Insulin resistance is associated with reductions in specific cognitive domains and increases in CSF tau in cognitively normal adults

Simon M Laws,Vincent Doré,Scott Gaskin,Samantha Burnham,Tenielle Porter,Qiao‐Xin Li ,Olivier Salvado,Velandai Srikanth,Victor L Villemagne,Philip Newsholme,Paul E Fraser,Colin L Masters,Nadeeja Wijesekara,Ralph N Martins,Paul Maruff,Amy Woodfield,Christopher C Rowe,David Bruce,Giuseppe Verdile

doi:10.1038/s41598-017-09577-4

Abstract

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’s 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 β-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 Aβ42, T-tau/P-tau, hippocampal volume and neocortical Aβ-amyloid burden). We reveal that HOMA-IR (p < 0.001) 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 = 0.010), executive function (p = 0.046) and global cognition (p = 0.007), as well as with higher CSF T-tau (p = 0.008) and P-tau (p = 0.014) levels. No association was observed with CSF Aβ 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.

Highlights

Epidemiological studies indicate that Type 2 diabetes (T2D) is associated with an increased risk of dementia[1,2,3,4,5]
A significant difference in age and frequency of the Apolipoprotein E (APOE) ε4 allele was observed across all diagnostic groups (Table 1), with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) being older and having a significantly higher APOE ε4 frequency compared to cognitively normal (CN) (p < 0.001)
Serum glucose levels were increased significantly in AD and MCI compared with CN (p = 0.014) (AD > MCI > CN), and a non-significant trend was observed for serum insulin HOMA-insulin resistance (IR), but not for HOMA-B (Table 1)

Summary

Introduction

Epidemiological studies indicate that Type 2 diabetes (T2D) is associated with an increased risk of dementia[1,2,3,4,5]. In AD, PET studies of cerebral glucose metabolism (18F-deoxyglucose PET: FDG-PET) and Aβ deposition (e.g. C11-Pittsburg compound B-PET: PiB-PET) show that reduced neuronal glucose metabolism and increased levels of neocortical Aβ accumulation are features that occur early in the disease In the Baltimore, longitudinal study of Ageing (BLSA), no association was observed between measures of peripheral IR or glucose tolerance and neocortical Aβ load (in a PiB-PET scanned cohort) or other pathological features of AD in post-mortem brain[17]. More recently in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study, no association was shown betweenT2D and accumulation of neocortical Aβ load (PiB-PET) or increases in CSF Aβ4210. The relationship between IR and clinical and pathological features of the early stages of AD, and sex specific effects, requires further study, in normoglycaemic individuals and prior to the onset of cognitive impairment

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