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Background: Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD)., Objective: To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype., Methods: From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42, total (t-)Tau, and phosphorylated (p-)Tau., Results: CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient -0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029)., Conclusion: Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin.

Objective: To study to what extent differences in cognitive performance between individuals with different glucose metabolism status are potentially attributable to hyperglycemia, insulin resistance, and blood pressure-related variables., Research Design and Methods: We used cross-sectional data from 2,531 participants from the Maastricht Study (mean age ± SD, 60 ± 8 years; 52% men; n = 666 with type 2 diabetes), all of whom completed a neuropsychological test battery. Hyperglycemia was assessed by a composite index of fasting glucose, postload glucose, glycated hemoglobin (HbA 1c ), and tissue advanced glycation end products; insulin resistance by the HOMA of insulin resistance index; and blood pressure-related variables included 24-h ambulatory pressures, their weighted SDs, and the use of antihypertensive medication. Linear regression analyses were used to estimate mediating effects., Results: After adjustment for age, sex, and education, individuals with type 2 diabetes, compared with those with normal glucose metabolism, performed worse in all cognitive domains (mean differences in composite z scores for memory -0.087, processing speed -0.196, executive function and attention -0.182; P values <0.032), whereas individuals with prediabetes did not. Diabetes-associated differences in processing speed and executive function and attention were largely explained by hyperglycemia (mediating effect 79.6% [bootstrapped 95% CI 36.6; 123.4] and 50.3% [0.6; 101.2], respectively) and, for processing speed, to a lesser extent by blood pressure-related variables (17.7% [5.6; 30.1]), but not by insulin resistance. None of the factors explained the differences in memory function., Conclusions: Our cross-sectional data suggest that early glycemic and blood pressure control, perhaps even in the prediabetic stage, may be promising therapeutic targets for the prevention of diabetes-associated decrements in cognitive performance., (© 2017 by the American Diabetes Association.)

Aims: Type 2 diabetes, hyperinsulinemia, and insulin resistance are associated with cognitive impairment. Experimental studies indicate that insulin signaling in the brain is related to cognitive performance. Here we evaluated whether insulin-related variables contribute to the variance in cognitive performance among individuals with type 2 diabetes., Methods: A total of 806 individuals with type 2 diabetes (mean age 62±8years, HbA1c 6.9±1.1%) completed a neuropsychological test battery. Insulin-related variables evaluated were: fasting plasma insulin, C-peptide, and the Homeostasis Model Assessment (HOMA2-IR; in individuals without insulin treatment; n=641). The unadjusted coefficient of determination (R 2 ), obtained from multiple linear regression analyses, was used to estimate the proportion of variance in cognition explained by insulin-related variables., Results: Sex, age, and educational level together explained 18.0% (R 2 ) of the variance in memory function, 26.5% in information processing speed, and 22.8% in executive function and attention. Fasting insulin, C-peptide, or HOMA2-IR did not increase the explained variance (maximum ΔR 2 0.3%, P≥0.14). Similar results were obtained when insulin-related variables were added to models that additionally included glycemic control, cardiovascular risk factors, and depression., Conclusions: Our results show that measures of peripheral insulin resistance are unrelated to cognitive performance among individuals with adequately controlled type 2 diabetes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Type 2 diabetes is associated with cognitive dysfunction and structural brain changes. Abnormalities in glucose regulation are involved in several complications related to type 2 diabetes, but their role in these cerebral complications is unclear. We systematically reviewed studies of the association between glucose regulation (glycaemia, hypoglycaemic events, insulin concentration, insulin resistance, and glucose-lowering treatment) and cognitive function and brain abnormalities on MRI in people with type 2 diabetes. The 86 papers included showed that glycaemia, particularly high HbA1c concentration and glucose variability, are negatively associated with cognitive function in people with type 2 diabetes without dementia. However, the strength of this association is weak, and HbA1c generally accounted for less than 10% of the variance in cognition. Importantly, few studies have measured long-term cerebral outcomes, such as dementia and structural brain changes on MRI, and the effect of glucose-lowering treatment on these outcomes. More randomised controlled trials are needed to establish the effect of glucose-lowering treatment on long-term cognitive function in people with type 2 diabetes., (Copyright © 2015 Elsevier Ltd. All rights reserved.)