Calcineurin inhibition may prevent Alzheimer disease in people with Down syndrome

Virtually all people with Down syndrome will develop Alzheimer disease pathology during their lifetime. As Alzheimer disease is the third leading cause of death and a significant factor in end-of-life complications for adults with Down syndrome, identifying interventions is a medical necessity. Calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, has recently been investigated as a possible Alzheimer treatment. This review explores the histories behind Down syndrome and Alzheimer disease, and their intersecting pathologies. This is followed by the role that calcineurin and its U.S. Food and Drug Administration-approved pharmacological inhibitor, tacrolimus, may play in the prevention or treatment of Alzheimer disease. Finally, this review discusses the gap in the literature surrounding the role of calcineurin, its regulators, and calcineurin inhibitors in the context of Down syndrome and comorbid Alzheimer disease. Future studies investigating the role that calcineurin plays in this pathology will be essential in determining the viability of calcineurin inhibitors to treat Alzheimer disease in people with Down syndrome. HIGHLIGHTS: Calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, has become prominent as a possible therapeutic target to treat Alzheimer disease. People with Down syndrome develop Alzheimer pathology as they age, requiring novel therapeutics for treatment. People with Down syndrome may exhibit contraindications to calcineurin inhibition-based therapy, as they overexpress RCAN1 and DYRK1A, regulators of calcineurin. There is a significant gap in the literature involving the expression of calcineurin, RCAN1 and DYRK1A, in people with Down syndrome and Alzheimer disease, which must be addressed to determine the efficacy and safety of newly developed therapeutics.