{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T13:09:31Z","timestamp":1793106571213,"version":"4.5.0"},"reference-count":83,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,8,29]],"date-time":"2017-08-29T00:00:00Z","timestamp":1503964800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,8,29]],"date-time":"2017-08-29T00:00:00Z","timestamp":1503964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Growing evidence supports the hypothesis that type 2 diabetes (T2D) increases the risk of developing dementia. Experimental evidence from mouse models demonstrates that the induction of T2D\/insulin resistance (IR) can promote the accumulation of Alzheimer\u2019s disease (AD) pathological features. However, the association of T2D with pathological and clinical phenotypes in humans is unclear. Here we investigate the relationship of indices of IR (HOMA-IR) and pancreatic \u03b2-cell function (HOMA-B) with cognitive performance across several domains (Verbal\/Visual Episodic Memory, Executive Function, Language and a measure of Global cognition) and AD biomarkers (CSF A\u03b242, T-tau\/P-tau, hippocampal volume and neocortical A\u03b2-amyloid burden). We reveal that HOMA-IR (p\u2009&lt;\u20090.001) incrementally increases across diagnostic groups, becoming significantly elevated in the AD group compared with cognitively normal (CN) adults. In CN adults, higher HOMA-IR was associated with poorer performance on measures of verbal episodic memory (p\u2009=\u20090.010), executive function (p\u2009=\u20090.046) and global cognition (p\u2009=\u20090.007), as well as with higher CSF T-tau (p\u2009=\u20090.008) and P-tau (p\u2009=\u20090.014) levels. No association was observed with CSF A\u03b2 or imaging modalities. Together our data suggest that IR may contribute to reduced cognitive performance and the accumulation of CSF tau biomarkers in cognitively normal adults.<\/jats:p>","DOI":"10.1038\/s41598-017-09577-4","type":"journal-article","created":{"date-parts":[[2017,8,23]],"date-time":"2017-08-23T09:33:21Z","timestamp":1503480801000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":80,"title":["Insulin resistance is associated with reductions in specific cognitive domains and increases in CSF tau in cognitively normal adults"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4355-7082","authenticated-orcid":false,"given":"Simon M.","family":"Laws","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Gaskin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Woodfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Velandai","family":"Srikanth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Bruce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul E.","family":"Fraser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tenielle","family":"Porter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Newsholme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadeeja","family":"Wijesekara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Burnham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Dor\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiao-Xin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Maruff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin L.","family":"Masters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Rainey-Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher C.","family":"Rowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Salvado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor L.","family":"Villemagne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph N.","family":"Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Verdile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,8,29]]},"reference":[{"key":"9577_CR1","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1111\/j.1749-6632.1997.tb48496.x","volume":"826","author":"CL Leibson","year":"1997","unstructured":"Leibson, C. L. et al. The risk of dementia among persons with diabetes mellitus: a population-based cohort study. Ann NY Acad Sci 826, 422\u2013427 (1997).","journal-title":"Ann N Y Acad Sci"},{"key":"9577_CR2","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1212\/01.WNL.0000138432.16676.4B","volume":"63","author":"Z Arvanitakis","year":"2004","unstructured":"Arvanitakis, Z. et al. Diabetes mellitus and progression of rigidity and gait disturbance in older persons. Neurology 63, 996\u20131001 (2004).","journal-title":"Neurology"},{"key":"9577_CR3","doi-asserted-by":"publisher","first-page":"1937","DOI":"10.1212\/WNL.53.9.1937","volume":"53","author":"A Ott","year":"1999","unstructured":"Ott, A. et al. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 53, 1937\u20131942 (1999).","journal-title":"Neurology"},{"key":"9577_CR4","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.2337\/diabetes.51.4.1256","volume":"51","author":"R Peila","year":"2002","unstructured":"Peila, R., Rodriguez, B. L., Launer, L. J. & Honolulu-Asia Aging, S. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes 51, 1256\u20131262 (2002).","journal-title":"Diabetes"},{"key":"9577_CR5","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1212\/01.WNL.0000140291.86406.D1","volume":"63","author":"WL Xu","year":"2004","unstructured":"Xu, W. L., Qiu, C. X., Wahlin, A., Winblad, B. & Fratiglioni, L. Diabetes mellitus and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Neurology 63, 1181\u20131186 (2004).","journal-title":"Neurology"},{"key":"9577_CR6","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.2337\/diabetes.55.04.06.db05-1323","volume":"55","author":"SM Manschot","year":"2006","unstructured":"Manschot, S. M. et al. Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes. Diabetes 55, 1106\u20131113 (2006).","journal-title":"Diabetes"},{"key":"9577_CR7","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1159\/000098054","volume":"57","author":"B van Harten","year":"2007","unstructured":"van Harten, B., Oosterman, J. M., Potter van Loon, B. J., Scheltens, P. & Weinstein, H. C. Brain lesions on MRI in elderly patients with type 2 diabetes mellitus. Eur Neurol 57, 70\u201374, doi:10.1159\/000098054 (2007).","journal-title":"Eur Neurol"},{"key":"9577_CR8","doi-asserted-by":"publisher","first-page":"4036","DOI":"10.2337\/dc13-0143","volume":"36","author":"C Moran","year":"2013","unstructured":"Moran, C. et al. Brain atrophy in type 2 diabetes: regional distribution and influence on cognition. Diabetes Care 36, 4036\u20134042, doi:10.2337\/dc13-0143 (2013).","journal-title":"Diabetes Care"},{"key":"9577_CR9","doi-asserted-by":"publisher","first-page":"2244","DOI":"10.2337\/db14-0348","volume":"63","author":"GJ Biessels","year":"2014","unstructured":"Biessels, G. J. & Reijmer, Y. D. Brain changes underlying cognitive dysfunction in diabetes: what can we learn from MRI? Diabetes 63, 2244\u20132252, doi:10.2337\/db14-0348 (2014).","journal-title":"Diabetes"},{"key":"9577_CR10","doi-asserted-by":"publisher","first-page":"279","DOI":"10.2337\/db14-0506","volume":"64","author":"C Moran","year":"2015","unstructured":"Moran, C. et al. Type 2 diabetes, skin autofluorescence, and brain atrophy. Diabetes 64, 279\u2013283, doi:10.2337\/db14-0506 (2015).","journal-title":"Diabetes"},{"key":"9577_CR11","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.jns.2013.06.019","volume":"332","author":"M Kooistra","year":"2013","unstructured":"Kooistra, M. et al. Diabetes mellitus and progression of vascular brain lesions and brain atrophy in patients with symptomatic atherosclerotic disease. The SMART-MR study. J Neurol Sci 332, 69\u201374, doi:10.1016\/j.jns.2013.06.019 (2013).","journal-title":"J Neurol Sci"},{"key":"9577_CR12","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1212\/WNL.0b013e3181f25f06","volume":"75","author":"SG van Elderen","year":"2010","unstructured":"van Elderen, S. G. et al. Progression of brain atrophy and cognitive decline in diabetes mellitus: a 3-year follow-up. Neurology 75, 997\u20131002, doi:10.1212\/WNL.0b013e3181f25f06 (2010).","journal-title":"Neurology"},{"key":"9577_CR13","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.nbd.2015.04.008","volume":"84","author":"G Verdile","year":"2015","unstructured":"Verdile, G., Fuller, S. J. & Martins, R. N. The role of type 2 diabetes in neurodegeneration. Neurobiol Dis 84, 22\u201338, doi:10.1016\/j.nbd.2015.04.008 (2015).","journal-title":"Neurobiol Dis"},{"key":"9577_CR14","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/105828","volume":"2015","author":"G Verdile","year":"2015","unstructured":"Verdile, G. et al. Inflammation and Oxidative Stress: The Molecular Connectivity between Insulin Resistance, Obesity, and Alzheimer\u2019s Disease. Mediators Inflamm 2015, 105828, doi:10.1155\/2015\/105828 (2015).","journal-title":"Mediators Inflamm"},{"key":"9577_CR15","doi-asserted-by":"publisher","unstructured":"Cohen, A. D. & Klunk, W. E. Early detection of Alzheimer\u2019s disease using PiB and FDG PET. Neurobiol Dis 72 Pt A, 117\u2013122, doi:10.1016\/j.nbd.2014.05.001 (2014).","DOI":"10.1016\/j.nbd.2014.05.001"},{"key":"9577_CR16","doi-asserted-by":"publisher","first-page":"759","DOI":"10.2967\/jnumed.113.132647","volume":"55","author":"RO Roberts","year":"2014","unstructured":"Roberts, R. O. et al. Diabetes and elevated hemoglobin A1c levels are associated with brain hypometabolism but not amyloid accumulation. J Nucl Med 55, 759\u2013764, doi:10.2967\/jnumed.113.132647 (2014).","journal-title":"J Nucl Med"},{"key":"9577_CR17","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1001\/jamaneurol.2013.284","volume":"70","author":"M Thambisetty","year":"2013","unstructured":"Thambisetty, M. et al. Glucose intolerance, insulin resistance, and pathological features of Alzheimer disease in the Baltimore Longitudinal Study of Aging. JAMA Neurol 70, 1167\u20131172, doi:10.1001\/jamaneurol.2013.284 (2013).","journal-title":"JAMA Neurol"},{"key":"9577_CR18","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1016\/j.jalz.2014.03.011","volume":"11","author":"AA Willette","year":"2015","unstructured":"Willette, A. A. et al. Insulin resistance predicts brain amyloid deposition in late middle-aged adults. Alzheimers Dement 11, 504\u2013510, e501, doi:10.1016\/j.jalz.2014.03.011 (2015).","journal-title":"Alzheimers Dement"},{"key":"9577_CR19","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1136\/bmj.38678.389583.7C","volume":"332","author":"R Huxley","year":"2006","unstructured":"Huxley, R., Barzi, F. & Woodward, M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ 332, 73\u201378, doi:10.1136\/bmj.38678.389583.7C (2006).","journal-title":"BMJ"},{"key":"9577_CR20","doi-asserted-by":"publisher","first-page":"300","DOI":"10.2337\/dc15-1588","volume":"39","author":"S Chatterjee","year":"2016","unstructured":"Chatterjee, S. et al. Type 2 Diabetes as a Risk Factor for Dementia in Women Compared With Men: A Pooled Analysis of 2.3 Million People Comprising More Than 100,000 Cases of Dementia. Diabetes Care 39, 300\u2013307, doi:10.2337\/dc15-1588 (2016).","journal-title":"Diabetes Care"},{"key":"9577_CR21","doi-asserted-by":"publisher","first-page":"1973","DOI":"10.1016\/S0140-6736(14)60040-4","volume":"383","author":"SA Peters","year":"2014","unstructured":"Peters, S. A., Huxley, R. R. & Woodward, M. Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes. Lancet 383, 1973\u20131980, doi:10.1016\/S0140-6736(14)60040-4 (2014).","journal-title":"Lancet"},{"key":"9577_CR22","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/181643","volume":"2015","author":"KN Keane","year":"2015","unstructured":"Keane, K. N., Cruzat, V. F., Carlessi, R., de Bittencourt, P. I. Jr. & Newsholme, P. Molecular Events Linking Oxidative Stress and Inflammation to Insulin Resistance and beta-Cell Dysfunction. Oxid Med Cell Longev 2015, 181643, doi:10.1155\/2015\/181643 (2015).","journal-title":"Oxid Med Cell Longev"},{"key":"9577_CR23","doi-asserted-by":"publisher","first-page":"4291","DOI":"10.2337\/db14-0375","volume":"63","author":"M Vandal","year":"2014","unstructured":"Vandal, M. et al. Insulin reverses the high-fat diet-induced increase in brain Abeta and improves memory in an animal model of Alzheimer disease. Diabetes 63, 4291\u20134301, doi:10.2337\/db14-0375 (2014).","journal-title":"Diabetes"},{"key":"9577_CR24","doi-asserted-by":"publisher","first-page":"1749","DOI":"10.1016\/j.metabol.2013.08.007","volume":"62","author":"S Park","year":"2013","unstructured":"Park, S., Kim, D. S., Kang, S. & Moon, N. R. beta-Amyloid-induced cognitive dysfunction impairs glucose homeostasis by increasing insulin resistance and decreasing beta-cell mass in non-diabetic and diabetic rats. Metabolism 62, 1749\u20131760, doi:10.1016\/j.metabol.2013.08.007 (2013).","journal-title":"Metabolism"},{"key":"9577_CR25","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1016\/j.neurobiolaging.2008.08.019","volume":"31","author":"J Miklossy","year":"2010","unstructured":"Miklossy, J. et al. Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes. Neurobiol Aging 31, 1503\u20131515, doi:10.1016\/j.neurobiolaging.2008.08.019 (2010).","journal-title":"Neurobiol Aging"},{"key":"9577_CR26","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/0197-4580(95)02002-0","volume":"17","author":"S Craft","year":"1996","unstructured":"Craft, S. et al. Memory improvement following induced hyperinsulinemia in Alzheimer\u2019s disease. Neurobiol Aging 17, 123\u2013130 (1996).","journal-title":"Neurobiol Aging"},{"key":"9577_CR27","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1212\/WNL.50.1.164","volume":"50","author":"S Craft","year":"1998","unstructured":"Craft, S. et al. Cerebrospinal fluid and plasma insulin levels in Alzheimer\u2019s disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology 50, 164\u2013168 (1998).","journal-title":"Neurology"},{"key":"9577_CR28","doi-asserted-by":"publisher","first-page":"323","DOI":"10.3233\/JAD-2008-13309","volume":"13","author":"MA Reger","year":"2008","unstructured":"Reger, M. A. et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis 13, 323\u2013331 (2008).","journal-title":"J Alzheimers Dis"},{"key":"9577_CR29","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/j.neurobiolaging.2013.09.033","volume":"35","author":"JK Morris","year":"2014","unstructured":"Morris, J. K., Vidoni, E. D., Honea, R. A. & Burns, J. M. & Alzheimer\u2019s Disease Neuroimaging, I. Impaired glycemia increases disease progression in mild cognitive impairment. Neurobiol Aging 35, 585\u2013589, doi:10.1016\/j.neurobiolaging.2013.09.033 (2014).","journal-title":"Neurobiol Aging"},{"key":"9577_CR30","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.phrs.2017.03.008","volume":"120","author":"G Pucci","year":"2017","unstructured":"Pucci, G. et al. Sex- and gender-related prevalence, cardiovascular risk and therapeutic approach in metabolic syndrome: A review of the literature. Pharmacol Res 120, 34\u201342, doi:10.1016\/j.phrs.2017.03.008 (2017).","journal-title":"Pharmacol Res"},{"key":"9577_CR31","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1046\/j.1464-5491.2002.00835.x","volume":"19","author":"N Unwin","year":"2002","unstructured":"Unwin, N., Shaw, J., Zimmet, P. & Alberti, K. G. Impaired glucose tolerance and impaired fasting glycaemia: the current status on definition and intervention. Diabet Med 19, 708\u2013723 (2002).","journal-title":"Diabet Med"},{"key":"9577_CR32","doi-asserted-by":"publisher","first-page":"1568","DOI":"10.1001\/archinte.168.14.1568","volume":"168","author":"I Janssen","year":"2008","unstructured":"Janssen, I., Powell, L. H., Crawford, S., Lasley, B. & Sutton-Tyrrell, K. Menopause and the metabolic syndrome: the Study of Women\u2019s Health Across the Nation. Arch Intern Med 168, 1568\u20131575, doi:10.1001\/archinte.168.14.1568 (2008).","journal-title":"Arch Intern Med"},{"key":"9577_CR33","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1038\/ijo.2008.25","volume":"32","author":"JC Lovejoy","year":"2008","unstructured":"Lovejoy, J. C., Champagne, C. M., de Jonge, L., Xie, H. & Smith, S. R. Increased visceral fat and decreased energy expenditure during the menopausal transition. Int J Obes (Lond) 32, 949\u2013958, doi:10.1038\/ijo.2008.25 (2008).","journal-title":"Int J Obes (Lond)"},{"key":"9577_CR34","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1002\/jnr.23827","volume":"95","author":"CJ Pike","year":"2017","unstructured":"Pike, C. J. Sex and the development of Alzheimer\u2019s disease. J Neurosci Res 95, 671\u2013680, doi:10.1002\/jnr.23827 (2017).","journal-title":"J Neurosci Res"},{"key":"9577_CR35","doi-asserted-by":"publisher","first-page":"488","DOI":"10.2337\/dc11-2075","volume":"35","author":"C Benedict","year":"2012","unstructured":"Benedict, C. et al. Impaired insulin sensitivity as indexed by the HOMA score is associated with deficits in verbal fluency and temporal lobe gray matter volume in the elderly. Diabetes Care 35, 488\u2013494, doi:10.2337\/dc11-2075 (2012).","journal-title":"Diabetes Care"},{"key":"9577_CR36","doi-asserted-by":"publisher","first-page":"2545","DOI":"10.1007\/s00125-015-3715-4","volume":"58","author":"LL Ekblad","year":"2015","unstructured":"Ekblad, L. L. et al. Insulin resistance is associated with poorer verbal fluency performance in women. Diabetologia 58, 2545\u20132553, doi:10.1007\/s00125-015-3715-4 (2015).","journal-title":"Diabetologia"},{"key":"9577_CR37","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1007\/s10654-010-9476-y","volume":"25","author":"M Schuur","year":"2010","unstructured":"Schuur, M. et al. Insulin-resistance and metabolic syndrome are related to executive function in women in a large family-based study. Eur J Epidemiol 25, 561\u2013568, doi:10.1007\/s10654-010-9476-y (2010).","journal-title":"Eur J Epidemiol"},{"key":"9577_CR38","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1001\/archneur.57.6.808","volume":"57","author":"MF Elias","year":"2000","unstructured":"Elias, M. F. et al. The preclinical phase of alzheimer disease: A 22-year prospective study of the Framingham Cohort. Arch Neurol 57, 808\u2013813 (2000).","journal-title":"Arch Neurol"},{"key":"9577_CR39","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1017\/S1355617708080302","volume":"14","author":"E Grober","year":"2008","unstructured":"Grober, E. et al. Memory impairment, executive dysfunction, and intellectual decline in preclinical Alzheimer\u2019s disease. J Int Neuropsychol Soc 14, 266\u2013278, doi:10.1017\/S1355617708080302 (2008).","journal-title":"J Int Neuropsychol Soc"},{"key":"9577_CR40","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1212\/WNL.0b013e31828ab2c9","volume":"80","author":"CA Derby","year":"2013","unstructured":"Derby, C. A. et al. Screening for predementia AD: time-dependent operating characteristics of episodic memory tests. Neurology 80, 1307\u20131314, doi:10.1212\/WNL.0b013e31828ab2c9 (2013).","journal-title":"Neurology"},{"key":"9577_CR41","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1017\/S1355617713001483","volume":"20","author":"P Palta","year":"2014","unstructured":"Palta, P., Schneider, A. L., Biessels, G. J., Touradji, P. & Hill-Briggs, F. Magnitude of cognitive dysfunction in adults with type 2 diabetes: a meta-analysis of six cognitive domains and the most frequently reported neuropsychological tests within domains. J Int Neuropsychol Soc 20, 278\u2013291, doi:10.1017\/S1355617713001483 (2014).","journal-title":"J Int Neuropsychol Soc"},{"key":"9577_CR42","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1097\/PSY.0000000000000103","volume":"77","author":"C Vincent","year":"2015","unstructured":"Vincent, C. & Hall, P. A. Executive Function in Adults With Type 2 Diabetes: A Meta-Analytic Review. Psychosom Med 77, 631\u2013642, doi:10.1097\/PSY.0000000000000103 (2015).","journal-title":"Psychosom Med"},{"key":"9577_CR43","doi-asserted-by":"publisher","first-page":"145","DOI":"10.3233\/JAD-131238","volume":"39","author":"J Mehla","year":"2014","unstructured":"Mehla, J., Chauhan, B. C. & Chauhan, N. B. Experimental induction of type 2 diabetes in aging-accelerated mice triggered Alzheimer-like pathology and memory deficits. J Alzheimers Dis 39, 145\u2013162, doi:10.3233\/JAD-131238 (2014).","journal-title":"J Alzheimers Dis"},{"key":"9577_CR44","doi-asserted-by":"publisher","first-page":"1821","DOI":"10.1016\/j.neurobiolaging.2014.02.010","volume":"35","author":"EM Knight","year":"2014","unstructured":"Knight, E. M., Martins, I. V., Gumusgoz, S., Allan, S. M. & Lawrence, C. B. High-fat diet-induced memory impairment in triple-transgenic Alzheimer\u2019s disease (3xTgAD) mice is independent of changes in amyloid and tau pathology. Neurobiol Aging 35, 1821\u20131832, doi:10.1016\/j.neurobiolaging.2014.02.010 (2014).","journal-title":"Neurobiol Aging"},{"key":"9577_CR45","doi-asserted-by":"publisher","first-page":"7036","DOI":"10.1073\/pnas.1000645107","volume":"107","author":"S Takeda","year":"2010","unstructured":"Takeda, S. et al. Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes. Proc Natl Acad Sci USA 107, 7036\u20137041, doi:10.1073\/pnas.1000645107 (2010).","journal-title":"Proc Natl Acad Sci USA"},{"key":"9577_CR46","doi-asserted-by":"publisher","first-page":"451","DOI":"10.3233\/JAD-140972","volume":"43","author":"Y Wang","year":"2015","unstructured":"Wang, Y. et al. Synergistic exacerbation of mitochondrial and synaptic dysfunction and resultant learning and memory deficit in a mouse model of diabetic Alzheimer\u2019s disease. J Alzheimers Dis 43, 451\u2013463, doi:10.3233\/JAD-140972 (2015).","journal-title":"J Alzheimers Dis"},{"key":"9577_CR47","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1096\/fj.03-0978fje","volume":"18","author":"L Ho","year":"2004","unstructured":"Ho, L. et al. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer\u2019s disease. FASEB J 18, 902\u2013904, doi:10.1096\/fj.03-0978fje (2004).","journal-title":"FASEB J"},{"key":"9577_CR48","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.3233\/JAD-160110","volume":"52","author":"SM Hoscheidt","year":"2016","unstructured":"Hoscheidt, S. M. et al. Insulin Resistance is Associated with Increased Levels of Cerebrospinal Fluid Biomarkers of Alzheimer\u2019s Disease and Reduced Memory Function in At-Risk Healthy Middle-Aged Adults. J Alzheimers Dis 52, 1373\u20131383, doi:10.3233\/JAD-160110 (2016).","journal-title":"J Alzheimers Dis"},{"key":"9577_CR49","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X16663214","author":"SM Hoscheidt","year":"2016","unstructured":"Hoscheidt, S. M. et al. Insulin resistance is associated with lower arterial blood flow and reduced cortical perfusion in cognitively asymptomatic middle-aged adults. J Cereb Blood Flow Metab. doi:10.1177\/0271678X16663214 (2016).","journal-title":"J Cereb Blood Flow Metab"},{"key":"9577_CR50","doi-asserted-by":"publisher","first-page":"6820","DOI":"10.1073\/pnas.0900345106","volume":"106","author":"EM Reiman","year":"2009","unstructured":"Reiman, E. M. et al. Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer\u2019s disease. Proc Natl Acad Sci USA 106, 6820\u20136825, doi:10.1073\/pnas.0900345106 (2009).","journal-title":"Proc Natl Acad Sci USA"},{"key":"9577_CR51","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3002156","volume":"3","author":"JM Castellano","year":"2011","unstructured":"Castellano, J. M. et al. Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med 3, 89ra57, doi:10.1126\/scitranslmed.3002156 (2011).","journal-title":"Sci Transl Med"},{"key":"9577_CR52","doi-asserted-by":"publisher","first-page":"6771","DOI":"10.1523\/JNEUROSCI.0887-09.2009","volume":"29","author":"KR Bales","year":"2009","unstructured":"Bales, K. R. et al. Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice. J Neurosci 29, 6771\u20136779, doi:10.1523\/JNEUROSCI.0887-09.2009 (2009).","journal-title":"J Neurosci"},{"key":"9577_CR53","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1002\/ana.21843","volume":"67","author":"JC Morris","year":"2010","unstructured":"Morris, J. C. et al. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol 67, 122\u2013131, doi:10.1002\/ana.21843 (2010).","journal-title":"Ann Neurol"},{"key":"9577_CR54","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1016\/j.jalz.2012.07.004","volume":"9","author":"YY Lim","year":"2013","unstructured":"Lim, Y. Y. et al. Abeta amyloid, cognition, and APOE genotype in healthy older adults. Alzheimer\u2019s & dementia: the journal of the Alzheimer\u2019s Association 9, 538\u2013545, doi:10.1016\/j.jalz.2012.07.004 (2013).","journal-title":"Alzheimer\u2019s & dementia: the journal of the Alzheimer\u2019s Association"},{"key":"9577_CR55","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1016\/j.neurobiolaging.2014.12.008","volume":"36","author":"YY Lim","year":"2015","unstructured":"Lim, Y. Y. et al. APOE epsilon4 moderates amyloid-related memory decline in preclinical Alzheimer\u2019s disease. Neurobiol Aging 36, 1239\u20131244, doi:10.1016\/j.neurobiolaging.2014.12.008 (2015).","journal-title":"Neurobiol Aging"},{"key":"9577_CR56","doi-asserted-by":"crossref","first-page":"23403","DOI":"10.1016\/S0021-9258(17)31529-6","volume":"269","author":"MJ LaDu","year":"1994","unstructured":"LaDu, M. J. et al. Isoform-specific binding of apolipoprotein E to beta-amyloid. J Biol Chem 269, 23403\u201323406 (1994).","journal-title":"J Biol Chem"},{"key":"9577_CR57","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1016\/S0306-4522(98)00561-2","volume":"90","author":"DS Yang","year":"1999","unstructured":"Yang, D. S. et al. Apolipoprotein E promotes the binding and uptake of beta-amyloid into Chinese hamster ovary cells in an isoform-specific manner. Neuroscience 90, 1217\u20131226 (1999).","journal-title":"Neuroscience"},{"key":"9577_CR58","doi-asserted-by":"publisher","first-page":"303","DOI":"10.3233\/JAD-2005-7406","volume":"7","author":"E Hone","year":"2005","unstructured":"Hone, E. et al. Alzheimer\u2019s disease amyloid-beta peptide modulates apolipoprotein E isoform specific receptor binding. J Alzheimers Dis 7, 303\u2013314 (2005).","journal-title":"J Alzheimers Dis"},{"key":"9577_CR59","doi-asserted-by":"publisher","first-page":"4002","DOI":"10.1172\/JCI36663","volume":"118","author":"R Deane","year":"2008","unstructured":"Deane, R. et al. apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest 118, 4002\u20134013, doi:10.1172\/JCI36663 (2008).","journal-title":"J Clin Invest"},{"key":"9577_CR60","doi-asserted-by":"publisher","first-page":"403","DOI":"10.3233\/JAD-2010-100141","volume":"21","author":"MJ Sharman","year":"2010","unstructured":"Sharman, M. J. et al. APOE genotype results in differential effects on the peripheral clearance of amyloid-beta42 in APOE knock-in and knock-out mice. J Alzheimers Dis 21, 403\u2013409, doi:10.3233\/JAD-2010-100141 (2010).","journal-title":"J Alzheimers Dis"},{"key":"9577_CR61","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1111\/j.1471-4159.2004.02581.x","volume":"90","author":"MC Irizarry","year":"2004","unstructured":"Irizarry, M. C. et al. Apolipoprotein E modulates gamma-secretase cleavage of the amyloid precursor protein. J Neurochem 90, 1132\u20131143, doi:10.1111\/j.1471-4159.2004.02581.x (2004).","journal-title":"J Neurochem"},{"key":"9577_CR62","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1007\/s004380100473","volume":"265","author":"S Hass","year":"2001","unstructured":"Hass, S., Weidemann, A., Utermann, G. & Baier, G. Intracellular apolipoprotein E affects Amyloid Precursor Protein processing and amyloid Abeta production in COS-1 cells. Mol Genet Genomics 265, 791\u2013800 (2001).","journal-title":"Mol Genet Genomics"},{"key":"9577_CR63","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1016\/j.cmet.2015.08.016","volume":"22","author":"M Ishii","year":"2015","unstructured":"Ishii, M. & Iadecola, C. Metabolic and Non-Cognitive Manifestations of Alzheimer\u2019s Disease: The Hypothalamus as Both Culprit and Target of Pathology. Cell Metab 22, 761\u2013776, doi:10.1016\/j.cmet.2015.08.016 (2015).","journal-title":"Cell Metab"},{"key":"9577_CR64","doi-asserted-by":"publisher","unstructured":"Bharadwaj, P. et al. The Link between Type 2 Diabetes and Neurodegeneration: Roles for Amyloid-beta, Amylin, and Tau Proteins. J Alzheimers Dis, doi:10.3233\/JAD-161192 (2017).","DOI":"10.3233\/JAD-161192"},{"key":"9577_CR65","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1002\/ana.10669","volume":"54","author":"PJ Nestor","year":"2003","unstructured":"Nestor, P. J., Fryer, T. D., Smielewski, P. & Hodges, J. R. Limbic hypometabolism in Alzheimer\u2019s disease and mild cognitive impairment. Ann Neurol 54, 343\u2013351, doi:10.1002\/ana.10669 (2003).","journal-title":"Ann Neurol"},{"key":"9577_CR66","doi-asserted-by":"publisher","first-page":"1278","DOI":"10.2967\/jnumed.112.116558","volume":"54","author":"DJ Cross","year":"2013","unstructured":"Cross, D. J. et al. Loss of olfactory tract integrity affects cortical metabolism in the brain and olfactory regions in aging and mild cognitive impairment. J Nucl Med 54, 1278\u20131284, doi:10.2967\/jnumed.112.116558 (2013).","journal-title":"J Nucl Med"},{"key":"9577_CR67","unstructured":"Macesic, M. et al. Impaired Insulin Sensitivity And Secretion In Patients With Alzheimer\u2019s Disease: The Relationship With Other Atherosclerosis Risk Factors. Curr Vasc Pharmacol (2016)."},{"key":"9577_CR68","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1017\/S1041610209009405","volume":"21","author":"KA Ellis","year":"2009","unstructured":"Ellis, K. A. et al. The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging: methodology and baseline characteristics of 1112 individuals recruited for a longitudinal study of Alzheimer\u2019s disease. Int Psychogeriatr 21, 672\u2013687, doi:10.1017\/S1041610209009405 (2009).","journal-title":"Int Psychogeriatr"},{"key":"9577_CR69","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.3233\/JAD-143015","volume":"46","author":"SC Burnham","year":"2015","unstructured":"Burnham, S. C. et al. Novel Statistically-Derived Composite Measures for Assessing the Efficacy of Disease-Modifying Therapies in Prodromal Alzheimer\u2019s Disease Trials: An AIBL Study. J Alzheimers Dis 46, 1079\u20131089, doi:10.3233\/JAD-143015 (2015).","journal-title":"J Alzheimers Dis"},{"key":"9577_CR70","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.2337\/diacare.27.6.1487","volume":"27","author":"TM Wallace","year":"2004","unstructured":"Wallace, T. M., Levy, J. C. & Matthews, D. R. Use and abuse of HOMA modeling. Diabetes Care 27, 1487\u20131495 (2004).","journal-title":"Diabetes Care"},{"key":"9577_CR71","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1007\/BF00280883","volume":"28","author":"DR Matthews","year":"1985","unstructured":"Matthews, D. R. et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412\u2013419 (1985).","journal-title":"Diabetologia"},{"key":"9577_CR72","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.2337\/diacare.21.12.2191","volume":"21","author":"JC Levy","year":"1998","unstructured":"Levy, J. C., Matthews, D. R. & Hermans, M. P. Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care 21, 2191\u20132192 (1998).","journal-title":"Diabetes Care"},{"key":"9577_CR73","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1212\/WNL.0000000000000867","volume":"83","author":"BM Brown","year":"2014","unstructured":"Brown, B. M. et al. Influence of BDNF Val66Met on the relationship between physical activity and brain volume. Neurology 83, 1345\u20131352, doi:10.1212\/WNL.0000000000000867 (2014).","journal-title":"Neurology"},{"key":"9577_CR74","doi-asserted-by":"publisher","first-page":"175","DOI":"10.3233\/JAD-150247","volume":"48","author":"QX Li","year":"2015","unstructured":"Li, Q. X. et al. Alzheimer\u2019s Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-beta Characterized Subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. J Alzheimers Dis 48, 175\u2013187, doi:10.3233\/JAD-150247 (2015).","journal-title":"J Alzheimers Dis"},{"key":"9577_CR75","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.jalz.2011.07.004","volume":"8","author":"H Vanderstichele","year":"2012","unstructured":"Vanderstichele, H. et al. Standardization of preanalytical aspects of cerebrospinal fluid biomarker testing for Alzheimer\u2019s disease diagnosis: a consensus paper from the Alzheimer\u2019s Biomarkers Standardization Initiative. Alzheimers Dement 8, 65\u201373, doi:10.1016\/j.jalz.2011.07.004 (2012).","journal-title":"Alzheimers Dement"},{"key":"9577_CR76","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1016\/j.neurobiolaging.2010.04.007","volume":"31","author":"CC Rowe","year":"2010","unstructured":"Rowe, C. C. et al. Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol Aging 31, 1275\u20131283, doi:10.1016\/j.neurobiolaging.2010.04.007 (2010).","journal-title":"Neurobiol Aging"},{"key":"9577_CR77","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1001\/jama.2010.2008","volume":"305","author":"CM Clark","year":"2011","unstructured":"Clark, C. M. et al. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 305, 275\u2013283, doi:10.1001\/jama.2010.2008 (2011).","journal-title":"JAMA"},{"key":"9577_CR78","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1002\/ana.22068","volume":"68","author":"R Vandenberghe","year":"2010","unstructured":"Vandenberghe, R. et al. 18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trial. Ann Neurol 68, 319\u2013329, doi:10.1002\/ana.22068 (2010).","journal-title":"Ann Neurol"},{"issue":"Suppl 1","key":"9577_CR79","doi-asserted-by":"publisher","first-page":"S159","DOI":"10.1016\/j.neurobiolaging.2014.04.033","volume":"36","author":"P Bourgeat","year":"2015","unstructured":"Bourgeat, P. et al. Comparison of MR-less PiB SUVR quantification methods. Neurobiol Aging 36(Suppl 1), S159\u2013166, doi:10.1016\/j.neurobiolaging.2014.04.033 (2015).","journal-title":"Neurobiol Aging"},{"key":"9577_CR80","doi-asserted-by":"publisher","first-page":"723","DOI":"10.9734\/AIR\/2014\/11599","volume":"2","author":"V Villemagne","year":"2014","unstructured":"Villemagne, V. et al. En Attendant Centiloid. Advances in Research 2, 723\u2013729 (2014).","journal-title":"Advances in Research"},{"key":"9577_CR81","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1212\/WNL.0b013e3181c918b5","volume":"74","author":"P Bourgeat","year":"2010","unstructured":"Bourgeat, P. et al. Beta-amyloid burden in the temporal neocortex is related to hippocampal atrophy in elderly subjects without dementia. Neurology 74, 121\u2013127, doi:10.1212\/WNL.0b013e3181c918b5 (2010).","journal-title":"Neurology"},{"key":"9577_CR82","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1001\/jamaneurol.2013.1062","volume":"70","author":"V Dore","year":"2013","unstructured":"Dore, V. et al. Cross-sectional and longitudinal analysis of the relationship between Abeta deposition, cortical thickness, and memory in cognitively unimpaired individuals and in Alzheimer disease. JAMA Neurol 70, 903\u2013911, doi:10.1001\/jamaneurol.2013.1062 (2013).","journal-title":"JAMA Neurol"},{"key":"9577_CR83","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/j.2517-6161.1964.tb00553.x","volume":"26","author":"GEP Box","year":"1964","unstructured":"Box, G. E. P. & Cox, D. R. An Analysis of Transformations. J Roy Stat Soc B 26, 211\u2013252 (1964).","journal-title":"J Roy Stat Soc B"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-09577-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-09577-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-09577-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T12:29:09Z","timestamp":1719404949000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-09577-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,29]]},"references-count":83,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["9577"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-09577-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,29]]},"assertion":[{"value":"4 April 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 July 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 August 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"CLM is an advisor to Prana Biotechnology Ltd and a consultant to Eli Lilly. PM is a full-time employee of Cogstate Ltd. DA has served on scientific advisory boards for Novartis, Eli Lilly, Janssen, and Pfizer Inc. RNM is a consultant to Alzhyme. SML has previously been a paid consultant to Alzhyme. CCR has served on scientific advisory boards for Bayer Pharma, Elan Corporation, GE Healthcare and AstraZeneca; has received speaker honoraria from Bayer Pharma and GE Healthcare; and has received research support from Bayer Pharma, GE Healthcare, Piramal Lifesciences and Avid Radiopharmaceuticals. VLV served as a consultant for Bayer Pharma; and received research support from a NEDO grant from Japan. All other authors have nothing to disclose.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"9766"}}