Expert Consensus on Cognitive Dysfunction in Diabetes

Abstract

The incidence of diabetes is gradually increasing in China, and diabetes and associated complications, such as cognitive dysfunction have gained much attention in recent time. However, the concepts, clinical treatment, and prevention of cognitive dysfunction in patients with diabetes remain unclear. The Chinese Society of Endocrinology investigated the current national and overseas situation of cognitive dysfunction associated with diabetes. Based on research both in China and other countries worldwide, the Expert Consensus on Cognitive Dysfunction in Diabetes was established to guide physicians in the comprehensive standardized management of cognitive dysfunction in diabetes and to improve clinical outcomes in Chinese patients. This consensus presents an overview, definition and classification, epidemiology and pathogenesis, risk factors, screening, diagnosis, differential diagnosis, treatment, and prevention of cognitive dysfunction in patients with diabetes.

Keywords

diabetes / cognitive dysfunction / antidiabetic agents

References

[1] XuY, WangL, HeJ, et al.. Prevalence and control of diabetes in Chinese adults. Jama, 2013, 310(9): 948-959

[2] BiesselsGJ, StaekenborgS, BrunnerE, et al.. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol, 2006, 5(1): 64-74

[3] Reske-NielsenE, LundbækK, RafaelsenOJ. Pathological changes in the central and peripheral nervous system of young long-term diabetics: I. Diabetic encephalopathy. Diabetologia, 1966, 1(3–4): 233-241

[4] FeinkohlI, KellerM, RobertsonCM, et al.. Clinical and subclinical macrovascular disease as predictors of cognitive decline in older patients with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes Care, 2013, 36(9): 2779-2786

[5] OttA, StolkRP, van HarskampF, et al.. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology, 1999, 53(9): 1937-1942

[6] ChengG, HuangC, DengH, et al.. Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J, 2012, 42(5): 484-491

[7] Barbiellini AmideiC, FayosseA, DumurgierJ, et al.. Association Between Age at Diabetes Onset and Subsequent Risk of Dementia. Jama, 2021, 325(16): 1640-1649

[8] YuJT, XuW, TanCC, et al.. Evidence-based prevention of Alzheimer’s disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry, 2020, 91(11): 1201-1209

[9] Association AD. 12. Older adults: Standards of Medical Care in Diabetes. Diabetes Care, 2021, 44(Suppl.1): S168-S179

[10] BiesselsGJ, DespaF. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol, 2018, 14(10): 591-604

[11] SachdevPS, BlackerD, BlazerDG, et al.. Classifying neurocognitive disorders: the DSM-5 approach. Nat Rev Neurol, 2014, 10(11): 634-42

[12] Chinese guidelines for diagnosis and management of cognitive impairment and dementia (I): dementia subtypes and their criteria. Zhonghua Yi Xue Za Zhi (Chinese), 2018,98(13):965–970

[13] 2015 W A s R. Global Impact of Dementia. Medscape. August 27, 2015.

[14] Schnaider BeeriM, GoldbourtU, SilvermanJM, et al.. Diabetes mellitus in midlife and the risk of dementia three decades later. Neurology, 2004, 63(10): 1902-1907

[15] SrikanthV, SinclairAJ, Hill-BriggsF, et al.. Type 2 diabetes and cognitive dysfunction-towards effective management of both comorbidities. Lancet Diabetes Endocrinol, 2020, 8(6): 535-545

[16] KoekkoekPS, RuttenGE, BiesselsGJ. Cognitive disorders in diabetic patients. Handb Clin Neurol, 2014, 126: 145-166

[17] ZhangZ, BiY. Pay attention to the early evaluation and diagnosis for cognitive decline in type 2 diabetes. Chin J Endocrinol Metab (Chinese), 2019, 35(9): 731-735

[18] ExaltoLG, BiesselsGJ, KarterAJ, et al.. Severe diabetic retinal disease and dementia risk in type 2 diabetes. J Alzheimers Dis, 2014, 42(Suppl3): S109-117 0 3

[19] ZhangJ, ChenC, HuaS, et al.. An updated meta-analysis of cohort studies: Diabetes and risk of Alzheimer’s disease. Diabetes Res Clin Pract, 2017, 124: 41-47

[20] Cukierman-YaffeT, GersteinHC, WilliamsonJD, et al.. Relationship between baseline glycemic control and cognitive function in individuals with type 2 diabetes and other cardiovascular risk factors: the action to control cardiovascular risk in diabetes-memory in diabetes (ACCORD-MIND) trial. Diabetes Care, 2009, 32(2): 221-226

[21] DingJ, StrachanMW, ReynoldsRM, et al.. Diabetic retinopathy and cognitive decline in older people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes, 2010, 59(11): 2883-2889

[22] XuW, CaraccioloB, WangHX, et al.. Accelerated progression from mild cognitive impairment to dementia in people with diabetes. Diabetes, 2010, 59(11): 2928-2935

[23] LangaKM, LevineDA. The diagnosis and management of mild cognitive impairment: a clinical review. Jama, 2014, 312(23): 2551-2561

[24] HanssonO, LehmannS, OttoM, et al.. Advantages and disadvantages of the use of the CSF Amyloid β (Aβ) 42/40 ratio in the diagnosis of Alzheimer’s Disease. Alzheimers Res Ther, 2019, 11(1): 34

[25] SutphenCL, JasielecMS, ShahAR, et al.. Longitudinal Cerebrospinal Fluid Biomarker Changes in Preclinical Alzheimer Disease During Middle Age. JAMA Neurol, 2015, 72(9): 1029-1042

[26] WangL, BenzingerTL, HassenstabJ, et al.. Spatially distinct atrophy is linked to β-amyloid and tau in preclinical Alzheimer disease. Neurology, 2015, 84(12): 1254-1260

[27] OlssonB, LautnerR, AndreassonU, et al.. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol, 2016, 15(7): 673-684

[28] MattsonMP, ArumugamTV. Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States. Cell Metab, 2018, 27(6): 1176-1199

[29] LouG, PalikarasK, LautrupS, et al.. Mitophagy and Neuroprotection. Trends Mol Med, 2020, 26(1): 8-20

[30] Chinese guidelines for diagnosis and management of cognitive impairment and dementia (VII): risk factors and intervention in Alzheimer’s Disease. Zhonghua Yi Xue Za Zhi (Chinese), 2018,98(19):1461–1466

[31] KivipeltoM, MangialascheF, NganduT. Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease. Nat Rev Neurol, 2018, 14(11): 653-666

[32] XueM, XuW, OuYN, et al.. Diabetes mellitus and risks of cognitive impairment and dementia: A systematic review and meta-analysis of 144 prospective studies. Ageing Res Rev, 2019, 55: 100944

[33] StoeckelLE, ArvanitakisZ, GandyS, et al.. Complex mechanisms linking neurocognitive dysfunction to insulin resistance and other metabolic dysfunction. F1000Res, 2016, 5: 353

[34] SuF, ShuH, YeQ, et al.. Brain insulin resistance deteriorates cognition by altering the topological features of brain networks. Neuroimage Clin, 2017, 13: 280-287

[35] DenverP, McCleanPL. Distinguishing normal brain aging from the development of Alzheimer’s disease: inflammation, insulin signaling and cognition. Neural Regen Res, 2018, 13(10): 1719-1730

[36] FrolichL, Blum-DegenD, BernsteinHG, et al.. Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J Neural Transm (Vienna), 1998, 105(4–5): 423-438

[37] Jiménez-PalomaresM, Ramos-RodríguezJJ, López-AcostaJF, et al.. Increased Aβ production prompts the onset of glucose intolerance and insulin resistance. Am J Physiol Endocrinol Metab, 2012, 302(11): E1373-80

[38] GaspariniL, GourasGK, WangR, et al.. Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci, 2001, 21(8): 2561-2570

[39] CranePK, WalkerR, HubbardRA, et al.. Glucose levels and risk of dementia. N Engl J Med, 2013, 369(6): 540-548

[40] ValenteT, GellaA, Fernàndez-BusquetsX, et al.. Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer’s disease and diabetes mellitus. Neurobiol Dis, 2010, 37(1): 67-76

[41] YuanXY, WangXG. Mild cognitive impairment in type 2 diabetes mellitus and related risk factors: a review. Rev Neurosci, 2017, 28(7): 715-723

[42] HuangR, TianS, ZhangH, et al.. Chronic hyperglycemia induces tau hyperphosphorylation by downregulating OGT-involved O-GlcNAcylation in vivo and in vitro. Brain Res Bull, 2020, 156: 76-85

[43] MaloneJI, HannaS, SaportaS, et al.. Hyperglycemia not hypoglycemia alters neuronal dendrites and impairs spatial memory. Pediatr Diabetes, 2008, 9(6): 531-539

[44] SmithL, ChakrabortyD, BhattacharyaP, et al.. Exposure to hypoglycemia and risk of stroke. Ann N Y Acad Sci, 2018, 1431(1): 25-34

[45] LeeAK, WarrenB, LeeCJ, et al.. The Association of Severe Hypoglycemia With Incident Cardiovascular Events and Mortality in Adults With Type 2 Diabetes. Diabetes Care, 2018, 41(1): 104-111

[46] FeinkohlI, AungPP, KellerM, et al.. Severe hypoglycemia and cognitive decline in older people with type 2 diabetes: the Edinburgh type 2 diabetes study. Diabetes Care, 2014, 37(2): 507-515

[47] LeeAK, RawlingsAM, LeeCJ, et al.. Severe hypoglycaemia, mild cognitive impairment, dementia and brain volumes in older adults with type 2 diabetes: the Atherosclerosis Risk in Communities (ARIC) cohort study. Diabetologia, 2018, 61(9): 1956-1965

[48] Crosby-NwaobiR, SivaprasadS, ForbesA. A systematic review of the association of diabetic retinopathy and cognitive impairment in people with Type 2 diabetes. Diabetes Res Clin Pract, 2012, 96(2): 101-110

[49] LiJ, PanJ, LiB, et al.. Positive correlation between cognitive impairment and renal microangiopathy in patients with type 2 diabetic nephropathy: a multicenter retrospective study. J Int Med Res, 2018, 46(12): 5040-5051

[50] MehrabianS, RaychevaM, GatevaA, et al.. Cognitive dysfunction profile and arterial stiffness in type 2 diabetes. J Neurol Sci, 2012, 322(1–2): 152-156

[51] PetrovaM, ProkopenkoS, ProninaE, et al.. Diabetes type 2, hypertension and cognitive dysfunction in middle age women. J Neurol Sci, 2010, 299(1–2): 39-41

[52] UmegakiH, IimuroS, ShinozakiT, et al.. Risk factors associated with cognitive decline in the elderly with type 2 diabetes: pooled logistic analysis of a 6-year observation in the Japanese Elderly Diabetes Intervention Trial. Geriatr Gerontol Int, 2012, 12(Suppl1): 110-116

[53] de LuisDA, FernandezN, ArranzM, et al.. Total homocysteine and cognitive deterioration in people with type 2 diabetes. Diabetes Res Clin Pract, 2002, 55(3): 185-190

[54] LopezOL, JagustWJ, DulbergC, et al.. Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2. Arch Neurol, 2003, 60(10): 1394-1399

[55] 12. Older Adults: Standards of Medical Care in Diabetes-2020. Diabetes Care, 2020,43(Suppl 1):S152-S162

[56] ZhangZ, ZhangB, WangX, et al.. Olfactory Dysfunction Mediates Adiposity in Cognitive Impairment of Type 2 Diabetes: Insights From Clinical and Functional Neuroimaging Studies. Diabetes Care, 2019, 42(7): 1274-1283

[57] GeijselaersSLC, SepSJS, StehouwerCDA, et al.. Glucose regulation, cognition, and brain MRI in type 2 diabetes: a systematic review. Lancet Diabetes Endocrinol, 2015, 3(1): 75-89

[58] MoyerVA. Screening for cognitive impairment in older adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med, 2014, 160(11): 791-797

[59] O’DriscollC, ShaikhM. Cross-Cultural Applicability of the Montreal Cognitive Assessment (MoCA): A Systematic Review. J Alzheimers Dis, 2017, 58(3): 789-801

[60] MorrisJC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology, 1993, 43(11): 2412-4

[61] ZhouY, GuoQH, HongZ. Cognitive Abilities Screening Instrument—Chinese Revised Version in Participants with Mild Cognitive Impairment and Alzheimer’s Disease. Chin J Clin Neurosci (Chinese), 2009, 17(1): 49-53

[62] WangXX, LuoH. Application of several cognitive assessment scales in screening for Alzheimer’s disease. Chin J Clin Rational Drug Use (Chinese), 2015, 8(6): 173-174

[63] JiaJP, ChenSDNeurology, 20137th editionBeijing, People’s Medical Publishing House: 123-124

[64] CuiR, LiuM. Hippocampus Analysis by Combination of 3-D DenseNet and Shapes for Alzheimer’s Disease Diagnosis. IEEE J Biomed Health Inform, 2019, 23(5): 2099-2107

[65] JagustW, ThistedR, DevousMDSr., et al.. SPECT perfusion imaging in the diagnosis of Alzheimer’s disease: a clinical-pathologic study. Neurology, 2001, 56(7): 950-956

[66] BohnenNI, DjangDS, HerholzK, et al.. Effectiveness and safety of 18F-FDG PET in the evaluation of dementia: a review of the recent literature. J Nucl Med, 2012, 53(1): 59-71

[67] WhitwellJL, JosephsKA, MurrayME, et al.. MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study. Neurology, 2008, 71(10): 743-9

[68] Chinese guidelines for diagnosis and management of cognitive impairment and dementia (IV): auxiliary examination in cognitive disorders. Zhonghua Yi Xue Za Zhi (Chinese), 2018,98(15):1130–1142

[69] BlennowK, HampelH. CSF markers for incipient Alzheimer’s disease. Lancet Neurol, 2003, 2(10): 605-613

[70] RitchieC, SmailagicN, Noel-StorrAH, et al.. Plasma and cerebrospinal fluid amyloid beta for the diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev, 2014, 2014(6): Cd008782

[71] LewczukP, LelentalN, SpitzerP, et al.. Amyloid-β 42/40 cerebrospinal fluid concentration ratio in the diagnostics of Alzheimer’s disease: validation of two novel assays. J Alzheimers Dis, 2015, 43(1): 183-191

[72] PritchardSM, DolanPJ, VitkusA, et al.. The toxicity of tau in Alzheimer disease: turnover, targets and potential therapeutics. J Cell Mol Med, 2011, 15(8): 1621-1635

[73] PorteliusE, Westman-BrinkmalmA, ZetterbergH, et al.. Determination of beta-amyloid peptide signatures in cerebrospinal fluid using immunoprecipitation-mass spectrometry. J Proteome Res, 2006, 5(4): 1010-6

[74] BlennowK, ZetterbergH. Cerebrospinal fluid biomarkers for Alzheimer’s disease. J Alzheimers Dis, 2009, 18(2): 413-417

[75] GrossmanM, FarmerJ, LeightS, et al.. Cerebrospinal fluid profile in frontotemporal dementia and Alzheimer’s disease. Ann Neurol, 2005, 57(5): 721-729

[76] SchönknechtP, PantelJ, HuntA, et al.. Levels of total tau and tau protein phosphorylated at threonine 181 in patients with incipient and manifest Alzheimer’s disease. Neurosci Lett, 2003, 339(2): 172-174

[77] MoranC, BeareR, PhanTG, et al.. Type 2 diabetes mellitus and biomarkers of neurodegeneration. Neurology, 2015, 85(13): 1123-1130

[78] JanelidzeS, MattssonN, PalmqvistS, et al.. Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med, 2020, 26(3): 379-386

[79] KarikariTK, PascoalTA, AshtonNJ, et al.. Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol, 2020, 19(5): 422-433

[80] PalmqvistS, JanelidzeS, QuirozYT, et al.. Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. Jama, 2020, 324(8): 772-781

[81] JiaL, QiuQ, ZhangH, et al.. Concordance between the assessment of Aβ42, T-tau, and P-T181-tau in peripheral blood neuronal-derived exosomes and cerebrospinal fluid. Alzheimers Dement, 2019, 15(8): 1071-1080

[82] McKhannG, DrachmanD, FolsteinM, et al.. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology, 1984, 34(7): 939-944

[83] McKhannGM, KnopmanDS, ChertkowH, et al.. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement, 2011, 7(3): 263-269

[84] DuboisB, FeldmanHH, JacovaC, et al.. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol, 2014, 13(6): 614-629

[85] Chinese cognitive impairment and dementia (II): guidelines for diagnosis and management of Alzhimer’s Disease. Zhonghua Yi Xue Za Zhi (Chinese), 2018, 98(13):971–977

[86] EricksonKI, HillmanC, StillmanCM, et al.. Physical Activity, Cognition, and Brain Outcomes: A Review of the 2018 Physical Activity Guidelines. Med Sci Sports Exerc, 2019, 51(6): 1242-1251

[87] CroweM, AndelR, PedersenNL, et al.. Does participation in leisure activities lead to reduced risk of Alzheimer’s disease? A prospective study of Swedish twins. J Gerontol B Psychol Sci Soc Sci, 2003, 58(5): P249-255

[88] Martínez-LapiscinaEH, ClaveroP, ToledoE, et al.. Mediterranean diet improves cognition: the PREDIMED-NAVARRA randomised trial. J Neurol Neurosurg Psychiatry, 2013, 84(12): 1318-1325

[89] LehtisaloJ, LevälahtiE, LindströmJ, et al.. Dietary changes and cognition over 2 years within a multidomain intervention trial-The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). Alzheimers Dement, 2019, 15(3): 410-417

[90] Valls-PedretC, Sala-VilaA, Serra-MirM, et al.. Mediterranean Diet and Age-Related Cognitive Decline: A Randomized Clinical Trial. JAMA Intern Med, 2015, 175(7): 1094-1103

[91] SofiF, ValecchiD, BacciD, et al.. Physical activity and risk of cognitive decline: a meta-analysis of prospective studies. J Intern Med, 2011, 269(1): 107-117

[92] HamerM, ChidaY. Physical activity and risk of neurodegenerative disease: a systematic review of prospective evidence. Psychol Med, 2009, 39(1): 3-11

[93] AbbottRD, WhiteLR, RossGW, et al.. Walking and dementia in physically capable elderly men. Jama, 2004, 292(12): 1447-1453

[94] TranahGJ, BlackwellT, StoneKL, et al.. Circadian activity rhythms and risk of incident dementia and mild cognitive impairment in older women. Ann Neurol, 2011, 70(5): 722-732

[95] Riemersma-van der LekRF, SwaabDF, TwiskJ, et al.. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. Jama, 2008, 299(22): 2642-55

[96] Forbes D, Blake CM, Thiessen EJ, et al. Light therapy for improving cognition, activities of daily living, sleep, challenging behaviour, and psychiatric disturbances in dementia. Cochrane Database Syst Rev, 2014,(2):Cd003946

[97] LaunerLJ, MillerME, WilliamsonJD, et al.. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy. Lancet Neurol, 2011, 10(11): 969-977

[98] TangX, CardosoMA, YangJ, et al.. Impact of Intensive Glucose Control on Brain Health: Meta-Analysis of Cumulative Data from 16,584 Patients with Type 2 Diabetes Mellitus. Diabetes Ther, 2021, 12(3): 765-779

[99] de GalanBE, ZoungasS, ChalmersJ, et al.. Cognitive function and risks of cardiovascular disease and hypoglycaemia in patients with type 2 diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Diabetologia, 2009, 52(11): 2328-2336

[100] HsuCC, WahlqvistML, LeeMS, et al.. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J Alzheimers Dis, 2011, 24(3): 485-493

[101] BoccardiV, MuraseccoI, MecocciP. Diabetes drugs in the fight against Alzheimer’s disease. Ageing Res Rev, 2019, 54: 100936

[102] Chin-HsiaoT. Metformin and the Risk of Dementia in Type 2 Diabetes Patients. Aging Dis, 2019, 10(1): 37-48

[103] RyanCM, FreedMI, RoodJA, et al.. Improving metabolic control leads to better working memory in adults with type 2 diabetes. Diabetes Care, 2006, 29(2): 345-351

[104] PorterKM, WardM, HughesCF, et al.. Hyperglycemia and Metformin Use Are Associated With B Vitamin Deficiency and Cognitive Dysfunction in Older Adults. J Clin Endocrinol Metab, 2019, 104(10): 4837-4847

[105] SatoT, HanyuH, HiraoK, et al.. Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging, 2011, 32(9): 1626-33

[106] ChengH, ShangY, JiangL, et al.. The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer’s disease and mild-to-moderate Alzheimer’s disease: a meta-analysis. Int J Neurosci, 2016, 126(4): 299-307

[107] CaoB, RosenblatJD, BrietzkeE, et al.. Comparative efficacy and acceptability of antidiabetic agents for Alzheimer’s disease and mild cognitive impairment: A systematic review and network meta-analysis. Diabetes Obes Metab, 2018, 20(10): 2467-2471

[108] ImfeldP, BodmerM, JickSS, et al.. Metformin, other antidiabetic drugs, and risk of Alzheimer’s disease: a population-based case-control study. J Am Geriatr Soc, 2012, 60(5): 916-921

[109] SeaquistER, MillerME, FonsecaV, et al.. Effect of thiazolidinediones and insulin on cognitive outcomes in ACCORD-MIND. J Diabetes Complications, 2013, 27(5): 485-491

[110] GejlM, GjeddeA, EgefjordL, et al.. In Alzheimer’s Disease, 6-Month Treatment with GLP-1 Analog Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial. Front Aging Neurosci, 2016, 8: 108

[111] Cukierman-YaffeT, GersteinHC, ColhounHM, et al.. Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial. Lancet Neurol, 2020, 19(7): 582-590

[112] LinB, KoibuchiN, HasegawaY, et al.. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol, 2014, 13: 148

[113] CraftS, RamanR, ChowTW, et al.. Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA Neurol, 2020, 77(9): 1099-1109

[114] JoeE, RingmanJM. Cognitive symptoms of Alzheimer’s disease: clinical management and prevention. BMJ, 2019, 367: l6217

[115] TariotPN, SolomonPR, MorrisJC, et al.. A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology, 2000, 54(12): 2269-2276

[116] RogersSL, FriedhoffLT. The efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a US Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial. The Donepezil Study Group. Dementia, 1996, 7(6): 293-303

[117] RogersSL, DoodyRS, MohsRC, et al.. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Intern Med, 1998, 158(9): 1021-1031

[118] ErkinjunttiT, KurzA, GauthierS, et al.. Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial. Lancet, 2002, 359(9314): 1283-1290

[119] QaseemA, SnowV, CrossJTJr., et al.. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med, 2008, 148(5): 370-378

[120] FarlowMR, SallowayS, TariotPN, et al.. Effectiveness and tolerability of high-dose (23 mg/d) versus standarddose (10 mg/d) donepezil in moderate to severe Alzheimer’s disease: A 24-week, randomized, doubleblind study. Clin Ther, 2010, 32(7): 1234-1251

[121] WinbladB, MachadoJC. Use of rivastigmine transdermal patch in the treatment of Alzheimer’s disease. Expert Opin Drug Deliv, 2008, 5(12): 1377-1386

[122] TariotPN, FarlowMR, GrossbergGT, et al.. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. Jama, 2004, 291(3): 317-324

[123] MecocciP, BladströmA, StenderK. Effects of memantine on cognition in patients with moderate to severe Alzheimer’s disease: post-hoc analyses of ADAS-cog and SIB total and single-item scores from six randomized, double-blind, placebo-controlled studies. Int J Geriatr Psychiatry, 2009, 24(5): 532-538

[124] YangZ, ZhouX, ZhangQ. Effectiveness and safety of memantine treatment for Alzheimer’s disease. J Alzheimers Dis, 2013, 36(3): 445-458

[125] WilkinsonD, AndersenHF. Analysis of the effect of memantine in reducing the worsening of clinical symptoms in patients with moderate to severe Alzheimer’s disease. Dement Geriatr Cogn Disord, 2007, 24(2): 138-145

[126] WilkinsonD, WirthY, GoebelC. Memantine in patients with moderate to severe Alzheimer’s disease: meta-analyses using realistic definitions of response. Dement Geriatr Cogn Disord, 2014, 37(1–2): 71-85