Reduced Prevalence of Dementia in Patients Prescribed Tacrolimus, Sirolimus, or Cyclosporine

BACKGROUND 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. OBJECTIVE 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. METHODS 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. RESULTS 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. CONCLUSION 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.

[1]  T. Sargeant,et al.  Rapamycin and Alzheimer disease: a hypothesis for the effective use of rapamycin for treatment of neurodegenerative disease , 2023, Autophagy.

[2]  M. Bhat,et al.  Microglial mTOR Activation Upregulates Trem2 and Enhances β-Amyloid Plaque Clearance in the 5XFAD Alzheimer's Disease Model , 2022, The Journal of Neuroscience.

[3]  R. Nixon,et al.  Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques , 2022, Nature Neuroscience.

[4]  Simiao Chen,et al.  Role of Calcium Homeostasis in Alzheimer’s Disease , 2022, Neuropsychiatric disease and treatment.

[5]  V. Cavalli,et al.  FK506-binding protein-like and FK506-binding protein 8 regulate dual leucine zipper kinase degradation and neuronal responses to axon injury , 2022, The Journal of biological chemistry.

[6]  L. Puskás,et al.  Tacrolimus Protects against Age-Associated Microstructural Changes in the Beagle Brain , 2021, The Journal of Neuroscience.

[7]  G. Cantarella,et al.  Repositioning of Immunomodulators: A Ray of Hope for Alzheimer’s Disease? , 2020, Frontiers in Neuroscience.

[8]  Asad Ali,et al.  Does Obesity Increase the Risk of Dementia: A Literature Review , 2018, Cureus.

[9]  T. Iida,et al.  Role of autophagy in the pathogenesis of inflammatory bowel disease , 2017, World journal of gastroenterology.

[10]  Nirmal Singh,et al.  Calcineurin inhibitors improve memory loss and neuropathological changes in mouse model of dementia , 2017, Pharmacology Biochemistry and Behavior.

[11]  M. Fakhoury.  Immune-mediated processes in neurodegeneration: where do we stand? , 2016, Journal of Neurology.

[12]  G. Taglialatela,et al.  Reduced Incidence of Dementia in Solid Organ Transplant Patients Treated with Calcineurin Inhibitors , 2015, Journal of Alzheimer's disease : JAD.

[13]  Justus J. Randolph,et al.  A Step-by-Step Guide to Propensity Score Matching in R , 2014 .

[14]  K. Kuwata,et al.  FK506 reduces abnormal prion protein through the activation of autolysosomal degradation and prolongs survival in prion-infected mice , 2013, Autophagy.

[15]  A. Hakim,et al.  Heart disease as a risk factor for dementia , 2013, Clinical epidemiology.

[16]  C. Bauvy,et al.  Activation of lysosomal function in the course of autophagy via mTORC1 suppression and autophagosome-lysosome fusion , 2013, Cell Research.

[17]  H. Eguchi,et al.  Rapamycin Causes Upregulation of Autophagy and Impairs Islets Function Both In Vitro and In Vivo , 2012, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[18]  G. Taglialatela,et al.  A Role for Calcineurin in Alzheimer’s Disease , 2011, Current neuropharmacology.

[19]  Smita Majumder,et al.  Inducing Autophagy by Rapamycin Before, but Not After, the Formation of Plaques and Tangles Ameliorates Cognitive Deficits , 2011, Alzheimer's & Dementia.

[20]  Gary King,et al.  MatchIt: Nonparametric Preprocessing for Parametric Causal Inference , 2011 .

[21]  Amy L. Byers,et al.  Depression and risk of developing dementia , 2011, Nature Reviews Neurology.

[22]  C. Norris,et al.  Proteolysis of calcineurin is increased in human hippocampus during mild cognitive impairment and is stimulated by oligomeric Abeta in primary cell culture , 2011, Aging cell.

[23]  G. Taglialatela,et al.  Amyloid‐β oligomers impair fear conditioned memory in a calcineurin‐dependent fashion in mice , 2010, Journal of neuroscience research.

[24]  Fred H. Gage,et al.  Mechanisms Underlying Inflammation in Neurodegeneration , 2010, Cell.

[25]  G. Taglialatela,et al.  Neuroimmunomodulation by calcineurin in aging and Alzheimer's disease. , 2010, Aging and disease.

[26]  H. Abdul,et al.  Cognitive Decline in Alzheimer's Disease Is Associated with Selective Changes in Calcineurin/NFAT Signaling , 2009, The Journal of Neuroscience.

[27]  Jen‐Hau Chen,et al.  Risk factors for dementia. , 2009, Journal of the Formosan Medical Association = Taiwan yi zhi.

[28]  G. Taglialatela,et al.  Intermediate- and long-term recognition memory deficits in Tg2576 mice are reversed with acute calcineurin inhibition , 2009, Behavioural Brain Research.

[29]  G. Taglialatela,et al.  Selective induction of calcineurin activity and signaling by oligomeric amyloid beta , 2008, Aging cell.

[30]  S. Berg,et al.  Overweight and Obesity in Old Age Are Not Associated with Greater Dementia Risk , 2008, Journal of the American Geriatrics Society.

[31]  G. Taglialatela,et al.  Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice , 2007, Neurobiology of Learning and Memory.

[32]  K. Tomizawa,et al.  Truncation and Activation of Calcineurin A by Calpain I in Alzheimer Disease Brain* , 2005, Journal of Biological Chemistry.

[33]  S. Nishimura,et al.  Pharmacokinetic animal PET study of FK506 as a potent neuroprotective agent. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[34]  I. Mansuy.  Calcineurin in memory and bidirectional plasticity. , 2003, Biochemical and biophysical research communications.

[35]  Hongkui Zeng,et al.  Forebrain-Specific Calcineurin Knockout Selectively Impairs Bidirectional Synaptic Plasticity and Working/Episodic-like Memory , 2001, Cell.

[36]  W. Almawi,et al.  Clinical and mechanistic differences between FK506 (tacrolimus) and cyclosporin A. , 2000, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[37]  K. Tanaka,et al.  Effect of Cyclosporin Analogues and FK506 on Transcellular Transport of Daunorubicin and Vinblastine via P-glycoprotein , 1996, Pharmaceutical Research.

[38]  J. Heitman,et al.  Immunosuppressant Target Protein FKBP12 Is Required for P-Glycoprotein Function in Yeast* , 1996, The Journal of Biological Chemistry.

[39]  J. Heitman,et al.  Molecular mechanisms of immunosuppression by cyclosporine, FK506, and rapamycin , 1995, Current opinion in nephrology and hypertension.

[40]  T. Terasaki,et al.  Restricted transport of cyclosporin A across the blood-brain barrier by a multidrug transporter, P-glycoprotein. , 1993, Biochemical pharmacology.

[41]  K. Kawahara,et al.  INHIBITION OF THE MULTIDRUG EFFLUX PUMP IN ISOLATED HEPATOCYTE COUPLETS BY IMMUNOSUPPRESSANTS FK506 AND CYCLOSPORINE , 1993, Transplantation.

[42]  D. Begley,et al.  Permeability of the Blood‐Brain Barrier to the Immunosuppressive Cyclic Peptide Cyclosporin A , 1990, Journal of neurochemistry.

[43]  S. Son,et al.  FK506 reduces amyloid plaque burden and induces MMP-9 in AβPP/PS1 double transgenic mice. , 2010, Journal of Alzheimer's disease : JAD.

[44]  D. Rubinsztein,et al.  Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies , 2009, Cell Death and Differentiation.

[45]  R. Abraham,et al.  Immunopharmacology of rapamycin. , 1996, Annual review of immunology.