Diabetes Care Volume 40, June 2017 751 Laura L. Ekblad,1 Juha O. Rinne,1,2 Insulin Resistance Predicts Pauli Puukka,3 Hanna Laine,4,5 Satu Ahtiluoto,6 Raimo Sulkava,6 Cognitive Decline: An 11-Year Matti Viitanen,4,7 and Antti Jula3 Follow-up of a Nationally Representative Adult Population Sample Diabetes Care 2017;40:751–758 | https://doi.org/10.2337/dc16-2001 EPIDEMIOLOGY/HEALTH SERVICES RESEARCH OBJECTIVE The aim of this study was to examine whether insulin resistance, assessed by HOMA of insulin resistance (HOMA-IR), is an independent predictor of cognitive decline. RESEARCH DESIGN AND METHODS The roles of HOMA-IR, fasting insulin and glucose, HbA1c, and hs-CRP as predictors of cognitive performance and its change were evaluated in the Finnish nationwide, population-based Health 2000 Health Examination Survey and its 11-year follow- up, the Health 2011 study (n = 3,695, mean age at baseline 49.3 years, 55.5% women). fl Categorical verbal uency, word-list learning, and word-list delayed recall were used 1Turku PET Centre, University of Turku, Turku, as measures of cognitive function. Multivariate linear regression analysis was per- Finland formed and adjusted for previously reported risk factors for cognitive decline. 2Division of Clinical Neurosciences, Turku Uni- versity Hospital, Turku, Finland RESULTS 3National Institute for Health and Welfare, Turku, Finland Higher baseline HOMA-IR and fasting insulin levels were independent predictors of 4Turku City Hospital, University of Turku, Turku, poorer verbal fluency performance (P = 0.0002 for both) and of a greater decline in Finland verbal fluency during the follow-up time (P = 0.004 for both). Baseline HOMA-IR and 5Department of Medicine, Turku University Hos- pital, University of Turku, Turku, Finland insulin did not predict word-list learning or word-list delayed recall scores. There 6 « APOE34 University of Eastern Finland, Kuopio, Finland were no interactions between HOMA-IR and apolipoprotein E 4( ) genotype, 7Clinical Geriatrics, Karolinska Institutet, Karo- hs-CRP, or type 2 diabetes on the cognitive tests. Fasting glucose and hs-CRP levels at linska University Hospital, Huddinge, Sweden baseline were not associated with cognitive functioning. Corresponding author: Laura L. Ekblad, llekbl@ utu.fi. CONCLUSIONS Received 17 September 2016 and accepted 8 Our results show that higher serum fasting insulin and insulin resistance predict March 2017. poorer verbal fluency and a steeper decline in verbal fluency during 11 years in a This article contains Supplementary Data online representative sample of an adult population. Prevention and treatment of insulin at http://care.diabetesjournals.org/lookup/ resistance might help reduce cognitive decline later in life. suppl/doi:10.2337/dc16-2001/-/DC1. This article is featured in a podcast available at http://www.diabetesjournals.org/content/ Alzheimer disease, the most common type of dementia, has become a major public diabetes-core-update-podcasts. health concern in recent years. Targeting modifiable risk factors for cognitive decline in © 2017 by the American Diabetes Association. midlife could delay the onset of Alzheimer disease and thus help reduce the economic Readers may use this article as long as the work is properly cited, the use is educational and not burden associated especially with the late stages of the disease (1). Diabetes is an for profit, and the work is not altered. More infor- acknowledged risk factor for Alzheimer disease and cognitive impairment (2–4). A re- mation is available at http://www.diabetesjournals cent review concluded that individuals with diabetes typically perform 0.3–0.5 SD units .org/content/license. 752 Insulin Resistance and Cognitive Decline Diabetes Care Volume 40, June 2017 lower on cognitive tests across all age- associated with the metabolic syndrome hs-CRP values .10 mg/L in 2000 (n = groups compared with the general popula- (20), which is why we hypothesized that 105) were excluded to eliminate the con- tion. The mechanisms underlying these even the association of IR and cognition founding effects of an infectious disease. subtle cognitive decrements, however, are could be modified by inflammation grade. The mean age in 2000 was 49.3 years not yet well established. These decrements To test these hypotheses, we studied (range 30–86), and 55.5% were women. most likely do not indicate early stages of 3,695 individuals who participated in dementia, but it is possible that they lower the Finnish population-based Health Measurements the threshold for developing clinical symp- 2000 and Health 2011 studies. Blood pressure was measured at baseline toms of dementia later in life (5). in a sitting position from the right arm Insulin resistance (IR) is closely associ- RESEARCH DESIGN AND METHODS with a standard mercury manometer ated with obesity, chronic low-grade in- Study Population (Mercuro 300; Speidel & Keller, Jungin- flammation, and low levels of physical The data for this study were acquired from gen, Germany), and the average of two activity and it can be seen as the hallmark the Health 2000 Health Examination Sur- measurements was used for the analyses. of the metabolic syndrome and type 2 di- vey and its 11-year follow-up survey, Baseline fasting blood samples were abetes (DM2) (6). Epidemiological studies Health 2011. The surveys were conducted drawn, the duration of fasting time was have shown that the metabolic syndrome by the Finnish National Institute for recorded, and the samples were stored in midlife increases the risk for cognitive Health and Welfare in 2000–2001 and at 270°C until analyzed. decline (7,8). Recent evidence suggests 2011 (21,22). The Health 2000 survey Serum cholesterol, HDL cholesterol, tri- that brain IR could be an important trig- was a nationwide, comprehensive, popu- glycerides, glucose, hs-CRP, and insulin gering factor in the development of Alz- lation-based examination survey repre- values were determined from the frozen heimer disease neuropathology (9) and sentative of the Finnish adult population. samples. Cholesterol values were deter- possibly a key link between the metabolic A total of 8,028 individuals aged 30 years mined by a CHOD PAP test (Olympus syndrome and cognitive decline (10). or older were randomly selected from the System Reagent; OLYMPUS, Hamburg, Treatment with intranasally administered Finnish population register from 80 health Germany), HDL cholesterol values by a insulin has been shown to improve mem- service districts throughout Finland HDL-C Plus test (Roche Diagnostics, ory in patients with Alzheimer disease and using a two-stage stratified cluster sam- Mannheim, Germany), triglycerides by a mild cognitive impairment (11). Previous pling procedure. Of the study population, GPO PAP test (Olympus System Reagent), studies indicate that the response to in- 84% (n = 6,770) attended the health ex- and glucose values by a hexokinase test tranasal insulin varies according to the amination proper or the health examina- (Olympus System Reagent). Serum insulin patients’ sex and APOE«4 genotype (12). tion at home (21). was determined by a microparticle en- There are a number of cross-sectional In 2011 all the individuals alive who zyme immunoassay (Abbott Laboratories studies linking IR with poorer cognitive belonged to the Health 2000 study sam- Dainabot, Tokyo, Japan). HbA1c was de- performance (13–17). Only two previous ple, who still lived in Finland and who had termined with an immunoturbidimetric longitudinal studies, to our knowledge, not refused to participate in the upcom- method (Hemoglobin A1c assay; Abbott examined the effects of insulin or IR on ing follow-up studies, were invited to the Laboratories). Serum hs-CRP was ana- cognitive decline over time. A study on Health 2011 study (22). lyzed by an automated analyzer (Optima; 999 men showed that higher insulin levels Both studies were approved by the Thermo Electron Oy, Vantaa, Finland) and at age 50 years predicted lower cognitive Ethics Committee for Epidemiology and an ultrasensitive immunoturbidimetric test scores 20 years later (18). The Ath- Public Health in the hospital district of test (Ultrasensitive CRP; Orion Diagnos- erosclerosis Risk in Communities (ARIC) Helsinki and Uusimaa, Finland. All partic- tica, Espoo, Finland). The detection limit cohort study (19) examined 7,148 individ- ipants gave written informed consent for for quantitation of the CRP assay was uals at baseline for fasting insulin and participating in the studies. 0.20 mg/L (23). Those who fell below HOMA-IR. Cognitive performance was Altogether, 3,695 individuals who had this limit were given the value 0.2 mg/L evaluated 3 and 9 years after baseline. attended the health examination proper divided by 2 = 0.1 mg/L. Non-HDL choles- The study concluded that both fasting in- in 2000 (n = 6,354) and who attended the terol was counted as total cholesterol sulin and HOMA-IR were associated with health examination or the home health minus HDL cholesterol. HOMA-IR was poorer cognition 3 years after baseline examination in 2011 and thus had been used as a measure of IR and counted by and with a decline in cognitive test scores tested for cognition on both occasions the equation fasting insulin (mU/mL) during the 6-year follow-up for cognitive were included in this study. Participants times fasting glucose (mmol/L) divided functioning. who, at baseline, had fasted for ,4h(n = by 22.5 as previously described (24). The aim of this study was to assess 226); who had insulin treatment or un- whether IR is a risk factor for cognitive known diabetes medication (n = 59); and Cognitive Tests decline during 11 years. We hypothe- who had not completed the cognitive The participants were tested at baseline sizedthatIR,estimatedwithHOMA-IR, tests (n = 127) or had missing HOMA-IR and at follow-up for verbal fluency and is an independent risk factor for cogni- values (n =4)wereexcluded.Atotalof encoding and retaining verbal material tive decline and that, based on previous 789 individuals had died or were lost to according to the Finnish version of the studies, APOE«4 genotype (12,15) and sex follow-up.