sirolimus and Dementia

Evidence suggests patients prescribed calcineurin inhibitors (CNIs) have a reduced prevalence of dementia, including Alzheimer's disease (AD); however, this result has never been replicated in a large cohort and the involved mechanism(s) and site of action (central versus periphery) remain unclear.. We aim to determine if prescription of CNIs is associated with reduced prevalence of dementia, including AD, in a large, diverse patient population. Furthermore, we aim to gain insight into the mechanism(s) and site of action for CNIs to reduce dementia prevalence.. Electronic health records (EHRs) from patients prescribed tacrolimus, cyclosporine, or sirolimus were analyzed to compare prevalence, odds, and hazard ratios related to dementia diagnoses among cohorts. EHRs from a random, heterogeneous population from the same network were obtained to generate a general population-like control.. All drugs examined reduced dementia prevalence compared to the general population-like control. There were no differences in dementia diagnoses upon comparing tacrolimus and sirolimus; however, patients prescribed tacrolimus had a reduced dementia prevalence relative to cyclosporine.. Converging mechanisms of action between tacrolimus and sirolimus likely explain the similar dementia prevalence between the cohorts. Calcineurin inhibition within the brain has a greater probability of reducing dementia relative to peripherally-restricted calcineurin inhibition. Overall, immunosuppressants provide a promising therapeutic avenue for dementia, with emphasis on the brain-penetrant CNI tacrolimus.

Topics: Calcineurin; Calcineurin Inhibitors; Cyclosporine; Dementia; Humans; Kidney Transplantation; Prevalence; Sirolimus; Tacrolimus

The currently available clinical diagnostic tools do not allow an accurate and reliable diagnosis of Alzheimer's disease (AD) in other than demented patients. Furthermore, they do not allow the identification of subjects with pre-clinical AD. Cell cycle regulatory failure in neurones appears to be a very early event in the pathogenesis of AD. Our earlier findings indicate that there is a specific failure of the G1/S transition checkpoint that may not be restricted to neurones alone. We tested the possibility that lymphocytes of AD sufferers may also show signs of G1 regulatory failure. We found that the in vitro responsiveness of lymphocytes to G1 inhibitor treatment was significantly less effective in AD patients than in control subjects. Additionally, in subjects showing neuropsychological signs of pre-clinical AD, the lymphocyte response was similar to that seen in AD patients. We present direct evidence to support the hypothesis that the failure of the G1/S transition control is not restricted to neurones in AD patients, but occurs in peripheral cells, such as lymphocytes, as well. Our findings could provide the basis for new clinical tests that rely on eliciting the activation of the G1/S transition checkpoint in lymphocyte cultures. We propose that the introduction of the test could be useful in identifying people who do not yet fulfil the requirements of the NINCDS criteria for dementia, but who would benefit from the use of preventive measures for AD.

Topics: Alzheimer Disease; Cell Cycle Proteins; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p27; Dementia; Diagnosis, Differential; Doxorubicin; G1 Phase; Humans; Immunosuppressive Agents; Lymphocyte Activation; Lymphocytes; Neurons; Neuropsychological Tests; Organ Specificity; Oxidative Stress; Phytohemagglutinins; Risk Assessment; Sirolimus; Tumor Suppressor Proteins