An increased risk for Alzheimer's disease is associated with dyslipidemia and insulin resistance. A separate literature shows the genetic risk for developing Alzheimer's disease is strongly correlated to the presence of the E4 isoform of the apolipoprotein E carrier protein. Understanding how apolipoprotein E carrier protein, lipids, amyloid β peptides, glucose, central nervous system insulin, and peripheral insulin interact with one another in Alzheimer's disease is an area of increasing interest. Here, we will review the evidence relating apolipoprotein E carrier protein, lipids, and insulin action to Alzheimer's disease and Aβ peptides and then propose mechanisms as to how these factors might interact with one another to impair cognition and promote Alzheimer's disease.
LeeEB. Obesity, leptin, and Alzheimer's disease. Ann N Y Acad Sci2011; 1243: 15–29.
2.
LiuCCKanekiyoTXuHBuG. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol2013; 9: 106–18.
3.
SperlingRAAisenPSBeckettLABennettDACraftSFaganAMIwatsuboTJackCRJr.KayeJMontineTJParkDCReimanEMRoweCCSiemersESternYYaffeKCarrilloMCThiesBMorrison-BogoradMWagsterMVPhelpsCH. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers & Dement2011; 7: 280–92.
4.
PaquetCAminJMouton-LigerFNasserMLoveSGrayFPickeringRMNicollJARHolmesCHugonJBocheD. Effect of active Aβ immunotherapy on neurons in human Alzheimer's disease. J Pathol2015; 235: 721–30.
DemeesterNCastroGDesrumauxCDe GeitereCFruchartJCSantensPMullenersEEngelborghsSDe DeynPPVandekerckhoveJRosseneuMLabeurC. 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 Res2000; 41: 963–74.
8.
BellRDZlokovicBV. Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer's disease. Acta Neuropathol2009; 118: 103–13.
9.
EricksonMANiehoffMLFarrSAMorleyJEDillmanLALynchKMBanksWA. Peripheral administration of antisense oligonucleotides targeting the amyloid-beta protein precursor reverses AbetaPP and LRP-1 overexpression in the aged SAMP8 mouse brain. J Alzheimers Dis2012; 28: 951–60.
10.
FanJDonkinJWellingtonC. Greasing the wheels of Abeta clearance in Alzheimer's disease: the role of lipids and apolipoprotein E. Biofactors2009; 35: 239–48.
11.
KimJBasakJMHoltzmanDM. The role of apolipoprotein E in Alzheimer's disease. Neuron2009; 63: 287–303.
12.
BellRDWinklerEASinghISagareAPDeaneRWuZHoltzmanDMBetsholtzCArmulikASallstromJBerkBCZlokovicBV. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature2012; 485: 512–6.
13.
FullertonSMShirmanGAStrittmatterWJMatthewWD. Impairment of the blood-nerve and blood-brain barriers in apolipoprotein E knockout mice. Exp Neurol2001; 169: 13–22.
14.
DonahueJEJohansonCE. Apolipoprotein E, amyloid-beta, and blood-brain barrier permeability in Alzheimer disease. J Neuropathol Exp Neurol2008; 67: 261–70.
15.
EricksonMABanksWA. Blood-brain barrier dysfunction as a cause and consequence of Alzheimer's disease. J Cereb Blood Flow Metab2013; 33: 1500–13.
16.
PhillipsMC. Apolipoprotein E isoforms and lipoprotein metabolism. IUBMB Life2014; 66: 616–23.
17.
MahleyRWHuangY. Apolipoprotein E sets the stage: response to injury triggers neuropathology. Neuron2012; 76: 871–85.
18.
HawkesCASullivanPMHandsSWellerRONicollJARCarareRO. Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ɛ4 allele. PLoS One2012; 7: e41636–e41636.
19.
YipAGMcKeeACGreenRCWellsJYoungHCupplesLAFarrerLA. APOE, vascular pathology, and the AD brain. Neurology2005; 65: 259–65.
20.
PremkumarDRCohenDLHederaPFriedlandRPKalariaRN. Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer's disease. Am J Pathol1996; 148: 2083–95.
21.
SallowaySGurTBerzinTTavaresRZipserBCorreiaSHovanesianVFallonJKuo-LeblancVGlassDHuletteCRosenbergCVitekMStopaE. Effect of APOE genotype on microvascular basement membrane in Alzheimer's disease. J Neurol Sci2002; 203–204: 183–7.
22.
ZlokovicBV. Cerebrovascular effects of apolipoprotein E: implications for Alzheimer disease. JAMA Neurol2013; 70: 440–4.
23.
NishitsujiKHosonoTNakamuraTBuGMichikawaM. Apolipoprotein E regulates the integrity of tight junctions in an isoform-dependent manner in an in vitro blood-brain barrier model. J Biol Chem2011; 286: 17536–42.
24.
DeaneRSagareAHammKParisiMLaneSFinnMBHoltzmanDMZlokovicBV. apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest2008; 118: 4002–13.
25.
BennetAMDi AngelantonioEYeZWensleyFDahlinAAhlbomAKeavneyBCollinsRWimanBde FaireUDaneshJ. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA2007; 298: 1300–11.
26.
CaselliRJ. Does an Alzheimer's disease susceptibility gene influence the cognitive effects of cancer therapy?Pediat Blood Cancer2013; 10: 1739–42.
27.
CholertonBBakerLDCraftS. Insulin resistance and pathological brain ageing. DiabMed2011; 28: 1463–75.
28.
de la MonteSM. Relationships between diabetes and cognitive impairment. Endocrinol Metabol Clin North Am2014; 43: 245–67.
29.
BlazquezEVelázquez SánchezEHurtado-CarneiroVRuiz AlbusacJM. Insulin in the brain: its pathophysiological implications for states related with central insulin resistance, type 2 diabetes and Alzheimer's disease. Front Endocrinol2014; 5: 1–21.
30.
OttAStolkRPvan HarskampFPolsHAHofmanABretelerMM. Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology1999; 53: 1937–42.
31.
NewsholmePCruzatVArfusoFKeaneK. Nutrient regulation of insulin secretion and action. J Endocrinol2014; 221: R105–20.
32.
NolanCJMadirajuMSDelghingaro-AugustoVPeyotMLPrentkiM. Fatty acid signaling in the beta-cell and insulin secretion. Diabetes2006; 55(Suppl 2): S16–23.
33.
GoldbergELDixitVD. Drivers of age-related inflammation and strategies for healthspan extension. Immunol Rev2015; 265: 63–74.
34.
HenekaMTCarsonMJEl KhouryJLandrethGEBrosseronFFeinsteinDLJacobsAHWyss-CorayTVitoricaJRansohoffRMHerrupKFrautschySAFinsenBBrownGCVerkhratskyAYamanakaKKoistinahoJLatzEHalleAPetzoldGCTownTMorganDShinoharaMLPerryVHHolmesCBazanNGBrooksDJHunotSJosephBDeigendeschNGaraschukOBoddekeEDinarelloCABreitnerJCColeGMGolenbockDTKummerMP. Neuroinflammation in Alzheimer's disease. Lancet Neurol2015; 14: 388–405.
35.
GhasemiRHaeriADargahiLMohamedZAhmadianiA. Insulin in the brain: sources, localization and functions. Mol Neurobiol2013; 47: 145–71.
36.
PorteDJr.SeeleyRJWoodsSCBaskinDGFiglewiczDPSchwartzMW. Obesity, diabetes and the central nervous system. Diabetologia1998; 41: 863–81.
37.
ArmbrechtHJSiddiquiAMGreenMFarrSAKumarVBBanksWAPatrickPShahGNMorleyJE. Antisense against amyloid-beta protein precursor reverses memory deficits and alters gene expression in neurotropic and insulin-signaling pathways in SAMP8 mice. J Alzheimers Dis2015; 46: 535–48.
38.
FreiherrJHallschmidMFreyWH2ndBrunnerYFChapmanCDHolscherCCraftSDe FeliceFGBenedictC. Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence. CNS Drugs2013; 27: 505–14.
39.
BanksWAJaspanJBKastinAJ. Effect of diabetes mellitus on the permeability of the blood-brain barrier to insulin. Peptides1997; 18: 1577–84.
40.
RiveraEJGoldinAFulmerNTavaresRWandsJRde la MonteSM. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine. J Alzheimers Dis2005; 8: 247–68.
41.
LiuYLiuFGrundke-IqbalIIqbalKGongCX. Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes. J Pathol2011; 225: 54–62.
42.
SteenETerryBMRiveraEJCannonJLNeelyTRTavaresRXuXJWandsJRde la MonteSM. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease – is this type 3 diabetes?J Alzheimers Dis2005; 7(1): 63–80.
43.
RickleABogdanovicNVolkmanIWinbladBRavidRCowburnRF. Akt activity in Alzheimer's disease and other neurodegenerative disorders. Neuroreport2004; 15: 955–9.
44.
TalbotKWangHYKaziHHanLYBakshiKPStuckyAFuinoRLKawaguchiKRSamoyednyAJWilsonRSArvanitakisZSchneiderJAWolfBABennettDATrojanowskiJQArnoldSE. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest2012; 122: 1316–38.
45.
CraftSPeskindESchwartzMWSchellenbergGDRaskindMPorteDJr. Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology1998; 50: 164–8.
46.
GhasemiRDargahiLHaeriAMoosaviMMohamedZAhmadianiA. Brain insulin dysregulation: implication for neurological and neuropsychiatric disorders. Mol Neurobiol2013; 47: 1045–65.
47.
LochheadJJThorneRG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev2012; 64: 614–28.
48.
MeredithMESalamehTBanksW. Intranasal delivery of proteins and peptides in the treatment of neurodegenerative diseases. AAPS J2015; 17: 780–7.
49.
ShibaKKageyamaHTakenoyaFShiodaS. Galanin-like peptide and the regulation of feeding behavior and energy metabolism. FEBS J2010; 277: 5006–13.
50.
ShiodaSKageyamaHTakenoyaFShibaK. Galanin-like peptide: a key player in the homeostatic regulation of feeding and energy metabolism?Int J Obes2011; 35: 619–28.
51.
AminFMHougaardASchytzHWAsgharMSLundholmEParvaizAIde KoningPJHAndersenMRLarssonHBWFahrenkrugJOlesenJAshinaM. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain2014; 137: 779–94.
52.
KinhultJAdnerMUddmanRCardellLO. Pituitary adenylate cyclase-activating polypeptide, effects in the human nose. Clin Exp Allerg2003; 33: 942–9.
53.
UenoHMizutaMShiiyaTTsuchimochiWNomaKNakashimaNFujiharaMNakazatoM. Exploratory trial of intranasal administration of glucagon-like peptide-1 in Japanese patients with type 2 diabetes. Diab Care2014; 37: 2024–7.
54.
CraftSBakerLDMontineTJMinoshimaSWatsonGSClaxtonAArbuckleMCallaghanMTsaiEPlymateSRGreenPSLeverenzJCrossDGertonB. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment. Arch Neurol2012; 69: 29–38.
55.
RegerMAWatsonGSFreyWH2ndBakerLDCholertonBKeelingMLBelongiaDAFishelMAPlymateSRSchellenbergGDCherrierMMCraftS. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging2006; 27: 451–8.
56.
RegerMAWatsonGSGreenPSWilkinsonCWBakerLDCholertonBFishelMAPlymateSRBreitnerJCDeGroodtWMehtaPCraftS. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology2008; 70: 440–8.
57.
BenedictCHallschmidMHatkeASchultesBFehmHLBornJKernW. Intranasal insulin improves memory in humans. Psychoneuroendocrinology2004; 29: 1326–34.
58.
SridharGRLakshmiGNagamaniG. Emerging links between type 2 diabetes and Alzheimer's disease. World J Diab2015; 6: 744–51.
59.
BenedictCHallschmidMHatkeASchultesBFehmHLBornJKernW. Intranasal insulin improves memory in humans. Psychoneuroendocrinology2004; 29: 1326–34.
60.
SalamehTSBullockKMHujoelIANiehoffMLWolden-HansonTKimJMorleyJEFarrSABanksWA. Central nervous system delivery of intranasal insulin: mechanisms of uptake and effects on cognition. J Alzheimers Dis2015; 47: 715–28.
61.
ChenYZhaoYDaiC-lLiangZRunXIqbalKLiuFGongC-X. Intranasal insulin restores insulin signaling, increases synaptic proteins, and reduces Aβ level and microglia activation in the brains of 3xTg-AD mice. Exp Neurol2014; 261: 610–9.
62.
BanksWAOwenJBEricksonMA. Insulin in the brain: there and back again. Pharmacol Therapeut2012; 136: 82–93.
63.
MatsuzakiTSasakiKTanizakiYHataJFujimiKMatsuiYSekitaASuzukiSOKanbaSKiyoharaYIwakiT. Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology2010; 75: 764–70.
DumurgierJPaquetCPeoc'hKLapalusPMouton-LigerFBenistySChasseigneauxSChabriatHHugonJ. CSF Abeta1-42 levels and glucose metabolism in Alzheimer's Disease. J Alzheimers Dis2011; 27: 845–51.
67.
RegerMAWatsonGSGreenPSBakerLDCholertonBFishelMAPlymateSRCherrierMMSchellenbergGDFreyWH2ndCraftS. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis2008; 13: 323–31.
68.
ClaxtonABakerLDWilkinsonCWTrittschuhEHChapmanaDWatsonGSCholertonBPlymateSRArbuckleMCraftS. Sex and ApoE genotype differences in treatment response to two doses of intranasal insulin in adults with mild cognitive impairment or Alzheimer's disease. J Alzheimers Dis2013; 35: 789–97.
69.
RosenbloomMHBarclayTRPyleMOwensBLCaganABAndersonCPFreyWHHansonLR. A single-dose pilot trial of intranasal rapid-acting insulin in apolipoprotein E4 carriers with mild-moderate Alzheimer's disease. CNS Drugs2014; 28: 1185–9.
70.
ClaxtonABakerLDHansonATrittschuhEHCholertonBMorganACallaghanMArbuckleMBehlCCraftS. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer's disease dementia. J Alzheimers Dis2014; 44: 897–906.
71.
CraftSAsthanaSSchellenbergGBakerLCherrierMBoytAAMartinsRNRaskindMPeskindEPlymateS. Insulin effects on glucose metabolism, memory, and plasma amyloid precursor protein in Alzheimer's disease differ according to apolipoprotein-E genotype. Ann N Y Acad Sci2000; 903: 222–8.
72.
HansonAJBayerJLBakerLDCholertonBVanFossenBTrittschuhERissmanRADonohueMCMoghadamSHPlymateSRCraftS. Differential effects of meal challenges on cognition, metabolism, and biomarkers for apolipoprotein E varepsilon4 carriers and adults with mild cognitive impairment. J Alzheimers Dis2015; 48: 205–18.
73.
WanamakerBLSwigerKJBlumenthalRSMartinSS. Cholesterol, statins, and dementia: what the cardiologist should know. Clin Cardiol2015; 38: 243–50.
CreeganRHuntWMcManusARainey-SmithSR. Diet, nutrients and metabolism: cogs in the wheel driving Alzheimer's disease pathology?Br J Nutr2015; 113: 1499–517.
76.
FoleyP. Lipids in Alzheimer's disease: a century-old story. Biochim Biophys Acta2010; 1801: 750–3.
77.
LuchsingerJAMayeuxR. Dietary factors and Alzheimer's disease. Lancet Neurol2004; 3: 579–87.
78.
LimWLMartinsIJMartinsRN. The involvement of lipids in Alzheimer's disease. J Genet Genom2014; 41: 261–74.
79.
Di PaoloGKimTW. Linking lipids to Alzheimer's disease: cholesterol and beyond. Nat Rev Neurosci2011; 12: 284–96.
80.
RubinJBerglundL. Apolipoprotein E and diets: a case of gene-nutrient interaction?Curr Opin Lipidol2002; 13: 25–32.
81.
KanoskiSEMeiselRLMullinsAJDavidsonTL. The effects of energy-rich diets on discrimination reversal learning and on BDNF in the hippocampus and prefrontal cortex of the rat. Behav Brain Res2007; 182: 57–66.
82.
MaesakoMUemuraMTashiroYSasakiKWatanabeKNodaYUedaKAsada-UtsugiMKubotaMOkawaKIharaMShimohamaSUemuraKKinoshitaA. High fat diet enhances beta-site cleavage of amyloid precursor protein (APP) via promoting beta-site APP cleaving enzyme 1/adaptor protein 2/clathrin complex formation. PLoS One2015; 10: e0131199–e0131199.
83.
HardyJAHigginsGA. Alzheimer's disease: the amyloid cascade hypothesis. Science1992; 256: 184–5.
84.
BanksWACoonABRobinsonSMMoinuddinAShultzJMNakaokeRMorleyJE. Triglycerides induce leptin resistance at the blood-brain barrier. Diabetes2004; 53: 1253–60.
85.
UrayamaABanksWA. Starvation and triglycerides reverse the obesity-induced impairment of insulin transport at the blood-brain barrier. Endocrinology2008; 149: 3592–7.
86.
BanksWABurneyBORobinsonSM. Effects of triglycerides, obesity, and starvation on ghrelin transport across the blood-brain barrier. Peptides2008; 29: 2061–5.
87.
DianoSFarrSABenoitSCMcNayECda SilvaIHorvathBGaskinFSNonakaNJaegerLBBanksWAMorleyJEPintoSSherwinRSXuLYamadaKASleemanMWTschopMHHorvathTL. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci2006; 9: 381–8.
88.
DurakoglugilMIrvingAJHarveyJ. Leptin induces a novel form of NMDA receptor-dependent long-term depression. J Neurochem2005; 95: 396–405.
89.
ShanleyLJIrvingAJHarveyJ. Leptin enhances NMDA receptor function and modulates hippocampal synaptic plasticity. J Neurosc2001; 21: RC186–RC186.
90.
JaneMJWilliamTHDavidWFStevenJGGeorgePThomasJMJohnQTLeslieMSAshfordJWNikolaosT. Low plasma leptin in cognitively impaired ADNI subjects: gender differences and diagnostic and therapeutic potential. Curr Alzheimer Res2014; 11: 165–74.
91.
JohnstonJMGrecoSJHamzelouAAshfordJWTezapsidisN. Repositioning leptin as a therapy for Alzheimer's disease. Therapy2011; 8: 481–90.
92.
ChangG-QKaratayevODavydovaZLeibowitzSF. Circulating triglycerides impact on orexigenic peptides and neuronal activity in hypothalamus. Endocrinology2004; 145: 3904–12.
93.
WortleyKEChangG-QDavydovaZLeibowitzSF. Orexin gene expression is increased during states of hypertriglyceridemia. Am J Physiol Regul Integr Comp Physiol2003; 284: R1454–65.
OomuraYNakamuraTSugimoriMYamadaY. Effect of free fatty acid on the rat lateral hypothalamic neurons. Physiol Behav1975; 14: 483–6.
96.
ShenLCareyKWangDQHWoodsSCLiuM. Food-entrained rhythmic expression of apolipoprotein E expression in the hypothalamus of rats. Brain Res2009; 1273: 66–71.
97.
CordnerZATamashiroKLK. Effects of high-fat diet exposure on learning & memory. Physiol Behav2015; 152(Part B): 363–71.
98.
MorleyJE. The metabolic syndrome and aging. J Gerontol A Biol Sci Med Sci2004; 59: M139–M42.
99.
FarrSAYamadaKAButterfieldDAAbdulHMXuLMillerNEBanksWAMorleyJE. Obesity and hypertriglyceridemia produce cognitive impairment. Endocrinology2008; 149: 2628–36.
100.
JohnsonLAZuloagaKLKugelmanTLMaderKSMorréJTZuloagaDGWeberSMarzullaTMulfordAButtonDLindnerJRAlkayedNJStevensJFRaberJ. Amelioration of metabolic syndrome-associated cognitive impairments in mice via a reduction in dietary fat content or infusion of non-diabetic plasma. EBioMedicine2015; 3: 26–42.
101.
HansonAJBayer-CarterJLGreenPSMontineTJWilkinsonCWBakerLDWatsonGSBonnerLMCallaghanMLeverenzJBTsaiEPostupnaNZhangJLampeJCraftS. Effect of apolipoprotein E genotype and diet on apolipoprotein E lipidation and amyloid peptides: randomized clinical trial. JAMA Neurol2013; 70: 972–80.
102.
HuangTLZandiPPTuckerKLFitzpatrickALKullerLHFriedLPBurkeGLCarlsonMC. Benefits of fatty fish on dementia risk are stronger for those without APOE epsilon4. Neurology2005; 65: 1409–14.
103.
Barberger-GateauPSamieriCFeartCPlourdeM. Dietary omega 3 polyunsaturated fatty acids and Alzheimer's disease: interaction with apolipoprotein E genotype. Curr Alzheimer Res2011; 8: 479–91.
104.
HendersonST. High carbohydrate diets and Alzheimer's disease. Med Hypotheses2004; 62: 689–700.
105.
HendersonSTPoirierJ. Pharmacogenetic analysis of the effects of polymorphisms in APOE, IDE and IL1B on a ketone body based therapeutic on cognition in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled study. BMC Med Genet2011; 12: 137–137.
106.
RegerMACraftS. Intranasal insulin administration: a method for dissociating central and peripheral effects of insulin. Drugs Today2006; 42: 729–39.
