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2000
Volume 22, Issue 2
  • ISSN: 1567-2050
  • E-ISSN: 1875-5828

Abstract

Objective/Background

Type 2 Diabetes Mellitus (T2D) and Alzheimer's disease (AD) are two diseases with a high prevalence today that share common pathophysiological mechanisms, suggesting a potential causal relationship between them. AD is also known as Type 3 Diabetes Mellitus (T3D). A complete understanding of this complex issue (T2D-AD) is necessary to develop fully effective and easily applicable therapies that do not yet exist. A critical update on the subject is presented, delving into the pathophysiological implications and defining new research for promoting new therapeutic interventions.

Methods

Revision and critical analysis of the described and observed cellular and molecular common pathogenic T2D-AD mechanisms in human and model studies.

Results

Both diseases exhibit common genetic, epigenetic, biochemical and physiological characteristics. Pathogenic mechanisms such as peripheral inflammation, mitochondrial dysfunction, oxidative stress, insulin resistance, hyperglycemia, formation of advanced glycation end products, neuroinflammation, neuroglial dysfunctions, and deposition of aberrant misfolded proteins are commonly displayed in dysmetabolic diseases and AD. The T2D, AD and T2D-AD pathogenic courses present several close key contacts (or identities). The clinical course of T2D has different incidence in the neurodegenerative course of AD (from its onset to its aggravation). There are theoretical, practical and interpretative problems in studies on human and experimental models, as well as in the clinical and pathological interpretation of T2D-AD dementia, which are of great importance in the development of knowledge of this subject and the therapeutic application of its results.

Conclusion

In recent years, there has been a great advance in the study of the relationships between T2D (and related dysmetabolic diseases) and AD. There is no doubt about their close relationship and/or the inclusion of AD as a metabolic disease (T3D). Joint therapies seem to be absolutely necessary. Key pathogenic processes (insulin resistance, genetic and epigenetic regulation, peripheral inflammation and neuroinflammation) must be investigated to develop new and effective therapies.

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References

  1. HoyerS. NitschR. Cerebral excess release of neurotransmitter amino acids subsequent to reduced cerebral glucose metabolism in early-onset dementia of Alzheimer type.J. Neural Transm.198975322723210.1007/BF012586342926384
     [Google Scholar]
  2. HoyerS. The brain insulin signal transduction system and sporadic (type II) Alzheimer disease: An update.J. Neural Transm.2002109334136010.1007/s00702020002811956956
     [Google Scholar]
  3. HoyerS. Glucose metabolism and insulin receptor signal transduction in Alzheimer disease.Eur. J. Pharmacol.20044901-311512510.1016/j.ejphar.2004.02.04915094078
     [Google Scholar]
  4. Salkovic-PetrisicM. HoyerS. Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: An experimental approach.J. Neural Transm. Suppl.20077221723310.1007/978‑3‑211‑73574‑9_2817982898
     [Google Scholar]
  5. NicollsM. The clinical and biological relationship between Type II diabetes mellitus and Alzheimer’s disease.Curr. Alzheimer Res.200411475410.2174/156720504348055515975085
     [Google Scholar]
  6. de la MonteS.M. WandsJ.R. Alzheimer’s disease is type 3 diabetes-evidence reviewed.J. Diabetes Sci. Technol.2008261101111310.1177/19322968080020061919885299
     [Google Scholar]
  7. DemetriusL.A. DriverJ. Alzheimer’s as a metabolic disease.Biogerontology201314664164910.1007/s10522‑013‑9479‑724249045
     [Google Scholar]
  8. ZhaoW.Q. TownsendM. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer’s disease.Biochim. Biophys. Acta Mol. Basis Dis.20091792548249610.1016/j.bbadis.2008.10.01419026743
     [Google Scholar]
  9. Rosales-CorralS. TanD.X. ManchesterL. ReiterR.J. Diabetes and Alzheimer disease, two overlapping pathologies with the same background: Oxidative stress.Oxid. Med. Cell. Longev.2015201511410.1155/2015/98584525815110
     [Google Scholar]
  10. Rodriguez-CasadoA. Toledano-DíazA. ToledanoA. Defective insulin signalling, mediated by inflammation, connects obesity to Alzheimer disease; Relevant pharmacological therapies and preventive dietary interventions.Curr. Alzheimer Res.201714889491110.2174/156720501466617031616184828317485
     [Google Scholar]
  11. Kianpour RadS. AryaA. KarimianH. MadhavanP. RizwanF. KoshyS. PrabhuG. Mechanism involved in insulin resistance via accumulation of β-amyloid and neurofibrillary tangles: Link between type 2 diabetes and Alzheimer’s disease.Drug Des. Devel. Ther.2018123999402110.2147/DDDT.S17397030538427
     [Google Scholar]
  12. NetoA. FernandesA. BarateiroA. The complex relationship between obesity and neurodegenerative diseases: An updated review.Front. Cell. Neurosci.202317129442010.3389/fncel.2023.129442038026693
     [Google Scholar]
  13. JamesB.D. BennettD.A. Causes and patterns of dementia: An update in the era of redefining Alzheimer’s disease.Annu. Rev. Public Health2019401658410.1146/annurev‑publhealth‑040218‑04375830642228
     [Google Scholar]
  14. MoyseE. HaddadM. BenlabiodC. RamassamyC. KranticS. Common pathological mechanisms and risk factors for Alzheimer’s disease and type-2 diabetes: Focus on inflammation.Curr. Alzheimer Res.20191611986100610.2174/156720501666619110609435631692443
     [Google Scholar]
  15. KacířováM. ZmeškalováA. KořínkováL. ŽeleznáB. KunešJ. MaletínskáL. Inflammation: major denominator of obesity, Type 2 diabetes and Alzheimer’s disease-like pathology?Clin. Sci.2020134554757010.1042/CS2019131332167154
     [Google Scholar]
  16. RamasubbuK. Devi RajeswariV. Impairment of insulin signaling pathway PI3K/Akt/mTOR and insulin resistance induced AGEs on diabetes mellitus and neurodegenerative diseases: A perspective review.Mol. Cell. Biochem.202347861307132410.1007/s11010‑022‑04587‑x36308670
     [Google Scholar]
  17. HuangC. WenX. XieH. HuD. LiK. Identification and experimental validation of marker genes between diabetes and Alzheimer’s disease.Oxid. Med. Cell. Longev.2022202212410.1155/2022/812253235996379
     [Google Scholar]
  18. MakkiB.E. RahmanS. Alzheimer’s disease in diabetic patients: A lipidomic prospect.Neuroscience2023530799410.1016/j.neuroscience.2023.08.03337652288
     [Google Scholar]
  19. MichailidisM. MoraitouD. TataD.A. KalinderiK. PapamitsouT. PapaliagkasV. Alzheimer’s disease as type 3 diabetes: Common pathophysiological mechanisms between Alzheimer’s disease and type 2 diabetes.Int. J. Mol. Sci.2022235268710.3390/ijms2305268735269827
     [Google Scholar]
  20. BurilloJ. MarquésP. JiménezB. González-BlancoC. BenitoM. GuillénC. Insulin resistance and diabetes mellitus in Alzheimer’s disease.Cells2021105123610.3390/cells1005123634069890
     [Google Scholar]
  21. Diniz PereiraJ. Gomes FragaV. Morais SantosA.L. CarvalhoM.G. CaramelliP. Braga GomesK. Alzheimer’s disease and type 2 diabetes mellitus: A systematic review of proteomic studies.J. Neurochem.2021156675377610.1111/jnc.1516632909269
     [Google Scholar]
  22. PaulS. SahaD. BkB. Mitochondrial dysfunction and mitophagy closely cooperate in neurological deficits associated with Alzheimer’s disease and type 2 diabetes.Mol. Neurobiol.20215883677369110.1007/s12035‑021‑02365‑233797062
     [Google Scholar]
  23. KhanM.S. IkramM. ParkT.J. KimM.O. Pathology, risk factors, and oxidative damage related to type 2 diabetes-mediated Alzheimer’s disease and the rescuing effects of the potent antioxidant anthocyanin.Oxid. Med. Cell. Longev.202120211405120710.1155/2021/405120733728019
     [Google Scholar]
  24. YouY. LiuZ. ChenY. XuY. QinJ. GuoS. HuangJ. TaoJ. The prevalence of mild cognitive impairment in type 2 diabetes mellitus patients: A systematic review and meta-analysis.Acta Diabetol.202158667168510.1007/s00592‑020‑01648‑933417039
     [Google Scholar]
  25. MarranoN. BiondiG. BorrelliA. RellaM. ZambettaT. Di GioiaL. CaporussoM. LogroscinoG. PerriniS. GiorginoF. NatalicchioA. Type 2 diabetes and Alzheimer’s disease: The emerging role of cellular lipotoxicity.Biomolecules202313118310.3390/biom1301018336671568
     [Google Scholar]
  26. CarvalhoC. MoreiraP.I. Metabolic defects shared by Alzheimer’s disease and diabetes: A focus on mitochondria.Curr. Opin. Neurobiol.20237910269410.1016/j.conb.2023.10269436842275
     [Google Scholar]
  27. DavidsonS. AllenbackG. DecourtB. SabbaghM.N. Type 2 diabetes comorbidity and cognitive decline in patients with Alzheimer’s disease.J. Alzheimers Dis.20239541573158410.3233/JAD‑23048937718812
     [Google Scholar]
  28. GoodarziG. TehraniS.S. FanaS.E. Moradi-SardarehH. PanahiG. ManiatiM. MeshkaniR. Crosstalk between Alzheimer’s disease and diabetes: A focus on anti-diabetic drugs.Metab. Brain Dis.20233861769180010.1007/s11011‑023‑01225‑337335453
     [Google Scholar]
  29. LemcheE. KillickR. MitchellJ. CatonP.W. ChoudharyP. HowardJ.K. Molecular mechanisms linking type 2 diabetes mellitus and late-onset Alzheimer’s disease: A systematic review and qualitative meta-analysis.Neurobiol. Dis.202419610648510.1016/j.nbd.2024.10648538643861
     [Google Scholar]
  30. ChoS.B. Comorbidity genes of Alzheimer’s disease and type 2 diabetes associated with memory and cognitive function.Int. J. Mol. Sci.2024254221110.3390/ijms2504221138396891
     [Google Scholar]
  31. AbdallaM.M.I. Insulin resistance as the molecular link between diabetes and Alzheimer’s disease.World J. Diabetes20241571430144710.4239/wjd.v15.i7.143039099819
     [Google Scholar]
  32. RheaE.M. LeclercM. YassineH.N. CapuanoA.W. TongH. PetyukV.A. MacauleyS.L. FioramontiX. CarmichaelO. CalonF. ArvanitakisZ. State of the science on brain insulin resistance and cognitive decline due to Alzheimer’s disease.Aging Dis.2023154010.14336/AD.2023.081437611907
     [Google Scholar]
  33. SunH. SaeediP. KarurangaS. PinkepankM. OgurtsovaK. DuncanB.B. SteinC. BasitA. ChanJ.C.N. MbanyaJ.C. PavkovM.E. RamachandaranA. WildS.H. JamesS. HermanW.H. ZhangP. BommerC. KuoS. BoykoE.J. MaglianoD.J. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045.Diabetes Res. Clin. Pract.202218310911910.1016/j.diabres.2021.10911934879977
     [Google Scholar]
  34. SaeediP. PetersohnI. SalpeaP. MalandaB. KarurangaS. UnwinN. ColagiuriS. GuariguataL. MotalaA.A. OgurtsovaK. ShawJ.E. BrightD. WilliamsR. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the international diabetes federation diabetes atlas, 9th edition.Diabetes Res. Clin. Pract.201915710784310.1016/j.diabres.2019.10784331518657
     [Google Scholar]
  35. NicholsE. SteinmetzJ.D. VollsetS.E. FukutakiK. ChalekJ. Abd-AllahF. AbdoliA. AbualhasanA. Abu-GharbiehE. AkramT.T. Al HamadH. AlahdabF. AlaneziF.M. AlipourV. AlmustanyirS. AmuH. AnsariI. ArablooJ. AshrafT. Astell-BurtT. AyanoG. Ayuso-MateosJ.L. BaigA.A. BarnettA. BarrowA. BauneB.T. BéjotY. BezabheW.M.M. BezabihY.M. BhagavathulaA.S. BhaskarS. BhattacharyyaK. BijaniA. BiswasA. BollaS.R. BoloorA. BrayneC. BrennerH. BurkartK. BurnsR.A. CámeraL.A. CaoC. CarvalhoF. Castro-de-AraujoL.F.S. Catalá-LópezF. CerinE. ChavanP.P. CherbuinN. ChuD-T. CostaV.M. CoutoR.A.S. DadrasO. DaiX. DandonaL. DandonaR. De la Cruz-GóngoraV. DhamnetiyaD. Dias da SilvaD. DiazD. DouiriA. EdvardssonD. EkholuenetaleM. El SayedI. El-JaafaryS.I. EskandariK. EskandariehS. EsmaeilnejadS. FaresJ. FaroA. FarooqueU. FeiginV.L. FengX. FereshtehnejadS-M. FernandesE. FerraraP. FilipI. FillitH. FischerF. GaidhaneS. GalluzzoL. GhashghaeeA. GhithN. GialluisiA. GilaniS.A. GlavanI-R. GnedovskayaE.V. GolechhaM. GuptaR. GuptaV.B. GuptaV.K. HaiderM.R. HallB.J. HamidiS. HanifA. HankeyG.J. HaqueS. HartonoR.K. HasaballahA.I. HasanM.T. HassanA. HayS.I. HayatK. HegazyM.I. HeidariG. Heidari-SoureshjaniR. HerteliuC. HousehM. HussainR. HwangB-F. IacovielloL. IavicoliI. IlesanmiO.S. IlicI.M. IlicM.D. IrvaniS.S.N. IsoH. IwagamiM. JabbarinejadR. JacobL. JainV. JayapalS.K. JayawardenaR. JhaR.P. JonasJ.B. JosephN. KalaniR. KandelA. KandelH. KarchA. KasaA.S. KassieG.M. KeshavarzP. KhanM.A.B. KhatibM.N. KhojaT.A.M. KhubchandaniJ. KimM.S. KimY.J. KisaA. KisaS. KivimäkiM. KoroshetzW.J. KoyanagiA. KumarG.A. KumarM. LakH.M. LeonardiM. LiB. LimS.S. LiuX. LiuY. LogroscinoG. LorkowskiS. LucchettiG. Lutzky SauteR. MagnaniF.G. MalikA.A. MassanoJ. MehndirattaM.M. MenezesR.G. MeretojaA. MohajerB. Mohamed IbrahimN. MohammadY. MohammedA. MokdadA.H. MondelloS. MoniM.A.A. MoniruzzamanM. MossieT.B. NagelG. NaveedM. NayakV.C. Neupane KandelS. NguyenT.H. OanceaB. OtstavnovN. OtstavnovS.S. OwolabiM.O. Panda-JonasS. Pashazadeh KanF. PasovicM. PatelU.K. PathakM. PeresM.F.P. PerianayagamA. PetersonC.B. PhillipsM.R. PinheiroM. PiradovM.A. PondC.D. PotashmanM.H. PottooF.H. PradaS.I. RadfarA. RaggiA. RahimF. RahmanM. RamP. RanasingheP. RawafD.L. RawafS. RezaeiN. RezapourA. RobinsonS.R. RomoliM. RoshandelG. SahathevanR. SahebkarA. SahraianM.A. SathianB. SattinD. SawhneyM. SaylanM. SchiavolinS. SeylaniA. ShaF. ShaikhM.A. ShajiK.S. ShannawazM. ShettyJ.K. ShigematsuM. ShinJ.I. ShiriR. SilvaD.A.S. SilvaJ.P. SilvaR. SinghJ.A. SkryabinV.Y. SkryabinaA.A. SmithA.E. SoshnikovS. SpurlockE.E. SteinD.J. SunJ. Tabarés-SeisdedosR. ThakurB. TimalsinaB. Tovani-PaloneM.R. TranB.X. TsegayeG.W. Valadan TahbazS. ValdezP.R. VenketasubramanianN. VlassovV. VuG.T. VuL.G. WangY-P. WimoA. WinklerA.S. YadavL. Yahyazadeh JabbariS.H. YamagishiK. YangL. YanoY. YonemotoN. YuC. YunusaI. ZadeyS. ZastrozhinM.S. ZastrozhinaA. ZhangZ-J. MurrayC.J.L. VosT. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the global burden of disease study 2019.Lancet Public Health202272e105e12510.1016/S2468‑2667(21)00249‑834998485
     [Google Scholar]
  36. PattersonC. World Alzheimer report 2018.LondonAlzheimer’s Disease International2018
     [Google Scholar]
  37. ScheltensP. De StrooperB. KivipeltoM. HolstegeH. ChételatG. TeunissenC.E. CummingsJ. van der FlierW.M. Alzheimer’s disease.Lancet2021397102841577159010.1016/S0140‑6736(20)32205‑433667416
     [Google Scholar]
  38. Diabetes AtlasI.D.F. Committee. IDF Diabetes Atlas.10th edInternational Diabetes Federation2021www.diabetesatlas.org
     [Google Scholar]
  39. The Lancet Diabetes & Endocrinology Undiagnosed type 2 diabetes: an invisible risk factor.Lancet Diabetes Endocrinol.202412421510.1016/S2213‑8587(24)00072‑X38460527
     [Google Scholar]
  40. KerznerL.J. Diagnosis and treatment of Alzheimer’s disease.Adv. Intern. Med.1984294474706369932
     [Google Scholar]
  41. JiangW. ZhangY. MengF. LianB. ChenX. YuX. DaiE. WangS. LiuX. LiX. WangL. LiX. Identification of active transcription factor and miRNA regulatory pathways in Alzheimer’s disease.Bioinformatics201329202596260210.1093/bioinformatics/btt42323990414
     [Google Scholar]
  42. OgishimaS. MizunoS. KikuchiM. MiyashitaA. KuwanoR. TanakaH. NakayaJ. AlzPathway, an updated map of curated signaling pathways: Towards deciphering Alzheimer’s disease pathogenesis.Methods Mol. Biol.2016130342343210.1007/978‑1‑4939‑2627‑5_2526235082
     [Google Scholar]
  43. BrownG.C. HenekaM.T. The endotoxin hypothesis of Alzheimer’s disease.Mol. Neurodegener.20241913010.1186/s13024‑024‑00722‑y38561809
     [Google Scholar]
  44. KorczynA.D. GrinbergL.T. Is Alzheimer disease a disease?Nat. Rev. Neurol.202420424525110.1038/s41582‑024‑00940‑438424454
     [Google Scholar]
  45. SureshS. Singh SA. RushendranR. VellapandianC. PrajapatiB. Alzheimer’s disease: The role of extrinsic factors in its development, an investigation of the environmental enigma.Front. Neurol.202314130311110.3389/fneur.2023.130311138125832
     [Google Scholar]
  46. CirovicA. CirovicA. OrisakweO.E. LimaR.R. Local and systemic hypoxia as inductors of increased aluminum and iron brain accumulation promoting the onset of Alzheimer’s disease.Biol. Trace Elem. Res.2023201115134514210.1007/s12011‑023‑03599‑y36757557
     [Google Scholar]
  47. ChouM.L. BabamaleA.O. WalkerT.L. CognasseF. BlumD. BurnoufT. Blood–brain crosstalk: The roles of neutrophils, platelets, and neutrophil extracellular traps in neuropathologies.Trends Neurosci.202346976477910.1016/j.tins.2023.06.00537500363
     [Google Scholar]
  48. Gómez-PeraltaF. Pinés-CorralesP.J. SantosE. CuestaM. González-AlbarránO. AzrielS. On behalf the agora diabetes collaborative group. Diabetes management based on the phenotype and stage of the disease: An expert proposal from the AGORA Diabetes Collaborative Group.J. Clin. Med.20241316483910.3390/jcm1316483939200982
     [Google Scholar]
  49. HandelsmanY. AndersonJ.E. BakrisG.L. BallantyneC.M. BhattD.L. BloomgardenZ.T. BozkurtB. BudoffM.J. ButlerJ. CherneyD.Z.I. DeFronzoR.A. Del PratoS. EckelR.H. FilippatosG. FonarowG.C. FonsecaV.A. GarveyW.T. GiorginoF. GrantP.J. GreenJ.B. GreeneS.J. GroopP.H. GrunbergerG. JastreboffA.M. JellingerP.S. KhuntiK. KleinS. KosiborodM.N. KushnerP. LeiterL.A. LeporN.E. MantzorosC.S. MathieuC. MendeC.W. MichosE.D. MoralesJ. PlutzkyJ. PratleyR.E. RayK.K. RossingP. SattarN. SchwarzP.E.H. StandlE. StegP.G. TokgözoğluL. TuomilehtoJ. UmpierrezG.E. ValensiP. WeirM.R. WildingJ. WrightE.E.Jr DCRM 2.0: Multispecialty practice recommendations for the management of diabetes, cardiorenal, and metabolic diseases.Metabolism202415915593110.1016/j.metabol.2024.15593138852020
     [Google Scholar]
  50. VadadokhauU. VargaI. KáplárM. EmriM. CsőszÉ. Examination of the complex molecular landscape in obesity and type 2 diabetes.Int. J. Mol. Sci.2024259478110.3390/ijms2509478138732002
     [Google Scholar]
  51. SuzukiK. HatzikotoulasK. SouthamL. TaylorH.J. YinX. LorenzK.M. MandlaR. Huerta-ChagoyaA. MelloniG.E.M. KanoniS. RaynerN.W. BocherO. ArrudaA.L. SoneharaK. NambaS. LeeS.S.K. PreussM.H. PettyL.E. SchroederP. VanderwerffB. KalsM. BraggF. LinK. GuoX. ZhangW. YaoJ. KimY.J. GraffM. TakeuchiF. NanoJ. LamriA. NakatochiM. MoonS. ScottR.A. CookJ.P. LeeJ.J. PanI. TaliunD. ParraE.J. ChaiJ.F. BielakL.F. TabaraY. HaiY. ThorleifssonG. GrarupN. SoferT. WuttkeM. SarnowskiC. GiegerC. NousomeD. TrompetS. KwakS.H. LongJ. SunM. TongL. ChenW.M. NongmaithemS.S. NoordamR. LimV.J.Y. TamC.H.T. JooY.Y. ChenC.H. RaffieldL.M. PrinsB.P. NicolasA. YanekL.R. ChenG. BrodyJ.A. KabagambeE. AnP. XiangA.H. ChoiH.S. CadeB.E. TanJ. BroadawayK.A. WilliamsonA. KamaliZ. CuiJ. ThangamM. AdairL.S. AdeyemoA. Aguilar-SalinasC.A. AhluwaliaT.S. AnandS.S. BertoniA. Bork-JensenJ. BrandslundI. BuchananT.A. BurantC.F. ButterworthA.S. CanouilM. ChanJ.C.N. ChangL.C. CheeM.L. ChenJ. ChenS.H. ChenY.T. ChenZ. ChuangL.M. CushmanM. DaneshJ. DasS.K. de SilvaH.J. DedoussisG. DimitrovL. DoumateyA.P. DuS. DuanQ. EckardtK.U. EmeryL.S. EvansD.S. EvansM.K. FischerK. FloydJ.S. FordI. FrancoO.H. FraylingT.M. FreedmanB.I. GenterP. GersteinH.C. GiedraitisV. González-VillalpandoC. González-VillalpandoM.E. Gordon-LarsenP. GrossM. GuareL.A. HackingerS. HakasteL. HanS. HattersleyA.T. HerderC. HorikoshiM. HowardA.G. HsuehW. HuangM. HuangW. HungY.J. HwangM.Y. HwuC.M. IchiharaS. IkramM.A. IngelssonM. IslamM.T. IsonoM. JangH.M. JasmineF. JiangG. JonasJ.B. JørgensenT. KamanuF.K. KandeelF.R. KasturiratneA. KatsuyaT. KaurV. KawaguchiT. KeatonJ.M. KhoA.N. KhorC.C. KibriyaM.G. KimD.H. KronenbergF. KuusistoJ. LällK. LangeL.A. LeeK.M. LeeM.S. LeeN.R. LeongA. LiL. LiY. Li-GaoR. LigthartS. LindgrenC.M. LinnebergA. LiuC.T. LiuJ. LockeA.E. LouieT. LuanJ. LukA.O. LuoX. LvJ. LynchJ.A. LyssenkoV. MaedaS. MamakouV. MansuriS.R. MatsudaK. MeitingerT. MelanderO. MetspaluA. MoH. MorrisA.D. MouraF.A. NadlerJ.L. NallsM.A. NayakU. NtallaI. OkadaY. OrozcoL. PatelS.R. PatilS. PeiP. PereiraM.A. PetersA. PirieF.J. PolikowskyH.G. PornealaB. PrasadG. Rasmussen-TorvikL.J. ReinerA.P. RodenM. RohdeR. RollK. SabanayagamC. SandowK. SankareswaranA. SattarN. SchönherrS. ShahriarM. ShenB. ShiJ. ShinD.M. ShojimaN. SmithJ.A. SoW.Y. StančákováA. SteinthorsdottirV. StilpA.M. StrauchK. TaylorK.D. ThorandB. ThorsteinsdottirU. TomlinsonB. TranT.C. TsaiF.J. TuomilehtoJ. Tusie-LunaT. UdlerM.S. Valladares-SalgadoA. van DamR.M. van KlinkenJ.B. VarmaR. Wacher-RodarteN. WheelerE. WickremasingheA.R. van DijkK.W. WitteD.R. YajnikC.S. YamamotoK. YamamotoK. YoonK. YuC. YuanJ.M. YusufS. ZawistowskiM. ZhangL. ZhengW. KanonaS. van HeelD.A. RaffelL.J. IgaseM. IppE. RedlineS. ChoY.S. LindL. ProvinceM.A. FornageM. HanisC.L. IngelssonE. ZondermanA.B. PsatyB.M. WangY-X. RotimiC.N. BeckerD.M. MatsudaF. LiuY. YokotaM. KardiaS.L.R. PeyserP.A. PankowJ.S. EngertJ.C. BonnefondA. FroguelP. WilsonJ.G. SheuW.H.H. WuJ-Y. HayesM.G. MaR.C.W. WongT-Y. Mook-KanamoriD.O. TuomiT. ChandakG.R. CollinsF.S. BharadwajD. ParéG. SaleM.M. AhsanH. MotalaA.A. ShuX-O. ParkK-S. JukemaJ.W. CruzM. ChenY-D.I. RichS.S. McKean-CowdinR. GrallertH. ChengC-Y. GhanbariM. TaiE-S. DupuisJ. KatoN. LaaksoM. KöttgenA. KohW-P. BowdenD.W. PalmerC.N.A. KoonerJ.S. KooperbergC. LiuS. NorthK.E. SaleheenD. HansenT. PedersenO. WarehamN.J. LeeJ. KimB-J. MillwoodI.Y. WaltersR.G. StefanssonK. AhlqvistE. GoodarziM.O. MohlkeK.L. LangenbergC. HaimanC.A. LoosR.J.F. FlorezJ.C. RaderD.J. RitchieM.D. ZöllnerS. MägiR. MarstonN.A. RuffC.T. van HeelD.A. FinerS. DennyJ.C. YamauchiT. KadowakiT. ChambersJ.C. NgM.C.Y. SimX. BelowJ.E. TsaoP.S. ChangK-M. McCarthyM.I. MeigsJ.B. MahajanA. SpracklenC.N. MercaderJ.M. BoehnkeM. RotterJ.I. VujkovicM. VoightB.F. MorrisA.P. ZegginiE. Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.Nature2024627800334735710.1038/s41586‑024‑07019‑638374256
     [Google Scholar]
  52. LuX. XieQ. PanX. ZhangR. ZhangX. PengG. ZhangY. ShenS. TongN. Type 2 diabetes mellitus in adults: Pathogenesis, prevention and therapy.Signal Transduct. Target. Ther.20249126210.1038/s41392‑024‑01951‑939353925
     [Google Scholar]
  53. RakusanovaS. CajkaT. Metabolomics and lipidomics for studying metabolic Syndrome: Insights into cardiovascular diseases, Type 1 & 2 diabetes, and metabolic dysfunction-associated steatotic liver disease.Physiol. Res.202473S1Suppl. 1S165S18310.33549/physiolres.93544339212142
     [Google Scholar]
  54. HaoK. Di NarzoA.F. HoL. LuoW. LiS. ChenR. LiT. DubnerL. PasinettiG.M. Shared genetic etiology underlying Alzheimer’s disease and type 2 diabetes.Mol. Aspects Med.201543-44667610.1016/j.mam.2015.06.00626116273
     [Google Scholar]
  55. WangX.F. LinX. LiD.Y. ZhouR. GreenbaumJ. ChenY.C. ZengC.P. PengL.P. WuK.H. AoZ.X. LuJ.M. GuoY.F. ShenJ. DengH.W. Linking Alzheimer’s disease and type 2 diabetes: Novel shared susceptibility genes detected by cFDR approach.J. Neurol. Sci.201738026227210.1016/j.jns.2017.07.04428870582
     [Google Scholar]
  56. VishalK. BhuiyanP. QiJ. ChenY. ZhangJ. YangF. LiJ. Unraveling the mechanism of immunity and inflammation related to molecular signatures crosstalk among obesity, T2D, and AD: Insights from bioinformatics approaches.Bioinform. Biol. Insights2023171177932223116797710.1177/1177932223116797737124128
     [Google Scholar]
  57. YuanX. WangH. ZhangF. ZhangM. WangQ. WangJ. The common genes involved in the pathogenesis of Alzheimer’s disease and type 2 diabetes and their implication for drug repositioning.Neuropharmacology202322310932710.1016/j.neuropharm.2022.10932736368623
     [Google Scholar]
  58. WijesekaraN. GonçalvesR.A. De FeliceF.G. FraserP.E. Impaired peripheral glucose homeostasis and Alzheimer's disease.Neuropharmacology2018136Pt B17218110.1016/j.neuropharm.2017.11.02729169962
     [Google Scholar]
  59. RohmT.V. MeierD.T. OlefskyJ.M. DonathM.Y. Inflammation in obesity, diabetes, and related disorders.Immunity2022551315510.1016/j.immuni.2021.12.01335021057
     [Google Scholar]
  60. MoreiraP.I. High-sugar diets, type 2 diabetes and Alzheimerʼs disease.Curr. Opin. Clin. Nutr. Metab. Care201316444044510.1097/MCO.0b013e328361c7d123657152
     [Google Scholar]
  61. SultanaM. HiaR. AkinsikuO. HegdeV. Peripheral mitochondrial dysfunction: A potential contributor to the development of metabolic disorders and Alzheimer’s disease.Biology2023127101910.3390/biology1207101937508448
     [Google Scholar]
  62. PruzinJ.J. NelsonP.T. AbnerE.L. ArvanitakisZ. Review: Relationship of type 2 diabetes to human brain pathology.Neuropathol. Appl. Neurobiol.201844434736210.1111/nan.1247629424027
     [Google Scholar]
  63. De FeliceF.G. FerreiraS.T. Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease.Diabetes20146372262227210.2337/db13‑195424931033
     [Google Scholar]
  64. BharadwajP. WijesekaraN. LiyanapathiranaM. NewsholmeP. IttnerL. FraserP. VerdileG. The link between type 2 diabetes and neurodegeneration: Roles for Amyloid-β, Amylin, and Tau proteins.J. Alzheimers Dis.201759242143210.3233/JAD‑16119228269785
     [Google Scholar]
  65. SankarS.B. Infante-GarciaC. WeinstockL.D. Ramos-RodriguezJ.J. Hierro-BujalanceC. Fernandez-PonceC. WoodL.B. Garcia-AllozaM. Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer’s mouse model.J. Neuroinflammation20201713810.1186/s12974‑020‑1707‑x31992349
     [Google Scholar]
  66. SankarT.J. SuryanarayanaR. KamathB.T.P. SunilB.N. ReddyM.M. To determine the survival, prevalence and associated factors of exclusive breastfeeding practices in South India.J. Family Med. Prim. Care2023121364110.4103/jfmpc.jfmpc_784_2237025235
     [Google Scholar]
  67. YoonJ.H. HwangJ. SonS.U. ChoiJ. YouS.W. ParkH. ChaS.Y. MaengS. How can insulin resistance cause Alzheimer’s disease?Int. J. Mol. Sci.2023244350610.3390/ijms2404350636834911
     [Google Scholar]
  68. DuarteA.I. CandeiasE. CorreiaS.C. SantosR.X. CarvalhoC. CardosoS. PlácidoA. SantosM.S. OliveiraC.R. MoreiraP.I. Crosstalk between diabetes and brain: Glucagon-like peptide-1 mimetics as a promising therapy against neurodegeneration.Biochim. Biophys. Acta Mol. Basis Dis.20131832452754110.1016/j.bbadis.2013.01.00823314196
     [Google Scholar]
  69. MorrisJ.K. BurnsJ.M. Insulin: An emerging treatment for Alzheimer’s disease dementia?Curr. Neurol. Neurosci. Rep.201212552052710.1007/s11910‑012‑0297‑022791280
     [Google Scholar]
  70. ToledanoA. Rodríguez-CasadoA. ÄlvarezM.I. Toledano-DíazA. Alzheimer’s disease, obesity, and type 2 diabetes: Focus on common neuroglial dysfunctions (critical review and new data on human brain and models).Brain Sci.20241411110110.3390/brainsci1411110139595866
     [Google Scholar]
  71. ZhangW. XiaoD. MaoQ. XiaH. Role of neuroinflammation in neurodegeneration development.Signal Transduct. Target. Ther.20238126710.1038/s41392‑023‑01486‑537433768
     [Google Scholar]
  72. FauziA. ThoeE.S. QuanT.Y. YinA.C.Y. Insights from insulin resistance pathways: Therapeutic approaches against Alzheimer associated diabetes mellitus.J. Diabetes Complications2023371110862910.1016/j.jdiacomp.2023.10862937866274
     [Google Scholar]
  73. MittalK. ManiR.J. KatareD.P. Type 3 diabetes: Cross talk between differentially regulated proteins of type 2 diabetes mellitus and Alzheimer’s disease.Sci. Rep.2016612558910.1038/srep2558927151376
     [Google Scholar]
  74. NisarO. PervezH. MandaliaB. WaqasM. SraH.K. Type 3 diabetes mellitus: A link between Alzheimer’s disease and type 2 diabetes mellitus.Cureus20201211e1170310.7759/cureus.1170333391936
     [Google Scholar]
  75. SarnowskiC. HuanT. MaY. JoehanesR. BeiserA. DeCarliC.S. Heard-CostaN.L. LevyD. LinH. LiuC.T. LiuC. MeigsJ.B. SatizabalC.L. FlorezJ.C. HivertM.F. DupuisJ. De JagerP.L. BennettD.A. SeshadriS. MorrisonA.C. Multi-tissue epigenetic analysis identifies distinct associations underlying insulin resistance and Alzheimer’s disease at CPT1A locus.Clin. Epigenetics202315117310.1186/s13148‑023‑01589‑437891690
     [Google Scholar]
  76. StanciuG.D. BildV. AbabeiD.C. RusuR.N. CobzaruA. PaduraruL. BuleaD. Link between diabetes and Alzheimer’s disease due to the shared amyloid aggregation and deposition involving both neurodegenerative changes and neurovascular damages.J. Clin. Med.202096171310.3390/jcm906171332503113
     [Google Scholar]
  77. JolivaltC.G. HurfordR. LeeC.A. DumaopW. RockensteinE. MasliahE. Type 1 diabetes exaggerates features of Alzheimer’s disease in APP transgenic mice.Exp. Neurol.2010223242243110.1016/j.expneurol.2009.11.00519931251
     [Google Scholar]
  78. Ramos-RodriguezJ.J. OrtizO. Jimenez-PalomaresM. KayK.R. BerrocosoE. Murillo-CarreteroM.I. PerdomoG. Spires-JonesT. Cozar-CastellanoI. Lechuga-SanchoA.M. Garcia-AllozaM. Differential central pathology and cognitive impairment in pre-diabetic and diabetic mice.Psychoneuroendocrinology201338112462247510.1016/j.psyneuen.2013.05.01023790682
     [Google Scholar]
  79. TakedaS. SatoN. IkimuraK. NishinoH. RakugiH. MorishitaR. Increased blood–brain barrier vulnerability to systemic inflammation in an Alzheimer disease mouse model.Neurobiol. Aging20133482064207010.1016/j.neurobiolaging.2013.02.01023561508
     [Google Scholar]
  80. Ionescu-TîrgovişteC. GagniucP.A. GujaC. Structural properties of gene promoters highlight more than two phenotypes of diabetes.PLoS One2015109e013795010.1371/journal.pone.013795026379145
     [Google Scholar]
  81. PanN YangS NiuX. Latent autoimmune diabetes in adults and metabolic syndrome-A mini review.Front. Endocrinol.20221391337310.3389/fendo.2022.91337335837301
     [Google Scholar]
  82. LeeY.N. HudaM.S.B. Uncommon forms of diabetes.Clin. Med.2021214e337e34110.7861/clinmed.2021‑036935192474
     [Google Scholar]
  83. ZhouZ. XuM. XiongP. YuanJ. ZhengD. PiaoS. Prognosis and outcome of latent autoimmune diabetes in adults: T1DM or T2DM?Diabetol. Metab. Syndr.202416124210.1186/s13098‑024‑01479‑639375804
     [Google Scholar]
  84. SinghK. MartinellM. LuoZ. EspesD. StålhammarJ. SandlerS. CarlssonP-O. Cellular immunological changes in patients with LADA are a mixture of those seen in patients with type 1 and type 2 diabetes.Clin. Exp. Immunol.20191971647310.1111/cei.1328930843600
     [Google Scholar]
  85. AndersenM.K. HansenT. Genetic aspects of latent autoimmune diabetes in adults: A mini-review.Curr. Diabetes Rev.201915319419810.2174/157339981466618073012322630058494
     [Google Scholar]
  86. BuzzettiR. TuomiT. MauricioD. PietropaoloM. ZhouZ. PozzilliP. LeslieR.D. Management of latent autoimmune diabetes in adults: A consensus statement from an international expert panel.Diabetes202069102037204710.2337/dbi20‑001732847960
     [Google Scholar]
  87. JonesA.G. McDonaldT.J. ShieldsB.M. HagopianW. HattersleyA.T. Latent autoimmune diabetes of adults (LADA) is likely to represent a mixed population of autoimmune (type 1) and nonautoimmune (type 2) diabetes.Diabetes Care20214461243125110.2337/dc20‑283434016607
     [Google Scholar]
  88. LeeB.K. PakK. PockrosP.J. Latent autoimmune diabetes in adults (LADA) occurring in a patient with primary biliary cholangitis.Am. J. Med.20251381394110.1016/j.amjmed.2024.09.01239304076
     [Google Scholar]
  89. RavikumarV AhmedA AnjankarA. A review on latent autoimmune diabetes in adults.Cureus20231510e4791510.7759/cureus.4791538034250
     [Google Scholar]
  90. RamuD. RamaswamyS. RaoS. PaulS.F.D. The worldwide prevalence of latent autoimmune diabetes of adults among adult-onset diabetic individuals: A systematic review and meta-analysis.Endocrine2023821284110.1007/s12020‑023‑03424‑537428296
     [Google Scholar]
  91. MohammadiM. Prevalence of latent autoimmune diabetes in adults and insulin resistance: A systematic review and meta-analysis.Eur. J. Transl. Myol.20243431269410.4081/ejtm.2024.1269439221599
     [Google Scholar]
  92. HernándezM. MauricioD. Latent autoimmune diabetes in adults: A review of clinically relevant issues.Adv. Exp. Med. Biol.20201307294110.1007/5584_2020_53332424495
     [Google Scholar]
  93. BuzzettiR. MaddaloniE. GagliaJ. LeslieR.D. WongF.S. BoehmB.O. Adult-onset autoimmune diabetes.Nat. Rev. Dis. Primers2022816310.1038/s41572‑022‑00390‑636138034
     [Google Scholar]
  94. VaxillaireM. BonnefondA. LiatisS. Ben Salem HachmiL. JoticA. BoisselM. GagetS. DurandE. VaillantE. DerhourhiM. CanouilM. LarcherN. AllegaertF. MedlejR. ChadliA. BelhadjA. ChaiebM. RaposoJ.F. IlkovaH. LoizouD. LalicN. VassalloJ. MarreM. FroguelP. MODY-MGSD Study Group Monogenic diabetes characteristics in a transnational multicenter study from Mediterranean countries.Diabetes Res. Clin. Pract.202117110855310.1016/j.diabres.2020.10855333242514
     [Google Scholar]
  95. StratiM. MoustakiM. PsaltopoulouT. VryonidouA. PaschouS.A. Early onset type 2 diabetes mellitus: An update.Endocrine202485396597810.1007/s12020‑024‑03772‑w38472622
     [Google Scholar]
  96. AlexanderM. ChoE. GliozheniE. SalemY. CheungJ. IchiiH. Pathology of diabetes-induced immune dysfunction.Int. J. Mol. Sci.20242513710510.3390/ijms2513710539000211
     [Google Scholar]
  97. KosyrevaA. SentyabrevaA. TsvetkovI. MakarovaO. Alzheimer’s disease and inflammaging.Brain Sci.2022129123710.3390/brainsci1209123736138973
     [Google Scholar]
  98. NewcombeE.A. Camats-PernaJ. SilvaM.L. ValmasN. HuatT.J. MedeirosR. Inflammation: The link between comorbidities, genetics, and Alzheimer’s disease.J. Neuroinflammation201815127610.1186/s12974‑018‑1313‑330249283
     [Google Scholar]
  99. ReaI.M. GibsonD.S. McGilliganV. McNerlanS.E. AlexanderH.D. RossO.A. Age and age-related diseases: Role of inflammation triggers and cytokines.Front. Immunol.2018958610.3389/fimmu.2018.0058629686666
     [Google Scholar]
  100. DorszewskaJ. PrendeckiM. OczkowskaA. DezorM. KozubskiW. Molecular basis of familial and sporadic Alzheimer’s disease.Curr. Alzheimer Res.201613995296310.2174/156720501366616031415050126971934
     [Google Scholar]
  101. Toledano-GascaA. Hypotheses concerning the aetiology of Alzheimer’s disease.Pharmacopsychiatry198821S 1Suppl. 1172510.1055/s‑2007‑10170603064109
     [Google Scholar]
  102. DringenbergH.C. Alzheimer’s disease: More than a ‘cholinergic disorder’ — Evidence that cholinergic–monoaminergic interactions contribute to EEG slowing and dementia.Behav. Brain Res.2000115223524910.1016/S0166‑4328(00)00261‑811000423
     [Google Scholar]
  103. CraigL.A. HongN.S. McDonaldR.J. Revisiting the cholinergic hypothesis in the development of Alzheimer’s disease.Neurosci. Biobehav. Rev.20113561397140910.1016/j.neubiorev.2011.03.00121392524
     [Google Scholar]
  104. MisiakB. LeszekJ. KiejnaA. Metabolic syndrome, mild cognitive impairment and Alzheimer’s disease—The emerging role of systemic low-grade inflammation and adiposity.Brain Res. Bull.2012893-414414910.1016/j.brainresbull.2012.08.00322921944
     [Google Scholar]
  105. StreitW.J. KhoshboueiH. BechmannI. The role of microglia in sporadic Alzheimer’s disease.J. Alzheimers Dis.202179396196810.3233/JAD‑20124833361603
     [Google Scholar]
  106. ToledanoA. ÁlvarezM.I. Toledano-DíazA. MerinoJ.J. Julio RodríguezJ. Brain local and regional neuroglial alterations in Alzheimers Disease: Cell types, responses and implications.Curr. Alzheimer Res.201613432134210.2174/156720501366615111614121726567738
     [Google Scholar]
  107. Toledano-DíazA. ÁlvarezM.I. ToledanoA. The relationships between neuroglial alterations and neuronal changes in Alzheimer’s disease, and the related controversies I: Gliopathogenesis and glioprotection.J. Cent. Nerv. Syst. Dis.2022141179573522112870310.1177/1179573522112870336238130
     [Google Scholar]
  108. GleichmannM. MattsonM.P. Alzheimer’s disease and neuronal network activity.Neuromolecular Med.2010121444710.1007/s12017‑009‑8100‑319885650
     [Google Scholar]
  109. BondaD.J. WangX. LeeH.G. SmithM.A. PerryG. ZhuX. Neuronal failure in Alzheimer’s disease: A view through the oxidative stress looking-glass.Neurosci. Bull.201430224325210.1007/s12264‑013‑1424‑x24733654
     [Google Scholar]
  110. LopesJ. OliveiraC. AgostinhoP. Cell cycle re-entry in Alzheimer’s disease: A major neuropathological characteristic?Curr. Alzheimer Res.20096320521210.2174/15672050978848659019519302
     [Google Scholar]
  111. KleinW.L. Synaptotoxic amyloid-β oligomers: A molecular basis for the cause, diagnosis, and treatment of Alzheimer’s disease?J. Alzheimers Dis.201233s1Suppl. 1S49S6510.3233/JAD‑2012‑12903922785404
     [Google Scholar]
  112. PansariK. GuptaA. ThomasP. Alzheimer’s disease and vascular factors: Facts and theories.Int. J. Clin. Pract.200256319720310.1111/j.1742‑1241.2002.tb11233.x12018826
     [Google Scholar]
  113. SmithM.A. SayreL.M. MonnierV.M. PerryG. Radical AGEing in Alzheimer’s disease.Trends Neurosci.199518417217610.1016/0166‑2236(95)93897‑77778188
     [Google Scholar]
  114. KocagoncuE. QuinnA. FirouzianA. CooperE. GreveA. GunnR. GreenG. WoolrichM.W. HensonR.N. LovestoneS. RoweJ.B. Tau pathology in early Alzheimer’s disease is linked to selective disruptions in neurophysiological network dynamics.Neurobiol. Aging20209214115210.1016/j.neurobiolaging.2020.03.00932280029
     [Google Scholar]
  115. BehlC. Brain aging and late-onset Alzheimer’s disease: Many open questions.Int. Psychogeriatr.201224Suppl. 1S3S910.1017/S104161021200052X22784426
     [Google Scholar]
  116. NeillD. Should Alzheimer’s disease be equated with human brain ageing?: A maladaptive interaction between brain evolution and senescence.Ageing Res. Rev.201211110412210.1016/j.arr.2011.06.00421763787
     [Google Scholar]
  117. TrevisanK. Cristina-PereiraR. Silva-AmaralD. Aversi-FerreiraT.A. Theories of aging and the prevalence of Alzheimer’s disease.BioMed. Res. Int.201920191910.1155/2019/917142431317043
     [Google Scholar]
  118. SwerdlowR.H. KhanS.M. The Alzheimer’s disease mitochondrial cascade hypothesis: An update.Exp. Neurol.2009218230831510.1016/j.expneurol.2009.01.01119416677
     [Google Scholar]
  119. AgnatiL.F. GuidolinD. BaluskaF. BarlowP.W. CaroneC. GenedaniS. GenedaniS. A new hypothesis of pathogenesis based on the divorce between mitochondria and their host cells: Possible relevance for Alzheimer’s disease.Curr. Alzheimer Res.20107430732210.2174/15672051079116239519860724
     [Google Scholar]
  120. AlbensiB.C. Dysfunction of mitochondria: Implications for Alzheimer’s disease.Int. Rev. Neurobiol.2019145132710.1016/bs.irn.2019.03.00131208523
     [Google Scholar]
  121. HardyJ.A. HigginsG.A. Alzheimer’s disease: The amyloid cascade hypothesis.Science1992256505418418510.1126/science.15660671566067
     [Google Scholar]
  122. NeveR.L. RobakisN.K. Alzheimer’s disease: A re-examination of the amyloid hypothesis.Trends Neurosci.1998211151910.1016/S0166‑2236(97)01168‑59464679
     [Google Scholar]
  123. CastellaniR.J. Plascencia-VillaG. PerryG. The amyloid cascade and Alzheimer’s disease therapeutics: Theory versus observation.Lab. Invest.201999795897010.1038/s41374‑019‑0231‑z30760863
     [Google Scholar]
  124. MaC. HongF. YangS. Amyloidosis in Alzheimer’s disease: Pathogeny, etiology, and related therapeutic directions.Molecules2022274121010.3390/molecules2704121035209007
     [Google Scholar]
  125. CastellaniR.J. PerryG. The complexities of the pathology–pathogenesis relationship in Alzheimer disease.Biochem. Pharmacol.201488467167610.1016/j.bcp.2014.01.00924447936
     [Google Scholar]
  126. Toledano-DíazA. ÁlvarezM.I. ToledanoA. The relationships between neuroglial and neuronal changes in Alzheimer’s disease, and the related controversies II: gliotherapies and multimodal therapy.J. Cent. Nerv. Syst. Dis.2022141179573522112389610.1177/1179573522112389636407561
     [Google Scholar]
  127. WiedemannS.J. TrimigliozziK. DrorE. MeierD.T. Molina-TijerasJ.A. RachidL. Le FollC. MagnanC. SchulzeF. StawiskiM. HäuselmannS.P. MéreauH. Böni-SchnetzlerM. DonathM.Y. The cephalic phase of insulin release is modulated by IL-1β.Cell Metab.20223479911003.e610.1016/j.cmet.2022.06.00135750050
     [Google Scholar]
  128. DuarteI. de SouzaM.C.M. CuringaR.M. MendonçaH.M. de Lacerda de OliveiraL. MilenkovicD. HassimottoN.M.A. CostaA.M. MalaquiasJ.V. dos Santos BorgesT.K. Effect of Passiflora setacea juice and its phenolic metabolites on insulin resistance markers in overweight individuals and on microglial cell activity.Food Funct.202213126498650910.1039/D1FO04334J35621054
     [Google Scholar]
  129. BanerjeeJ. DorfmanM.D. FasnachtR. DouglassJ.D. Wyse-JacksonA.C. BarriaA. ThalerJ.P. CX3CL1 action on microglia protects from diet-induced obesity by restoring POMC neuronal excitability and melanocortin system activity impaired. By high-fat diet feeding.Int. J. Mol. Sci.20222312638010.3390/ijms2312638035742824
     [Google Scholar]
  130. TakedaS. SatoN. Uchio-YamadaK. SawadaK. KuniedaT. TakeuchiD. KurinamiH. ShinoharaM. RakugiH. MorishitaR. Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Aβ deposition in an Alzheimer mouse model with diabetes.Proc. Natl. Acad. Sci. USA2010107157036704110.1073/pnas.100064510720231468
     [Google Scholar]
  131. Bello-ChavollaO.Y. Antonio-VillaN.E. Vargas-VázquezA. Ávila-FunesJ.A. Aguilar-SalinasC.A. Pathophysiological mechanisms linking Type 2 Diabetes and dementia: Review of evidence from clinical, translational and epidemiological research.Curr. Diabetes Rev.201915645647010.2174/157339981566619012915565430648514
     [Google Scholar]
  132. Moreno-GonzalezI. EdwardsG.III SalvadoresN. ShahnawazM. Diaz-EspinozaR. SotoC. Molecular interaction between type 2 diabetes and Alzheimer’s disease through cross-seeding of protein misfolding.Mol. Psychiatry20172291327133410.1038/mp.2016.23028044060
     [Google Scholar]
  133. AbrahamM.J. El SherbiniA. El-DiastyM. AskariS. SzewczukM.R. Restoring epigenetic reprogramming with diet and exercise to improve health-related metabolic diseases.Biomolecules202313231810.3390/biom1302031836830687
     [Google Scholar]
  134. TianY. JingG. ZhangM. Insulin-degrading enzyme: Roles and pathways in ameliorating cognitive impairment associated with Alzheimer’s disease and diabetes.Ageing Res. Rev.20239010199910.1016/j.arr.2023.10199937414154
     [Google Scholar]
  135. AzamM.S. WahiduzzamanM. Reyad-ul-FerdousM. IslamM.N. RoyM. Inhibition of insulin degrading enzyme to control diabetes Mellitus and its applications on some other chronic disease: A critical review.Pharm. Res.202239461162910.1007/s11095‑022‑03237‑735378698
     [Google Scholar]
  136. HongM.G. ReynoldsC. GatzM. JohanssonB. PalmerJ.C. GuH.F. BlennowK. KehoeP.G. de FaireU. PedersenN.L. PrinceJ.A. Evidence that the gene encoding insulin degrading enzyme influences human lifespan.Hum. Mol. Genet.200817152370237810.1093/hmg/ddn13718448515
     [Google Scholar]
  137. KangP. WangZ. QiaoD. ZhangB. MuC. CuiH. LiS. Dissecting genetic links between Alzheimer’s disease and type 2 diabetes mellitus in a systems biology way.Front. Genet.202213101986010.3389/fgene.2022.101986036186446
     [Google Scholar]
  138. Torres-ValadezR. Ramos-LopezO. Frías DelgadilloK.J. Flores-GarcíaA. Rojas CarrilloE. Aguiar-GarcíaP. Bernal PérezJ.A. Martinez-LopezE. MartínezJ.A. Zepeda-CarrilloE.A. Impact of APOE alleles-by-diet interactions on glycemic and lipid features- A cross-sectional study of a cohort of Type 2 Diabetes patients from western Mexico: Implications for personalized medicine.Pharm. Genomics Pers. Med.20201365566310.2147/PGPM.S27795233273843
     [Google Scholar]
  139. ArdanazC.G. RamírezM.J. SolasM. Brain metabolic alterations in Alzheimer’s disease.Int. J. Mol. Sci.2022237378510.3390/ijms2307378535409145
     [Google Scholar]
  140. KnezovicA. LoncarA. HomolakJ. SmailovicU. Osmanovic BarilarJ. GanociL. BozinaN. RiedererP. Salkovic-PetrisicM. Rat brain glucose transporter-2, insulin receptor and glial expression are acute targets of intracerebroventricular streptozotocin: risk factors for sporadic Alzheimer’s disease?J. Neural Transm.2017124669570810.1007/s00702‑017‑1727‑628470423
     [Google Scholar]
  141. ZhangS. ZhangY. WenZ. YangY. BuT. BuX. NiQ. Cognitive dysfunction in diabetes: Abnormal glucose metabolic regulation in the brain.Front. Endocrinol.202314119260210.3389/fendo.2023.119260237396164
     [Google Scholar]
  142. MengZ. LiangH. ZhaoJ. GaoJ. LiuC. MaX. LiuJ. LiangB. JiaoX. CaoJ. WangY. HMOX1 upregulation promotes ferroptosis in diabetic atherosclerosis.Life Sci.202128411993510.1016/j.lfs.2021.11993534508760
     [Google Scholar]
  143. GholizadehE. KhaleghianA. Najafgholi SeyfiD. KarbalaeiR. Showing NAFLD, as a key connector disease between Alzheimer’s disease and diabetes via analysis of systems biology.Gastroenterol. Hepatol. Bed Bench202013Suppl. 1S89S9733585009
     [Google Scholar]
  144. CiudinA. Diabetes mellitus and Alzheimer's disease: An unforgettable relation.Endocrinol Nutr201663519119310.1016/j.endonu.2015.12.00426826774
     [Google Scholar]
  145. Lyra e SilvaN.M. GonçalvesR.A. PascoalT.A. Lima-FilhoR.A.S. ResendeE.P.F. VieiraE.L.M. TeixeiraA.L. de SouzaL.C. PenyJ.A. FortunaJ.T.S. FurigoI.C. HashiguchiD. Miya-CoreixasV.S. ClarkeJ.R. AbisambraJ.F. LongoB.M. DonatoJ.Jr FraserP.E. Rosa-NetoP. CaramelliP. FerreiraS.T. De FeliceF.G. Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer’s disease.Transl. Psychiatry202111125110.1038/s41398‑021‑01349‑z33911072
     [Google Scholar]
  146. VeselovI.M. VinogradovaD.V. MaltsevA.V. ShevtsovP.N. SpirkovaE.A. BachurinS.O. ShevtsovaE.F. Mitochondria and oxidative stress as a link between Alzheimer’s Disease and diabetes Mellitus.Int. J. Mol. Sci.202324191445010.3390/ijms24191445037833898
     [Google Scholar]
  147. ZhongH. GengR. ZhangY. DingJ. LiuM. DengS. TuQ. Effects of peroxisome proliferator-activated receptor-Gamma agonists on cognitive function: A systematic review and meta-analysis.Biomedicines202311224610.3390/biomedicines1102024636830783
     [Google Scholar]
  148. BuryJ.J. ChambersA. HeathP.R. InceP.G. ShawP.J. MatthewsF.E. BrayneC. SimpsonJ.E. WhartonS.B. Type 2 diabetes mellitus-associated transcriptome alterations in cortical neurones and associated neurovascular unit cells in the ageing brain.Acta Neuropathol. Commun.202191510.1186/s40478‑020‑01109‑y33407907
     [Google Scholar]
  149. BoukhalfaW. JmelH. KherijiN. GouizaI. DallaliH. HechmiM. KefiR. Decoding the genetic relationship between Alzheimer’s disease and type 2 diabetes: potential risk variants and future direction for North Africa.Front. Aging Neurosci.202315111481010.3389/fnagi.2023.111481037342358
     [Google Scholar]
  150. CaputoV. TermineA. StrafellaC. GiardinaE. CascellaR. Shared (epi)genomic background connecting neurodegenerative diseases and type 2 diabetes.World J. Diabetes202011515516410.4239/wjd.v11.i5.15532477452
     [Google Scholar]
  151. SmithU. Abdominal obesity: A marker of ectopic fat accumulation.J. Clin. Invest.201512551790179210.1172/JCI8150725932676
     [Google Scholar]
  152. GhoshS. Ectopic fat: The potential target for obesity management.JOMR201411303810.4103/2347‑9906.123883
     [Google Scholar]
  153. BlüherM. Metabolically healthy obesity.Endocr. Rev.2020413bnaa00410.1210/endrev/bnaa00432128581
     [Google Scholar]
  154. SmithG.I. MittendorferB. KleinS. Metabolically healthy obesity: Facts and fantasies.J. Clin. Invest.2019129103978398910.1172/JCI12918631524630
     [Google Scholar]
  155. HildebrandtX. IbrahimM. PeltzerN. Cell death and inflammation during obesity: “Know my methods, WAT(son)”.Cell Death Differ.202330227929210.1038/s41418‑022‑01062‑436175539
     [Google Scholar]
  156. ReillyS.M. SaltielA.R. Adapting to obesity with adipose tissue inflammation.Nat. Rev. Endocrinol.2017131163364310.1038/nrendo.2017.9028799554
     [Google Scholar]
  157. AcharyaN.K. LevinE.C. CliffordP.M. HanM. TourtellotteR. ChamberlainD. PollaroM. CorettiN.J. KosciukM.C. NageleE.P. DeMarshallC. FreemanT. ShiY. GuanC. MacpheeC.H. WilenskyR.L. NageleR.G. Diabetes and hypercholesterolemia increase blood-brain barrier permeability and brain amyloid deposition: Beneficial effects of the LpPLA2 inhibitor darapladib.J. Alzheimers Dis.201335117919810.3233/JAD‑12225423388174
     [Google Scholar]
  158. BoscoD. FavaA. PlastinoM. MontalciniT. PujiaA. Possible implications of insulin resistance and glucose metabolism in Alzheimer’s disease pathogenesis.J. Cell. Mol. Med.20111591807182110.1111/j.1582‑4934.2011.01318.x21435176
     [Google Scholar]
  159. ContrerasC. González-GarcíaI. Martínez-SánchezN. Seoane-CollazoP. JacasJ. MorganD.A. SerraD. GallegoR. GonzalezF. CasalsN. NogueirasR. RahmouniK. DiéguezC. LópezM. Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance.Cell Rep.20149136637710.1016/j.celrep.2014.08.05725284795
     [Google Scholar]
  160. TongM. NeusnerA. LongatoL. LawtonM. WandsJ.R. de la MonteS.M. Nitrosamine exposure causes insulin resistance diseases: Relevance to type 2 diabetes mellitus, non-alcoholic steatohepatitis, and Alzheimer’s disease.J. Alzheimers Dis.200917482784410.3233/JAD‑2009‑111520387270
     [Google Scholar]
  161. CapeauJ. Insulin resistance and steatosis in humans.Diabetes Metab.200834664965710.1016/S1262‑3636(08)74600‑719195626
     [Google Scholar]
  162. ToledanoA. Growth and aging factors in physiological senility and Alzheimer's disease.Rev. Neurol.199725146159216029462990
     [Google Scholar]
  163. Toledano-DíazA. ÁlvarezM.I. ToledanoA. Glial alterations in aging and Alzheimer’s disease: A novel basis to understand, prevent and treat the degenerative process.OBM Geriat.20204213410.21926/obm.geriatr.2002117
     [Google Scholar]
  164. RiosA. FujitaK. IsomuraY. SatoN. Adaptive circuits for action and value information in rodent operant learning.Neurosci Res20254626810.1016/j.neures.2024.09.00339341460
     [Google Scholar]
  165. HilleM. KühnS. KempermannG. BonhoefferT. LindenbergerU. From animal models to human individuality: Integrative approaches to the study of brain plasticity.Neuron2024112213522354110.1016/j.neuron.2024.10.00639461332
     [Google Scholar]
  166. JiangJ. FoyardE. van RossumM.C.W. Reinforcement learning when your life depends on it: A neuro-economic theory of learning.PLOS Comput. Biol.20242010e101255410.1371/journal.pcbi.101255439466882
     [Google Scholar]
  167. MuganU HoffmanSL RedishAD Environmental complexity modulates information processing and the balance between decision-making systems.Neuron20241122440964114e1010.1016/j.neuron.2024.10.00439476843
     [Google Scholar]
  168. GriffithE.C. WestA.E. GreenbergM.E. Neuronal enhancers fine-tune adaptive circuit plasticity.Neuron2024112183043305710.1016/j.neuron.2024.08.00239208805
     [Google Scholar]
  169. MooreJ.J. GenkinA. TournoyM. Pughe-SanfordJ.L. de Ruyter van SteveninckR.R. ChklovskiiD.B. The neuron as a direct data-driven controller.Proc. Natl. Acad. Sci. USA202412127e231189312110.1073/pnas.231189312138913890
     [Google Scholar]
  170. ChausseB. MalornyN. LewenA. PoschetG. BerndtN. KannO. Metabolic flexibility ensures proper neuronal network function in moderate neuroinflammation.Sci. Rep.20241411440510.1038/s41598‑024‑64872‑138909138
     [Google Scholar]
  171. UrbinM.A. Adaptation in the spinal cord after stroke: Implications for restoring cortical control over the final common pathway.J. Physiol.20256033685-72110.1113/JP28556338787922
     [Google Scholar]
  172. ZeddeM. PascarellaR. The cerebrovascular side of plasticity: Microvascular architecture across health and neurodegenerative and vascular diseases.Brain Sci.2024141098310.3390/brainsci1410098339451997
     [Google Scholar]
  173. SteffensS. MäkinenH. StenbergT. WigrenH.K. Microglial morphology aligns with vigilance stage-specific neuronal oscillations in a brain region-dependent manner.Glia202472122344235610.1002/glia.2461739301843
     [Google Scholar]
  174. FaustT.E. DevlinB.A. Farhy-TselnickerI. FerroA. PostolacheM. XinW. Glial control of cortical neuronal circuit maturation and plasticity.J. Neurosci.20244440e120824202410.1523/JNEUROSCI.1208‑24.202439358028
     [Google Scholar]
  175. VerkhratskyA. ZorecR. Neuroglia in cognitive reserve.Mol. Psychiatry202429123962396710.1038/s41380‑024‑02644‑z38956370
     [Google Scholar]
  176. NassifC. KawlesA. AyalaI. MinogueG. GillN.P. ShepardR.A. ZouridakisA. KeszyckiR. ZhangH. MaoQ. FlanaganM.E. BigioE.H. MesulamM.M. RogalskiE. GeulaC. GefenT. Integrity of neuronal size in the entorhinal cortex is a biological substrate of exceptional cognitive aging.J. Neurosci.202242458587859410.1523/JNEUROSCI.0679‑22.202236180225
     [Google Scholar]
  177. MorrisonJ.H. HofP.R. Life and death of neurons in the aging brain.Science1997278533741241910.1126/science.278.5337.4129334292
     [Google Scholar]
  178. HofP.R. Morphology and neurochemical characteristics of the vulnerable neurons in brain aging and Alzheimer’s disease.Eur. Neurol.1997372718110.1159/0001174149058061
     [Google Scholar]
  179. DucoteA.L. VoglewedeR.L. MostanyR. Dendritic spines of layer 5 pyramidal neurons of the aging somatosensory cortex exhibit reduced volumetric remodeling.J. Neurosci.20244450e137824202410.1523/JNEUROSCI.1378‑24.202439448263
     [Google Scholar]
  180. VerkhratskyA. ButtA.M. Neuroglia: Function and Pathology.New York, NY, USAElsevier2023
     [Google Scholar]
  181. de la MonteS.M. Malignant brain aging: The formidable link between dysregulated signaling through mechanistic target of rapamycin pathways and Alzheimer’s disease (type 3 diabetes).J. Alzheimers Dis.20239541301133710.3233/JAD‑23055537718817
     [Google Scholar]
  182. ParkJ. LeeK. KimK. YiS.J. The role of histone modifications: From neurodevelopment to neurodiseases.Signal Transduct. Target. Ther.20227121710.1038/s41392‑022‑01078‑935794091
     [Google Scholar]
  183. GengH. ChenH. WangH. WangL. The histone modifications of neuronal plasticity.Neural Plast.202120211710.1155/2021/669052333628222
     [Google Scholar]
  184. De SousaR.A.L. Improta-CariaA.C. Regulation of microRNAs in Alzheimer´s disease, type 2 diabetes, and aerobic exercise training.Metab. Brain Dis.202237355958010.1007/s11011‑022‑00903‑y35075500
     [Google Scholar]
  185. NigiL. GriecoG.E. VentrigliaG. BruscoN. MancarellaF. FormichiC. DottaF. SebastianiG. MicroRNAs as regulators of insulin signaling: Research updates and potential therapeutic perspectives in Type 2 diabetes.Int. J. Mol. Sci.20181912370510.3390/ijms1912370530469501
     [Google Scholar]
  186. DasK. RaoL.V.M. The role of microRNAs in inflammation.Int. J. Mol. Sci.202223241547910.3390/ijms23241547936555120
     [Google Scholar]
  187. WangJ. GongB. ZhaoW. TangC. VargheseM. NguyenT. BiW. BilskiA. BegumS. VempatiP. KnableL. HoL. PasinettiG.M. Epigenetic mechanisms linking diabetes and synaptic impairments.Diabetes201463264565410.2337/db13‑106324154559
     [Google Scholar]
  188. AggarwalA. YadavB. SharmaN. KaurR. RishiV. Disruption of histone acetylation homeostasis triggers cognitive dysfunction in experimental diabetes.Neurochem. Int.202317010559210.1016/j.neuint.2023.10559237598859
     [Google Scholar]
  189. KanherkarR.R. Bhatia-DeyN. CsokaA.B. Epigenetics across the human lifespan.Front. Cell Dev. Biol.201424910.3389/fcell.2014.0004925364756
     [Google Scholar]
  190. HinteL.C. Castellano-CastilloD. GhoshA. MelroseK. GasserE. NoéF. MassierL. DongH. SunW. HoffmannA. WolfrumC. RydénM. MejhertN. BlüherM. von MeyennF. Adipose tissue retains an epigenetic memory of obesity after weight loss.Nature2024636804245746510.1038/s41586‑024‑08165‑739558077
     [Google Scholar]
  191. FlickerL. Modifiable lifestyle risk factors for Alzheimer’s disease.J. Alzheimers Dis.201020380381110.3233/JAD‑2010‑09162420182016
     [Google Scholar]
  192. SolfrizziV. FrisardiV. SeripaD. LogroscinoG. ImbimboB.P. D’OnofrioG. AddanteF. SancarloD. CascavillaL. PilottoA. PanzaF. Mediterranean diet in predementia and dementia syndromes.Curr. Alzheimer Res.20118552054210.2174/15672051179639180921605047
     [Google Scholar]
  193. ShahR. The role of nutrition and diet in Alzheimer disease: A systematic review.J. Am. Med. Dir. Assoc.201314639840210.1016/j.jamda.2013.01.01423419980
     [Google Scholar]
  194. HamzéR. DelangreE. ToluS. MoreauM. JanelN. BailbéD. MovassatJ. Type 2 diabetes Mellitus and Alzheimer’s disease: Shared molecular mechanisms and potential common therapeutic targets.Int. J. Mol. Sci.202223231528710.3390/ijms23231528736499613
     [Google Scholar]
  195. PalaviciniJ.P. ChenJ. WangC. WangJ. QinC. BaeuerleE. WangX. WooJ.A. KangD.E. MusiN. DupreeJ.L. HanX. Early disruption of nerve mitochondrial and myelin lipid homeostasis in obesity-induced diabetes.JCI Insight2020521e13728610.1172/jci.insight.13728633148881
     [Google Scholar]
  196. GalizziG. Di CarloM. Insulin and its key role for mitochondrial function/dysfunction and quality control: A shared link between dysmetabolism and neurodegeneration.Biology202211694310.3390/biology1106094335741464
     [Google Scholar]
  197. ArnoldS.E. ArvanitakisZ. Macauley-RambachS.L. KoenigA.M. WangH.Y. AhimaR.S. CraftS. GandyS. BuettnerC. StoeckelL.E. HoltzmanD.M. NathanD.M. Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums.Nat. Rev. Neurol.201814316818110.1038/nrneurol.2017.18529377010
     [Google Scholar]
  198. TalbotK. WangH.Y. KaziH. HanL.Y. BakshiK.P. StuckyA. FuinoR.L. KawaguchiK.R. SamoyednyA.J. WilsonR.S. ArvanitakisZ. SchneiderJ.A. WolfB.A. BennettD.A. TrojanowskiJ.Q. ArnoldS.E. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline.J. Clin. Invest.201212241316133810.1172/JCI5990322476197
     [Google Scholar]
  199. de la MonteS.M. Type 3 diabetes is sporadic Alzheimer׳s disease: Mini-review.Eur. Neuropsychopharmacol.201424121954196010.1016/j.euroneuro.2014.06.00825088942
     [Google Scholar]
  200. WilliamsonA. NorrisD.M. YinX. BroadawayK.A. MoxleyA.H. VadlamudiS. WilsonE.P. JacksonA.U. AhujaV. AndersenM.K. ArzumanyanZ. BonnycastleL.L. BornsteinS.R. BretschneiderM.P. BuchananT.A. ChangY.C. ChuangL.M. ChungR.H. ClausenT.D. DammP. DelgadoG.E. de MelloV.D. DupuisJ. DwivediO.P. ErdosM.R. SilvaL.F. FraylingT.M. GiegerC. GoodarziM.O. GuoX. GustafssonS. HakasteL. HammarU. HatemG. HerrmannS. HøjlundK. HornK. HsuehW.A. HungY.J. HwuC.M. JonssonA. KårhusL.L. KleberM.E. KovacsP. LakkaT.A. LauzonM. LeeI.T. LindgrenC.M. LindströmJ. LinnebergA. LiuC.T. LuanJ. AlyD.M. MathiesenE. MoisslA.P. MorrisA.P. NarisuN. PerakakisN. PetersA. PrasadR.B. RodionovR.N. RollK. RundstenC.F. SarnowskiC. SavonenK. ScholzM. SharmaS. StinsonS.E. SulemanS. TanJ. TaylorK.D. UusitupaM. VistisenD. WitteD.R. WaltherR. WuP. XiangA.H. ZetheliusB. de MelloV.D. AhlqvistE. BergmanR.N. ChenY-D.I. CollinsF.S. FallT. FlorezJ.C. FritscheA. GrallertH. GroopL. HansenT. KoistinenH.A. KomulainenP. LaaksoM. LindL. LoefflerM. MärzW. MeigsJ.B. RaffelL.J. RauramaaR. RotterJ.I. SchwarzP.E.H. StumvollM. SundströmJ. TönjesA. TuomiT. TuomilehtoJ. WagnerR. BarrosoI. WalkerM. GrarupN. BoehnkeM. WarehamN.J. MohlkeK.L. WheelerE. O’RahillyS. FazakerleyD.J. LangenbergC. Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake.Nat. Genet.202355697398310.1038/s41588‑023‑01408‑937291194
     [Google Scholar]
  201. FrisardiV PanzaF SolfrizziV SeripaD PilottoA Plasma lipid disturbances and cognitive decline.J. Am. Geriatr. Soc.201058122429243010.1111/j.1532‑5415.2010.03164.x21143446
     [Google Scholar]
  202. FrisardiV. SolfrizziV. CapursoC. ImbimboB.P. VendemialeG. SeripaD. PilottoA. PanzaF. Is insulin resistant brain state a central feature of the metabolic-cognitive syndrome?J. Alzheimers Dis.2010211576310.3233/JAD‑2010‑10001520421697
     [Google Scholar]
  203. OdettiP. PicciniA. GilibertoL. BorghiR. NataleA. MonacelliF. MarcheseM. AssiniA. ColucciM. CammarataS. TabatonM. Plasma levels of insulin and amyloid β42 are correlated in patients with amnestic mild cognitive impairment.J. Alzheimers Dis.20058324324510.3233/JAD‑2005‑830316340082
     [Google Scholar]
  204. ShenZ. LiZ.Y. YuM.T. TanK.L. ChenS. Metabolic perspective of astrocyte dysfunction in Alzheimer’s disease and type 2 diabetes brains.Biomed. Pharmacother.202315811420610.1016/j.biopha.2022.11420636916433
     [Google Scholar]
  205. FrölichL. Blum-DegenD. BernsteinH.G. EngelsbergerS. HumrichJ. LauferS. MuschnerD. ThalheimerA. TürkA. HoyerS. ZöchlingR. BoisslK.W. JellingerK. RiedererP. Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease.J. Neural Transm.1998105442343810.1007/s0070200500689720972
     [Google Scholar]
  206. Lyra e SilvaN.M. GonçalvesR.A. BoehnkeS.E. Forny-GermanoL. MunozD.P. De FeliceF.G. De FeliceF.G. Understanding the link between insulin resistance and Alzheimer’s disease: Insights from animal models.Exp. Neurol.201931611110.1016/j.expneurol.2019.03.01630930096
     [Google Scholar]
  207. AkhtarA. DhaliwalJ. SahS.P. 7,8-Dihydroxyflavone improves cognitive functions in ICV-STZ rat model of sporadic Alzheimer’s disease by reversing oxidative stress, mitochondrial dysfunction, and insulin resistance.Psychopharmacology202123871991200910.1007/s00213‑021‑05826‑733774703
     [Google Scholar]
  208. LevengaJ. WongH. MilsteadR.A. KellerB.N. LaPlanteL.E. HoefferC.A. AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity.eLife20176e3064010.7554/eLife.3064029173281
     [Google Scholar]
  209. LevengaJ. WongH. MilsteadR. LaPlanteL. HoefferC.A. Immunohistological examination of AKT isoforms in the brain: Cell-type specificity that may underlie AKT’s role in complex brain disorders and neurological disease.Cereb. Cortex Commun.202122tgab03610.1093/texcom/tgab03634296180
     [Google Scholar]
  210. GabboujS. RyhänenS. MarttinenM. WittrahmR. TakaloM. KemppainenS. MartiskainenH. TanilaH. HaapasaloA. HiltunenM. NatunenT. Altered insulin signaling in Alzheimer’s disease brain – Special emphasis on PI3K-Akt pathway.Front. Neurosci.20191362910.3389/fnins.2019.0062931275108
     [Google Scholar]
  211. GriffithCM EidT RoseGM PatryloPR Evidence for altered insulin receptor signaling in Alzheimer's disease.Neuropharmacology2018136Pt B20221510.1016/j.neuropharm.2018.01.00829353052
     [Google Scholar]
  212. SharmaC. KimS.R. Linking oxidative stress and proteinopathy in Alzheimer’s disease.Antioxidants2021108123110.3390/antiox1008123134439479
     [Google Scholar]
  213. BaoH. LiuY. ZhangM. ChenZ. ZhangW. GeY. KangD. GaoF. ShenY. Increased β-site APP cleaving enzyme 1-mediated insulin receptor cleavage in type 2 diabetes mellitus with cognitive impairment.Alzheimers Dement.20211771097110810.1002/alz.1227633410588
     [Google Scholar]
  214. Gómez-SintesR. HernándezF. LucasJ.J. AvilaJ. GSK-3 mouse models to study neuronal apoptosis and neurodegeneration.Front. Mol. Neurosci.201144510.3389/fnmol.2011.0004522110426
     [Google Scholar]
  215. Méndez-FloresO.G. Hernández-KellyL.C. Olivares-BañuelosT.N. López-RamírezG. OrtegaA. Brain energetics and glucose transport in metabolic diseases: Role in neurodegeneration.Nutr. Neurosci.202427101199121010.1080/1028415X.2024.230642738294500
     [Google Scholar]
  216. CunnaneS.C. TrushinaE. MorlandC. PrigioneA. CasadesusG. AndrewsZ.B. BealM.F. BergersenL.H. BrintonR.D. de la MonteS. EckertA. HarveyJ. JeggoR. JhamandasJ.H. KannO. la CourC.M. MartinW.F. MithieuxG. MoreiraP.I. MurphyM.P. NaveK.A. NurielT. OlietS.H.R. SaudouF. MattsonM.P. SwerdlowR.H. MillanM.J. Brain energy rescue: An emerging therapeutic concept for neurodegenerative disorders of ageing.Nat. Rev. Drug Discov.202019960963310.1038/s41573‑020‑0072‑x32709961
     [Google Scholar]
  217. Berlanga-AcostaJ. Guillén-NietoG. Rodríguez-RodríguezN. Bringas-VegaM.L. García-del-Barco-HerreraD. Berlanga-SaezJ.O. García-OjalvoA. Valdés-SosaM.J. Valdés-SosaP.A. Insulin resistance at the crossroad of Alzheimer disease pathology: A review.Front. Endocrinol.20201156037510.3389/fendo.2020.56037533224105
     [Google Scholar]
  218. KwonH.S. KohS.H. Neuroinflammation in neurodegenerative disorders: The roles of microglia and astrocytes.Transl. Neurodegener.2020914210.1186/s40035‑020‑00221‑233239064
     [Google Scholar]
  219. Llorián-SalvadorM. Cabeza-FernándezS. Gomez-SanchezJ.A. de la FuenteA.G. Glial cell alterations in diabetes-induced neurodegeneration.Cell. Mol. Life Sci.20248114710.1007/s00018‑023‑05024‑y38236305
     [Google Scholar]
  220. ValkoM. LeibfritzD. MoncolJ. CroninM.T.D. MazurM. TelserJ. Free radicals and antioxidants in normal physiological functions and human disease.Int. J. Biochem. Cell Biol.2007391448410.1016/j.biocel.2006.07.00116978905
     [Google Scholar]
  221. HouldsworthA. Role of oxidative stress in neurodegenerative disorders: A review of reactive oxygen species and prevention by antioxidants.Brain Commun.202361fcad35610.1093/braincomms/fcad35638214013
     [Google Scholar]
  222. BhattiJ.S. SehrawatA. MishraJ. SidhuI.S. NavikU. KhullarN. KumarS. BhattiG.K. ReddyP.H. Oxidative stress in the pathophysiology of type 2 diabetes and related complications: Current therapeutics strategies and future perspectives.Free Radic. Biol. Med.202218411413410.1016/j.freeradbiomed.2022.03.01935398495
     [Google Scholar]
  223. GonzálezP. LozanoP. RosG. SolanoF. Hyperglycemia and oxidative stress: An integral, updated and critical overview of their metabolic interconnections.Int. J. Mol. Sci.20232411935210.3390/ijms2411935237298303
     [Google Scholar]
  224. ButterfieldD.A. Di DomenicoF. BaroneE. Elevated risk of type 2 diabetes for development of Alzheimer disease: A key role for oxidative stress in brain.Biochim. Biophys. Acta Mol. Basis Dis.2014184291693170610.1016/j.bbadis.2014.06.01024949886
     [Google Scholar]
  225. YuanT YangT ChenH FuD HuY WangJ New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis.Redox Biol20192024726010.1016/j.redox.2018.09.02530384259
     [Google Scholar]
  226. LeeK.H. ChaM. LeeB.H. Neuroprotective effect of antioxidants in the brain.Int. J. Mol. Sci.20202119715210.3390/ijms2119715232998277
     [Google Scholar]
  227. NakajimaK. KohsakaS. Microglia: Activation and their significance in the central nervous system.J. Biochem.2001130216917510.1093/oxfordjournals.jbchem.a00296911481032
     [Google Scholar]
  228. TönniesE. TrushinaE. Oxidative stress, synaptic dysfunction, and Alzheimer’s disease.J. Alzheimers Dis.20175741105112110.3233/JAD‑16108828059794
     [Google Scholar]
  229. ChenZ. ZhongC. Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: Implications for diagnostic and therapeutic strategies.Prog. Neurobiol.2013108214310.1016/j.pneurobio.2013.06.00423850509
     [Google Scholar]
  230. DakterzadaF. JovéM. CanteroJ.L. PamplonaR. Piñoll-RipollG. Plasma and cerebrospinal fluid nonenzymatic protein damage is sustained in Alzheimer’s disease.Redox Biol.20236410277210.1016/j.redox.2023.10277237339560
     [Google Scholar]
  231. EvansJ.L. GoldfineI.D. MadduxB.A. GrodskyG.M. Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction?Diabetes20035211810.2337/diabetes.52.1.112502486
     [Google Scholar]
  232. PotenzaM.A. SgarraL. DesantisV. NacciC. MontagnaniM. Diabetes and Alzheimer’s disease: Might mitochondrial dysfunction help deciphering the common path?Antioxidants2021108125710.3390/antiox1008125734439505
     [Google Scholar]
  233. Sims-RobinsonC. KimB. RoskoA. FeldmanE.L. How does diabetes accelerate Alzheimer disease pathology?Nat. Rev. Neurol.201061055155910.1038/nrneurol.2010.13020842183
     [Google Scholar]
  234. LuoJ.S. NingJ.Q. ChenZ.Y. LiW.J. ZhouR.L. YanR.Y. ChenM.J. DingL.L. The role of mitochondrial quality control in cognitive dysfunction in diabetes.Neurochem. Res.20224782158217210.1007/s11064‑022‑03631‑y35661963
     [Google Scholar]
  235. ZuoW. ZhangS. XiaC.Y. GuoX.F. HeW.B. ChenN.H. Mitochondria autophagy is induced after hypoxic/ischemic stress in a Drp1 dependent manner: The role of inhibition of Drp1 in ischemic brain damage.Neuropharmacology20148610311510.1016/j.neuropharm.2014.07.00225018043
     [Google Scholar]
  236. NunomuraA. CastellaniR.J. ZhuX. MoreiraP.I. PerryG. SmithM.A. Involvement of oxidative stress in Alzheimer disease.J. Neuropathol. Exp. Neurol.200665763164110.1097/01.jnen.0000228136.58062.bf16825950
     [Google Scholar]
  237. SchillingM.A. Unraveling Alzheimer’s: Making sense of the relationship between diabetes and Alzheimer’s disease1.J. Alzheimers Dis.201651496197710.3233/JAD‑15098026967215
     [Google Scholar]
  238. BhatiaS. RawalR. SharmaP. SinghT. SinghM. SinghV. Mitochondrial dysfunction in Alzheimer’s disease: Opportunities for drug development.Curr. Neuropharmacol.202220467569210.2174/1570159X1966621051711401633998995
     [Google Scholar]
  239. BaduiniI.R. Castro VildosolaJ.E. KavehmoghaddamS. KiliçF. NadeemS.A. NizamaJ.J. RowandM.A. AnnapureddyD. BryanC.A. DoL.H. HsiaoS. JonnalagaddaS.A. KasturiA. MandavaN. MuppavaramS. RamirezB. SinerA. SuotoC.N. TamajalN. ScomaE.R. Da CostaR.T. SolesioM.E. Type 2 diabetes mellitus and neurodegenerative disorders: The mitochondrial connection.Pharmacol. Res.202420910743910.1016/j.phrs.2024.10743939357690
     [Google Scholar]
  240. Rovira-LlopisS. BañulsC. Diaz-MoralesN. Hernandez-MijaresA. RochaM. VictorV.M. Mitochondrial dynamics in type 2 diabetes: Pathophysiological implications.Redox Biol.20171163764510.1016/j.redox.2017.01.01328131082
     [Google Scholar]
  241. MoreiraP. CardosoS. PereiraC. SantosM. OliveiraC. Mitochondria as a therapeutic target in Alzheimer’s disease and diabetes.CNS Neurol. Disord. Drug Targets20098649251110.2174/18715270978982465119702564
     [Google Scholar]
  242. CarvalhoC. CardosoS. CorreiaS.C. SantosR.X. SantosM.S. BaldeirasI. OliveiraC.R. MoreiraP.I. Metabolic alterations induced by sucrose intake and Alzheimer’s disease promote similar brain mitochondrial abnormalities.Diabetes20126151234124210.2337/db11‑118622427376
     [Google Scholar]
  243. ReddyP.H. OliverD.M.A. Amyloid beta and phosphorylated Tau-induced defective autophagy and mitophagy in Alzheimer’s disease.Cells20198548810.3390/cells805048831121890
     [Google Scholar]
  244. KamphuisW. MamberC. MoetonM. KooijmanL. SluijsJ.A. JansenA.H.P. VerveerM. de GrootL.R. SmithV.D. RangarajanS. RodríguezJ.J. OrreM. HolE.M. GFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease.PLoS One201278e4282310.1371/journal.pone.004282322912745
     [Google Scholar]
  245. OrreM. KamphuisW. OsbornL.M. JansenA.H.P. KooijmanL. BossersK. HolE.M. Isolation of glia from Alzheimer’s mice reveals inflammation and dysfunction.Neurobiol. Aging201435122746276010.1016/j.neurobiolaging.2014.06.00425002035
     [Google Scholar]
  246. WangL.P. GengJ. LiuC. WangY. ZhangZ. YangG.Y. Diabetes Mellitus-related neurobehavioral deficits in mice are associated with oligodendrocyte precursor cell dysfunction.Front. Aging Neurosci.20221484673910.3389/fnagi.2022.84673935693337
     [Google Scholar]
  247. StottN.L. MarinoJ.S. High fat rodent models of Type 2 diabetes: From rodent to human.Nutrients20201212365010.3390/nu1212365033261000
     [Google Scholar]
  248. VelazquezR. TranA. IshimweE. DennerL. DaveN. OddoS. DineleyK.T. Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer’s disease.Neurobiol. Aging20175811310.1016/j.neurobiolaging.2017.06.00328688899
     [Google Scholar]
  249. EidSA O’BrienPD HinderLM HayesJM MendelsonFE ZhangH Differential effects of minocycline on microvascular complications in murine models of type 1 and type 2 diabetes.J Transl Sci20217110.15761/jts.100043110.15761/JTS.100043133868719
     [Google Scholar]
  250. HuK. WuS. XuJ. ZhangY. ZhangY. WuX. MiaoJ. YaoY. ZhuS. ChenG. RenJ. Pongamol alleviates neuroinflammation and promotes autophagy in Alzheimer’s disease by regulating the Akt/mTOR signaling pathway.J. Agric. Food Chem.202472241363413645Epub ahead of print10.1021/acs.jafc.4c0083638841893
     [Google Scholar]
  251. Carranza-NavalM.J. Vargas-SoriaM. Hierro-BujalanceC. Baena-NietoG. Garcia-AllozaM. Infante-GarciaC. del MarcoA. Alzheimer’s disease and diabetes: Role of diet, microbiota and inflammation in preclinical models.Biomolecules202111226210.3390/biom1102026233578998
     [Google Scholar]
  252. HuangX. HuangS. FuF. SongJ. ZhangY. YueF. Characterization of preclinical Alzheimer’s disease model: Spontaneous type 2 diabetic cynomolgus monkeys with systemic pro-inflammation, positive biomarkers and developing AD-like pathology.Alzheimers Res. Ther.20241615210.1186/s13195‑024‑01416‑938459540
     [Google Scholar]
  253. ToledanoA. ÁlvarezM.I. López-RodríguezA.B. Toledano-DíazA. Fernández-VerdeciaC.I. Does Alzheimer’s disease exist in all primates? Alzheimer pathology in non-human primates and its pathophysiological implications (II).Neurología2014291425510.1016/j.nrl.2011.05.00421871692
     [Google Scholar]
  254. ToledanoA. AlvarezM.I. López-RodríguezA.B. Toledano-DíazA. Fernández-VerdeciaC.I. Does Alzheimer’s disease exist in all primates? Alzheimer pathology in non-human primates and its pathophysiological implications (I).Neurología201227635436910.1016/j.nrl.2011.05.00822197064
     [Google Scholar]
  255. NgocKH JeonY KoJ UmJW Multifarious astrocyte-neuron dialog in shaping neural circuit architecture.Trends Cell Biol2025351748710.1016/j.tcb.2024.05.00238853082
     [Google Scholar]
  256. PathakD. SriramK. Neuron-astrocyte omnidirectional signaling in neurological health and disease.Front. Mol. Neurosci.202316116932010.3389/fnmol.2023.116932037363320
     [Google Scholar]
  257. LiuY. ShenX. ZhangY. ZhengX. CepedaC. WangY. DuanS. TongX. Interactions of glial cells with neuronal synapses, from astrocytes to microglia and oligodendrocyte lineage cells.Glia20237161383140110.1002/glia.2434336799296
     [Google Scholar]
  258. NagayachA. BhaskarR. PatroI. Microglia activation and inflammation in hippocampus attenuates memory and mood functions during experimentally induced diabetes in rat.J. Chem. Neuroanat.202212510216010.1016/j.jchemneu.2022.10216036089179
     [Google Scholar]
  259. Hernández-RodríguezM. ClementeC.F. Macías-PérezM.E. Rodríguez-FonsecaR.A. VázquezM.I.N. MartínezJ. RuvalcabaR.M. RosasM.M. JiménezE.M. Contribution of hyperglycemia-induced changes in microglia to Alzheimer’s disease pathology.Pharmacol. Rep.202274583284610.1007/s43440‑022‑00405‑936042131
     [Google Scholar]
  260. ThakurS. DhapolaR. SarmaP. MedhiB. ReddyD.H. Neuroinflammation in Alzheimer’s disease: Current progress in molecular signaling and therapeutics.Inflammation202346111710.1007/s10753‑022‑01721‑135986874
     [Google Scholar]
  261. SinghD. Astrocytic and microglial cells as the modulators of neuroinflammation in Alzheimer’s disease.J. Neuroinflammation202219120610.1186/s12974‑022‑02565‑035978311
     [Google Scholar]
  262. OyarceK. CepedaM.Y. LagosR. GarridoC. Vega-LetterA.M. Garcia-RoblesM. Luz-CrawfordP. Elizondo-VegaR. Neuroprotective and neurotoxic effects of glial-derived exosomes.Front. Cell. Neurosci.20221692068610.3389/fncel.2022.92068635813501
     [Google Scholar]
  263. BerumenJ. OrozcoL. Gallardo-RincónH. RivasF. BarreraE. BenutoR.E. García-OrtizH. Marin-MedinaM. Juárez-TorresE. Alvarado-SilvaA. Ramos-MartinezE. MartÍnez-JuárezL.A. Lomelín-GascónJ. MontoyaA. Ortega-MontielJ. Alvarez-HernándezD.A. Larriva-ShadJ. Tapia-ConyerR. Sex differences in the influence of type 2 diabetes (T2D)-related genes, parental history of T2D, and obesity on T2D development: A case–control study.Biol. Sex Differ.20231413910.1186/s13293‑023‑00521‑y37291636
     [Google Scholar]
  264. NatunenT. MartiskainenH. MarttinenM. GabboujS. KoivistoH. KemppainenS. KaipainenS. TakaloM. SvobodováH. LeppänenL. KemiläinenB. RyhänenS. KuulasmaaT. RahunenE. JuutinenS. MäkinenP. MiettinenP. RauramaaT. PihlajamäkiJ. HaapasaloA. LeinonenV. TanilaH. HiltunenM. Diabetic phenotype in mouse and humans reduces the number of microglia around β-amyloid plaques.Mol. Neurodegener.20201516610.1186/s13024‑020‑00415‑233168021
     [Google Scholar]
  265. ChenW. HuangQ. LazdonE.K. GomesA. WongM. StephensE. RoyalT.G. FrenkelD. CaiW. KahnC.R. Loss of insulin signaling in astrocytes exacerbates Alzheimer-like phenotypes in a 5xFAD mouse model.Proc. Natl. Acad. Sci. USA202312021e222068412010.1073/pnas.222068412037186836
     [Google Scholar]
  266. Latva-RaskuA. HonkaM.J. StančákováA. KoistinenH.A. KuusistoJ. GuanL. ManningA.K. StringhamH. GloynA.L. LindgrenC.M. CollinsF.S. MohlkeK.L. ScottL.J. KarjalainenT. NummenmaaL. BoehnkeM. NuutilaP. LaaksoM. A partial loss-of-function variant in AKT2 is associated with reduced insulin-mediated glucose uptake in multiple insulin-sensitive tissues: A genotype-based callback positron emission tomography study.Diabetes201867233434210.2337/db17‑114229141982
     [Google Scholar]
  267. MotA.I. DeppC. NaveK.A. An emerging role of dysfunctional axon-oligodendrocyte coupling in neurodegenerative diseases.Dialogues Clin. Neurosci.201820428329210.31887/dcns.2018.20.4/amot30936768
     [Google Scholar]
  268. BartzokisG. CummingsJ.L. SultzerD. HendersonV.W. NuechterleinK.H. MintzJ. White matter structural integrity in healthy aging adults and patients with Alzheimer disease: A magnetic resonance imaging study.Arch. Neurol.200360339339810.1001/archneur.60.3.39312633151
     [Google Scholar]
  269. ZhouJ. ZhangP. ZhangB. KongY. White matter damage in Alzheimer’s disease: Contribution of oligodendrocytes.Curr. Alzheimer Res.202219962964010.2174/156720502066622102111532136281858
     [Google Scholar]
  270. PaulS. BhardwajJ. BinukumarB.K. Cdk5-mediated oligodendrocyte myelin breakdown and neuroinflammation: Implications for the link between type 2 diabetes and Alzheimer’s disease.Biochim. Biophys. Acta Mol. Basis Dis.20241870216698610.1016/j.bbadis.2023.16698638092158
     [Google Scholar]
  271. SpaasJ. van VeggelL. SchepersM. TianeA. van HorssenJ. WilsonD.M.III MoyaP.R. PiccartE. HellingsN. EijndeB.O. DeraveW. SchreiberR. VanmierloT. Oxidative stress and impaired oligodendrocyte precursor cell differentiation in neurological disorders.Cell. Mol. Life Sci.202178104615463710.1007/s00018‑021‑03802‑033751149
     [Google Scholar]
  272. VanzulliI. PapanikolaouM. De-La-RochaI.C. PieropanF. RiveraA.D. Gomez-NicolaD. VerkhratskyA. RodríguezJ.J. ButtA.M. Disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of Alzheimer’s disease.Neurobiol. Aging20209413013910.1016/j.neurobiolaging.2020.05.01632619874
     [Google Scholar]
  273. LinL. BasuR. ChatterjeeD. TemplinA.T. FlakJ.N. JohnsonT.S. Disease-associated astrocytes and microglia markers are upregulated in mice fed high fat diet.Sci. Rep.20231311291910.1038/s41598‑023‑39890‑037558676
     [Google Scholar]
  274. GottesmanR.F. SchneiderA.L.C. ZhouY. CoreshJ. GreenE. GuptaN. KnopmanD.S. MintzA. RahmimA. SharrettA.R. WagenknechtL.E. WongD.F. MosleyT.H. Association between midlife vascular risk factors and estimated brain amyloid deposition.JAMA2017317141443145010.1001/jama.2017.309028399252
     [Google Scholar]
  275. VemuriP. LesnickT.G. PrzybelskiS.A. KnopmanD.S. LoweV.J. Graff-RadfordJ. RobertsR.O. MielkeM.M. MachuldaM.M. PetersenR.C. JackC.R.Jr Age, vascular health, and Alzheimer disease biomarkers in an elderly sample.Ann. Neurol.201782570671810.1002/ana.2507129023983
     [Google Scholar]
  276. ArvanitakisZ. SchneiderJ.A. WilsonR.S. LiY. ArnoldS.E. WangZ. BennettD.A. Diabetes is related to cerebral infarction but not to AD pathology in older persons.Neurology200667111960196510.1212/01.wnl.0000247053.45483.4e17159101
     [Google Scholar]
  277. AbnerE.L. NelsonP.T. KryscioR.J. SchmittF.A. FardoD.W. WoltjerR.L. CairnsN.J. YuL. DodgeH.H. XiongC. MasakiK. TyasS.L. BennettD.A. SchneiderJ.A. ArvanitakisZ. Diabetes is associated with cerebrovascular but not Alzheimer’s disease neuropathology.Alzheimers Dement.201612888288910.1016/j.jalz.2015.12.00626812281
     [Google Scholar]
  278. BiesselsG.J. DespaF. Cognitive decline and dementia in diabetes mellitus: Mechanisms and clinical implications.Nat. Rev. Endocrinol.2018141059160410.1038/s41574‑018‑0048‑730022099
     [Google Scholar]
  279. WestermarkP. AnderssonA. WestermarkG.T. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus.Physiol. Rev.201191379582610.1152/physrev.00042.200921742788
     [Google Scholar]
  280. WangY. WestermarkG.T. The Amyloid forming peptides islet amyloid polypeptide and amyloid β interact at the molecular level.Int. J. Mol. Sci.202122201115310.3390/ijms22201115334681811
     [Google Scholar]
  281. Martinez-ValbuenaI. Valenti-AzcarateR. Amat-VillegasI. RiverolM. MarcillaI. de AndreaC.E. Sánchez-AriasJ.A. del Mar Carmona-AbellanM. MartiG. ErroM.E. Martínez-VilaE. TuñonM.T. LuquinM.R. Amylin as a potential link between type 2 diabetes and alzheimer disease.Ann. Neurol.201986453955110.1002/ana.2557031376172
     [Google Scholar]
  282. LyH. VermaN. WuF. LiuM. SaatmanK.E. NelsonP.T. SlevinJ.T. GoldsteinL.B. BiesselsG.J. DespaF. Brain microvascular injury and white matter disease provoked by diabetes-associated hyperamylinemia.Ann. Neurol.201782220822210.1002/ana.2499228696548
     [Google Scholar]
  283. Guerrero-BerroaE. SchmeidlerJ. BeeriM.S. Neuropathology of type 2 diabetes: A short review on insulin-related mechanisms.Eur. Neuropsychopharmacol.201424121961196610.1016/j.euroneuro.2014.01.01924529419
     [Google Scholar]
  284. Ramos-RodriguezJ.J. Ortiz-BarajasO. Gamero-CarrascoC. de la RosaP.R. Infante-GarciaC. Zopeque-GarciaN. Lechuga-SanchoA.M. Garcia-AllozaM. Prediabetes-induced vascular alterations exacerbate central pathology in APPswe/PS1dE9 mice.Psychoneuroendocrinology20144812313510.1016/j.psyneuen.2014.06.00524998414
     [Google Scholar]
  285. NiedowiczD.M. ReevesV.L. PlattT.L. KohlerK. BeckettT.L. PowellD.K. LeeT.L. SextonT.R. SongE.S. BrewerL.D. LatimerC.S. KranerS.D. LarsonK.L. OzcanS. NorrisC.M. HershL.B. PorterN.M. WilcockD.M. MurphyM.P. Obesity and diabetes cause cognitive dysfunction in the absence of accelerated β-amyloid deposition in a novel murine model of mixed or vascular dementia.Acta Neuropathol. Commun.2014216410.1186/2051‑5960‑2‑6424916066
     [Google Scholar]
  286. GaoC. JiangJ. TanY. ChenS. Microglia in neurodegenerative diseases: Mechanism and potential therapeutic targets.Signal Transduct. Target. Ther.20238135910.1038/s41392‑023‑01588‑037735487
     [Google Scholar]
  287. Clodfelder-MillerB.J. ZmijewskaA.A. JohnsonG.V.W. JopeR.S. Tau is hyperphosphorylated at multiple sites in mouse brain in vivo after streptozotocin-induced insulin deficiency.Diabetes200655123320332510.2337/db06‑048517130475
     [Google Scholar]
  288. GreenyA. NairA. SadanandanP. SatarkerS. FamurewaA.C. NampoothiriM. Epigenetic alterations in Alzheimer’s disease: Impact on insulin signaling and advanced drug delivery systems.Biology202413315710.3390/biology1303015738534427
     [Google Scholar]
  289. JiangJ. ShiH. JiangS. WangA. ZouX. WangY. LiW. ZhangY. SunM. RenQ. XuJ. Nutrition in Alzheimer’s disease: A review of an underappreciated pathophysiological mechanism.Sci. China Life Sci.202366102257227910.1007/s11427‑022‑2276‑637058185
     [Google Scholar]
  290. MaesakoM. UemuraK. KubotaM. KuzuyaA. SasakiK. HayashidaN. Asada-UtsugiM. WatanabeK. UemuraM. KiharaT. TakahashiR. ShimohamaS. KinoshitaA. Exercise is more effective than diet control in preventing high fat diet-induced β-amyloid deposition and memory deficit in amyloid precursor protein transgenic mice.J. Biol. Chem.201228727230242303310.1074/jbc.M112.36701122563077
     [Google Scholar]
  291. SunW. ChenY. YangY. WangP. GongJ. HanX. XuC. LuanH. LiS. LiR. WenB. LvS. WeiC. Characteristics and transcriptomic analysis of cholinergic neurons derived from induced pluripotent stem cells with APP mutation in Alzheimer’s disease.J. Alzheimers Dis.2024101263764910.3233/JAD‑24029939213067
     [Google Scholar]
  292. WeinerS.P. CarrK.D. Behavioral tests of the insulin-cholinergic-dopamine link in nucleus accumbens and inhibition by high fat-high sugar diet in male and female rats.Physiol. Behav.202428411464710.1016/j.physbeh.2024.11464739067780
     [Google Scholar]
  293. Villeda-GonzálezJ.D. Gómez-OlivaresJ.L. Baiza-GutmanL.A. New paradigms in the study of the cholinergic system and metabolic diseases: Acetyl-and-butyrylcholinesterase.J. Cell. Physiol.20242398e3127410.1002/jcp.3127438605655
     [Google Scholar]
  294. IzuoN. WatanabeN. NodaY. SaitoT. SaidoT.C. YokoteK. HottaH. ShimizuT. Insulin resistance induces earlier initiation of cognitive dysfunction mediated by cholinergic deregulation in a mouse model of Alzheimer’s disease.Aging Cell20232211e1399410.1111/acel.1399437822109
     [Google Scholar]
  295. SinghS. BhattL.K. Targeting cellular senescence: A potential therapeutic approach for Alzheimer’s disease.Curr. Mol. Pharmacol.2024171e01062321754337264659
     [Google Scholar]
  296. ChowH.M. ShiM. ChengA. GaoY. ChenG. SongX. SoR.W.L. ZhangJ. HerrupK. Age-related hyperinsulinemia leads to insulin resistance in neurons and cell-cycle-induced senescence.Nat. Neurosci.201922111806181910.1038/s41593‑019‑0505‑131636448
     [Google Scholar]
  297. NelsonP.T. SmithC.D. AbnerE.A. SchmittF.A. ScheffS.W. DavisG.J. KellerJ.N. JichaG.A. DavisD. Wang-XiaW. HartmanA. KatzD.G. MarkesberyW.R. Human cerebral neuropathology of Type 2 diabetes mellitus.Biochim. Biophys. Acta Mol. Basis Dis.20091792545446910.1016/j.bbadis.2008.08.00518789386
     [Google Scholar]
  298. MoranC. LacyM.E. WhitmerR.A. TsaiA.L. QuesenberryC.P. KarterA.J. AdamsA.S. GilsanzP. Glycemic control over multiple decades and dementia risk in people with type 2 diabetes.JAMA Neurol.202380659760410.1001/jamaneurol.2023.069737067815
     [Google Scholar]
  299. BallB.K. ParkJ.H. ProctorE. BrubakerD.K. Cross-disease modeling of peripheral blood identifies biomarkers of type 2 diabetes predictive of Alzheimer’s disease.bioRxiv2024212.11.627991.10.1101/2024.12.11.627991
     [Google Scholar]
  300. LuQ.S. MaL. JiangW.J. WangX.B. LuM. KAT7/HMGN1 signaling epigenetically induces tyrosine phosphorylation-regulated kinase 1A expression to ameliorate insulin resistance in Alzheimer’s disease.World J. Psychiatry202414344545510.5498/wjp.v14.i3.44538617985
     [Google Scholar]
  301. EscartínC. GaleaE. LakatosA. O’CallaghanJ.P. PetzoldG.C. Serrano-PozoA. SteinhäuserC. VolterraA. CarmignotoG. AgarwalA. AllenN.J. AraqueA. BarbeitoL. BarzilaiA. BerglesD.E. BonventoG. ButtA.M. ChenW.T. Cohen-SalmonM. CunninghamC. DeneenB. De StrooperB. Díaz-CastroB. FarinaC. FreemanM. GalloV. GoldmanJ.E. GoldmanS.A. GötzM. GutiérrezA. HaydonP.G. HeilandD.H. HolE.M. HoltM.G. IinoM. KastanenkaK.V. KettenmannH. KhakhB.S. KoizumiS. LeeC.J. LiddelowS.A. MacVicarB.A. MagistrettiP. MessingA. MishraA. MolofskyA.V. MuraiK.K. NorrisC.M. OkadaS. OlietS.H.R. OliveiraJ.F. PanatierA. ParpuraV. PeknaM. PeknyM. PellerinL. PereaG. Pérez-NievasB.G. PfriegerF.W. PoskanzerK.E. QuintanaF.J. RansohoffR.M. Riquelme-PerezM. RobelS. RoseC.R. RothsteinJ.D. RouachN. RowitchD.H. SemyanovA. SirkoS. SontheimerH. SwansonR.A. VitoricaJ. WannerI.B. WoodL.B. WuJ. ZhengB. ZimmerE.R. ZorecR. SofroniewM.V. VerkhratskyA. Reactive astrocyte nomenclature, definitions, and future directions.Nat. Neurosci.202124331232510.1038/s41593‑020‑00783‑433589835
     [Google Scholar]
  302. PumoA. LegeayS. The dichotomous activities of microglia: A potential driver for phenotypic heterogeneity in Alzheimer’s disease.Brain Res.2024183214881710.1016/j.brainres.2024.14881738395249
     [Google Scholar]
/content/journals/car/10.2174/0115672050375461250325074826
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Relationship between Alzheimer's Disease and Type 2 Diabetes: Critical Review On Cellular and Molecular Common Pathogenic Mechanisms
Curr Alzheimer Res 22, 92 (2025); https://doi.org/10.2174/0115672050375461250325074826
/content/journals/car/10.2174/0115672050375461250325074826
/content/journals/car/10.2174/0115672050375461250325074826
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  • Article Type:     Review Article
Keyword(s): Alzheimer's disease (AD); epigenetic causes; genetic causes; hyperglycemia; insulin resistance; mitochondrial dysfunction; neuroglial dysfunction; neuroinflammation; neuronal degeneration; oxidative stress; pathogenic mechanisms; peripheral inflammation; type 2 diabetes (T2D); Type 3 diabetes (T3D)

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