{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T13:52:46Z","timestamp":1782741166891,"version":"3.54.5"},"reference-count":52,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T00:00:00Z","timestamp":1678147200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2023,3,7]]},"abstract":"<jats:p>Background: Diabetes increases the risk for cognitive decline, but the mechanisms behind this association remain unknown. Impaired early insulin secretion in elderly men and insulin resistance, both of which are pathophysiological features of type 2 diabetes, have previously been linked to Alzheimer\u2019s disease. Objective: To examine if the early insulin response to oral glucose load predicts cognitive performance after 10 years in men and women aged 45-74 years. Methods: This study was based on a subpopulation of the Health 2000 Survey, a Finnish nationwide, population-based health examination study, and its follow-up, the Health 2011 Study. In total, 961 45\u201374-year-old individuals (mean age at baseline 55.6 years, 55.8% women) were examined. An oral glucose tolerance test was performed in 2001\u20132002, and early insulin response was defined as the ratio of the 30-min increment in insulin concentration to that of glucose concentration. Cognitive function was evaluated at baseline and follow-up with categorical verbal fluency, word-list learning, and word-list delayed recall. Statistical analyses were performed using multivariable linear models adjusted for age, sex, education, APOE &amp;z.epsi;4 genotype, vascular risk factors including diabetes, and depressive symptoms. Results: A lower early insulin response to glucose load predicted lower performance (\u03b2: 0.21, p\u200a=\u200a0.03) and greater decline (\u03b2: 0.19, p\u200a=\u200a0.03) in the word-list delayed recall test. Baseline early insulin response did not predict verbal fluency or word-list learning (all p-values\u22650.13). Conclusion: Our results suggest that decreased early insulin secretion predicts episodic memory decline in middle-aged to elderly men and women.<\/jats:p>","DOI":"10.3233\/jad-220894","type":"journal-article","created":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T11:56:45Z","timestamp":1675166205000},"page":"349-359","source":"Crossref","is-referenced-by-count":3,"title":["Impaired Early Insulin Response to Glucose Load Predicts Episodic Memory Decline: A 10-Year Population-Based Cohort Follow-Up of 45\u201374-Year-Old Men and Women"],"prefix":"10.1177","volume":"92","author":[{"given":"Sini","family":"Toppala","sequence":"first","affiliation":[{"name":"Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland"},{"name":"Kuopio City Home Care, Rehabilitation and Medical Services for Elderly, Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura L.","family":"Ekblad","sequence":"additional","affiliation":[{"name":"Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matti","family":"Viitanen","sequence":"additional","affiliation":[{"name":"City of Turku, Welfare Division, Department of Geriatrics, Turku City Hospital and University of Turku, Turku, Finland"},{"name":"Division of Clinical Geriatrics, NVS, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juha O.","family":"Rinne","sequence":"additional","affiliation":[{"name":"Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland"},{"name":"InFLAMES Research Flagship Center, University of Turku, Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antti","family":"Jula","sequence":"additional","affiliation":[{"name":"National Institute for Health and Welfare, Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"key":"10.3233\/JAD-220894_ref1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.diabres.2016.10.024","article-title":"An updated meta-analysis of cohort studies: Diabetes and risk of Alzheimer\u2019s disease","volume":"124","author":"Zhang","year":"2017","journal-title":"Diabetes Res Clin Pract"},{"key":"10.3233\/JAD-220894_ref2","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1111\/j.1445-5994.2012.02758.x","article-title":"Diabetes as a risk factor for dementia and mild cognitive impairment: A meta-analysis of longitudinal studies","volume":"42","author":"Cheng","year":"2012","journal-title":"Intern Med J"},{"key":"10.3233\/JAD-220894_ref3","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.jalz.2018.06.3060","article-title":"Prediabetes and diabetes accelerate cognitive decline and predict microvascular lesions: A population-based cohort study","volume":"15","author":"Marseglia","year":"2019","journal-title":"Alzheimers Dement"},{"key":"10.3233\/JAD-220894_ref4","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1007\/s00125-011-2095-7","article-title":"Glycated haemoglobin and cognitive decline: The Atherosclerosis Risk in Communities (ARIC) study","volume":"54","author":"Christman","year":"2011","journal-title":"Diabetologia"},{"key":"10.3233\/JAD-220894_ref5","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S2213-8587(14)70148-2","article-title":"Glucose regulation, cognition, and brain MRI in type 2 diabetes: A systematic review","volume":"3","author":"Geijselaers","year":"2015","journal-title":"Lancet Diabetes Endocrinol"},{"key":"10.3233\/JAD-220894_ref6","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1212\/01.wnl.0000435561.00234.ee","article-title":"Higher glucose levels associated with lower memory and reduced hippocampal microstructure","volume":"81","author":"Kerti","year":"2013","journal-title":"Neurology"},{"key":"10.3233\/JAD-220894_ref7","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1056\/NEJMoa1215740","article-title":"Glucose levels and risk of dementia","volume":"369","author":"Crane","year":"2013","journal-title":"N Engl J Med"},{"key":"10.3233\/JAD-220894_ref8","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/S1474-4422(22)00395-7","article-title":"Diabetes and Alzheimer\u2019s disease: Shared genetic susceptibility","volume":"21","author":"Hardy","year":"2022","journal-title":"Lancet Neurol"},{"key":"10.3233\/JAD-220894_ref9","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/j.jalz.2015.12.006","article-title":"Diabetes is associated with cerebrovascular but not Alzheimer\u2019s disease neuropathology","volume":"12","author":"Abner","year":"2016","journal-title":"Alzheimers Dement"},{"key":"10.3233\/JAD-220894_ref10","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.3233\/JAD-170179","article-title":"Diabetes is not associated with Alzheimer\u2019s disease neuropathology","volume":"60","author":"Dos Santos Matioli","year":"2017","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-220894_ref11","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1093\/brain\/awac354","article-title":"Diabetes and hypertension are related to amyloid-beta burden in the population-based Rotterdam Study","volume":"146","author":"van Arendonk","year":"2023","journal-title":"Brain"},{"key":"10.3233\/JAD-220894_ref12","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/S2213-8587(13)70088-3","article-title":"Dementia and cognitive decline in type 2 diabetes and prediabetic stages: Towards targeted interventions","volume":"2","author":"Biessels","year":"2014","journal-title":"Lancet Diabetes Endocrinol"},{"key":"10.3233\/JAD-220894_ref13","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S2213-8587(20)30118-2","article-title":"Type 2 diabetes and cognitive dysfunction\u2014 towards effective management of both comorbidities","volume":"8","author":"Srikanth","year":"2020","journal-title":"Lancet Diabetes Endocrinol"},{"key":"10.3233\/JAD-220894_ref14","doi-asserted-by":"crossref","first-page":"751","DOI":"10.2337\/dc16-2001","article-title":"Insulin resistance predicts cognitive decline: An 11-year follow-up of a nationally representative adult population sample","volume":"40","author":"Ekblad","year":"2017","journal-title":"Diabetes Care"},{"key":"10.3233\/JAD-220894_ref15","doi-asserted-by":"crossref","first-page":"215","DOI":"10.3233\/JAD-190691","article-title":"Midlife insulin resistance as a predictor for late-life cognitive function and cerebrovascular lesions","volume":"72","author":"Toppala","year":"2019","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-220894_ref16","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1136\/bmj.315.7115.1045","article-title":"Association between features of the insulin resistance syndrome and Alzheimer\u2019s disease independently of apolipoprotein E4 phenotype: Cross sectional population based study","volume":"315","author":"Kuusisto","year":"1997","journal-title":"BMJ"},{"key":"10.3233\/JAD-220894_ref17","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1212\/01.wnl.0000306313.89165.ef","article-title":"Central obesity and increased risk of dementia more than three decades later","volume":"71","author":"Whitmer","year":"2008","journal-title":"Neurology"},{"key":"10.3233\/JAD-220894_ref18","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1212\/WNL.0b013e3181ffe4f6","article-title":"Insulin metabolism and the risk of Alzheimer disease: The Rotterdam Study","volume":"75","author":"Schrijvers","year":"2010","journal-title":"Neurology"},{"key":"10.3233\/JAD-220894_ref19","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1161\/01.HYP.22.5.771","article-title":"Essential hypertension and cognitive function: The role of hyperinsulinemia","volume":"22","author":"Kuusisto","year":"1993","journal-title":"Hypertension"},{"key":"10.3233\/JAD-220894_ref20","doi-asserted-by":"crossref","first-page":"447","DOI":"10.2337\/db11-0995","article-title":"Distinct \u03b2-cell defects in impaired fasting glucose and impaired glucose tolerance","volume":"61","author":"Kanat","year":"2012","journal-title":"Diabetes"},{"key":"10.3233\/JAD-220894_ref21","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.1016\/S0140-6736(12)60283-9","article-title":"Prediabetes: A high-risk state for diabetes development","volume":"379","author":"Tabak","year":"2012","journal-title":"Lancet"},{"key":"10.3233\/JAD-220894_ref22","doi-asserted-by":"crossref","first-page":"89","DOI":"10.2337\/diacare.24.1.89","article-title":"Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development","volume":"24","author":"Weyer","year":"2001","journal-title":"Diabetes Care"},{"key":"10.3233\/JAD-220894_ref23","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.1056\/NEJM199312303292703","article-title":"Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus: Prospective studies of Pima Indians","volume":"329","author":"Lillioja","year":"1993","journal-title":"N Engl J Med"},{"key":"10.3233\/JAD-220894_ref24","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1007\/s00125-009-1393-9","article-title":"Glucose metabolism and the risk of Alzheimer\u2019s disease and dementia: A population-based 12 year follow-up study in 71-year-old men","volume":"52","author":"R\u00f6nnemaa","year":"2009","journal-title":"Diabetologia"},{"key":"10.3233\/JAD-220894_ref25","doi-asserted-by":"crossref","first-page":"e1150","DOI":"10.1212\/WNL.0000000000005214","article-title":"Midlife insulin resistance, APOE genotype, and late-life brain amyloid accumulation","volume":"90","author":"Ekblad","year":"2018","journal-title":"Neurology"},{"key":"10.3233\/JAD-220894_ref26","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.2337\/dc21-0042","article-title":"Oral glucose tolerance test predicts episodic memory decline: A 10-year population-based follow-up study","volume":"44","author":"Toppala","year":"2021","journal-title":"Diabetes Care"},{"key":"10.3233\/JAD-220894_ref30","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1194\/jlr.M400250-JLR200","article-title":"Active and low-active forms of serum phospholipid transfer protein in a normal Finnish population sample","volume":"45","author":"J\u00e4nis","year":"2004","journal-title":"J Lipid Res"},{"key":"10.3233\/JAD-220894_ref32","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.envres.2012.09.007","article-title":"Fish consumption, omega-3 fatty acids, and environmental contaminants in relation to low-grade inflammation and early atherosclerosis","volume":"120","author":"Turunen","year":"2013","journal-title":"Environ Res"},{"key":"10.3233\/JAD-220894_ref33","doi-asserted-by":"crossref","first-page":"4575","DOI":"10.1210\/jc.2009-0666","article-title":"Association of variation in the interleukin-1 gene family with diabetes and glucose homeostasis","volume":"94","author":"Luotola","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"10.3233\/JAD-220894_ref34","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1002\/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S","article-title":"Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation","volume":"15","author":"Alberti","year":"1998","journal-title":"Diabet Med"},{"key":"10.3233\/JAD-220894_ref35","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1007\/BF00280883","article-title":"Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man","volume":"28","author":"Matthews","year":"1985","journal-title":"Diabetologia"},{"key":"10.3233\/JAD-220894_ref36","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1212\/WNL.39.9.1159","article-title":"The consortium to establish a registry for Alzheimer\u2019s disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer\u2019s disease","volume":"39","author":"Morris","year":"1989","journal-title":"Neurology"},{"key":"10.3233\/JAD-220894_ref37","first-page":"1967","article-title":"Kognitiiviset testit muistih\u00e4iri\u00f6iden ja alkavan dementian varhaisdiagnostiikassa: CERAD-teht\u00e4v\u00e4sarja. [Cognitive tests in diagnosing memory disorders and early dementia: CERAD-nb]","volume":"15","author":"H\u00e4nninen","year":"1999","journal-title":"Suom Laakaril"},{"key":"10.3233\/JAD-220894_ref38","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1212\/01.wnl.0000310646.32212.3a","article-title":"Impaired insulin secretion increases the risk of Alzheimer disease","volume":"71","author":"R\u00f6nnemaa","year":"2008","journal-title":"Neurology"},{"key":"10.3233\/JAD-220894_ref39","doi-asserted-by":"crossref","first-page":"2688","DOI":"10.2337\/dc06-0915","article-title":"Hyperinsulinemia and cognitive decline in a middle-aged cohort","volume":"29","author":"Young","year":"2006","journal-title":"Diabetes Care"},{"key":"10.3233\/JAD-220894_ref40","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1212\/01.WNL.0000140292.04932.87","article-title":"Hyperinsulinemia and risk of Alzheimer disease","volume":"63","author":"Luchsinger","year":"2004","journal-title":"Neurology"},{"key":"10.3233\/JAD-220894_ref41","doi-asserted-by":"crossref","first-page":"772","DOI":"10.3389\/fpsyg.2014.00772","article-title":"What do verbal fluency tasks measure? Predictors of verbal fluency performance in older adults","volume":"5","author":"Shao","year":"2014","journal-title":"Front Psychol"},{"key":"10.3233\/JAD-220894_ref42","doi-asserted-by":"crossref","first-page":"c3666","DOI":"10.1136\/bmj.c3666","article-title":"The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: Systematic review and meta-analysis","volume":"341","author":"Debette","year":"2010","journal-title":"BMJ"},{"key":"10.3233\/JAD-220894_ref43","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1161\/STROKEAHA.107.491795","article-title":"Subcortical lacunes are associated with executive dysfunction in cognitively normal elderly","volume":"39","author":"Carey","year":"2008","journal-title":"Stroke"},{"key":"10.3233\/JAD-220894_ref44","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/S1474-4422(16)00062-4","article-title":"Defeating Alzheimer\u2019s disease and other dementias: A priority for European science and society","volume":"15","author":"Winblad","year":"2016","journal-title":"Lancet Neurol"},{"key":"10.3233\/JAD-220894_ref45","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S1474-4422(09)70299-6","article-title":"Hypothetical model of dynamic biomarkers of the Alzheimer\u2019s pathological cascade","volume":"9","author":"Jack","year":"2010","journal-title":"Lancet Neurol"},{"key":"10.3233\/JAD-220894_ref46","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1212\/WNL.0b013e3181eee25f","article-title":"Insulin resistance is associated with the pathology of Alzheimer disease: The Hisayama study","volume":"75","author":"Matsuzaki","year":"2010","journal-title":"Neurology"},{"key":"10.3233\/JAD-220894_ref47","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1001\/jamaneurol.2013.284","article-title":"Glucose intolerance, insulin resistance, and pathological features of Alzheimer disease in the Baltimore longitudinal study of aging","volume":"70","author":"Thambisetty","year":"2013","journal-title":"JAMA Neurol"},{"key":"10.3233\/JAD-220894_ref48","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.2337\/diacare.22.9.1462","article-title":"Insulin sensitivity indices obtained from oral glucose tolerance testing: Comparison with the euglycemic insulin clamp","volume":"22","author":"Matsuda","year":"1999","journal-title":"Diabetes Care"},{"key":"10.3233\/JAD-220894_ref49","doi-asserted-by":"crossref","first-page":"347","DOI":"10.2337\/dc07-1574","article-title":"Isolated impaired fasting glucose and peripheral insulin sensitivity: Not a simple relationship","volume":"31","author":"Kim","year":"2008","journal-title":"Diabetes Care"},{"key":"10.3233\/JAD-220894_ref50","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.2337\/db05-1200","article-title":"Insulin secretion and action in subjects with impairedfasting glucose and impaired glucose tolerance: Results from theveterans administration genetic epidemiology study.","volume":"55","author":"Abdul-Ghani","year":"2006","journal-title":"Diabetes"},{"key":"10.3233\/JAD-220894_ref51","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.2337\/diacare.27.6.1433","article-title":"Insulin resistance, impaired early insulin response, and insulin propeptides as predictors of the development of type 2 diabetes: A population-based, 7-year follow-up study in 70-year-old men","volume":"27","author":"Zethelius","year":"2004","journal-title":"Diabetes Care"},{"key":"10.3233\/JAD-220894_ref52","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1016\/S0140-6736(09)60619-X","article-title":"Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: An analysis from the Whitehall II study","volume":"373","author":"Tabak","year":"2009","journal-title":"Lancet"},{"key":"10.3233\/JAD-220894_ref53","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/S1474-4422(20)30231-3","article-title":"Brain insulin resistance in Alzheimer\u2019s disease and related disorders: Mechanisms and therapeutic approaches","volume":"19","author":"Kellar","year":"2020","journal-title":"Lancet Neurol"},{"key":"10.3233\/JAD-220894_ref54","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.ejphar.2013.08.008","article-title":"Insulin, cognition, and dementia","volume":"719","author":"Cholerton","year":"2013","journal-title":"Eur J Pharmacol"},{"key":"10.3233\/JAD-220894_ref55","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1038\/s41366-020-0535-5","article-title":"Liraglutide improves memory in obese patients with prediabetes or early type 2 diabetes: A randomized, controlled study","volume":"44","author":"Vadini","year":"2020","journal-title":"Int J Obes"},{"key":"10.3233\/JAD-220894_ref56","doi-asserted-by":"crossref","first-page":"e1110","DOI":"10.1212\/WNL.0000000000012534","article-title":"Association of dipeptidyl peptidase-4 inhibitor use and amyloid burden in diabetic patients with AD-related cognitive impairment","volume":"97","author":"Jeong","year":"2021","journal-title":"Neurology"}],"container-title":["Journal of Alzheimer's Disease"],"original-title":[],"link":[{"URL":"https:\/\/content.iospress.com\/download?id=10.3233\/JAD-220894","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T10:07:12Z","timestamp":1777370832000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/full\/10.3233\/JAD-220894"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,7]]},"references-count":52,"journal-issue":{"issue":"1"},"URL":"https:\/\/doi.org\/10.3233\/jad-220894","relation":{},"ISSN":["1387-2877","1875-8908"],"issn-type":[{"value":"1387-2877","type":"print"},{"value":"1875-8908","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,7]]}}}