, et al. Mild cognitive impairment with a high risk of progression to Alzheimer’s Disease Dementia (MCI-HR-AD): effect of Souvenaid(®) treatment on cognition and (18)F-FDG PET scans. J Alzheimers Dis Rep. 2019;3(1):95–102. doi:10.3233/adr-190109|||Matthews DC, Davies M, Murray J, et al. Physical activity, mediterranean diet and biomarkers-assessed risk of Alzheimer’s: a multi-modality brain imaging study. Adv J Mol Imaging. 2014;4(4):43–57. doi:10.4236/ami.2014.44006|||Rai G, Wright G, Scott L, Beston B, Rest J, Exton-Smith AN. Double-blind, placebo controlled study of acetyl-l-carnitine in patients with Alzheimer’s dementia. Curr Med Res Opin. 1990;11(10):638–647. doi:10.1185/03007999009112690|||Spagnoli A, Lucca U, Menasce G, et al. Long-term acetyl-L-carnitine treatment in Alzheimer’s disease. Neurology. 1991;41(11):1726–1732. doi:10.1212/wnl.41.11.1726|||Thal LJ, Calvani M, Amato A, Carta A. A 1-year controlled trial of acetyl-l-carnitine in early-onset AD. Neurology. 2000;55(6):805–810. doi:10.1212/wnl.55.6.805|||Remington R, Bechtel C, Larsen D, et al. Maintenance of cognitive performance and mood for individuals with Alzheimer’s disease following consumption of a nutraceutical formulation: a one-year, open-label study. J Alzheimers Dis. 2016;51(4):991–995. doi:10.3233/jad-151098|||Fang EF, Lautrup S, Hou Y, et al. NAD+ in aging: molecular mechanisms and translational implications. Trends Mol Med. 2017;23(10):899–916. doi:10.1016/j.molmed.2017.08.001|||Hou Y, Wei Y, Lautrup S, et al. NAD(+) supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer’s disease via cGAS-STING. Proc Natl Acad Sci U S A. 2021;118(37):e2011226118. doi:10.1073/pnas.2011226118|||Harrison DE, Strong R, Reifsnyder P, et al. 17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex. Aging Cell. 2021;20(5):e13328. doi:10.1111/acel.13328|||Reiten OK, Wilvang MA, Mitchell SJ, Hu Z, Fang EF. Preclinical and clinical evidence of NAD+ precursors in health, disease, and ageing. Mech Ageing Dev. 2021;199:111567. doi:10.1016/j.mad.2021.111567|||de Vadder F, Mithieux G. Gut-brain signaling in energy homeostasis: the unexpected role of microbiota-derived succinate. J Endocrinol. 2018;236(2):R105–R8. doi:10.1530/JOE-17-0542|||Braniste V, Al-Asmakh M, Kowal C, et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med. 2014;6(263):263ra158. doi:10.1126/scitranslmed.3009759|||Valvassori SS, Resende WR, Budni J, et al. Sodium butyrate, a histone deacetylase inhibitor, reverses behavioral and mitochondrial alterations in animal models of depression induced by early- or late-life stress. Curr Neurovasc Res. 2015;12(4):312–320. doi:10.2174/1567202612666150728121121|||Sampson TR, Debelius JW, Thron T, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s Disease. Cell. 2016;167(6):1469–1480 e12. doi:10.1016/j.cell.2016.11.018|||Nurrahma BA, Tsao SP, Wu CH, et al. Probiotic supplementation facilitates recovery of 6-OHDA-induced motor deficit via improving mitochondrial function and energy metabolism. Front Aging Neurosci. 2021;13:668775. doi:10.3389/fnagi.2021.668775|||Chunchai T, Thunapong W, Yasom S, et al. Decreased microglial activation through gut-brain axis by prebiotics, probiotics, or synbiotics effectively restored cognitive function in obese-insulin resistant rats. J Neuroinflammation. 2018;15(1):11. doi:10.1186/s12974-018-1055-2|||Blacher E, Bashiardes S, Shapiro H, et al. Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature. 2019;572(7770):474–480. doi:10.1038/s41586-019-1443-5|||Snow WM, Cadonic C, Cortes-Perez C, et al. Sex-specific effects of chronic creatine supplementation on hippocampal-mediated spatial cognition in the 3xTg mouse model of Alzheimer’s disease. Nutrients. 2020;12(11):3589. doi:10.3390/nu12113589|||Adlimoghaddam A, Odero GG, Glazner G, Turner RS, Albensi BC. Nilotinib improves bioenergetic profiling in brain astroglia in the 3xTg mouse model of Alzheimer’s disease. Aging Dis. 2021;12(2):441–465. doi:10.14336/ad.2020.0910|||Soro-Arnaiz I, Li QOY, Torres-Capelli M, et al. Role of mitochondrial complex IV in age-dependent obesity. Cell Rep. 2016;16(11):2991–3002. doi:10.1016/j.celrep.2016.08.041|||Hartz AMS, Rempe RG, Soldner ELB, et al. Cytosolic phospholipase A2 is a key regulator of blood-brain barrier function in epilepsy. FASEB J. 2019;33(12):14281–14295. doi:10.1096/fj.201901369RR|||Minhas PS, Latif-Hernandez A, McReynolds MR, et al. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature. 2021;590(7844):122–128. doi:10.1038/s41586-020-03160-0|||Loving BA, Tang M, Neal MC, et al. Lipoprotein lipase regulates microglial lipid droplet accumulation. Cells. 2021;10(2):198. doi:10.3390/cells10020198|||Buckner RL, Andrews-Hanna JR, Schacter DL. The brain’s default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci. 2008;1124:1–38. doi:10.1196/annals.1440.011|||Frere S, Slutsky I. Alzheimer’s disease: from firing instability to homeostasis network collapse. Neuron. 2018;97(1):32–58. doi:10.1016/j.neuron.2017.11.028|||Kapogiannis D, Mattson MP. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer’s disease. Lancet Neurol. 2011;10(2):187–198. doi:10.1016/s1474-4422(10)70277-5|||Kyrtata N, Emsley HCA, Sparasci O, Parkes LM, Dickie BR. A systematic review of glucose transport alterations in Alzheimer’s disease. Front Neurosci. 2021;15:626636. doi:10.3389/fnins.2021.626636|||Bradshaw PC. Acetyl-CoA metabolism and histone acetylation in the regulation of aging and lifespan. Antioxidants (Basel). 2021;10(4):572. doi:10.3390/antiox10040572|||Gräff J, Rei D, Guan JS, et al. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature. 2012;483(7388):222–226. doi:10.1038/nature10849|||Nativio R, Donahue G, Berson A, et al. Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease. Nat Neurosci. 2018;21(4):497–505. doi:10.1038/s41593-018-0101-9|||Nativio R, Lan Y, Donahue G, et al. An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease. Nat Genet. 2020;52(10):1024–1035. doi:10.1038/s41588-020-0696-0|||Camandola S, Mattson MP. Brain metabolism in health, aging, and neurodegeneration. Embo j. 2017;36(11):1474–1492. doi:10.15252/embj.201695810|||Wang X, Meng ZX, Chen YZ, et al. Enriched environment enhances histone acetylation of NMDA receptor in the hippocampus and improves cognitive dysfunction in aged mice. Neural Regen Res. 2020;15(12):2327–2334. doi:10.4103/1673-5374.285005|||Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai LH. Recovery of learning and memory is associated with chromatin remodelling. Nature. 2007;447(7141):178–182. doi:10.1038/nature05772|||Gomez-Pinilla F, Tyagi E. Diet and cognition: interplay between cell metabolism and neuronal plasticity. Curr Opin Clin Nutr Metab Care. 2013;16(6):726–733. doi:10.1097/MCO.0b013e328365aae3|||Davinelli S, Calabrese V, Zella D, Scapagnini G. Epigenetic nutraceutical diets in Alzheimer’s disease. J Nutr Health Aging. 2014;18(9):800–805. doi:10.1007/s12603-014-0552-y|||Hou N, Ren L, Gong M, et al. Vitamin A deficiency impairs spatial learning and memory: the mechanism of abnormal CBP-dependent histone acetylation regulated by retinoic acid receptor alpha. Mol Neurobiol. 2015;51(2):633–647. doi:10.1007/s12035-014-8741-6|||Ono K, Yamada M. Vitamin A and Alzheimer’s disease. Geriatr Gerontol Int. 2012;12(2):180–188. doi:10.1111/j.1447-0594.2011.00786.x|||Chiu S, Woodbury-Fariña MA, Shad MU, et al. The role of nutrient-based epigenetic changes in buffering against stress, aging, and Alzheimer’s disease. Psychiatr Clin North Am. 2014;37(4):591–623. doi:10.1016/j.psc.2014.09.001|||Athanasopoulos D, Karagiannis G, Tsolaki M. Recent findings in Alzheimer disease and nutrition focusing on epigenetics. Adv Nutr. 2016;7(5):917–927. doi:10.3945/an.116.012229|||Tomioka M, Toda Y, Mañucat NB, et al. Lysophosphatidylcholine export by human ABCA7. Biochim Biophys Acta Mol Cell Biol Lipids. 2017;1862(7):658–665. doi:10.1016/j.bbalip.2017.03.012|||Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet commission. Lancet. 2020;396(10248):413–446. doi:10.1016/s0140-6736(20)30367-6|||Toledo JB, Arnold M, Kastenmüller G, et al. Metabolic network failures in Alzheimer’s disease: a biochemical road map. Alzheimers Dement. 2017;13(9):965–984. doi:10.1016/j.jalz.2017.01.020|||Tokuoka SM, Kita Y, Shimizu T, Oda Y. Isobaric mass tagging and triple quadrupole mass spectrometry to determine lipid biomarker candidates for Alzheimer’s disease. PLoS One. 2019;14(12):e0226073. doi:10.1371/journal.pone.0226073. 358 Shimadzu Co., and Eisai Co. Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare|||Montine TJ, Markesbery WR, Morrow JD, Roberts LJ 2nd. Cerebrospinal fluid F2-isoprostane levels are increased in Alzheimer’s disease. Ann Neurol. 1998;44(3):410–413. doi:10.1002/ana.410440322|||Montine TJ, Kaye JA, Montine KS, McFarland L, Morrow JD, Quinn JF. Cerebrospinal fluid abeta42, tau, and f2-isoprostane concentrations in patients with Alzheimer disease, other dementias, and in age-matched controls. Arch Pathol Lab Med. 2001;125(4):510–512. doi:10.5858/2001-125-0510-CFATAF|||Cui Y, Liu X, Wang M, et al. Lysophosphatidylcholine and amide as metabolites for detecting Alzheimer disease using ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry-based metabonomics. J Neuropathol Exp Neurol. 2014;73(10):954–963. doi:10.1097/NEN.0000000000000116|||Fonteh AN, Harrington RJ, Huhmer AF, Biringer RG, Riggins JN, Harrington MG. Identification of disease markers in human cerebrospinal fluid using lipidomic and proteomic methods. Dis Markers. 2006;22(1–2):39–64. doi:10.1155/2006/202938|||Sagare AP, Sweeney MD, Makshanoff J, Zlokovic BV. Shedding of soluble platelet-derived growth factor receptor-β from human brain pericytes. Neurosci Lett. 2015;607:97–101. doi:10.1016/j.neulet.2015.09.025|||de Wilde MC, Kamphuis PJ, Sijben JW, Scheltens P. Utility of imaging for nutritional intervention studies in Alzheimer’s disease. Eur J Pharmacol. 2011;668(Suppl 1):S59–S69. doi:10.1016/j.ejphar.2011.07.011|||Scarmeas N, Luchsinger JA, Stern Y, et al. Mediterranean diet and magnetic resonance imaging-assessed cerebrovascular disease. Ann Neurol. 2011;69(2):257–268. doi:10.1002/ana.22317|||Gardener H, Scarmeas N, Gu Y, et al. Mediterranean diet and white matter hyperintensity volume in the Northern Manhattan Study. Arch Neurol. 2012;69(2):251–256. doi:10.1001/archneurol.2011.548|||Gu Y, Brickman AM, Stern Y, et al. Mediterranean diet and brain structure in a multiethnic elderly cohort. Neurology. 2015;85(20):1744–1751.|||Smeets PAM, Dagher A, Hare TA, et al. Good practice in food-related neuroimaging. Am J Clin Nutr. 2019;109(3):491–503. doi:10.1093/ajcn/nqy344|||Jensen DEA, Leoni V, Klein-Flügge MC, Ebmeier KP, Suri S. Associations of dietary markers with brain volume and connectivity: a systematic review of MRI studies. Ageing Res Rev. 2021;70:101360. doi:10.1016/j.arr.2021.101360|||Esposito G, Giovacchini G, Liow JS, et al. Imaging neuroinflammation in Alzheimer’s disease with radiolabeled arachidonic acid and PET. J Nucl Med. 2008;49(9):1414–1421. doi:10.2967/jnumed.107.049619|||Tallaksen CM, Bohmer T, Bell H. Concentrations of the water-soluble vitamins thiamin, ascorbic acid, and folic acid in serum and cerebrospinal fluid of healthy individuals. Am J Clin Nutr. 1992;56(3):559–564. doi:10.1093/ajcn/56.3.559|||Abdou E, Hazell AS. Thiamine deficiency: an update of pathophysiologic mechanisms and future therapeutic considerations. Neurochem Res. 2015;40(2):353–361. doi:10.1007/s11064-014-1430-z|||Anagnostouli M, Livaniou E, Nyalala JO, et al. Cerebrospinal fluid levels of biotin in various neurological disorders. Acta Neurol Scand. 1999;99(6):387–392. doi:10.1111/j.1600-0404.1999.tb07369.x|||Balashova OA, Visina O, Borodinsky LN. Folate action in nervous system development and disease. Dev Neurobiol. 2018;78(4):391–402. doi:10.1002/dneu.22579|||Serot JM, Christmann D, Dubost T, Béne MC, Faure GC. CSF-folate levels are decreased in late-onset AD patients. J Neural Transm (Vienna). 2001;108(1):93–99. doi:10.1007/s007020170100|||Nielsen MJ, Rasmussen MR, Andersen CBF, Nexø E, Moestrup SK. Vitamin B12 transport from food to the body’s cells—a sophisticated, multistep pathway. Nat Rev Gastroenterol Hepatol. 2012;9(6):345–354. doi:10.1038/nrgastro.2012.76|||Larsen C, Etzerodt A, Madsen M, Skjødt K, Moestrup SK, Andersen CBF. Structural assembly of the megadalton-sized receptor for intestinal vitamin B12 uptake and kidney protein reabsorption. Nat Commun. 2018;9(1):5204. doi:10.1038/s41467-018-07468-4|||Ikeda T, Furukawa Y, Mashimoto S, Takahashi K, Yamada M. Vitamin B12 levels in serum and cerebrospinal fluid of people with Alzheimer’s disease. Acta Psychiatr Scand. 1990;82(4):327–329. doi:10.1111/j.1600-0447.1990.tb01395.x|||Quinn J, Suh J, Moore MM, Kaye J, Frei B. Antioxidants in Alzheimer’s disease-vitamin C delivery to a demanding brain. J Alzheimers Dis. 2003;5(4):309–313. doi:10.3233/jad-2003-5406|||Harrison FE. A critical review of vitamin C for the prevention of age-related cognitive decline and Alzheimer’s disease. J Alzheimers Dis. 2012;29(4):711–726. doi:10.3233/jad-2012-111853|||Cole GM, Frautschy SA. DHA may prevent age-related dementia. J Nutr. 2010;140(4):869–874. doi:10.3945/jn.109.113910|||Pan Y, Scanlon MJ, Owada Y, Yamamoto Y, Porter CJH, Nicolazzo JA. Fatty acid-binding protein 5 facilitates the blood–brain barrier transport of docosahexaenoic acid. Mol Pharmaceutics. 2015;12(12):4375–4385. doi:10.1021/acs.molpharmaceut.5b00580|||Eyles DW, Liu PY, Josh P, Cui X. Intracellular distribution of the vitamin D receptor in the brain: comparison with classic target tissues and redistribution with development. Neuroscience. 2014;268:1–9. doi:10.1016/j.neuroscience.2014.02.042|||Lee D-H, Kim JH, Jung MH, Cho M-C. Total 25-hydroxy vitamin D level in cerebrospinal fluid correlates with serum total, bioavailable, and free 25-hydroxy vitamin D levels in Korean population. PLoS One. 2019;14(3):e0213389–e. doi:10.1371/journal.pone.0213389|||Soares JZ, Valeur J, Šaltyte Benth J, et al. Vitamin D in Alzheimer’s˙ disease: low levels in cerebrospinal fluid despite normal amounts in serum. J Alzheimers Dis. 2022;86(3):1301–1314. doi:10.3233/jad215536|||Morris MC, Tangney CC, Wang Y, et al. MIND diet slows cognitive decline with aging. Alzheimers Dement. 2015;11(9):1015–1022. doi:10.1016/j.jalz.2015.04.011|||Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH collaborative research group. N Engl J Med. 1997;336(16):1117–1124. doi:10.1056/NEJM199704173361601|||van den Brink AC, Brouwer-Brolsma EM, Berendsen AAM, van de Rest O. The Mediterranean, dietary approaches to stop hypertension (DASH), and Mediterranean-DASH intervention for neurodegenerative delay (MIND) diets are associated with less cognitive decline and a lower risk of Alzheimer’s disease-a review. Adv Nutr. 2019;10(6):1040–1065. doi:10.1093/advances/nmz054|||Panagiotakos DB, Tzima N, Pitsavos C, et al. The association between adherence to the Mediterranean diet and fasting indices of glucose homoeostasis: the ATTICA Study. J Am Coll Nutr. 2007;26(1):32–38. doi:10.1080/07315724.2007.10719583|||Scarmeas N, Stern Y, Tang MX, Mayeux R, Luchsinger JA. Mediterranean diet and risk for Alzheimer’s disease. Ann Neurol. 2006;59(6):912–921. doi:10.1002/ana.20854|||Bowman GL, Silbert LC, Howieson D, et al. Nutrient biomarker patterns, cognitive function, and MRI measures of brain aging. Neurology. 2012;78(4):241–249. doi:10.1212/WNL.0b013e3182436598|||Amadieu C, Lefevre-Arbogast S, Delcourt C, et al. Nutrient biomarker patterns and long-term risk of dementia in older adults. Alzheimers Dement. 2017;13(10):1125–1132. doi:10.1016/j.jalz.2017.01.025|||Bowman GL, Dodge HH, Guyonnet S, et al. A blood-based nutritional risk index explains cognitive enhancement and decline in the multidomain Alzheimer prevention trial. Alzheimers Dement (N Y). 2019;5:953–963. doi:10.1016/j.trci.2019.11.004|||Pottala JV, Yaffe K, Robinson JG, Espeland MA, Wallace R, Harris WS. Higher RBC EPA + DHA corresponds with larger total brain and hippocampal volumes: wHIMS-MRI study. Neurology. 2014;82(5):435–442. doi:10.1212/wnl.0000000000000080|||Ammann EM, Pottala JV, Robinson JG, Espeland MA, Harris WS. Erythrocyte omega-3 fatty acids are inversely associated with incident dementia: secondary analyses of longitudinal data from the Women’s Health Initiative Memory Study (WHIMS). Prostaglandins Leukot Essent Fatty Acids. 2017;121:68–75. doi:10.1016/j.plefa.2017.06.006|||Abdullah L, Evans JE, Emmerich T, et al. APOE epsilon4 specific imbalance of arachidonic acid and docosahexaenoic acid in serum phospholipids identifies individuals with preclinical mild cognitive impairment/Alzheimer’s disease. Aging. 2017;9(3):964–985. doi:10.18632/aging.101203|||Luzzi S, Papiri G, Viticchi G, et al. Association between homocysteine levels and cognitive profile in Alzheimer’s Disease. J Clin Neurosci. 2021;94:250–256. doi:10.1016/j.jocn.2021.09.033|||Wang Q, Zhao J, Chang H, Liu X, Zhu R. Homocysteine and folic acid: risk factors for Alzheimer’s disease-an updated meta-analysis. Front Aging Neurosci. 2021;13:665114. doi:10.3389/fnagi.2021.665114|||Zuin M, Cervellati C, Brombo G, Trentini A, Roncon L, Zuliani G. Elevated blood homocysteine and risk of Alzheimer’s dementia: an updated systematic review and meta-analysis based on prospective studies. J Prev Alzheimers Dis. 2021;8(3):329–334. doi:10.14283/jpad.2021.7|||Kalra A, Teixeira AL, Diniz BS. Association of vitamin D levels with incident all-cause dementia in longitudinal observational studies: a systematic review and meta-analysis. J Prev Alzheimers Dis. 2020;7(1):14–20. doi:10.14283/jpad.2019.44|||Goodwill AM, Szoeke C. A systematic review and meta-analysis of the effect of low vitamin D on cognition. J Am Geriatr Soc. 2017;65(10):2161–2168. doi:10.1111/jgs.15012|||Ciavardelli D, Piras F, Consalvo A, et al. Medium-chain plasma acylcarnitines, ketone levels, cognition, and gray matter volumes in healthy elderly, mildly cognitively impaired, or Alzheimer’s disease subjects. Neurobiol Aging. 2016;43:1–12. doi:10.1016/j.neurobiolaging.2016.03.005|||Castor KJ, Shenoi S, Edminster SP, et al. Urine dicarboxylic acids change in pre-symptomatic Alzheimer’s disease and reflect loss of energy capacity and hippocampal volume. PLoS One. 2020;15(4):e0231765. doi:10.1371/journal.pone.0231765. analysis by our consultant (JMP) from Cipher Biostatistics & Reporting does not alter our adherence to PLOS ONE policies on sharing data and materials.|||DelParigi A, Chen K, Salbe AD, et al. Successful dieters have increased neural activity in cortical areas involved in the control of behavior. Int J Obes (Lond). 2007;31(3):440–448. doi:10.1038/sj.ijo.0803431|||Kennedy DO, Haskell CF. Cerebral blood flow and behavioural effects of caffeine in habitual and non-habitual consumers of caffeine: a near infrared spectroscopy study. Biol Psychol. 2011;86(3):298–306. doi:10.1016/j.biopsycho.2010.12.010|||Dodd FL, Kennedy DO, Riby LM, Haskell-Ramsay CF. A double-blind, placebo-controlled study evaluating the effects of caffeine and L-theanine both alone and in combination on cerebral blood flow, cognition and mood. Psychopharmacology (Berl). 2015;232(14):2563–2576. doi:10.1007/s00213-015-3895-0|||Kennedy DO, Wightman EL, Reay JL, et al. Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation. Am J Clin Nutr. 2010;91(6):1590–1597. doi:10.3945/ajcn.2009.28641|||Wightman EL, Haskell CF, Forster JS, Veasey RC, Kennedy DO. Epigallocatechin gallate, cerebral blood flow parameters, cognitive performance and mood in healthy humans: a double-blind, placebo-controlled, crossover investigation. Hum Psychopharmacol. 2012;27(2):177–186. doi:10.1002/hup.1263|||Watanabe A, Kato N, Kato T. Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation. Neurosci Res. 2002;42(4):279–285. doi:10.1016/s0168-0102(02)00007-x|||Jackson PA, Reay JL, Scholey AB, Kennedy DO. DHA-rich oil modulates the cerebral haemodynamic response to cognitive tasks in healthy young adults: a near IR spectroscopy pilot study. Br J Nutr. 2012;107(8):1093–1098. doi:10.1017/s0007114511004041|||Cohen BM, Renshaw PF, Stoll AL, Wurtman RJ, Yurgelun-Todd D, Babb SM. Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study. JAMA. 1995;274(11):902–907|||Silveri MM, Dikan J, Ross AJ, et al. Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy. NMR Biomed. 2008;21(10):1066–1075. doi:10.1002/nbm.1281|||Brickman AM, Khan UA, Provenzano FA, et al. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nat Neurosci. 2014;17(12):1798–1803. doi:10.1038/nn.3850|||Gu Y, Vorburger RS, Gazes Y, et al. White matter integrity as a mediator in the relationship between dietary nutrients and cognition in the elderly. Ann Neurol. 2016;79(6):1014–1025. doi:10.1002/ana.24674|||Pelletier A, Barul C, Feart C, et al. Mediterranean diet and preserved brain structural connectivity in older subjects. Alzheimers Dement. 2015;11(9):1023–1031. doi:10.1016/j.jalz.2015.06.1888|||Zwilling CE, Talukdar T, Zamroziewicz MK, Barbey AK. Nutrient biomarker patterns, cognitive function, and fMRI measures of network efficiency in the aging brain. Neuroimage. 2019;188:239–251. doi:10.1016/j.neuroimage.2018.12.007|||Huhn S, Beyer F, Zhang R, et al. Effects of resveratrol on memory performance, hippocampus connectivity and microstructure in older adults - a randomized controlled trial. Neuroimage. 2018;174:177–190. doi:10.1016/j.neuroimage.2018.03.023|||Witte AV, Kerti L, Margulies DS, Flöel A. Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J Neurosci. 2014;34(23):7862–7870. doi:10.1523/jneurosci.0385-14.2014|||Meusel LC, Anderson ND, Parrott MD, et al. Brain function is linked to LDL cholesterol in older adults with cardiovascular risk. J Am Geriatr Soc. 2017;65(2):e51–e5. doi:10.1111/jgs.14663|||Petrie M, Rejeski WJ, Basu S, et al. Beet root juice: an ergogenic aid for exercise and the aging brain. J Gerontol A Biol Sci Med Sci. 2017;72(9):1284–1289. doi:10.1093/gerona/glw219