Insulin-Degrading Enzyme : A link between insulin resistance and Alzheimer's disease

Sammanfattning: Background: Prior research has demonstrated an elevated risk of Alzheimer's disease (AD) among individuals diagnosed with type 2 diabetes mellitus (T2DM). Insulin resistance is a potential common link between these conditions, and it is associated with AD due to the insulin-degrading enzyme (IDE), which also degrades amyloid-β (Aβ) in the brain. It has been suggested that high insulin levels may hinder IDE's effective degradation of Aβ, contributing to plaque formation. IDE is measurable in blood and is a promising biomarker for AD risk assessment and diagnosis. IDE has been demonstrated to decrease in blood from patients with cognitive impairment, but the overall knowledge about IDE in human blood is sparse. The aim of the thesis was to increase knowledge of the relationship between insulin resistance and AD, focusing on IDE as a biomarker for risk assessment and diagnosis of AD.Study participants: In study I, we included patients with type 2 diabetes (n=46) and compared them with patients without metabolic diseases (n=18). Serum samples were obtained from the Sophiahemmet biobank. In study II, we used post-mortem plasma samples from patients with Alzheimer's disease (n=18) and compared them with non-demented controls (n=6). These samples were obtained from the Netherlands Brain Bank. In study III, where we had three groups, we recruited patients with Alzheimer's disease (n=9) from a dementia care facility and healthy volunteers from Sophiahemmet University and Sophiahemmet Health Center (n=64). The serum samples from these individuals were then compared with serum samples from patients diagnosed with type 2 diabetes from Study I.In Study IV, we utilized data from the Swedish BPSD (Behavioral and Psychological Symptoms of Dementia) registry. This registry is used by healthcare units that work with patients with neurocognitive disorders and contains information about the patient's diagnosis, drug treatment, and behavioral and psychological symptoms. We selected a group of AD patients prescribed some form of antidiabetic drug treatment and analyzed whether the type of treatment impacted the registered behavioral and psychological symptoms.Methods: In study I-III, ELISA was used to analyze blood samples for levels of IDE and other metabolic markers. In study II, Luminex multiplex was used to measure inflammatory markers. These biomarkers and clinical data were analyzed statistically to investigate differences between groups and correlations between variables. In study IV, the association between BPSD and antidiabetic drug treatment was investigated using a bivariate logistic regression model, adjusted for age, sex, specific diagnosis, and drug treatment.Results: The results showed that patients with T2DM had higher serum IDE levels than patients without metabolic diseases, patients diagnosed with AD, and healthy volunteers. The results also indicated that higher IDE levels were associated with older age, higher weight, and elevated blood glucose. In the samples from the brain bank, we found that higher IDE levels were correlated to increased levels of inflammatory markers and total tau.In the analysis of registry data, we found that the prescription of metformin, one of the most common drugs for type 2 diabetes, was associated with lower odds for symptoms of depression and anxiety. This association was not observed for any other antidiabetic drug.Conclusion: The results suggest that IDE may be an essential factor in metabolic function but may also be associated with significant risk factors for neurocognitive disorders, such as inflammation. Although based on smaller studies, these findings contribute to the limited knowledge of IDE in human blood. Reduced IDE levels have been linked to an increased risk of AD. If patients diagnosed with T2DM have elevated IDE levels, a decrease in IDE levels possibly would indicate that the patient is at higher risk of or even in an early stage of AD. As interest in blood-based biomarkers grows, IDE emerges as a stable and reliable candidate in this thesis. Additionally, the research raises attractive possibilities for enhancing treatment strategies for AD patients experiencing affective symptoms. Metformin is believed to increase IDE levels and has previously been suggested to treat affective disorders and AD. Further investigation is needed to explore this promising avenue.