The influence of insulin resistance on cerebrospinal fluid and plasma biomarkers of Alzheimer’s pathology

Abstract

BackgroundInsulin resistance (IR) has previously been associated with an increased risk of developing Alzheimer’s disease (AD), although the relationship between IR and AD is not yet clear. Here, we examined the influence of IR on AD using plasma and cerebrospinal fluid (CSF) biomarkers related to IR and AD in cognitively healthy men. We also aimed to characterise the shared protein signatures between IR and AD.MethodsFifty-eight cognitively healthy men, 28 IR and 30 non-IR (age and APOE ε4 matched), were drawn from the Metabolic Syndrome in Men study in Kuopio, Finland. CSF AD biomarkers (amyloid β-peptide (Aβ), total tau and tau phosphorylated at the Thr181 epitope) were examined with respect to IR. Targeted proteomics using ELISA and Luminex xMAP assays were performed to assess the influence of IR on previously identified CSF and plasma protein biomarker candidates of AD pathology. Furthermore, CSF and plasma SOMAscan was performed to discover proteins that associate with IR and CSF AD biomarkers.ResultsCSF AD biomarkers did not differ between IR and non-IR groups, although plasma insulin correlated with CSF Aβ/tau across the whole cohort. In total, 200 CSF and 487 plasma proteins were differentially expressed between IR and non-IR subjects, and significantly enriched pathways, many of which have been previously implicated in AD, were identified. CSF and plasma proteins significantly associated with CSF AD biomarkers were also discovered, and those sensitive to both IR and AD were identified.ConclusionsThese data indicate that IR is not directly related to the level of CSF AD pathology in cognitively healthy men. Proteins that associated with both AD and IR are potential markers indicative of shared pathology.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-017-0258-6) contains supplementary material, which is available to authorized users.

Changes in Cerebrospinal Fluid Tau and β-Amyloid Levels in Diabetic and Prediabetic Patients: A Meta-Analysis

“…Tables 1 , 2 summarize the 7 studies included in this meta-analysis (Xijiu, 2005 ; Lu et al, 2011 ; Morris et al, 2014 ; Ouwens et al, 2014 ; Moran et al, 2015 ; Westwood et al, 2017 ; Li et al, 2018 ). All of these studies were identified to be of high or fair quality by using the Newcastle–Ottawa scale (Table 1 ).…”

“…Moreover, the risk of AD has also been shown to be increased in prediabetes individuals with high fasting glucose and/or impaired glucose tolerance due to IR and simultaneous exposure to abnormally high levels of insulin persisting for extended periods of time (hyperinsulinemia) (Roriz-Filhom et al, 2009 ). The IR and hyperinsulinemia are also reported to be linked with the pathological features of AD (Luchsinger et al, 2004 ; Westwood et al, 2017 ).…”

Review: Relationship of type 2 diabetes to human brain pathology

“…Main effects of HOMA‐IR on both tau and amyloid‐beta 42 (Aβ42) were not significant, nor were interactions of HOMA‐IR with APOE ε4 on Aβ42 cerebral spinal fluid (CSF) levels . Results overall for CSF biomarkers are mixed, especially with regard to tau with some studies finding an association with HOMA‐IR and increased tau while others did not . Higher HOMA‐IR is also associated with lower glucose metabolism on FDG‐PET in several brain regions, with the strongest association demonstrated in the left medial temporal lobe .…”

SCGN Administration prevents Insulin Resistance and Diabetic Complications in High-Fat Diet Fed Animals

“…Based on the available information and its logical acquaintance with SCGN function, we predicted the involvement of SCGN in the regulation of obesity and insulin resistance. Association of SCGN with body-weight QTC (14), downregulation of SCGN in HFD fed animals (7) and reduced CSF SCGN concentration in the insulin resistant subjects (15) offer confidence to our rationalized assumption. The development of glucose intolerance at an early life-stage and age associated progressive hyperglycemia in SCGN knockout mice further suggest a confounding role of SCGN in preserving euglycemia (16).…”