Search

Abstract INTRODUCTION Brain insulin resistance and deficiency is a consistent feature of Alzheimer's disease (AD). Insulin resistance can be mediated by the surface expression of the insulin receptor (IR). Cleavage of the IR generates the soluble IR (sIR). METHODS We measured the levels of sIR present in cerebrospinal fluid (CSF) from individuals along the AD diagnostic spectrum from two cohorts: Seattle (n = 58) and the Consortium for the Early Identification of Alzheimer's Disease‐Quebec (CIMA‐Q; n = 61). We further investigated the brain cellular contribution for sIR using human cell lines. RESULTS CSF sIR levels were not statistically different in AD. CSF sIR and amyloid beta (Aβ)42 and Aβ40 levels significantly correlated as well as CSF sIR and cognition in the CIMA‐Q cohort. Human neurons expressing the amyloid precursor protein “Swedish” mutation generated significantly greater sIR and human astrocytes were also able to release sIR in response to both an inflammatory and insulin stimulus. DISCUSSION These data support further investigation into the generation and role of sIR in AD. Highlights Cerebrospinal fluid (CSF) soluble insulin receptor (sIR) levels positively correlate with amyloid beta (Aβ)42 and Aβ40. CSF sIR levels negatively correlate with cognitive performance (Montreal Cognitive Assessment score). CSF sIR levels in humans remain similar across Alzheimer's disease diagnostic groups. Neurons derived from humans with the “Swedish” mutation in which Aβ42 is increased generate increased levels of sIR. Human astrocytes can also produce sIR and generation is stimulated by tumor necrosis factor α and insulin.

Brain glucose hypometabolism is an early sign of Alzheimer’s disease (AD), and interventions which offset this deficit, such as ketogenic diets, show promise as AD therapeutics. Conversely, high-fat feeding may exacerbate AD risk. We analyzed the metabolomic profile of cerebrospinal fluid (CSF) in a pilot study of older adults who underwent saline and triglyceride (TG) infusions. Older adults (12 cognitively normal (CN), age 65.3 ± 8.1, and 9 with cognitive impairment (CI), age 70.9 ± 8.6) underwent a 5 h TG or saline infusion on different days using a random crossover design; CSF was collected at the end of infusion. Aqueous metabolites were measured using a targeted mass spectroscopy (MS) platform focusing on 215 metabolites from over 35 different metabolic pathways. Data were analyzed using MetaboAnalyst 4.0 and SAS. Of the 215 targeted metabolites, 99 were detectable in CSF. Only one metabolite significantly differed by treatment: the ketone body 3-hydroxybutyrate (HBA). Post hoc analyses showed that HBA levels were associated with age and markers of metabolic syndrome and demonstrated different correlation patterns for the two treatments. When analyzed by cognitive diagnosis group, TG-induced increases in HBA were over 3 times higher for those with cognitive impairment (change score CN +9.8 uM ± 8.3, CI +32.4 ± 7.4, p = 0.0191). Interestingly, individuals with cognitive impairment had higher HBA levels after TG infusion than those with normal cognition. These results suggest that interventions that increase plasma ketones may lead to higher brain ketones in groups at risk for AD and should be confirmed in larger intervention studies.