Alzheimerdisease(AD)ischaracterizedbyanaccumula-tionofsenileplaques(SPs;composedmostlyoffibrillaryamyloid-β(Aβ)peptideanddystrophicneurites)andneurofibrillarytangles(NFTs;composedofhyperphos-phorylatedtauprotein)inthebrain,leadingtodysfunc-tionandlossofsynapsesandeventualneuronaldeath1,2.Clinically,ADischaracterizedbyseveralfeatures,nota-blyaprogressivecognitivedeclineinvolvinglossofmem-oryandhigherexecutivefunctioning1.Arguably,theearlieststageofADispreclinicalAD(PCAD),inwhichpersonshavenormalcognitivestatusbutupondeathandautopsytheirbrainsdisplayevidenceofsubstantialADneuro-pathology.Amnesticmildcognitiveimpairment(aMCI)isaprogressiveconditioninwhichthereissomedegreeofmemorylossandiswidelythoughttobeaprodromalearlystageofADinwhichADneuropathologyispres-ent,albeittoalesserdegree.IncontrasttopatientswithAD,however,aMCIindividualscanperformactivitiesofdailyliving.Ithasbeenestimatedthatapproximately15%ofpeoplewithaMCIprogresstoADannually3.ADpathologyoccurswellbefore(uptotwodecades)theonsetofclinicalsymptoms2–4.Itfollowsthattherapythatbeginswhensymptomsappearmaybetoolatetobeeffective,andunderstandingkeymolecularprocessesintheprogressionofADisneededtofacilitateearlierdiagnosisandtodevelopnewinterventionstosloworstopitsprogression.OneimportantprocessthatbecomesdysfunctionalinADandaMCIisthemetabolismofglucose5,6.GlucoseisnormallythemajorenergysourceforthebrainandismetabolizedtoATPviaglycolysis,thetricarboxylicacid(TCA)cycleandtheelectrontransportchain(ETC),asshowninFig.1.Glucoseentersthebrainfromthevascu-laturethroughhighlyefficientglucosetransportersandrequiresinsulinforoptimalcellularutilization7.InADandaMCI,however,braininsulinresistanceispresent6,7.Indeed,type2diabetes(T2DM),akeycomponentofwhichisinsulinresistance,isasubstantialriskfactorfordevelopingAD7.GiventheverylargeincreaseinT2DMdevelopmentworldwide,combinedwithageingpopulations,ADisamajorandgrowingproblem.ThisReviewsummarizestheroleofoxidativedamageinaMCIandAD,howitaffectsglucosemetabolismandhowitisakeyme...
