Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer’s Disease

Abstract

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.

Cachexia and advanced dementia

“…Accordingly, patients with AD were found to have lower cerebrospinal fluid insulin levels. 54,55 Type 2 diabetes is also associated with cognitive impairment, but as mentioned previously, it is characterized by hyperinsulinaemia and IR. Insulin is neurotrophic at moderate concentrations.…”

“…Insulin is able to cross the blood–brain barrier and exerts its effects by binding to a specific receptor, which is distributed throughout the brain (mainly in the hippocampus and the cortex), and although its role in the brain is not fully understood, insulin is known to be not only a regulator of energy homoeostasis and food intake but also a modulator of brain activities such as learning and memory, mainly through its influence upon the release and reuptake of other neurotransmitters. Accordingly, patients with AD were found to have lower cerebrospinal fluid insulin levels …”

Cognitive dysfunction: A growing link between diabetes and Alzheimer's disease

“…A positive correlation between higher levels of insulin in cerebrospinal fluid and cognitive impairment was observed in patients having cognitive impairment (Geijselaers et al, 2018). Insulin resistance was found to be associated with poor cognition in people aged more than 60 years (Sherzai, Shaheen, Jeffrey, Talbot, & Sherzai, 2018).…”

“…A connection between insulin signaling and the cognitive deficit was reflected when the levels of insulin receptor substrate (IRS‐1) and insulin‐like growth factor (IGF‐1) were altered with comorbid Aβ toxicity and ischemic rat model (Amtul, Hill, Arany, & Cechetto, ). A positive correlation between higher levels of insulin in cerebrospinal fluid and cognitive impairment was observed in patients having cognitive impairment (Geijselaers et al, ). Insulin resistance was found to be associated with poor cognition in people aged more than 60 years (Sherzai, Shaheen, Jeffrey, Talbot, & Sherzai, ).…”

Insulin resistance and impaired lipid metabolism as a potential link between diabetes and Alzheimer's disease

“…Injection of insulin into the vena cava activates brain insulin signaling, and this is lost with knockout of the IR (Bruning et al, 2000). While insulin is synthesized outside of the central nervous system (CNS) in the pancreatic β cells, it is readily measured in the CSF (Geijselaers et al, 2018). There is some evidence that small amounts of insulin may be synthesized locally in the brain, however, the physiologic consequence of this remains unclear (Devaskar et al, 1994;Devaskar, Singh, Carnaghi, Rajakumar, & Giddings, 1993).…”